Stroke Guidelines

Stroke Guidelines
2006 - Internet Stroke Center

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Acute Medicine: A practical guide to the management of medical emergencies

Acute Medicine: A practical guide to the management of medical emergencies

FOURTH EDITION
By David Sprigings, John B. Chambers
2008 David Sprigings and John B. Chambers
ISBN 978-1-4051-2962-6

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Innere Medizin

Innere Medizin

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Home Emergency Guide

Home Emergency Guide
Publisher: DK ADULT | ISBN: 0789493462 | edition 2003 | PDF | 260 pages | 15,2 mb
Providing the key to solving a wide range of problems in the home, the Home Emergency Guide features clear, user-friendly symptom charts to help readers determine whether to call an ambulance or a doctor, or to use self-help measures. From resuscitating a victim or making a sling to learning how to snake a toilet or dealing with a stovetop fire, as well as what to do in case of a hurricane, tornado, or earthquake, this all in one emergency guide explains what steps should be taken in order to keep the reader and family safe, before, during, and after the event.

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European Heart Journal - April 2009 (Vol.30 - N°7)

European Heart Journal - April 2009 (Vol.30 - N°7)

English | 135 pages | PDF | 4.88 MB

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Altitude sickness

Altitude sickness, also known as acute mountain sickness (AMS), altitude illness, hypobaropathy, or soroche, is a pathological effect of high altitude on humans (and animals), caused by acute exposure to low air pressure (usually outdoors at high altitudes). It commonly occurs above 2,400 metres (approximately 8,000 feet).[1][2] Acute mountain sickness can progress to high altitude pulmonary edema (HAPE) or high altitude cerebral edema (HACE).[1][3]

The cause of altitude sickness is not understood.[1][4] It occurs in low atmospheric pressure conditions but not necessarily in low oxygen conditions at sea level pressure. Although treatable to some extent by the administration of oxygen, most of the symptoms do not appear to be caused by low oxygen, but rather by the low CO2 levels causing a rise in blood pH, alkalosis. The percentage of oxygen in air remains essentially constant with altitude at 21% up until 70,000 feet (21,330 m), but the air pressure (and therefore the number of oxygen molecules) drops as altitude increases — consequently, the available amount of oxygen to sustain mental and physical alertness decreases above 10,000 feet (3,050 m).[5][6] Altitude sickness usually does not affect persons traveling in aircraft because modern aircraft passenger compartments are pressurized at an air pressure equivalent to an altitude of 8,000 feet (2,440 m).

A related condition,[citation needed] occurring only after prolonged exposure to high altitude, is chronic mountain sickness, also known as Monge's disease.[7]

injection of calcium gluconate slowly intravenously

Injections should be made slowly through a small needle into a large vein in order to avoid too rapid an increase in serum calcium and extravasation of calcium solution into the surrounding tissue with resulting necrosis. It is particularly important to prevent a high concentration of calcium from reaching the heart because of the danger of cardiac syncope. If injected into the ventricular cavity in cardiac resuscitation, it must not be injected into the myocardial tissue. 

Rapid injection of calcium gluconate may cause vasodilation, decreased blood pressure, bradycardia, cardiac arrhythmias, syncope and cardiac arrest.

Adverse Reactions: Parenteral calcium may cause flushing, nausea, vomiting, drowsiness, sweating and hypotension. Vasomotor collapse may ensue if i.v. injection is too rapid. 

Symptoms And Treatment Of Overdose: Symptoms: Untoward effects which may occur with parenterally administered calcium are related to the rate of injection. 

Nausea, vomiting, diarrhea, sensations of heat and sweating; arrhythmias, hypotension, circulatory collapse. 

Treatment: The patient should be in the horizontal position. Treat shock in the usual fashion. 

Dosage And Administration: The dose is dependent on the requirements of the individual patient. I.V. calcium gluconate injection must be administered slowly, e.g. approximately 1.5 mL over a period of 1 minute. 

To aid in converting: 1 g of elemental calcium=25 mmol elemental calcium=50 mEq elemental calcium=11.1 g calcium gluconate=111 mL of a 10% solution of calcium gluconate. 

Adults: Initially, 5 to 20 mL of a 10% solution (500 mg to 2 g) injected slowly i.v. This dose may be repeated until tetany is controlled. A 0.3 to 0.8% solution [30 to 40 mL of a 10% solution in 500 to 1 000 mL of sodium chloride injection or dextrose 5% in water (D5W)] may then be infused by slow drip within a 3 to 12-hour period. The maximum dosage for adults is 15 g (150 mL of a 10% solution). 

Children: The usual dose is 200 to 500 mg/kg/day well diluted and administered slowly i.v. in divided doses. Doses above 500 mg/kg/day are not recommended. 

Availability And Storage: Each mL of sterile, nonpyrogenic, hypertonic solution contains: total calcium 0.465 mEq (9.3 mg), derived from calcium gluconate 94 mg and calcium D-saccharate tetrahydrate 4.5 mg (equivalent to calcium D-saccharate anhydrous 3.5 mg) in water for injection. Calcium D-saccharate provides 6% of the total calcium and stabilizes the supersaturated solution of calcium gluconate. Preservative-free. Single use vials of 10 mL. 

Sodium hydroxide and/or hydrochloric acid is used to adjust pH to 6.0 to 8.2. The osmolality is 0.7 mOsmol/mL (calc.). 

Supersaturated solutions are prone to precipitation. If precipitation is evident, vials may be heated to 80°C in a dry heat oven for a minimum of 1 hour. Shake vigorously. Allow to cool to room temperature before dispensing. The solution should not be used if the precipitate remains after following the above procedure. 

Store at room temperature (15 to 30°C). Protect from freezing. Do not use if solution is unclear. Discard unused portion.

Using Insulin Pumps in Diabetes

Using Insulin Pumps in Diabetes

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Current Medical Diagnosis and Treatment 2008

Current Medical Diagnosis and Treatment 2008 | CHM | 71.3 MB

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Myocardial Imaging : Tissue Doppler and Speckle Tracking

  

Myocardial Imaging : Tissue Doppler and Speckle Tracking   
Publisher: Wiley-Blackwell | ISBN: 1405161132 | Edition 2007 | PDF | 336 Pages | 13,84 MB      

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Islets of Langerhans

Insulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy source. When insulin is absent (or low), glucose is not taken up by body cells, and the body begins to use fat as an energy source, for example, by transfer of lipids from adipose tissue to the liver for mobilization as an energy source. As its level is a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as amino acid uptake by body cells). It has several other anabolic effects throughout the body. When control of insulin levels fails, diabetes mellitus results.

Insulin is used medically to treat some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Patients with Type 2 diabetes mellitus are insulin resistant, and because of such resistance, may suffer from a relative insulin deficiency. Some patients with Type 2 diabetes may eventually require insulin when other medications fail to control blood glucose levels adequately.

Insulin is a peptide hormone composed of 51 amino acids and has a molecular weight of 5808 Da. It is produced in the islets of Langerhans in the pancreas. The name comes from the Latin insula for "island".

Insulin's structure varies slightly between species of animal. Insulin from animal sources differs somewhat in 'strength' (in carbohydrate metabolism control effects) in humans because of those variations. Porcine (pig) insulin is especially close to the human version.

Nature Medicine - July 2009

Nature Medicine - July 2009
English | 127 pages | PDF | 12.32 MB


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Heart Attack and Unstable Angina

What is a heart attack?

A heart attack occurs when blood flow to the heart is blocked. Without blood and the oxygen it carries, part of the heart starts to die. A heart attack doesn't have to be deadly. Quick treatment can restore blood flow to the heart and save your life.

Your doctor might call a heart attack a myocardial infarction, or MI. 
What is angina, and why is unstable angina a concern?

Angina (say "ANN-juh-nuh" or "ann-JY-nuh") is a type of chest pain or discomfort that occurs when there is not enough blood flow to the heart. Angina can be dangerous, so it is important to pay attention to chest pain, know what is typical for you, learn how to control it, and understand when you need to get treatment.

There are two types of angina:
Stable angina is chest pain that has a typical pattern. It happens when your heart is working harder and needs more oxygen, such as during exercise. The pain goes away when you rest.
Unstable angina is chest pain that is unexpected, and resting or taking nitroglycerin may not help. Your doctor will probably diagnose unstable angina if you are having chest pain for the first time or if your pain is getting worse, lasting longer, happening more often, or happening at rest.

Unstable angina is a warning sign that a heart attack may happen soon, so it requires treatment right away. But if you have any type of chest pain, see your doctor. 
What causes a heart attack?

Heart attacks happen when blood flow to the heart is blocked. This usually occurs because fatty deposits called plaque have built up inside the coronary arteries, which supply blood to the heart. If a plaque breaks open, the body tries to fix it by forming a clot around it. The clot can block the artery, preventing the flow of blood and oxygen to the heart. See a picture of how plaque causes a heart attack. 

This process of plaque buildup in the coronary arteries is called coronary artery disease, or CAD. In many people, plaque begins to form in childhood and gradually builds up over a lifetime. Plaque deposits may limit blood flow to the heart and cause angina. But too often, a heart attack is the first sign of CAD.

Things like intense exercise, sudden strong emotion, or illegal drug use (such as a stimulant, like cocaine) can trigger a heart attack. But in many cases, there is no clear reason why heart attacks occur when they do. 
What are the symptoms?

The most common symptom of a heart attack is severe chest pain. 
Many people describe the pain as discomfort, pressure, squeezing, or heaviness in the chest. 
People often put their fist to their chest when they describe the pain. 
The pain may spread down the left shoulder and arm and to other areas, such as the back, jaw, neck, or right arm. 

Many people also have at least one other symptom, such as: 
Pain in the upper belly, often mistaken for heartburn. 
Sweating. 
Nausea and vomiting. 
Trouble breathing. 
A feeling that their heart is racing or pounding (palpitations).
Feeling weak or very tired. 
Feeling dizzy or fainting. 

Not everyone has the classic symptom of severe chest pain during a heart attack. Women, older adults, and people with diabetes are less likely to have severe chest pain and more likely to have shortness of breath, dizziness, weakness or fainting, and belly pain. 
What should you do if you think you are having a heart attack?

If you have symptoms of a heart attack, act fast. Quick treatment could save your life.

If you are having chest pain and your doctor has prescribed nitroglycerin for angina:
Take 1 dose of nitroglycerin and wait 5 minutes.
If the chest pain doesn't improve or it gets worse, call 911 or other emergency services. Describe your symptoms, and say that you could be having a heart attack.
Stay on the phone. The emergency operator will tell you what to do. 

If you are having chest pain and you do not have nitroglycerin

The best choice is to go to the hospital in an ambulance. The paramedics can begin lifesaving treatments even before you arrive at the hospital. If you cannot reach emergency services, have someone drive you to the hospital right away. Do not drive yourself unless you have absolutely no other choice.

If you think you are having unstable angina but you are not sure, follow the steps listed above. Unstable angina can lead to a heart attack or death, so you need to have it checked right away.
How is a heart attack treated?

If you go to the hospital in an ambulance, treatment will be started right away to restore blood flow and limit damage to the heart. You may be given medicines, including:
Aspirin (if you have not already taken some) and other medicines to prevent blood clots.
Medicines that break up blood clots (thrombolytics). To work, these must be given within a few hours of the start of the heart attack.
Medicines to decrease the heart's workload, ease pain, and treat abnormal heart rhythms, which can be life-threatening.

At the hospital, you will have tests, such as:
Electrocardiogram (EKG or ECG). An EKG can detect signs of poor blood flow, heart muscle damage, abnormal heartbeats, and other heart problems.
Blood tests, including tests to see whether cardiac enzymes are high. Having these enzymes in the blood is usually a sign that the heart has been damaged.

If these tests show that you may be having a heart attack, you may have a cardiac catheterization. For this test, the doctor puts a thin, flexible tube (called a catheter) through an artery in the groin or arm and carefully guides it into the heart. (See a picture of catheter placement.) A dye is injected that makes the coronary arteries show up on a computer screen. The doctor then can see if the coronary arteries are blocked and how your heart is working.

If cardiac catheterization shows that an artery is blocked, the doctor may do angioplasty right away. The doctor guides the catheter into the narrowed artery, and a small balloon at the end of it is inflated. This widens the artery to help restore blood flow. Often a small wire-mesh tube called a stent is placed to keep the artery open. See a picture of angioplasty with stent placement.

Angioplasty, with or without a stent, is the preferred treatment for a heart attack. But if angioplasty is not available or cannot be done for some reason, “clot-busting” thrombolytic medicines may be used. Or the doctor may do emergency bypass surgery to redirect blood around the blocked artery.

After these treatments, medicines are given to prevent clots, reduce the heart’s workload, and lower cholesterol. These can help prevent another heart attack and heart failure. Most people who have had a heart attack take these and sometimes other medicines for the rest of their lives.

After you have had a heart attack, the chance that you will have another one is higher. Taking part in a cardiac rehab program helps lower this risk. A cardiac rehab program is designed for you and supervised by doctors and other specialists. It can help you learn how to eat a balanced diet and exercise safely to reduce your risk of more heart problems.

It is common to feel worried and afraid after a heart attack. But if you are feeling very sad or hopeless, ask your doctor about treatment. Getting treatment for depression may help you recover from a heart attack.
Can you prevent a heart attack?

Heart attacks are usually the result of heart disease, so taking steps to delay or reverse coronary artery disease can help prevent a heart attack. Heart disease is the number one killer of both men and women in the United States, so these steps are important for everyone.

To improve your heart health:
Don't smoke, and avoid secondhand smoke. Quitting smoking can quickly reduce the risk of another heart attack or death.
Eat a heart-healthy diet that includes plenty of fish, fruits, vegetables, beans, high-fiber grains and breads, and olive oil.
Get regular exercise on most, preferably all, days of the week. Your doctor can suggest a safe level of exercise for you.
Control your cholesterol and blood pressure.
If you have diabetes, keep your blood sugar as close to normal as possible.
Lower your stress level. Stress can damage your heart.
Take a daily aspirin if your doctor advises it.
Get a flu shot every year.
Take all of your medicines correctly. Taking medicine can lower your risk of having another heart attack or dying from coronary artery disease.
:Symptoms

The most common symptom of a heart attack is severe chest pain, although this sensation is not always present. In one study of people treated for a heart attack, almost half of them came to the emergency room because they had symptoms other than chest pain. These symptoms included shortness of breath, dizziness, weakness or fainting, and abdominal pain. 1 Women, older adults, and people with diabetes are less likely to have chest pain during a heart attack and more likely to have other symptoms.

It is possible to have a "silent heart attack" without any symptoms, but this is rare. Most people have chest pain and at least one other symptom, such as:
A feeling of choking or a "tight throat," a lump in the throat, or a need to keep swallowing.
A cold sweat.
Nausea.
A sense of impending doom.
Difficulty breathing or breathlessness.
Palpitations, or feeling your heart beat rapidly or irregularly. (Palpitations are very common and are usually harmless in a healthy heart, but they may signal coronary artery disease if brought on by exertion.)
Numbness or discomfort in either arm or hand.
Weakness.

People who are having a heart attack often describe their chest pain in various ways. The pain:
May feel like pressure, heaviness, weight, tightness, squeezing, discomfort, burning, a sharp ache (less common), or a dull ache. People often put their fist to their chest when describing the pain.
May radiate from the chest down the left shoulder and arm (the most common site) and also to other areas, including the left shoulder, middle of the back, upper portion of the abdomen, right arm, neck, and jaw. See a picture of the areas where you might have pain during a heart attack.
May be diffuse—the exact location of the pain is usually difficult to point out.
Is not made worse by taking a deep breath or pressing on the chest.
Usually begins at a low level, then gradually increases over several minutes to a peak. The discomfort may come and go. Chest pain that reaches its maximum intensity within seconds may represent another serious problem, such as an aortic aneurysm.

Women are more likely to have symptoms such as shortness of breath, heartburn, nausea, jaw pain, back pain, or fatigue.

Congenital Endocrinopathies: New Insights into Endocrine Diseases and Diabetes

Congenital Endocrinopathies: New Insights into Endocrine Diseases and Diabetes (Endocrine Development)
Publisher: S Karger Pub | ISBN: 3805583478 | edition 2007 | PDF | 158 pages | 3,66 MB


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The Circadian Clock: Good Rhythm May Play a Role in Type 2 Diabetes

Organisms ranging from bacteria to humans all rely on circadian rhythms as their molecular clocks. This complex network of molecular feedback loops not only helps to control wake-sleep patterns, but also helps to regulate body temperature, hormone levels, and metabolism, along with other systems. Whether it is from the disruption of sleep patterns through jetlag or seasonal affective disorder from the lack of sunlight, external stimuli can cause physical disturbances that are easily observable and can have serious outcomes. Along with these, perturbations can also occur that directly affect the molecular gears that keep the system running smoothly.

Although established Mendelian disorders such as familial advanced sleep-phase syndrome have been linked to circadian genes, complex disorders have remained more elusive. Recently, 3 papers published in Nature Genetics [1-3] reported such a link: a variant found within the melatonin receptor 1B (MTNR1B) is associated with both type 2 diabetes and fasting blood glucose levels.

Last summer, the first genome-wide association studies (GWAS) for fasting blood glucose levels were published using longitudinal cohorts.[4-6] Three markers were significantly associated. All were located in genes that were not surprising. The variants existed in the genes of glucokinase, glucokinase regulatory protein, and islet-specific glucose-6-phosphatase or glucose-6-phosphatase catalytic unit 2.[4-6] These 3 genes represented the most significant findings, but several other variants were near statistical significance after multiple hypothesis corrections for hundreds of thousands of tests. To gain statistical power, all 3 groups performed typing on an additional set of samples, thereby increasing their ability to discover alleles of lower penetrance. The 3 published papers represent the results of typing more than 60,000 individuals, leading to enough power to discern an association in MTNR1B as a true variant for fasting glucose levels.

Two papers, one by Lyssenko and colleagues[1] and the other by Prokopenko and colleagues on behalf of MAGIC (the Meta-Analysis of Glucose and Insulin-related traits Consortium),[2] along with several other groups who shared region-specific data, homed in on the same single nucleic polymorphism (SNP) within the MTNR1B locus. The SNP, rs10830963, maps to an 11.5-kilobase intron (regulatory region, not a protein-coding element) and does not appear to affect any known transcription factor-binding sites or cryptic splice sites. The effect of the variant reported from MAGIC and the additional cohorts of its meta-analysis, based on data from 35,812 subjects, had a per-allele effect of 0.072 mmol/L glucose and a P value of 3.2 x 10-50.[2] The 2 other studies, although they used slightly smaller datasets, showed a similar effect size and significance.

One difference in the study by Bouatia-Naji and colleagues[3] was that their highest association came from a different SNP, rs1387153. Although the strength of the association was very similar, this is a good example why functional analysis is the critical next step for all GWAS to determine the true causal variants. For MTNR1B, the true signal for association could be from either of the SNPs because they are in moderate linkage disequilibrium. Alternatively, the association could be from a separate variant for which the markers are both tagging. It is unlikely that the SNPs represent 2 separate signals because neither is significant after conditionally correcting for each other.

The ultimate goal of all GWAS is translation of the findings to a clinical setting, where they can have a positive impact on patients. However, this requires much more than just statistical significance. The current value of GWAS lies with the biological networks that the variant exposes as an underpinning of the phenotype. Both Lyssenko and colleagues[1] and Bouatia-Naji and colleagues[3] demonstrated direct expression of the MTNR1B gene in pancreatic beta cells. This finding, independently shown by both groups, reverses previous observations.[7] Preliminary data suggest that the G allele is linked with increased fasting blood glucose levels and may affect the MTNR1B transcription levels in the pancreatic islets of subjects older than 45 years of age.[1] 

These 3 papers provide another variant for fasting blood glucose levels, bringing the total attributable variance accounted for by the 4 known markers to around 1.5%.[2] It is of interest that while the association to fasting blood glucose levels is strong, the variant's link to type 2 diabetes is still very weak. This could be because conversion to type 2 diabetes status occurred in few patients in the longitudinal cohort during the study collection and follow-up periods. It could also be a hint that there are possible subtypes of diabetes that are manifested through different pathways, all of which lead to the same end-phenotype. Type 2 diabetes may actually represent several subtypes at the molecular, root level. Regardless, these findings strengthen prior research that our circadian rhythms can have strong influences on our metabolic system. Understanding and targeting malfunctions within our internal clock could prove a viable therapeutic strategy for type 2 diabetes

Near Drowning

Near drowning is severe oxygen deprivation (suffocation) caused by submersion in water but not resulting in death; when death occurs, the event is called drowning.

When a person is submerged under water, water enters the lungs. The vocal cords may go into severe spasm, temporarily preventing water from reaching the lungs. When filled with water, the lungs cannot efficiently transfer oxygen to the blood. The decrease in the level of oxygen in the blood that results may lead to brain damage and death. Water in the lungs, particularly water that is contaminated by bacteria, algae, sand, dirt, chemicals, or a person's vomit, can cause lung injury.

Children younger than 4 years are at greatest risk of near drowning because their energy and curiosity can easily lead them to fall into water, including bathtubs and large buckets, from which they cannot escape. In teenagers and adults, near drowning is common in those who are intoxicated, who have taken sedatives, who have had a seizure, or who are physically impaired because of a medical condition. Spinal injuries and paralysis caused by diving accidents, which are likely to occur when diving into shallow water, increase the chances of near drowning. People who intentionally hold their breath under water for extended periods may pass out and be unable to surface, thus increasing the risk of near drowning as well.

Submersion in cold water has both good and bad effects. Cooling of the muscles makes swimming difficult, and dangerously low body temperature (hypothermia) can impair judgment. Cold, however, protects tissues from the ill effects of oxygen deprivation. In addition, cold water may stimulate the mammalian diving reflex, which may prolong survival in cold water. The diving reflex slows the heartbeat and redirects the flow of blood from the hands, feet, and intestine to the heart and brain, thus helping to preserve these vital organs. The diving reflex is more pronounced in children than in adults; thus children have a greater chance of surviving prolonged submersion in cold water than adults.

Symptoms and Diagnosis

People who are drowning and struggling to breathe are usually unable to call for help. Children who are unable to swim may become submerged in less than 1 minute compared with adults, who may struggle longer.

People who are rescued may have symptoms ranging from anxiety to near death. They may be alert, drowsy, or comatose. Some may not be breathing. People who are breathing may gasp for breath or vomit, cough, or wheeze. The skin may appear blue (cyanosis), indicating insufficient oxygen in the blood. In some cases, respiratory problems may not become evident for several hours after near drowning.

A doctor diagnoses near drowning based on the events and the person's symptoms. Measurement of the level of oxygen in the blood and chest x-rays help reveal the extent of lung damage.

Prevention

Swimming pools should be adequately fenced, because they are one of the most common sites of near-drowning accidents. In addition, all doors and gates leading to the pool area should be locked. Children in or near any body of water, including pools and bathtubs, need constant supervision, regardless of whether flotation devices are used. Because a child can drown in only a few inches of water, even water-filled containers, such as buckets or ice chests, can be hazardous.

A person should not engage in swimming or boating when under the influence of alcohol or sedatives. Swimming should be curtailed if a person feels or looks very cold. People who have seizures that are well controlled need not avoid swimming but should be careful near water, whether boating, showering, or bathing.

To decrease the risk of drowning, a person should not swim alone and should swim only in areas patrolled by lifeguards. Ocean swimmers should learn to escape rip currents (strong currents that pull away from the shore) by swimming parallel to the beach rather than by swimming toward the beach. Wearing life jackets when in boats is encouraged for everyone and is required for nonswimmers and for small children, who should also wear a life jacket when playing near bodies of water. Spinal injuries can be prevented by not diving into shallow water.

Treatment

Immediate on-site resuscitation is the key to increasing the chance of survival without brain damage. Attempts should be made to revive the person even when the time under water is prolonged. Artificial respiration and CPR should be provided as necessary (see First Aid: First-Aid Treatment). The neck should be moved as little as possible if there is a chance of spinal injury. Anyone who nearly drowns must be transported to a hospital, by ambulance if possible.

In the hospital, most people need supplemental oxygen, in some cases given with the help of a ventilator. A ventilator can deliver oxygen using high pressures to reinflate collapsed sections of the lungs. If wheezing develops, bronchodilator drugs can help. In some cases, treatment with oxygen in a high-pressure (hyperbaric) chamber may be tried.

If the water was cold, the person may have a dangerously low body temperature (hypothermia) and may need warming (see Cold Injuries: Hypothermia). Spinal injury requires special treatment (see Spinal Cord Disorders: Treatment).

If a person who was submerged has only mild symptoms, discharge home may be possible, but only after several hours of observation in the emergency department. If symptoms persist for a few hours, or if the level of oxygen in the blood is low, the person needs to be admitted to the hospital.

Prognosis

The factors that most influence the chances of survival without permanent brain and lung damage are the duration of submersion, the water temperature (cold water accidents can have a better outcome), the person's age (children are more likely to have a better outcome), and how soon resuscitation begins. People who have consumed alcoholic beverages before submersion are especially likely to die or develop brain or lung damage. Survival is possible after submersion for as long as 40 minutes. Almost all people who are alert and conscious upon their arrival at the hospital recover fully. Many people who need CPR can also recover fully.

Angioedema

Angioedema and urticaria should be viewed as varying manifestations of the same pathologic process. Postcapillary venule inflammation results in fluid leakage and edema in both conditions. However, angioedema involves vessels in the layers of the skin below the dermis, while urticaria is localized superficial to the dermis. This results in varying clinical presentations.

The subdermal source of angioedema results in well-demarcated, localized, nonpitting edema. Urticaria is localized to the superficial portion of the dermis and is characterized by well-circumscribed wheals with raised erythematous borders and central blanching. These often coalesce to become giant wheals.

These conditions can occur together or separately. Recurrent episodes of one or both conditions for less than a 6-week duration are considered acute, whereas longer-lasting attacks are considered chronic.

Angioedema, with or without urticaria, is classified as allergic, hereditary, or idiopathic. Complications range from dysphonia or dysphagia to respiratory distress, complete airway obstruction, and death.

Pathophysiology

Angioedema involves vascular leakage beneath the dermis and subcutis. This response is mediated by vasoactive mediators, such as histamine, serotonin, and kinins (eg, bradykinins), which cause the arterioles to dilate while inducing a brief episode of vascular leakage in the venules, where the junction between the endothelial cells appears looser than in the capillaries and arterioles.

Frequency

United States

Approximately 15% of the general population is affected by recurrent idiopathic episodes. The most common kind does not have a discoverable cause.

Mortality/Morbidity

Morbidity and mortality are directly related to the severity of airway obstruction.

Race

No specific racial predilection exists.

Sex

Women tend to have more occurrences than men.

Age

Persons who are predisposed have an increase in frequency of attacks after adolescence, with the peak incidence occurring in the third decade of life.

Clinical

History

• General history
  • Urticarial eruptions usually appear at intervals and are intensely pruritic.
  • Patients with angioedema or urticaria should be questioned in detail to identify the offending antigen (in cases of allergic angioedema).
  • Any family history or history of recurrent episodes with the use of particular agents must be sought.
• Drugs associated with urticaria and angioedema include the following:
  • Radiocontrast agents
  • Opiates
  • Dextran
  • Angiotensin-converting enzyme (ACE) inhibitors
  • Aspirin
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Common sources of antigens that cause urticaria and angioedema include the following:
  • Hymenoptera envenomations
  • Food allergies such as fresh berries, shellfish, fish, nuts, tomatoes, eggs, milk, chocolate, food additives, and preservatives
  • Local trauma (eg, dental procedure, tonsillectomy)
  • Exposure to water, sunlight, cold, or heat
  • Animal dander (from scales of shed skin)
  • Emotional stress
  • Post infection or illness, including autoimmune disorders such as thyroid autoimmunity and leukemia
• Chronic urticaria (increasingly associated with Helicobacter pylori bacteria)

Physical

• General examinations
  • Patients usually present with the acute onset of well-demarcated cutaneous edema of distensible tissues (eg, lips, eyes, earlobes, tongue, uvula).
  • The face, extremities, and genitalia are most commonly affected.
• Airway assessment
  • First, determine airway patency.
  • Severe attacks can herald the onset of systemic anaphylaxis, characterized initially by dyspnea.
• Gastrointestinal (GI): Massive edema of the subcutaneous tissue in the abdominal region may present with abdominal distention and signs consistent with bowel obstruction.

Causes

• Immunoglobulin E (IgE)-mediated angioedema/urticaria may result from antigen ingestion (eg, food, drug) or from parenteral exposure (eg, medications, Hymenoptera).
• Complement-mediated angioedema/urticaria:
  • This angioedema involves immune complex–mediated necrotizing cutaneous venulitis manifested as serum sickness.
  • It is characterized by fever, angioedema, arthralgias, urticaria, and palpable purpura.
• Hereditary angioedema
  • This type of angioedema is characterized by recurrent self-limited attacks involving the skin, subcutaneous tissue, upper respiratory tract, or GI tract. Attacks may last from several hours to 2-3 days.
  • GI or upper respiratory tract attacks may be precipitated by local trauma (eg, dental procedures, tonsillectomy).
• Idiopathic angioedema appears to manifest due to direct mast cell–releasing agents in certain compounds (eg, radiocontrast media, opiates, dextran).
  • Other drugs may precipitate attacks by effects on arachidonic acid metabolism (eg, aspirin, NSAIDs, any compounds that are cyclooxygenase inhibitors).
  • ACE inhibitors precipitate attacks by directly interfering with the degradation of bradykinin, thereby potentiating its biological effect.

Preoperative Testing

Medical consultants are generally asked to assess preoperative risk in most patients who are to undergo surgery. The focus of discussion in this article applies to healthy people who are to undergo an elective surgical procedure.

Despite a low risk of perioperative complications, the use of laboratory tests before surgery became ingrained in clinical practice not only across the United States but also across the world in the latter half of the 20th century. At that time, clinicians thought it logical to order tests to detect abnormalities that might lead to increased morbidity or mortality in the perioperative period. Despite its widespread use, however, systematic evaluations of the clinical effectiveness and cost-effectiveness of routine laboratory testing were often lacking.

In the early and mid 1980s, several investigators published a number of papers demonstrating that routine preoperative testing was not cost-effective and did not benefit the patient. For example, in the mid 1980s, Kaplan and colleagues, in a retrospective review of the charts of 2000 patients who underwent elective surgery, demonstrated that 60% of these patients had laboratory tests ordered for no apparent reason, and that only 0.22% of the abnormal results influenced preoperative management. In another study, Turnbull and colleagues reviewed the charts of 2570 patients undergoing elective surgery, finding that only 104 of 5003 laboratory test results were abnormal and significant, and that only 4 patients would have benefited from "routine" laboratory testing.

To compound the problem, it appears that physicians are poor at evaluating the tests ordered. For example, in a study in which the records of 3782 elective surgery patients were reviewed, only 10 of 160 patients with abnormal test results were treated for such abnormalities. The lack of treatment of identified abnormalities therefore raises the issue of increased legal liability.

In the last 20 years, a progressive challenge to the use of gratuitous routine laboratory testing has developed, especially within the environment of cost-containment and managed care. What, then, should physicians do? A good history and physical examination followed by a review of a patient's chart are undoubtedly the most important routine tests needed.

For example, Narr and colleagues reviewed the charts of 1044 healthy patients who did not undergo any preoperative laboratory testing before their elective surgeries. These patients did not experience any significant perioperative morbidity or mortality. The use of previous laboratory results, performed within 4 months before elective surgery, was supported by a study in which 7549 laboratory results of 1109 patients were reviewed. This study showed that 47% of the laboratory test results duplicated those obtained within 1 year. Of the 3096 normal laboratory test results, only 13 (0.4%) repeated values were abnormal, most of which could have been predicted on the basis of patient history and physical findings.

Furthermore, 5% of healthy people have abnormal test results. This is due to arbitrary cut points that define the range of normal laboratory values to include 2 standard deviations with a 95% confidence interval. For example, the chance that the results of 1 of the 6 tests included in a basic metabolic profile will be abnormal is 26%; hence, the predictive value of the test will be low, especially if the prevalence of the disease is low. For example, based on the Bayes theorem, the positive predictive value of an abnormal hemoglobin test finding is 16.1%, since the prevalence of anemia in healthy individuals is approximately 1%. Accordingly, such abnormal laboratory values, with very low predictive values, may result in further unnecessary workup and delays in surgery.

In a review of studies of routine preoperative testing by Smetana et al (2003), the positive likelihood ratio was modest (>3) for hemoglobin, electrolytes, and renal dysfunction but had a low impact for change on preoperative management. Normal test results did not reduce the likelihood of postoperative complications. In a recent single center study, the incidence of unindicated preoperative screening tests was found to be more than 50%, but it did not add to any benefit to support this persistence of unwarranted testing.

Advancing age, especially older than 70 years, is associated with increased hospital stay and perioperative morbidity and mortality. However, most people in this age group have comorbid conditions, and it remains unclear if complications are secondary to comorbid conditions or age itself.

Contrary to the common belief, obesity does not increase postoperative complications. In a prospective cohort of 6336 patients undergoing general elective surgery, Dindo et al (2003) did not find obesity to be a risk factor for the development of postoperative complications.

For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Understanding X-rays.

Selective Workup

Laboratory studies:

• CBC count
  • Several studies reported a wide range of hemoglobin abnormality among elective surgery patients, based on different study populations. In healthy individuals undergoing elective surgery, the variation is estimated to be less than 1%. A mild hemoglobin abnormality was not associated with an increase of perioperative morbidity or mortality. Recent guidelines recommend preoperative hemoglobin testing if the history is suggestive of underlying anemia or if a significant blood loss is anticipated during the operation.
  • The prevalence of severe leukopenia or leukocytosis is extremely low and rarely leads to a change in patient management. Similarly, thrombocytopenia is found in fewer than 1% of healthy elective surgery patients; thus, routine preoperative WBC or platelet count is not recommended unless the cost of a CBC count is not substantially higher than that of hemoglobin. The cost of falsely pursuing an abnormal WBC or platelet count may not be substantial, although no studies in that regard are available except for platelets.
• Electrolytes
  • Unanticipated electrolyte abnormality (sodium, potassium, bicarbonate, chloride) ranges from 0.2-8.0% among surgery patients. A recent systemic literature review reported that unsuspected electrolyte abnormality is 1.4% among healthy elective surgery patients.
  • Although hypokalemia is considered a minor risk factor for perioperative cardiac complications based on the Goldman risk index, no study showed a relation between hypokalemia and perioperative morbidity and mortality.
  • Postoperative hyponatremia is common in certain types of surgeries, such as transurethral resection of prostate and neurosurgical procedures; however, it is still unclear how baseline electrolyte abnormality may affect physicians' decisions in postoperative management. Accordingly, electrolyte determination is not routinely recommended for elective surgery in healthy individuals.
• Creatinine
  • The prevalence of elevated creatinine levels in asymptomatic patients ranges from 0.2-2.4% and increases with age. Approximately 9.8% of patients aged 46-60 years have elevated creatinine levels.
  • Patients with mild-to-moderate renal insufficiency are usually asymptomatic but have an increased risk of perioperative morbidity and mortality. Accordingly, testing renal function with serum creatinine level is recommended for all patients older than 40 years, especially if hypotension or use of nephrotoxic medications is anticipated.
• Blood sugar
  • The frequency of abnormal glucose laboratory results in asymptomatic patients ranges from 1.8-5.5%. The frequency increases with age, so that nearly 25% of patients older than 60 years have a fasting blood sugar level above 120 mg/dL.
  • Only in certain operations, such as vascular surgery and coronary artery bypass grafting, was diabetes associated with higher perioperative risks; hence, routine blood sugar determination is not recommended unless the patient has high risk for diabetes (eg, obesity, steroids, strong family history) or will be undergoing vascular or bypass surgery.
• Liver enzymes
  • The frequency of a hepatic aminotransferase enzyme (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) abnormality is estimated to be approximately 0.3%. Although Powell-Jackson and colleagues showed that severe liver test abnormalities may lead to an increase in surgical morbidity and mortality risk, no evidence confirms that mild elevation in liver enzymes is associated with such an increased risk.
  • Because most patients with severe aminotransferase enzyme elevation are likely to be symptomatic, and jaundice may be detected by physical examination, routine preoperative screening is not recommended for healthy individuals.
• Hemostasis
  • In the absence of a history of bleeding diathesis in elective surgery patients, abnormal bleeding time, prothrombin time (PT), and activated partial thromboplastin time (aPTT) results are estimated to be less than 1%.
  • Suchman and colleagues showed that in low-risk patients, per history and physical examination, aPTT does not predict the risk of perioperative bleeding. Similarly, the bleeding time has no predictive value on the incidence of perioperative bleeding in healthy elective surgery patients. Accordingly, PT, aPTT, and bleeding time are not recommended for routine screening.
• Urinalysis
  • The primary rationale for ordering urinalysis (UA) preoperatively is to detect either asymptomatic renal disease or underlying urinary tract infection (UTI). To detect unsuspected renal insufficiency, serum creatinine measurement is recommended for any elective surgery patient older than 40 years, although it is unclear if any correlation exists between asymptomatic UTI and surgical wound infection.
  • One study that included 200 patients undergoing orthopedic procedures showed that physicians addressed only 5 of 27 abnormal urine test results. A further economic analysis showed that in order to prevent a single wound infection, approximately $1.5 million must be spent on UA; therefore, UA is not recommended routinely for asymptomatic patients.
• Fecal occult blood
  • The prevalence of positive fecal occult blood findings among healthy individuals undergoing elective surgery is unknown. In addition, the benefits of routine screening are unclear.
  • A decision-analysis study showed no benefit of routine screening; therefore, insufficient evidence exists to support routine screening for fecal occult blood.

Imaging studies:

• ECG
  • The prevalence of abnormal ECG findings among healthy elective surgery patients ranges from 14-53% and increases with age in a continuous fashion.
  • The rationale for obtaining ECG preoperatively is to identify high-risk patients with prior myocardial infarction or arrhythmia. Detecting a silent myocardial infarction is of main clinical benefit because numerous investigators showed an association between preoperative myocardial infarction and surgical mortality. One study showed that 25% of 708 myocardial infarctions in the Framingham study were detected by ECG. In addition, any rhythm other than sinus, including frequent premature ventricular contraction, is associated with an increase in surgical risk. Accordingly, routine ECG is recommended for all patients older than 40 years undergoing elective surgery.
  • In a recent retrospective study of 23,036 patients who underwent 28,457 surgical procedures, multivariate logistic regression was used to evaluate the relationship between ECG abnormalities and cardiovascular death. A total of 199 in-hospital cardiovascular deaths (0.7%) occurred. A higher incidence of cardiovascular death was observed in patients with an abnormal ECG than in those with normal ECG results (1.8% vs 0.3%; adjusted odds ratio 4.5, 95% confidence interval 3.3-6.0). However, there was no significant difference (0.5%) in the incidence of cardiovascular death in patients, with or without ECG abnormality, who underwent low-risk or low- to intermediate-risk surgery.
  • Noordzij et al (2006) concluded that preoperative ECG provides prognostic information in addition to clinical characteristics and the type of surgery. However, the usefulness of routine ECG testing in lower risk surgery is questionable.
• Chest radiograph
  • The frequency of abnormal chest radiograph (CXR) findings increases with age. One study showed that 0.3% of patients younger than 60 years had unsuspected abnormal CXR results or clinical findings suggestive of underlying cardiac or pulmonary disease compared to 22% of patients older than 60 years.
  • In addition, Goldman reported that CXR in patients with congestive heart failure does not independently add to the risk of perioperative mortality and morbidity. A meta-analysis of 21 studies that included 14,390 routine CXR showed that only 140 of 1444 abnormal results were not clinically expected and that only 14 affected physicians' decisions in managing their patients. Accordingly, routine CXR is recommended only for patients older than 60 years unless underlying heart or lung disease is a possibility.

Summary

Routine preoperative screening of healthy people undergoing elective surgery is not recommended. Instead, a selective strategy, as outlined above, is safe and cost-effective as long as a complete history and physical examination are obtained. Based on the available evidence, the authors recommend the following preoperative tests:

1. Hemoglobin level for major surgery with significant expected blood loss or CBC count if the cost is not substantially increased
2. Serum creatinine level for people older than 40 years
3. ECG in patients older than 40 years
4. CXR in patients older than 60 years

No laboratory test must be repeated if results were normal within 4 months of the surgery and no change in the patient's clinical status occurred. Finally, this strategy applies only to healthy, asymptomatic patients undergoing elective surgery. Patients with suspected pulmonary or cardiac disease or those undergoing urgent operation require additional evaluation that is beyond the scope of this article.

Altitude-Related Disorders

Mountains have fascinated and attracted humankind for millennia. Most peaks in the Alps had been climbed by the end of the 19th century. Some early climbers mentioned experiencing the symptoms now described as mountain sickness. By the beginning of the 20th century, hypoxia was known to be the main cause of these symptoms. Even today, many questions regarding the precise mechanism of altitude illness remain unanswered.

Despite the obvious dangers inherent in climbing and the altitude-related illness experienced by nearly all who spend significant time in the mountains, people continue to seek the remoteness and pleasures of high places. With the availability of easy transportation into the mountains, not just for climbing but also for skiing and other forms of recreation, thousands are exposed to high altitude each year. These individuals frequently experience acute illness soon after ascent. With longer stays at altitude, these symptoms improve in a process known as acclimatization.

This article describes the various medical problems associated with ascent to high altitude, amelioration of altitude-related symptoms through acclimatization, and treatment of the disorders when they occur.

A multitude of problems is associated with ascent to altitude. Some of these are merely an annoyance while others are life threatening. Fundamentally, all are caused by a lack of oxygen. However, in most cases, considerable uncertainty exists regarding the precise pathophysiology of these illnesses. Three major syndromes, acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema (HACE), are now commonly accepted. Other related problems, such as impaired sleep at high altitude, often coexist with the major syndromes and also deserve mention. Finally, the effects of ascent on certain special populations are discussed in this article.

For excellent patient education resources, visit eMedicine's Environmental Exposures and Injuries Center and eMedicine's patient education article Mountain Sickness. Additionally, Medscape's CME course To "Glow" Where No One Has Gone Before: The Risk for Radiation to Space Exploration may be of interest. Finally, related eMedicine articles include Altitude Illness - Cerebral Syndromes and Altitude Illness - Pulmonary Syndromes.

Acute Mountain Sickness

Case report

A 19-year-old student who lived at sea level drove to approximately 8000 ft (2440 m) in the Sierra Nevada Mountains to go skiing. After spending a restless night at altitude, he awoke the next morning with a severe headache. During the day, he felt tired, did not have much appetite, and vomited after attempting to eat lunch. By the next morning, however, he felt better and was able to ski with his friends.

Discussion

Symptoms of AMS occur in nearly everyone if the ascent to altitude is too rapid. The marked variability in symptoms is characteristic of the disorder. Although some experience only minor inconvenience, for others, the symptoms are incapacitating. The symptoms of AMS have been known for many years and were aptly described in 1881 by the physician Jacottet on Mont Blanc, "I was unable to sleep and passed so bad a night that I would not wish it on my worst enemy."

Another early description from South America graphically portrays other symptoms in a severely affected altitude sojourner: "I got up and tried once more to go on but I was only able to advance one or two steps at a time, and then I had to stop, panting for breath, my struggles alternating with violent fits of nausea. At times I would fall down, and each time had greater difficulty rising; black specks swam across my sight; I was like one walking in a dream, so dizzy and sick that the whole mountain seemed whirling about me...As I got lower...I improved."

A consensus conference was held during the 1991 Hypoxia and Mountain Medicine Symposium¹ at Lake Louise, Canada to define the various altitude syndromes. This group defined AMS as follows: "In the setting of a recent gain in altitude, the presence of headache and at least one of the following symptoms: gastrointestinal (anorexia, nausea or vomiting), fatigue or weakness, dizziness or lightheadedness, difficulty sleeping."

AMS is defined by its symptoms, but the exact cause of AMS is still unknown. Cerebral edema may play a role.

Incidence

Many factors affect the incidence and severity of AMS, such as the rate of ascent, altitude attained (especially altitude of sleep), duration of exposure to altitude, and amount of exercise undertaken at altitude. The most important and least understood variable is the underlying physiological susceptibility of the individual. Few people experience significant symptoms below 7,000-8,000 ft (2130-2440 m), whereas most unacclimatized persons ascending to 10,000 ft (3,050 m) or higher experience at least a few symptoms.

In a large study of tourists visiting Colorado, 71% had at least some symptoms of AMS after arrival at altitudes of 6900-9700 ft (2100-2960 m). Other studies of various altitudes generally confirm the conclusion that AMS is related to the rate of ascent and the altitude reached. Individuals with a history of altitude illness may tolerate ascent better if the rate of ascent is slowed or if they spend a day or two acclimatizing at an intermediate altitude. In some studies, women had more symptoms than men.

Prediction of AMS

A previous history of AMS suggests susceptibility to the syndrome and the likelihood of recurrence with reascent. However, accurately predicting who will develop AMS is impossible. Some studies have shown that individuals with a lower vital capacity and lower hypoxic ventilatory response are more likely to experience altitude illness.

Pathophysiology

The exact mechanism by which hypoxia causes AMS is still unknown. Hypoxia leads to increased cerebral blood flow, elevated hydrostatic capillary pressure, capillary leak, and, finally, edema. Sutton and Lassen² suggested that hypoxia stimulates increased cerebral blood flow, resulting in vasogenic cerebral edema. More recent MRI data support Sutton and Lassen's hypothesis. Hackett³ and Ross⁴ suggest that AMS develops in people who cannot compensate for brain swelling. People with a greater ratio of cerebrospinal fluid (CSF) to brain volume are less likely to develop AMS because the swelling brain is able to displace the CSF. Conversely, those with lesser CSF to brain volume ratio have limited space for compensation of brain swelling and are prone to AMS. The role of fluid retention in the pathogenesis of AMS remains uncertain. Secretion of antidiuretic hormone and atrial natriuretic factor is altered in AMS and may contribute to vasogenic edema.

Treatment and prevention of AMS

Slow, gradual ascent with adequate time for acclimatization provides the best protection from AMS. The ideal ascent rate varies based on individual susceptibility to AMS. Once symptoms of AMS occur, additional time for acclimatization before ascending further usually is the only treatment needed for mild AMS. If symptoms worsen despite additional time for acclimatization, descent to a lower altitude (especially sleeping altitude) is needed. A descent of 1000-3000 ft (300-900 m) usually is sufficient to ameliorate symptoms. Supplemental oxygen, although rarely available in sufficient quantities, also effectively relieves symptoms of AMS.

Pharmacological treatment of AMS

Acetazolamide (Diamox) is effective both for the prevention and for the treatment of AMS.^{5, 6, 7, 8, 9, 10, 11, 12} Forwand et al⁸ demonstrated that 250 mg of acetazolamide every 8 hours dramatically reduced symptoms of AMS compared to people taking a placebo during a stay at the 12,800-ft (3,900-m) summit of Mount Evans, Colorado. Others have confirmed these findings, and Sutton et al^{11, 12} found that acetazolamide decreased hypoxemia during sleep by reducing the amount of periodic breathing.

The mechanism of action of acetazolamide in AMS is unclear. The drug is a carbonic anhydrase inhibitor that causes a bicarbonate diuresis, resulting in metabolic acidosis. It also decreases production of cerebrospinal fluid. However, these actions do not adequately explain the effectiveness of acetazolamide in AMS. Current recommendations are 125-250 mg twice daily starting 1 day before ascent and continuing for a couple of days at altitude or even for the duration of stay at altitude. Smaller doses may be effective in some people.

Dexamethasone, 2-4 mg every 6 hours, is also effective in preventing and treating AMS.^{13, 14, 15, 16, 17, 18} The mechanisms of action of dexamethasone in relieving AMS symptoms are unknown. Its relative effectiveness compared to acetazolamide has not been established, but it likely is equivalent to acetazolamide.¹⁹

The over-the-counter herbal supplement Ginkgo biloba has gained interest in AMS prophylaxis, primarily due to its low adverse effect profile. Although early studies were promising, more recent ones do not support the use of Ginkgo biloba. Gertsch et al²⁰ and subsequently Chow et al⁶ demonstrated that Ginkgo biloba was no better than placebo in prophylaxis of AMS. As such, the mainstay of pharmacologic treatment remains acetazolamide and dexamethasone.

Portable hyperbaric bags (eg, Gamow bag) simulate descent to a lower altitude. These bags are effective for treating AMS, although they are rarely needed unless AMS is complicated with high-altitude cerebral or pulmonary edema (see High-Altitude Pulmonary Edema).

Sleep at High Altitude

Most newcomers to altitude frequently report difficulty sleeping at night, even in the absence of other symptoms. Sleep disruption at altitude results from a combination of many factors, including the cold windy environment and the often-crowded sleeping conditions, in addition to hypoxia. Periodic breathing during sleep causes further disruption of sleep continuity. At extreme altitude, loss of sleep is nearly complete, further compromising already exhausted climbers.

Frequent nighttime awakenings and arousals represent the major disruptors of high-altitude sleep. For purposes of this discussion, a distinction must be made between an arousal and an awakening. This distinction has not always been adhered to, especially in the earlier reports of sleep at altitude. Sleep stages traditionally have been scored on the basis of 30-second epochs (20-s epochs have been used in a few places). Using this strategy, an awakening is scored on the sleep record when half of the standard epoch is scored as wake time. An arousal, in contrast, is defined as a 2- to 5-second period of wakefulness within the epoch.

An awakening may be sufficient for the person to remember the next day, while an arousal is not. Despite the transient and unremembered nature of arousals, they serve to dramatically impair daytime performance, especially if they occur frequently.

The Operation Everest II (OEII)^{21, 22} decompression chamber study provided an opportunity to monitor changes in sleep across various altitudes up to an altitude equivalent to the South Col of Mount Everest (approximately 8040 m, barometric pressure 282 mm Hg). These studies found severe sleep fragmentation and periodic breathing (with central sleep apneas) at all altitudes studied but especially at the highest altitudes. These brief 2- to 5-second arousals from sleep (not full awakenings) increased from an average of 22 ± 6 times per hour at sea level to 161 ± 66 times per hour at 25,000 ft (7620 m, 282 mm Hg).

Even those people with the fewest arousals had more than 1 arousal from sleep every minute, while more severely affected individuals had 3-4 arousals each minute. Frequent arousals cause sleep fragmentation, which, in turn, impairs daytime performance, even without concomitant hypoxia. Arousals ordinarily are not remembered the next morning; however, the effects are similar to hypoxia, including altered judgment and performance. Often, the affected person is unaware of these alterations.

Periodic breathing is a common breathing pattern during sleep at high altitude. More than 100 years ago, Mosso²³ described this periodic breathing pattern, which consists of a series of 3-5 breaths followed by a short respiratory pause, or apnea. Nearly all sojourners to high altitude demonstrate this breathing pattern (see Media File 1), but the pattern is far less common among highland Sherpas, who have a blunted hypoxic ventilatory response.

The length of nighttime periodic breathing episodes is related, in part, to a person's ventilatory drive; those with the strongest hypoxic ventilatory response have more frequent episodes of periodic breathing. Periodic breathing may occur in all sleep stages, including rapid eye movement (REM) sleep; however, at very high altitude, the time spent in slow wave and REM sleep is markedly reduced.

Changes in sleep state, as well as conflicting effects of hypocapnia and hypoxia on the peripheral chemoreceptors, lead to a destabilization of the respiratory control system, which is responsible for the periodic breathing observed at high altitude. Khoo et al²⁴ developed a sophisticated model of periodic breathing and suggested that increases in chemoreceptor gain (such as occurs in those with a strong hypoxic ventilatory response) lead to destabilization of the respiratory system and periodic breathing. This model further predicts that cycle length (ie, time from one apnea to the next) decreases as altitude increases. Findings from studies on Mount Everest generally confirm this prediction, although cycle time decreased less than predicted by the model.

Much of the sleep disruption at high altitude has been attributed to periodic breathing. Transient arousals from sleep commonly occur at the onset of the hyperpneic phase of periodic breathing. Nearly one half of the apneic episodes observed in the OEII study were not associated with electroencephalogram (EEG) arousals. Thus, a complex interplay exists among sleep state ventilatory responsiveness, breathing pattern, and sleep fragmenting arousals.

Nighttime arterial oxygen saturation is lower than daytime (awake) values and thus represents the most profound hypoxic insult during a high-altitude sojourn. The mean arterial oxygen saturation (SaO₂) at night during the OEII studies at 25,000 ft (7620 m) was only 52 ± 2% compared with a daytime SaO₂ of 71 ± 7%. The lower nighttime SaO₂ may, in part, result from periodic breathing, although others have suggested that periodic breathing actually improves nighttime SaO₂. Periodic breathing appears to be a risk factor for high altitude illness, and carbonic anhydrase inhibitors (eg, acetazolamide) decrease nocturnal periodic breathing, improve arterial oxygen saturation, and ameliorate daytime symptoms of AMS.

High-Altitude Pulmonary Edema

Case report

A 25-year-old student and 2 companions drove from sea level to nearly 8000 ft (2440 m) in the Sierra Nevada Mountains of California. They then hiked to 9,000 ft (2,740 m), where they spent their first night. The next day, they continued to 11,000 ft (3,350 m), and on the third day, after considerable exertion digging a snow cave, they camped at 12,400 ft (3,780 m).

That night, the student developed a mild cough but otherwise was asymptomatic. On the morning of the fourth day, approximately 60 hours after leaving sea level, the group attempted an ice-climbing route. During the climb, the student noted considerable fatigue and shortness of breath, and he was unable to keep up with his climbing partners. By early afternoon, they abandoned the climb and began the descent. The student was, by then, extremely fatigued and reported a slight headache. His cough increased, and shortly thereafter, he began coughing up thin straw-colored fluid. He continued the descent unaided but with some difficulty. Finally, after approximately 12 hours of descent, the party arrived at their car. After driving to 4000 ft (1220 m), the student felt markedly improved but exhausted.

A chest radiograph obtained approximately 18 hours after descent revealed marked patchy opacities, particularly on the right side (see Media File 2). A follow-up chest film taken 3 days later showed considerable improvement.

Discussion

HAPE is a serious and potentially life-threatening manifestation of altitude illness. Early descriptions of HAPE include that of Mosso,²³ who, in 1898, described a fatal case on Mont Blanc. Fifteen years later, in 1913, Ravenhill²⁵ described the different types of mountain sicknesses, which included HAPE, in the Andes. These early reports ascribing HAPE to cardiac disease were largely ignored, as were additional descriptions from South America. With Houston's report²⁶ in the New England Journal of Medicine in 1960, the medical community finally began to recognize the significance of these reports. Subsequent reports have further clarified this unusual form of pulmonary edema and confirmed Houston's suggestion that heart failure was not the cause of the edema.

Signs and symptoms

The first symptoms of HAPE occur 1-3 days after arrival at altitude. In adults, these symptoms commonly occur after exercise and consist of cough, shortness of breath, chest tightness, and fatigue. In approximately half the cases, these symptoms are associated with the typical symptoms of AMS. Initially, the cough is nonproductive, but thin, clear, or yellowish sputum is later produced. In some cases, the sputum is tinged with blood. Fatigue may be the first symptom, occurring even before dyspnea develops and manifesting as the inability of the affected individual to maintain the pace of the group.

Physical findings in HAPE include cyanosis, temperature as high as 101°F (38.5°C, a higher fever creates suspicion of pneumonia), flat neck veins, and crackles over the mid chest. Heart and respiratory rates are increased.

Diagnosis

The diagnostic criteria for HAPE are at least 2 symptoms and 2 signs from the following list, in the setting of a recent gain in altitude:

• Symptoms (at least 2)
  • Dyspnea at rest
  • Cough
  • Weakness or decreased exercise performance
  • Chest tightness or congestion
• Signs (at least 2)
  • Rales or wheezing in at least 1 lung field
  • Central cyanosis
  • Tachypnea
  • Tachycardia

A chest radiograph, if facilities are available, and a measurement of arterial oxygen saturation may contribute to making the diagnosis and excluding other disorders. Marked hypoxemia is an important and common finding in HAPE.

Radiographic features

Chest radiographs are useful to confirm the diagnosis of HAPE and may show abnormalities, even 24-48 hours after descent to sea level. With HAPE, homogeneous or patchy opacities appear in the mid lung areas and involve one or both sides of the chest. Opacities are more likely to be present in the right lung than in the left lung. Unilateral involvement of only the left lung is rare and should raise the suspicion of a congenital absence or hypoplasia of the right pulmonary artery. The pulmonary arteries frequently are enlarged; however, the cardiac silhouette usually is normal. Kerley lines may or may not be present.

Incidence

The incidence of HAPE is affected by factors such as rate of ascent, age, sex, physical exertion, and, most importantly, individual susceptibility. The reported incidence ranges from 0.1% among 143 skiers traveling to 8,200 ft (2,500 m) in Colorado to 4.5% at 14,000 ft (4,270 m) among trekkers in Nepal. On Mount McKinley in Alaska, incidence is as high as 20-33%.

Early or subclinical cases of HAPE occur much more frequently than full-blown cases. Children, but not infants, appear to be more susceptible than adults. Males are more likely to develop HAPE than females, but the reasons are unclear.

A form of HAPE known as reascent HAPE or reentry HAPE occurs in acclimatized individuals who descend to lower altitude and then reascend. In these cases, individuals usually spent 3-5 days or as many as 10-14 days at low altitude before returning to higher elevations. For unknown reasons, these individuals have an increased likelihood of developing HAPE.

Pathophysiology

The exact pathophysiology of HAPE is hampered by the lack of a good animal model. Any model must account for several factors, as follows: (1) elevated pulmonary artery pressures with wedge and left atrial pressures within the reference range, (2) no evidence of left ventricular failure, (3) capillary and arterial thromboses (in many fatal cases of HAPE), and (4) intense exercise (makes HAPE more likely, while bedrest is beneficial). A summary of the pathogenesis of HAPE is shown in Media File 3.

Alveolar hypoxia leads to hypoxic pulmonary vasoconstriction following ascent to high altitude. The extent of vasoconstriction is highly variable among individuals, probably due to different genetic characteristics. Individuals susceptible to HAPE have more severe pulmonary arterial hypertension than normal at altitude; however, not everyone with exaggerated hypoxic pulmonary vasoconstriction develops HAPE.

Many years ago Hultgren^{27, 28} proposed the overperfusion concept for the development of HAPE. This overperfusion mechanism postulates that uneven hypoxic pulmonary vasoconstriction results in lung areas with decreased blood flow while other areas receive excessive flow. Leakage of edema fluid occurs in these overperfused lung regions. Magnetic resonance imaging studies from 2005 by Hopkins et al²⁹ confirm the increased blood flow heterogeneity in individuals susceptible to HAPE.

Bronchoalveolar lavage studies show that the edema fluid in HAPE has a high protein concentration, along with various inflammatory markers, such as complement C5a and leukotriene B4. These inflammatory markers are now felt to be an epiphenomenon rather than a direct cause of the pulmonary capillary leakage in HAPE.³⁰

West et al³¹ suggested that HAPE results from a rupture of pulmonary capillaries subjected to high wall stresses from high pressure in the vessels. The nonhomogeneous vasoconstriction proposed by Hultgren would allow high pulmonary artery pressures to be transmitted to pulmonary capillaries in overperfused areas of the lung.

Clearance of fluid from the alveoli and interstitial space is important in the prevention and resolution of pulmonary edema.³² The epithelial sodium channel (ENaC) appears to be the most important regulator of this process. Both beta agonists and steroids up-regulate the ENaC ion channels within the alveolar epithelial cells. Sartori et al³³ used this concept to show that inhaled salmeterol is useful in preventing HAPE. In 2004, Ruh et al³⁴ found a 60% reduction in the mRNA for the epithelial sodium channel in humans following acute exposure to high altitude.

Treatment of HAPE

Both the overperfusion and stress failure models for HAPE imply that a reduction of the excessive hypoxic pulmonary vasoconstriction is essential for the treatment of HAPE.

Oxygen and descent to low altitude both result in lowered pulmonary artery pressure. Rapid descent to lower altitude results in dramatic symptomatic improvement. Often, a descent of only 1000-3000 ft (300-900 m) is necessary. Thus, descent is the most important therapeutic modality. Early descent, before HAPE becomes severe, potentially can save more lives than any other treatment.

Use of supplemental oxygen reduces pulmonary artery pressure; however, sufficient quantities of oxygen are rarely available under field conditions, precluding reliance on oxygen alone.

Nifedipine and other vasodilators also are useful in treating HAPE. Patients with HAPE who were treated by Oelz et al³⁵ with 10 mg nifedipine followed by 20 mg of slow-release nifedipine every 6 hours showed improvement in oxygenation and overall condition, even without descent to lower altitude. Other vasodilators may also decrease pulmonary artery pressure and be useful in treating HAPE. Reliance on these medications should not delay early and rapid descent.

Portable hyperbaric bags (eg, Gamow bag) are now available. These fabric hyperbaric chambers increase the pressure approximately 2 pounds per square inch (PSI), ie 103 mm Hg, simulating descent, which is effective in treating HAPE.

The best treatment is prevention of HAPE by gradual ascent and early recognition of HAPE symptoms. Nifedipine³⁶ and phosphodiesterase-5 inhibitors³⁷ are useful in preventing HAPE among susceptible individuals by lowering pulmonary artery pressure and salmeterol³³ through their action on ion channels.

High-Altitude Cerebral Edema

HACE is an extreme form of mountain sickness. The Lake Louise definition¹ states that HACE "can be considered 'end stage' or severe AMS. In the setting of a recent gain in altitude, [HACE is] the presence of a change in mental status and/or ataxia in a person with AMS, or the presence of both mental status change and ataxia in a person without AMS." Without prompt treatment, further neurological deterioration and death are likely.

Although many cases of HAPE occur without coexisting HACE, most cases of HACE have coexisting HAPE. The incidence of HACE is considerably less common than HAPE. Singh et al³⁸ reported an incidence of HACE of 1.25%, while in 1979 Hackett and Rennie³⁹ reported an incidence of 1.8% in trekkers in Nepal. Whether males are more likely to develop HACE than females remains unclear, although more cases of HACE in males have been reported.

Signs and symptoms of HACE may progress rapidly (within 12 h) from minimal manifestations to coma. Typically, this progression occurs slowly. Often the symptoms of HACE begin at night, occasionally resulting in a loss of consciousness during sleep. Most cases of HACE occur after individuals have been at altitude for several days.

The pathophysiology of HACE shares many similarities with the pathophysiology of AMS. Despite similarities, the reason only a few persons with AMS develop HACE is unclear. MRI in patients with HACE shows edema of the white matter, especially in the corpus callosum. Hansen and Evans⁴⁰ suggested that cytotoxic cellular edema of the brain from hypoxia caused many of the signs and symptoms of both AMS and HACE. Lassen and Harper,⁴¹ however, suggested that HACE was caused by vasogenic edema resulting from increased cerebral blood flow, causing leakage of fluid into the brain. In 1995, Severinghaus⁴² proposed roles for angiogenesis, osmotic swelling, and ischemia in the pathogenesis of HACE.

Treatment

Mild cases of AMS do not require descent to lower altitude, whereas HACE may be lethal if not recognized and promptly treated; thus, early recognition of HACE is crucial. A change in the level of consciousness or the onset of ataxia requires immediate descent.

Supplemental oxygen, if available, should be administered along with dexamethasone at 4-8 mg initially and then 4 mg every 6 hours thereafter. Diuretics, such as furosemide and mannitol, should not be administered because they may result in orthostatic hypotension from decreased intravascular volume, which makes descent difficult or impossible.

Early use of a hyperbaric bag (ie, Gamow bag) may relieve symptoms and make descent easier but should not be considered a substitute for descent, especially because recovery often requires 10 or more days, even with treatment at low altitude.

Special Populations at High Altitude

Large numbers of individuals go to high altitudes for work and recreation, and some individuals have special medical problems. Despite similarities to altitude illness in healthy individuals, ascent to high altitude by persons with underlying cardiac disease, pulmonary disease, and sickle cell anemia deserves special mention.

Coronary artery disease

Unacclimatized persons with coronary artery disease may develop increased anginal symptoms following ascent to altitude because of an increase in cardiac work, as well as possible vasoconstriction of the coronary arteries. Cardiac arrhythmia, including atrial fibrillation or flutter, may worsen after rapid ascent to altitude, even without underlying coronary artery disease. During exercise testing at 10,150 ft (3,100 m), cardiac patients developed angina or ST segment depression at the same double product (ie, heart rate times systolic blood pressure) as they did at 5,280 ft (1,600 m). Thus, ascent to altitudes of 10,000 ft (approximately 3,000 m) has little direct effect on myocardial ischemia but may produce symptoms by increasing heart rate and blood pressure during submaximal exercise.

Despite the increase in cardiac symptoms following rapid ascent to high altitude, the increased risk for cardiac death is low. In a large survey of trekkers in Nepal, no deaths from cardiac disease were reported, although several individuals required evacuation for cardiac problems. Other studies conducted at moderate altitudes in the Colorado Rocky Mountains among unacclimatized elderly individuals suggest a relatively low risk. Hultgren⁴³ reviewed the effects of altitude on patients with cardiovascular disease and suggested an approach (including when to perform a pre-ascent exercise test) for the evaluation of a patient with heart disease prior to trekking at high altitude.

With sufficient time for acclimatization, patients with coronary heart disease are likely to experience decreased symptoms because of a lower blood pressure. With long-term exposure to altitude, coronary artery disease mortality rates in these individuals actually are lower than that observed at sea level.

Pulmonary disease

Chronic obstructive pulmonary disease

Shortness of breath occurs in everyone, including those without heart or lung disease, after ascent to altitude. Even at sea level, patients with chronic obstructive pulmonary disease (COPD) frequently are limited by impaired lung mechanics and dyspnea.

Because of the increased ventilatory requirements of exercise at altitude, patients with COPD may experience a worsening of their symptoms during exposure to altitude. Patients with COPD without evidence of cor pulmonale were exposed to 6300-ft (1920-m) altitude by Graham and Houston.⁴⁴ These patients developed few altitude-related symptoms except fatigue (and headache in one individual), despite a decrease in resting arterial partial pressure of oxygen (PO₂) from 66 to 52 mm Hg. In these patients, the authors attributed the lack of symptoms of AMS to partial acclimatization resulting from hypoxemia. They concluded that patients with mild or moderate COPD without cor pulmonale tolerate altitude exposure quite well.

Patients with COPD living at altitude, as opposed to sojourners, develop cor pulmonale and have an increased mortality rate when compared to similar patients living at low altitude. Although the cause for this increased mortality rate is unknown, it probably is related to the higher pulmonary artery pressure observed in these residents.

Pulmonary hypertension

Hypoxic pulmonary vasoconstriction raises pulmonary artery pressure in sojourners to high altitude. With primary pulmonary hypertension, ascent to altitude results in even higher pulmonary artery pressures. These patients are likely to experience additional symptoms, such as fatigue, dyspnea, or even syncope. An increase in supplemental oxygen or the use of pulmonary vasodilators may be helpful to ameliorate altitude symptoms. Prior to traveling to high altitude, persons with primary pulmonary hypertension should consult a physician familiar with altitude problems who can evaluate the potential risks. Primary pulmonary hypertension may be more common among persons living at high altitude, and these individuals should be encouraged to consider moving to lower altitude.

Asthma

Asthma is a common disorder affecting many young, active individuals; therefore, a significant number of altitude sojourners have asthma or reactive airways. The dry, cold air often encountered at high altitude may cause bronchoconstriction; however, this climate also contains fewer allergens. As a result, many people with asthma report doing as well or even better at high altitude than at lower elevations. The reduced barometric pressure results in decreased air density. Thus, even though the ventilatory demands of activity at high altitude are greater, the reduced air density at least partially compensates. Patients with asthma who want to travel to high altitude should be encouraged to do so, but they should bring an adequate supply of their medications and pay attention to their respiratory symptoms.

Air travel

As global travel becomes more readily available and affordable, more individuals with preexisting cardiac and pulmonary problems are traveling by air. Pressurized cabins on airliners increase the barometric pressure 385-445 mm Hg higher than the outside ambient pressure. Commercial aircraft fly at altitudes of 10,000-60,000 ft (3,048-18,288 m), thus acutely exposing passengers to high altitude. Cottrell⁴⁵ measured the cabin altitudes in more than 200 commercial flights. In these measurements, the median altitude was 6214 ft (1894 m), with an average cabin altitude of 5673 ft (1724 m) and a standard deviation of 2019 ft (615 m). In this study, the maximum altitude observed was 8915 ft (2717 m). Newer aircraft models had significantly higher cabin altitudes than those of older planes.

Healthy individuals readily adapt to these altitudes, but those who are hypoxic at sea level may require supplemental oxygen during their flight. Without supplemental oxygen, individuals with COPD develop significant arterial oxygen desaturation. In one study, the arterial PO₂ decreased from 68 ± 8 mm Hg to 51 ± 9 mm Hg; in another study, the arterial PO₂ decreased from approximately 72 to 47 mm Hg. Both of these studies indicate the need for in-flight oxygen supplementation for these patients.^{46, 47} An altitude stimulation test is useful for estimating the flow of oxygen required during flight. In this test, measurements of arterial blood gases are performed while the patient breathes a hypoxic gas mixture.

Diabetes

Several recent studies have highlighted the problems encountered at high altitude among individuals with type 1 diabetes. Individuals with type 1 diabetes can safely and successfully participate in high altitude climbing, although significant challenges must be overcome.^{48, 49}

Sickle cell disease

Many genetic variations occur in the hemoglobin molecule. Some individuals having hemoglobin with an unusually high oxygen affinity may have improved altitude acclimatization and function. A far more common hemoglobinopathy occurs in individuals with sickle cell disease and makes ascent to high altitude inadvisable.^{50, 51}

Sickle cell disease refers to several types of abnormal hemoglobins, including hemoglobin AS and hemoglobin S. Under conditions of hypoxia, the red blood cells in these individuals become deformed and take on the shape of a sickle, causing blood viscosity to increase, cells to clump together more readily, and microcirculation to become blocked. The concentration of hemoglobin S in the circulation is the major determination of sickling. Bone pain and splenic infarction may occur.

Approximately 6-8% of black people in the United States carry at lease 1 abnormal hemoglobin gene. Most of these individuals have sickle cell trait and are largely asymptomatic, while a few have a far more severe condition, sickle cell anemia. Those with sickle cell anemia probably already know about their disease, but those with only sickle cell trait may be unaware of the problem and, therefore, are more likely to go to high altitude and experience problems.

Exposure to the hypoxia at high altitude may precipitate a sickle cell crisis among those patients with sickle cell anemia. These individuals should not attempt to go to high altitude. Even the modest hypoxemia associated with airline travel may precipitate symptoms in susceptible individuals.

Consider providing supplemental oxygen to those individuals with sickle cell anemia during aircraft flights. Travel by commercial airline generally is safe for patients with sickle cell trait; however, rarely, they may experience symptoms during airplane flights. Similarly, those with sickle cell trait generally tolerate altitudes of 8,000-10,000 (2,440-3,048 m) without difficulty, although a few may become symptomatic. Although most persons with sickle cell disease are of African American ancestry, sickle cell trait, and even sickle cell crisis, may occur in white people.