3614 PART 14 Poisoning, Drug Overdose, and Envenomation

Large local reactions accompanied by erythema, edema, warmth,

and tenderness that spread ≥10 cm around the sting site over 1–2 days

are not uncommon. These reactions may resemble bacterial cellulitis

but are caused by hypersensitivity rather than by secondary infection. Such reactions tend to recur on subsequent exposure but are

seldom accompanied by anaphylaxis and are not prevented by venom

immunotherapy.

An estimated 0.4–4.0% of the U.S. population exhibits clinical

immediate-type hypersensitivity to hymenopteran stings, and 15% may

have asymptomatic sensitization manifested by positive skin tests. Persons who experience severe allergic reactions are likely to have similar

or more severe reactions after subsequent stings by the same or closely

related species. Mild anaphylactic reactions to insect stings, as to other

causes, consist of nausea, abdominal cramping, generalized urticaria or

angioedema, and flushing. Serious reactions, including upper airway

edema, bronchospasm, hypotension, and shock, may be rapidly fatal.

Severe reactions usually begin within 10 min of the sting and only

rarely develop after 5 h.

TREATMENT

Bee and Wasp Stings

Honeybee stingers embedded in the skin should be removed as

soon as possible to limit the quantity of venom delivered. The

stinger and venom sac may be scraped off with a blade, a fingernail,

or the edge of a credit card or may be removed with forceps. The site

should be cleansed and disinfected and ice packs applied to slow the

spread of venom. Elevation of the affected site and administration

of oral analgesics, oral antihistamines, and topical calamine lotion

help relieve symptoms.

Anaphylactic reactions to bee or wasp venom can be a

life-threatening emergency that requires prompt life-saving actions.

If the individual carries a bee-sting kit, then a subcutaneous injection of epinephrine hydrochloride (0.3 mL of a 1:1000 dilution)

should be considered, with treatment repeated every 20–30 min as

necessary. A tourniquet may slow the spread of venom. The patient

should be transferred to a hospital emergency room where treatment for profound shock, if required, can be administered safely.

Such treatment may entail the use of IV epinephrine and other

vasopressors, intubation or provision of supplemental oxygen, fluid

resuscitation, use of bronchodilators, and parenteral administration

of antihistamines. Patients should be observed for 24 h for recurrent

anaphylaxis, renal failure, or coagulopathy.

Persons with a history of allergy to insect stings should carry an

anaphylaxis kit with a preloaded syringe containing epinephrine for

self-administration. These patients should seek medical attention

immediately after using the kit.

Prophylactic immunotherapy may greatly reduce the risk of

life-threatening reactions to bee and wasp stings. Repeated injections of purified venom produce a blocking IgG antibody response

to venom and reduce the incidence of recurrent anaphylaxis. Honeybee, wasp, and yellow jacket venoms are commercially available

for desensitization and for skin testing. Results of skin tests and

venom-specific radioallergosorbent tests (RASTs) aid in the selection of patients for immunotherapy and guide the design of such

treatment.

■ STINGING ANTS

Stinging ants are an important medical problem in the United States.

Imported fire ants (Solenopsis species) infest southern states from Texas

to North Carolina, with colonies now established in California, New

Mexico, Arizona, and Virginia. Slight disturbances of their mound

nests have provoked massive outpourings of ants and as many as 10,000

stings on a single person. Elderly and immobile persons are at high risk

for attacks when fire ants invade dwellings.

Fire ants attach to skin with powerful mandibles and rotate their

bodies while repeatedly injecting venom with posteriorly situated

stingers. The alkaloid venom consists of cytotoxic and hemolytic

piperidines and several proteins with enzymatic activity. The initial

wheal-and-flare reaction, burning, and itching resolve in ~30 min,

and a sterile pustule develops within 24 h. The pustule ulcerates over

the next 48 h and then heals in ≥1 week. Large areas of erythema and

edema lasting several days are not uncommon and, in extreme cases,

may compress nerves and blood vessels. Anaphylaxis occurs in <2%

of victims; seizures and mononeuritis have been reported. Stings are

treated with ice packs, topical glucocorticoids, and oral antihistamines.

Pustules should be cleansed and then covered with bandages and antibiotic ointment to prevent bacterial infection. Epinephrine administration and supportive measures are indicated for anaphylactic reactions.

Fire ant whole-body extracts are available for skin testing and immunotherapy, which appear to lower the rate of anaphylactic reactions.

European fire (red) ants (Myrmica rubra) have recently become public health pests in the northeastern United States and southern Canada.

The western United States is home to harvester ants (Pogonomyrmex

species). The painful local reaction that follows harvester ant stings

often extends to lymph nodes and may be accompanied by anaphylaxis. The bullet or conga ant (Paraponera clavata) of South America

is known locally as hormiga veinticuatro (“24-hour ant”), a designation

that refers to the 24 h of throbbing, excruciating pain following a sting

that delivers the potent paralyzing neurotoxin poneratoxin.

■ DIPTERAN (FLY AND MOSQUITO) BITES

In the process of feeding on vertebrate blood and tissue fluids, adults of

certain fly species inflict painful bites, inject saliva that may cause vasodilation and produce local allergic reactions, and may transmit diverse

pathogenic agents. Bites of mosquitoes (culicids), tiny “no-see-um”

midges (ceratopogonids), and sand flies (phlebotomines) typically

produce a wheal and a pruritic papule. Small humpbacked black flies

(simuliids) lacerate skin, resulting in a lesion with serosanguineous

discharge that is often painful and pruritic. Regional lymphadenopathy, fever, or anaphylaxis occasionally ensues. The widely distributed

deerflies and horseflies as well as the tsetse flies of Africa are stout

flies that attack during the day and produce large and painful bleeding

punctures. House flies (Musca domestica) do not consume blood but

use rasping mouthparts to scarify skin and feed upon tissue fluids and

salt. Beyond direct injury from bites of any kind of fly, risks include

transmission of diverse pathogens and secondary bacterial infection

of the lesion.

TREATMENT

Fly and Mosquito Bites

Treatment of fly bites is symptom based. Topical application of

antipruritic agents, glucocorticoids, or antiseptic lotions may relieve

itching and pain. Allergic reactions may require oral antihistamines. Antibiotics may be necessary for the treatment of large bite

wounds that become secondarily infected.

■ FLEA BITES

Common human-biting fleas include the dog and cat fleas (Ctenocephalides species) and the rat flea (Xenopsylla cheopis), which infest

their respective hosts and their nests and resting sites. Sensitized

persons develop erythematous pruritic papules (papular urticaria) and

occasionally vesicles and bacterial superinfection at the site of the bite.

Symptom-based treatment consists of antihistamines, topical glucocorticoids, and topical antipruritic agents.

Flea infestations are eliminated by removal and treatment of animal

nests, frequent cleaning of pet bedding, and application of contact

and systemic insecticides to pets and the dwelling. Flea infestations

in the home may be abated or prevented if pets are regularly treated

with veterinary antiparasitic agents, insect growth regulators, or chitin

inhibitors.

Tunga penetrans, like other fleas, is a wingless, laterally flattened

insect that feeds on blood. Also known as the chigoe flea, sand flea,

3615Ectoparasite Infestations and Arthropod Injuries CHAPTER 461

or jigger (not to be confused with the chigger), it occurs in tropical

regions of Africa and the Americas. Adult female chigoes live in sandy

soil and burrow under the skin, usually between toes, under nails, or

on the soles of bare feet. Gravid chigoes engorge on the host’s blood

and grow from pinpoint to pea size during a 2-week interval. They

produce lesions that resemble a white pustule with a central black

depression and that may be pruritic or painful. Occasional complications include tetanus, bacterial infections, and autoamputation of

toes (ainhum). Tungiasis is treated by removal of the intact flea with

a sterile needle or scalpel, tetanus vaccination, and topical application

of antibiotics.

■ HEMIPTERAN/HETEROPTERAN (TRUE BUG)

BITES

Most true bugs feed on plants, but some are predaceous or feed on

blood. In order to feed or to defend themselves, they may inflict bites

that produce allergic reactions and are sometimes painful. Bites of the

cone-nose or “kissing bugs” (family Reduviidae) tend to occur at night

and are painless. Reactions to such bites depend on prior sensitization

and include tender and pruritic papules, vesicular or bullous lesions,

extensive urticaria, fever, lymphadenopathy, and (rarely) anaphylaxis.

Bug bites are treated with topical antipruritic agents or oral antihistamines. Persons with anaphylactic reactions to reduviid bites should

keep an epinephrine kit available. Some reduviids transmit Trypanosoma cruzi, the agent of New World trypanosomiasis (Chagas disease)

(Chap. 227).

The cosmopolitan and tropical bed bugs (Cimex lectularius and

C.  hemipterus) hide in crevices of mattresses, bed frames and other

furniture, walls, and picture frames and under loose wallpaper, actively

seeking blood meals at night. These bugs are now a common pest in

homes, dormitories, and hotels; on cruise ships; and even in medical

facilities. Their bite is painless. Bites on persons without prior exposure

to bedbugs may not be noticeable. Persons sensitized to bed bug saliva

develop erythema, itching, and wheals around a central hemorrhagic

punctum. Reactions may manifest within minutes of the bites, or they

may be delayed for days or even a week or more. Bed bugs are not

known to transmit pathogens.

■ CENTIPEDE BITES AND MILLIPEDE DERMATITIS

Two groups of myriapods (“many-footed” arthropods) can harm

humans. Centipedes, with one pair of legs per body segment, are

fast-moving, aggressive, and carnivorous. They stun and kill their

prey—usually other arthropods, earthworms, and rarely small

vertebrates—with a venomous bite. The fangs of centipedes of the

genus Scolopendra can penetrate human skin and deliver a venom

that produces intense burning pain, swelling, erythema, and sterile

lymphangitis. Dizziness, nausea, and anxiety are described occasionally, and rhabdomyolysis and renal failure have been reported. Treatment includes washing of the site, application of cold dressings, oral

analgesic administration or local lidocaine infiltration, and tetanus

prophylaxis.

Millipedes, with two pairs of legs per segment, are slow-moving,

docile, and feed mostly on decaying plant materials. They do not bite,

but some secrete defensive fluids that may burn and discolor human

skin. Affected skin turns brown overnight and may blister and exfoliate. Secretions in the eye cause intense pain and inflammation that

can result in corneal ulcers and even blindness. Management includes

irrigation with copious amounts of water or saline, use of analgesics,

and local care of denuded skin.

■ CATERPILLAR STINGS AND DERMATITIS

Caterpillars of several moth species are covered with hairs or spines

that produce mechanical irritation and may contain or be coated with

venom. Contact with these caterpillars or their hairs may lead to erucism (a pruritic urticarial or papular rash) or caterpillar envenomation.

The response typically consists of an immediate burning sensation

followed by local swelling and erythema and occasionally by regional

lymphadenopathy, nausea, vomiting, and headache. A rare reaction to

a South American caterpillar, Lonomia obliqua, can cause disseminated

coagulopathy and fatal hemorrhagic shock.

Dermatitis is most often associated with caterpillars of io, puss,

saddleback, and browntail moths in North America and with the oak

processionary moth in Europe. Even contact with detached hairs of

other caterpillars, such as gypsy moth larvae, can later produce erucism. Spines may be deposited on tree trunks or drying laundry or may

be airborne and cause irritation of the eyes and upper airways. Treatment of caterpillar stings consists of repeated application of adhesive

or cellophane tape to remove the hairs, which can then be identified

microscopically. Local ice packs, topical glucocorticoids, and oral antihistamines relieve symptoms.

Few adult moths cause human health problems. Adult yellowtail

moths (Hylesia species), found mainly in coastal mangrove zones along

the eastern coast of Central and South America, have bodies that are

covered by fine hairs or setae. The hairs on the ventral surface can

detach and, when in contact with human skin, cause an extremely pruritic reaction called “Carapito itch.” This issue is especially problematic

when the moths have population booms, creating swarms around

coastal communities.

■ BEETLE VESICATION AND DERMATITIS

Several families of beetles have independently developed the ability to

produce chemically unrelated vesicating toxins. When disturbed, blister beetles (family Meloidae) exude cantharidin, a low-molecular-weight

toxin that produces thin-walled blisters (≤5 cm in diameter) 2–5 h after

contact. The blisters are not painful or pruritic unless broken. They

resolve without treatment in ≤10 days. Nephritis may follow unusually

heavy cantharidin exposure.

The hemolymph of certain rove beetles (Paederus species, Staphylinidae family) contains pederin, a potent vesicant. When these beetles are

crushed or brushed against the skin, the released fluid causes painful,

red, flaccid bullae. These beetles occur worldwide but are most numerous and problematic in parts of Africa (where they are called “Nairobi

fly”) and southwestern Asia. Ocular lesions may develop after impact

with flying beetles at night or unintentional transfer of the vesicant on

the fingers. Treatment is rarely necessary, although ruptured blisters

should be kept clean and bandaged.

Larvae of common carpet beetles are adorned with dense arrays

of ornate hairs called hastisetae. Contact with these larvae or their

setae results in delayed dermal reactions in sensitized individuals. The

lesions are commonly mistaken for bites of bed bugs.

■ DELUSIONAL INFESTATIONS

The groundless conviction that one is infested with arthropods or

other parasites (Ekbom syndrome, delusory parasitosis, delusions of

parasitosis, and perhaps Morgellons syndrome) is extremely difficult

to treat and, unfortunately, is not uncommon (Fig. 461-2). Patients

describe uncomfortable sensations of something moving in or on their

skin. Excoriations and self-induced ulcerations typically accompany

the pruritus, dysesthesias, and imaginary insect bites. Patients often

believe that some invisible or as yet undescribed creatures are infesting

their skin, clothing, homes, or environment in general. Frequently,

patients submit as evidence of infestation specimens that consist of

plant-feeding and nonbiting peridomestic arthropods, pieces of skin,

vegetable matter, lint, and other inanimate detritus. In the evaluation of

a patient with possible delusional parasitosis, it is imperative to rule out

true infestations and bites by arthropods, endocrinopathies, sensory

disorders due to neuropathies, opiate and other drug use, environmental irritants (e.g., fiberglass threads), and other causes of tingling or

prickling sensations. Frequently, such patients repeatedly seek medical

consultations, resist alternative explanations for their symptoms, and

exacerbate their discomfort by self-treatment. Long-term pharmacotherapy with pimozide or other psychotropic agents has been more

helpful than psychotherapy in treating this disorder. Patients with delusory parasitosis often develop the unshakeable conviction that they are

infested by a previously unknown pathogen, while their personal lives,

family support, and employment collapse around them.

3616 PART 14 Poisoning, Drug Overdose, and Envenomation

■ FURTHER READING

Arlia LG, Morgan MS: A review of Sarcoptes scabiei: Past, present

and future. Parasit Vectors 10:297, 2017.

Goddard J: Infectious Diseases and Arthropods, 3rd ed. Totowa, NJ,

Humana Press, 2018.

Hinkle N: Ekbom syndrome: The challenge of “invisible bug” infestations. Annu Rev Entomol 55:77, 2010.

Mathison BA, Pritt BS : Laboratory identification of arthropod ectoparasites. Clin Microbiol Rev 27:48, 2014.

McGraw TA, Turiansky MC: Cutaneous myiasis. J Am Acad Dermatol 58:907, 2008.

Moraru GM, Goddard J II: The Goddard Guide to Arthropods of

Medical Importance, 7th ed. Boca Raton, FL, CRC Press, 2019.

Mullen G, Durden L: Medical and Veterinary Entomology, 2nd ed.

Amsterdam, Academic Press, 2009.

Pollack RJ, Marcus L: A travel medicine guide to arthropods of

medical importance. Infect Dis Clin North Am 19:169, 2005.

Richards SL et al: Do tick attachment times vary between different

tick–pathogen systems? Environments 4:37, 2017.

Ryan NM et al: Treatments for latrodectism—A systematic review on

their clinical effectiveness. Toxins 9:148, 2017.

Saucier JR: Arachnid envenomation. Emerg Med Clin North Am

22:405, 2004.

Steen CJ et al: Insect sting reactions to bees, wasps, and ants. Int J

Dermatol 44:91, 2005.

Thomas C et al: Ectoparasites: Scabies. J Am Acad Dermatol 82:533,

2020.

Vetter RS, Isbister GK: Medical aspects of spider bites. Annu Rev

Entomol 53:409, 2008.

FIGURE 461-2 Real (left) versus delusional (right) infestation: comparable images of the lower backs of two young adults with multiple lesions. Left: A young woman

developed innumerable widespread lesions during a camping ecotour near Manaus, Brazil. Note scattered clusters of irregularly spaced lesions, accompanied by dozens

of single or isolated lesions, consistent with the semi-random feeding pattern of biting flies. Lesions appear to be in roughly the same stage of development, a feature

indicating that they were acquired at roughly the same time. No lesions were present before her ecotour; none have arisen since. This patient scratches the intensely

pruritic lesions and causes superficial erosions. Unexcoriated lesions are also present on her midback, where she cannot scratch. Right: A young man has innumerable

widespread lesions that have accumulated for several years, with a few new lesions appearing several times a week. His lesions are in various stages of development

(fresh, crusted, re-epithelialized, pigmented, and scarred), a feature indicating a long-standing process. The lesions are distributed in a regular pattern consistent with

periodic “excavations” to remove alleged parasites that he believes are crawling through his skin. Scarring is due to manipulations that create dermal ulcers rather than

superficial excoriations and erosions. Parts of his upper midback, where he cannot scratch, are free of lesions.

Disorders Associated with Environmental Exposures PART 15

462

■ EPIDEMIOLOGY

Mountains cover one-fifth of the earth’s surface; 140 million people

live permanently at altitudes ≥2500 m, and 100 million people travel to

high-altitude locations each year. Skiers in the Alps or Aspen; tourists

to La Paz, Ladakh, or Lahsa; religious pilgrims to Kailash-Manasarovar

or Gosainkunda; trekkers and climbers to Kilimanjaro, Aconcagua, or

Everest; miners working in high-altitude sites in South America; and

military personnel deployed to high-altitude locations are all at risk

of developing acute mountain sickness (AMS), high-altitude cerebral

edema (HACE), high-altitude pulmonary edema (HAPE), and other

altitude-related problems. AMS is the benign form of altitude illness,

whereas HACE and HAPE are life-threatening. Altitude illness is likely

to occur above 2500 m but has been documented even at 1500–2500 m.

In the Mount Everest region of Nepal, ~50% of trekkers who walk to

altitudes >4000 m over ≥5 days develop AMS, as do 84% of people who

fly directly to 3860 m. The incidences of HACE and HAPE are much

lower than that of AMS, with estimates in the range of 0.1–4%. Finally,

reentry HAPE, which in the past was generally limited to highlanders

(long-term residents of altitudes >2500 m) in the Americas, is now

being seen in Himalayan and Tibetan highlanders—and often misdiagnosed as a viral illness—as a result of recent rapid air, train, and

motorable-road access to high-altitude settlements.

■ PHYSIOLOGY

Ascent to a high altitude subjects the body to a decrease in barometric

pressure that results in a decreased partial pressure of oxygen in the

inspired gas in the lungs. This change leads in turn to less pressure,

driving oxygen diffusion from the alveoli and throughout the oxygen

cascade. A normal initial “struggle response” to such an ascent includes

increased ventilation—the cornerstone of acclimatization—mediated

by the carotid bodies. Hyperventilation may cause respiratory alkalosis

and dehydration. Respiratory alkalosis may be extreme, with an arterial

blood pH of >7.7 (e.g., at the summit of Everest). Alkalosis may depress

the ventilatory drive during sleep, with consequent periodic breathing

and hypoxemia. During early acclimatization, renal suppression of carbonic anhydrase and excretion of dilute alkaline urine combat alkalosis

and tend to bring the pH of the blood to normal. Other physiologic

changes during normal acclimatization include increased sympathetic

tone; increased erythropoietin levels, leading to increased hemoglobin

levels and red blood cell mass; increased tissue capillary density and

mitochondrial numbers; and higher levels of 2,3-bisphosphoglycerate,

enhancing oxygen utilization. Even with normal acclimatization, however, ascent to a high altitude decreases maximal exercise capacity (by

~1% for every 100 m gained above 1500 m) and increases susceptibility

to cold injury due to peripheral vasoconstriction. If the ascent is made

faster than the body can adapt to the stress of hypobaric hypoxemia,

altitude-related disease states can result.

■ GENETICS

Hypoxia-inducible factor, which acts as a master switch in highaltitude adaptation, controls transcriptional responses to hypoxia

throughout the body and is involved in the release of vascular

endothelial growth factor (VEGF) in the brain, erythropoiesis, and

other pulmonary and cardiac functions at high altitudes. In particular,

the gene EPAS1, which codes for transcriptional regulator hypoxiainducible factor 2α, appears to play an important role in the adaptation

of Tibetans living at high altitude, resulting in lower hemoglobin concentrations than are found in Han Chinese or South American highlanders. Other genes implicated include EGLN1 and PPARA, which are

also associated with hemoglobin concentration. Some evidence indicates that these genetic changes occurred within the past 3000 years,

which is very fast in evolutionary terms. An intriguing question is

whether the Sherpas’ well-known mountain-climbing ability is partially attributable to their Tibetan ancestry, with overrepresentation of

variants of EPAS. A striking recent finding is that some of these genetic

characteristics may stem from those of Denisovan hominids who were

contemporaries of the Neanderthals.

For acute altitude illness, a single gene variant is unlikely to be

found, but differences in the susceptibility of individuals and populations, familial clustering of cases, and a positive association of some

genetic variants all clearly support a role for genetics.

■ ACUTE MOUNTAIN SICKNESS AND HIGHALTITUDE CEREBRAL EDEMA

AMS is a neurologic syndrome characterized by nonspecific symptoms

(headache, nausea, fatigue, and dizziness), with a paucity of physical

findings, developing 6–12 h after ascent to a high altitude. AMS is a

clinical diagnosis. For uniformity in research studies, the Lake Louise

Scoring System, created at the 1991 International Hypoxia Symposium,

is generally used without the sleep disturbance score. AMS must be

distinguished from exhaustion, dehydration, hypothermia, alcoholic

hangover, and hyponatremia. AMS and HACE are thought to represent

opposite ends of a continuum of altitude-related neurologic disorders.

HACE (but not AMS) is an encephalopathy whose hallmarks are

ataxia and altered consciousness with diffuse cerebral involvement

but generally without focal neurologic deficits. Progression to these

signal manifestations can be rapid. Papilledema and, more commonly,

retinal hemorrhages may develop. In fact, retinal hemorrhages occur

frequently at ≥5000 m, even in individuals without clinical symptoms

of AMS or HACE.

Risk Factors The most important risk factors for the development

of altitude illness are the rate of ascent and a prior history of highaltitude illness. Exertion is a risk factor, but lack of physical fitness is

not. An attractive but still speculative hypothesis proposes that AMS

develops in people who have inadequate cerebrospinal capacity to

buffer the brain swelling that occurs at high altitude. Children and

adults seem to be equally affected, but people >50 years of age may be

less likely to develop AMS than younger people. In general, there is no

gender difference in AMS incidence. Sleep desaturation—a common

phenomenon at high altitude—is associated with AMS. Debilitating

fatigue consistent with severe AMS on descent from a summit is an

important risk factor for death in mountaineers. A prospective study

involving trekkers and climbers who ascended to altitudes between

4000 and 8848 m showed that high oxygen desaturation and low ventilatory response to hypoxia during exercise are independent predictors

of severe altitude illness. However, because there may be a large overlap

between groups of susceptible and nonsusceptible individuals, accurate cutoff values are hard to define. Prediction is made more difficult

because the pretest probabilities of HAPE and HACE are low. Neck

irradiation or surgery damaging the carotid bodies, respiratory tract

infections, and dehydration appear to be other potential risk factors

for altitude illness. Unless guided by clinical signs and symptoms, pulse

oximeter readings alone on a trek should not be used to predict AMS.

Pathophysiology Hypobaric hypoxia is the main trigger for altitude illness. In established AMS, raised intracranial pressure, increased

sympathetic activity, relative hypoventilation, fluid retention and

redistribution, and impaired gas exchange have all been well noted;

these factors may play an important role in the pathophysiology of

AMS. Severe hypoxemia can lead to a greater than normal increase in

cerebral blood flow. However, the exact mechanisms underlying AMS

and HACE are unknown. Evidence points to a central nervous system

process. MRI studies have suggested that vasogenic (interstitial) cerebral edema is a component of the pathophysiology of HACE. In the

Altitude Illness

Buddha Basnyat, Geoffrey Tabin

3618 PART 15 Disorders Associated with Environmental Exposures

setting of high-altitude illness, the MRI findings shown in Fig. 462-1

are confirmatory of HACE, with increased signal in the white matter

and particularly in the splenium of the corpus callosum. In addition,

hemosiderin deposits in the corpus callosum have been characterized

as long-lasting footprints of HACE. Quantitative analysis in an MRI

study revealed that hypoxia is associated with mild vasogenic cerebral

edema irrespective of AMS. This finding is in keeping with case reports

of suddenly symptomatic brain tumors and of cranial nerve palsies

without AMS at high altitudes. Vasogenic edema may become cytotoxic (intracellular) in severe HACE.

Impaired cerebral autoregulation in the presence of hypoxic cerebral

vasodilation and altered permeability of the blood-brain barrier due

to hypoxia-induced chemical mediators like histamine, arachidonic

acid, and VEGF may all contribute to brain edema. In 1995, VEGF was

first proposed as a potent promoter of capillary leakage in the brain at

high altitude, and studies in mice have borne out this role. Although

studies of VEGF in climbers have yielded inconsistent results regarding its association with altitude illness, indirect evidence of a role for

this growth factor in AMS and HACE comes from the observation

that dexamethasone, when used in the prevention and treatment of

these conditions, blocks hypoxic upregulation of VEGF. Other factors

in the development of cerebral edema may be the release of calciummediated nitric oxide and neuronally mediated adenosine, which may

promote cerebral vasodilation. Venous outflow obstruction resulting

in increased brain capillary pressure is also thought to play an important role in the development of HACE. Lesions in the globus pallidum

(which is sensitive to hypoxia) leading to Parkinson’s disease have been

reported to be complications of HACE.

The pathophysiology of the most common and prominent symptom

of AMS—headache—remains unclear because the brain itself is an

insensate organ; only the meninges contain trigeminal sensory nerve

fibers. The cause of high-altitude headache is multifactorial. Various

chemicals and mechanical factors activate a final common pathway, the

trigeminovascular system. In the genesis of high-altitude headache, the

response to nonsteroidal anti-inflammatory drugs and glucocorticoids

provides indirect evidence for involvement of the arachidonic acid

pathway and inflammation.

Prevention and Treatment (Table 462-1) Gradual ascent, with

adequate time for acclimatization, is the best method for the prevention

of altitude illness. Even though there may be individual variation in the

rate of acclimatization, a conservative approach would be a graded

ascent of ≤300 m from the previous day’s sleeping altitude above 3000 m,

and taking every third day of gain in sleeping altitude as an extra day

for acclimatization is helpful. Spending one night at an intermediate

altitude before proceeding to a higher altitude may enhance acclimatization and attenuate the risk of AMS. Another protective factor in AMS

is high-altitude exposure during the preceding 2 months; for example,

the incidence and severity of AMS at 4300 m are reduced by 50% with

an ascent after 1 week at an altitude ≥2000 m rather than with an ascent

from sea level. However, regarding the benefits of acclimatization,

clear-cut randomized studies are lacking. Repeated exposure at low

altitudes to hypobaric or normobaric hypoxia is termed preacclimatization. Preacclimatization is gaining popularity. For example, many

Everest climbers in the spring of 2019 claimed to use commercially

available “tents” at home with a hypoxic environment for weeks to

months in preparation for the climb. However, the optimal method

based on robust studies for preacclimatization is yet to be determined.

Clearly, a flexible itinerary that permits additional rest days will

be helpful. Sojourners to high-altitude locations must be aware of the

symptoms of altitude illness and should be encouraged not to ascend

further if these symptoms develop. Any hint of HAPE (see below) or

HACE mandates descent. Proper hydration (but not overhydration) in

high-altitude trekking and climbing, aimed at countering fluid loss due

to hyperventilation and sweating, may play a role in avoiding AMS.

Pharmacologic prophylaxis at the time of travel to high altitudes is

warranted for people with a history of AMS or when a graded ascent

and acclimatization are not possible—e.g., when rapid ascent is necessary for rescue purposes or when flight to a high-altitude location is

required. Acetazolamide is the drug of choice for AMS prevention. It

inhibits renal carbonic anhydrase, causing prompt bicarbonate diuresis

that leads to metabolic acidosis and hyperventilation. Acetazolamide

(125 mg twice daily), administered for 1 day before ascent and continued for about 3 days at the same altitude, is effective. Treatment

can be restarted if symptoms return after discontinuation of the drug.

FIGURE 462-1 T2 magnetic resonance image of the brain of a patient with highaltitude cerebral edema (HACE) shows marked swelling and a hyperintense

posterior body and splenium of the corpus callosum (area with dense opacity). The

patient, a climber, went on to climb Mount Everest about 9 months after this episode

of HACE. (Source: FJ Trayers 3rd: Wilderness preventive medicine. Wilderness

Environ Med 15:53, 2004.)

TABLE 462-1 Management of Altitude Illness

CONDITION MANAGEMENT

Acute mountain sickness

(AMS), milda

Discontinuation of ascent

Treatment with acetazolamide (250 mg q12h)

Descentb

AMS, moderatea Immediate descent for worsening symptoms

Use of low-flow oxygen if available

Treatment with acetazolamide (250 mg q12h) and/or

dexamethasone (4 mg q6h)c

Hyperbaric therapyd

High-altitude cerebral

edema (HACE)

Immediate descent or evacuation

Administration of oxygen (2–4 L/min)

Treatment with dexamethasone (8 mg PO/IM/IV; then

4 mg q6h)

Hyperbaric therapy if descent is not possible

High-altitude pulmonary

edema (HAPE)

Immediate descent or evacuation

Minimization of exertion while patient is kept warm

Administration of oxygen (4–6 L/min) to bring O2

saturation to >90%

Adjunctive therapy with nifedipinee

 (30 mg, extendedrelease, q12h)

Hyperbaric therapy if descent is not possible

a

Categorization of cases as mild or moderate is a subjective judgment based on

the severity of headache and the presence and severity of other manifestations

(nausea, fatigue, dizziness). b

No fixed altitude is specified; the patient should

descend to a point below that at which symptoms developed. c

Acetazolamide treats

and dexamethasone masks symptoms. For prevention (as opposed to treatment) of

AMS, 125 mg of acetazolamide q12h or (when acetazolamide is contraindicated—

e.g., in people with a history of sulfa anaphylaxis) 4 mg of dexamethasone q12h

may be used. d

In hyperbaric therapy (Fig. 462-2), the patient is placed in a portable

altitude chamber or bag to simulate descent. e

Nifedipine at this dose is also

effective for the prevention of HAPE, as are tadalafil (10 mg twice daily), sildenafil

(50 mg three times per day), and dexamethasone (8 mg twice daily). Preventative

therapy should be continued for about 3 days after arriving at the target altitude.

If prompt descent follows arrival at target altitude, continuation of preventative

therapy is unnecessary.

3619Altitude Illness CHAPTER 462

Higher doses are not required. A meta-analysis limited to randomized

controlled trials revealed that 125 mg of acetazolamide twice daily was

effective in the prevention of AMS, with a relative-risk reduction of

~48% from values obtained with placebo. Even lower doses (62.5 mg

twice daily) have been reported to be effective. Paresthesia and a

tingling sensation are common side effects of acetazolamide. Some

other uncommon side effects are myopia and drowsiness. This drug

is a nonantibiotic sulfonamide that has low-level cross-reactivity with

sulfa antibiotics; as a result, severe reactions are rare. Dexamethasone

(8 mg/d in divided doses) is also effective. A large-scale, randomized,

double-blind, placebo-controlled trial in partially acclimatized trekkers

clearly showed that Ginkgo biloba is ineffective in the prevention of

AMS. In randomized studies, ibuprofen (600 mg three times daily) has

been shown to be beneficial in the prevention of AMS. Recently, acetaminophen (1 g three times daily) was as effective as ibuprofen at the

above dosage in a randomized, double-blind study, which did not have

a placebo arm. However, more definitive studies and (for ibuprofen) a

proper gastrointestinal bleeding risk assessment need to be conducted

before these drugs can be routinely recommended for AMS prevention.

Many drugs, including spironolactone, medroxyprogesterone, magnesium, calcium channel blockers, and antacids, confer no benefit in the

prevention of AMS. Starkly conflicting results from a number of trials

of inhaled budesonide for the prevention of AMS have recently been

published, but, in all likelihood, the drug is ineffective. Similarly, no

efficacy studies are available for coca leaves (a weak form of cocaine),

which are offered to high-altitude travelers in the Andes, or for soroche

pills, which contain aspirin, caffeine, and acetaminophen and are sold

over the counter in Bolivia and Peru. Finally, a word of caution applies

in the pharmacologic prevention of altitude illness. A fast-growing

population of climbers in pursuit of a summit are injudiciously using

prophylactic drugs such as glucocorticoids in an attempt to improve

their performance; the outcome can be tragic because of potentially

severe side effects of these drugs, especially if taken for a long duration.

For the treatment of mild AMS, rest alone with analgesic use may

be adequate. Descent and the use of acetazolamide and (if available)

oxygen are sufficient to treat most cases of moderate AMS. Even a minor

descent (400–500 m) may be adequate for symptom relief. For moderate

AMS or early HACE, dexamethasone (4 mg orally or parenterally) is

highly effective. For HACE, immediate descent is mandatory. When

descent is not possible because of poor weather conditions or darkness,

a simulation of descent in a portable hyperbaric chamber (Fig. 462-2)

can be very effective. Pressurization in the bag for 1–2 h often leads

to spectacular improvement and, like dexamethasone administration,

“buys time.” Thus, in certain high-altitude locations (e.g., remote

pilgrimage sites), the decision to bring along the lightweight hyperbaric

chamber may prove lifesaving. Like nifedipine, phosphodiesterase-5

inhibitors have no role in the treatment of AMS or HACE. Finally,

short-term oxygen inhalation using small cannisters of oxygen or by

visiting oxygen bars is unhelpful in the prevention of AMS.

■ HIGH-ALTITUDE PULMONARY EDEMA

Risk Factors and Manifestations Unlike HACE (a neurologic

disorder), HAPE is primarily a pulmonary problem and therefore is not

necessarily preceded by AMS. HAPE develops within 2–4 days after

arrival at high altitude; it rarely occurs after >4 or 5 days at the same

altitude, probably because of remodeling and adaptation that render

the pulmonary vasculature less susceptible to the effects of hypoxia.

A rapid rate of ascent, a history of HAPE, respiratory tract infections,

and cold environmental temperatures are risk factors. Men are more

susceptible than women. People with abnormalities of the cardiopulmonary circulation leading to pulmonary hypertension—e.g., mitral

stenosis, primary pulmonary hypertension, and unilateral absence

of the pulmonary artery—may be at increased risk of HAPE, even at

moderate altitudes. Although patent foramen ovale, a common condition, is four times more common among HAPE-susceptible individuals

than in the general population, there is no compelling evidence to

suggest causal effect. Echocardiography is recommended when HAPE

develops at relatively low altitudes (<3000 m) and whenever cardiopulmonary abnormalities predisposing to HAPE are suspected. The

differential diagnosis of HAPE includes anxiety attack, pneumonia,

pneumothorax, and pulmonary embolism.

The initial manifestation of HAPE may be a reduction in exercise

tolerance greater than that expected at the given altitude. Although a

dry, persistent cough may presage HAPE and may be followed by the

production of blood-tinged sputum, cough in the mountains is almost

universal and the mechanism is poorly understood. Tachypnea and

tachycardia, even at rest, are important markers as illness progresses.

Crackles may be heard on auscultation but are not diagnostic. HAPE

may be accompanied by signs of HACE. Patchy or localized opacities

(Fig. 462-3) or streaky interstitial edema may be noted on chest radiography. In the past, HAPE was mistaken for pneumonia due to the

cold or for heart failure due to hypoxia and exertion. Kerley B lines

or a bat-wing appearance are not seen on radiography. Electrocardiography may reveal right ventricular strain or even hypertrophy.

Hypoxemia and respiratory alkalosis are consistently present unless the

patient is taking acetazolamide, in which case metabolic acidosis may

supervene. Assessment of arterial blood gases is not necessary in the

evaluation of HAPE; an oxygen saturation reading with a pulse oximeter is generally adequate. The existence of a subclinical form of HAPE

has been suggested by an increased alveolar-arterial oxygen gradient

in Everest climbers near the summit, but hard evidence correlating

this abnormality with the development of clinically relevant HAPE is

FIGURE 462-2 A hyperbaric bag. The cylindrical, portable (<7 kg) nylon bag has

a one-way valve to prevent carbon dioxide buildup. A patient with severe acute

mountain sickness (AMS), high-altitude cerebral edema (HACE), or high-altitude

pulmonary edema (HAPE) is zipped inside the bag, which is continuously inflated

with a foot pedal. The increased barometric pressure (2 psi) inside the bag simulates

descent; for example, at 4250 m, the equivalent “elevation” inside the bag is ~2100 m.

No supplemental oxygen is required.

FIGURE 462-3 Chest radiograph of a patient with high-altitude pulmonary

edema shows opacity in the right middle and lower zones simulating pneumonic

consolidation. The opacity cleared almost completely in 2 days with descent and

supplemental oxygen.

3620 PART 15 Disorders Associated with Environmental Exposures

lacking. Comet-tail scoring—an ultrasound technique initially validated in cardiogenic pulmonary edema—has been used for evaluation

of extravascular lung water at high altitude and has proven to be useful

in detecting HAPE (clinical or subclinical) and even in ascertaining

whether the presence of extravascular lung water is a harbinger of

HAPE in patients with AMS.

Pathophysiology HAPE is a noncardiogenic pulmonary edema

with normal pulmonary artery wedge pressure. It is characterized by

patchy pulmonary hypoxic vasoconstriction that leads to overperfusion in some areas. This abnormality leads in turn to increased pulmonary capillary pressure (>18 mmHg) and capillary “stress” failure.

The exact mechanism for this hypoxic vasoconstriction is unknown.

Endothelial dysfunction due to hypoxia may play a role by impairing

the release of nitric oxide, an endothelium-derived vasodilator. At high

altitude, HAPE-prone persons have reduced levels of exhaled nitric

oxide. The effectiveness of phosphodiesterase-5 inhibitors in alleviating altitude-induced pulmonary hypertension, decreased exercise

tolerance, and hypoxemia supports the role of nitric oxide in the pathogenesis of HAPE. One study demonstrated that prophylactic use of

tadalafil, a phosphodiesterase-5 inhibitor, decreases the risk of HAPE

by 65%. In contrast, the endothelium also synthesizes endothelin-1, a

potent vasoconstrictor whose concentrations are higher than average

in HAPE-prone mountaineers.

Exercise and cold lead to increased pulmonary intravascular pressure

and may predispose to HAPE. In addition, hypoxia-triggered increases

in sympathetic drive may lead to pulmonary venoconstriction and

extravasation into the alveoli from the pulmonary capillaries. Consistent with this concept, phentolamine, which elicits α-adrenergic blockade, improves hemodynamics and oxygenation in HAPE more than do

other vasodilators. The study of tadalafil cited above also investigated

dexamethasone in the prevention of HAPE. Surprisingly, dexamethasone reduced the incidence of HAPE by 78%—a greater decrease than

with tadalafil. Besides possibly increasing the availability of endothelial

nitric oxide, dexamethasone may have altered the excessive sympathetic

activity associated with HAPE: the heart rate of participants in the dexamethasone arm of the study was significantly lowered. Finally, people

susceptible to HAPE also display enhanced sympathetic activity during

short-term hypoxic breathing at low altitudes.

Because many patients with HAPE have fever, peripheral leukocytosis, and an increased erythrocyte sedimentation rate, inflammation

has been considered an etiologic factor in HAPE. However, strong

evidence suggests that inflammation in HAPE is an epiphenomenon

rather than the primary cause. Nevertheless, inflammatory processes

(e.g., those elicited by viral respiratory tract infections) do predispose

persons to HAPE—even those who are constitutionally resistant to its

development.

Another proposed mechanism for HAPE is impaired transepithelial

clearance of sodium and water from the alveoli. β-Adrenergic agonists

upregulate the clearance of alveolar fluid in animal models. In a single

double-blind, randomized, placebo-controlled study of HAPE-susceptible

mountaineers, prophylactic inhalation of the β-adrenergic agonist salmeterol reduced the incidence of HAPE by 50%. However, the dosage

of salmeterol (125 μg twice daily) used was very high, which could

result in excessive tachycardia and tremors. Other effects of β agonists

may also contribute to the prevention of HAPE, and these findings are

in keeping with the concept that alveolar fluid clearance may play a

pathogenic role in this illness.

Prevention and Treatment (Table 462-1) Allowing sufficient

time for acclimatization by ascending gradually (as discussed above for

AMS and HACE) is the best way to prevent HAPE. Sustained-release

nifedipine (30 mg), given twice daily, prevents HAPE in people who

must ascend rapidly or who have a history of HAPE. Other drugs

for the prevention of HAPE are listed in Table 462-1 (footnote e).

Although dexamethasone is listed for prevention, its adverse effect

profile requires close monitoring. Acetazolamide has been shown to

blunt hypoxic pulmonary vasoconstriction in animal models, and this

observation warrants further study in HAPE prevention. However, one

large study failed to show a decrease in pulmonary vasoconstriction

in partially acclimatized individuals given acetazolamide. Inhaled

salmeterol is not recommended as clinical experience with this drug

is limited at high altitude. Finally, potent diuretics like furosemide

should be avoided in the treatment of HAPE. Early recognition is paramount in the treatment of HAPE, especially when it is not preceded

by the AMS symptoms of headache and nausea. Fatigue and dyspnea

at rest may be the only initial manifestations. Descent and the use of

supplementary oxygen (aimed at bringing oxygen saturation to >90%)

are the most effective therapeutic interventions. Exertion should be

kept to a minimum, and the patient should be kept warm. Hyperbaric

therapy (Fig. 462-2) in a portable altitude chamber may be lifesaving, especially if descent is not possible and oxygen is not available.

Oral sustained-release nifedipine (30 mg twice daily) can be used as

adjunctive therapy. No studies have investigated phosphodiesterase-5

inhibitors in the treatment of HAPE, but reports have described their

use in clinical practice. The mainstays of treatment remain descent and

(if available) oxygen.

In AMS, if symptoms abate (with or without acetazolamide), the

patient may reascend gradually to a higher altitude. Unlike that in acute

respiratory distress syndrome (another noncardiogenic pulmonary

edema), the architecture of the lung in HAPE is usually well preserved,

with rapid reversibility of abnormalities (Fig. 462-3). This fact has

allowed some people with HAPE to reascend slowly after a few days

of descent and rest. In HACE, reascent after a few days may not be

advisable during the same trip.

■ OTHER HIGH-ALTITUDE PROBLEMS

Sleep Impairment The mechanisms underlying sleep problems,

which are among the most common adverse reactions to high altitude,

include increased periodic breathing; changes in sleep architecture,

with increased time in lighter sleep stages; and changes in rapid eye

movement sleep. Sojourners should be reassured that sleep quality

improves with acclimatization. In cases where drugs do need to be

used, acetazolamide (125 mg before bedtime) is especially useful

because this agent decreases hypoxemic episodes and alleviates sleeping

disruptions caused by excessive periodic breathing. Whether combining acetazolamide with temazepam or zolpidem is more effective than

administering acetazolamide alone is unknown. In combinations, the

doses of temazepam and zolpidem should not be increased by >10 mg

at high altitudes. Limited evidence suggests that diazepam causes

hypoventilation at high altitudes and therefore is contraindicated. For

trekkers with obstructive sleep apnea who are using a continuous positive airway pressure (CPAP) machine, the addition of acetazolamide,

which will decrease centrally mediated sleep apnea, may be helpful.

There is evidence to show that obstructive sleep apnea at high altitude

may decrease and “convert” to central sleep apnea.

Gastrointestinal Issues High-altitude exposure may be associated with increased gastric and duodenal bleeding, but further studies

are required to determine whether there is a causal effect. Because of

decreased atmospheric pressure and consequent intestinal gas expansion at high altitudes, many sojourners experience abdominal bloating

and distension as well as excessive flatus expulsion. In the absence of

diarrhea, these phenomena are normal, if sometimes uncomfortable.

Accompanying diarrhea, however, may indicate the involvement of

bacteria or Giardia parasites, which are common at many high-altitude

locations in the developing world. Prompt treatment with fluids and

empirical antibiotics may be required to combat dehydration in the

mountains. Hemorrhoids are common on high-altitude treks; treatment includes hot soaks, application of hydrocortisone ointment, and

measures to avoid constipation.

High-Altitude Cough High-altitude cough can be debilitating

and is sometimes severe enough to cause rib fracture, especially at

>5000 m. The etiology of this common problem is probably multifactorial. Although high-altitude cough has been attributed to inspiration

of cold dry air, this explanation appears not to be sufficient by itself;

in long-duration studies in hypobaric chambers, cough has occurred

3621Altitude Illness CHAPTER 462

despite controlled temperature and humidity. The implication is that

hypoxia also plays a role. Exercise can precipitate cough at high altitudes, possibly because of water loss from the respiratory tract. In general, infection does not seem to be a common etiology. Many trekkers

find it useful to wear a balaclava to trap some moisture and heat. In

most situations, cough resolves upon descent.

High-Altitude Neurologic Events Unrelated to “Altitude

Illness” Transient ischemic attacks (TIAs) and strokes have been

well described in high-altitude sojourners outside the setting of altitude

sickness. However, these descriptions are not based on cause (hypoxia)

and effect. In general, symptoms of AMS present gradually, whereas

many of these neurologic events happen suddenly. The population that

suffers strokes and TIAs at sea level is generally an older age group with

other risk factors, whereas those so afflicted at high altitudes are generally younger and probably have fewer risk factors for atherosclerotic

vascular disease. Other mechanisms (e.g., migraine, vasospasm, focal

edema, hypocapneic vasoconstriction, hypoxia in the watershed zones

of minimal cerebral blood flow, or cardiac right-to-left shunt) may be

operative in TIAs and strokes at high altitude.

Subarachnoid hemorrhage, transient global amnesia, delirium,

and cranial nerve palsies (e.g., lateral rectus palsy) occurring at high

altitudes but outside the setting of altitude sickness have been well

described. Syncope is common at moderately high altitudes, generally occurs shortly after ascent, usually resolves without descent, and

appears to be a vasovagal event related to hypoxemia. Seizures occur

rarely with HACE, but hypoxemia and hypocapnia, which are prevalent

at high altitudes, are well-known triggers that may contribute to new

or breakthrough seizures in predisposed individuals. Nevertheless,

the consensus among experts is that sojourners with well-controlled

seizure disorders can ascend to high altitudes.

Finally, persons with hypercoagulable conditions (e.g., antiphospholipid syndrome, protein C deficiency) who are asymptomatic at

sea level may experience cerebral venous thrombosis (possibly due to

enhanced blood viscosity triggered by polycythemia and dehydration)

at high altitudes. Proper history taking, examination, and prompt

investigations where possible will help define these conditions as entities separate from altitude sickness. Administration of oxygen (where

available) and prompt descent are the cornerstones of treatment of

most of these neurologic conditions.

Ocular Problems Ocular issues are common in sojourners to high

altitudes. Hypoxemia induced by altitude leads to increased retinal

blood flow, which can be visible as engorged retinal veins on ophthalmoscopic examination. Both high flow and hypoxemic vascular damage causing permeability have been implicated in a breakdown of the

blood-retina barrier and the formation of retinal hemorrhages. Blot,

dot, flame, and white-centered hemorrhages can be observed. These

hemorrhages usually resolve spontaneously with descent, with only

mild symptoms and no lasting visual damage in most healthy eyes. The

exception is hemorrhage in the macular area. Macular hemorrhages

can cause devastating initial visual loss, particularly if bilateral, and

have been reported to cause permanently decreased vision in a few

cases.

Stroke syndromes such as retinal vein occlusion, retinal artery

occlusion, ischemic optic neuropathy, and cortical visual loss have

all been reported. With unilateral vision loss, it is always important

to check for a relative afferent pupillary defect. Increased hematocrit

combined with dehydration may contribute to these maladies. Glaucomatous optic nerve damage may progress with hypoxemia of altitude.

Acetazolamide is helpful both in combating the respiratory alkalosis

that comes with increased ventilation at high altitude and in lowering

the interocular pressure; its use should be considered in patients with

stable controlled glaucoma. Macular degeneration and diabetic eye

disease are not directly exacerbated by ascent to high altitude. Dry

eye and solar damage to the cornea, known as “snow blindness,” are

common. Wearing of high-quality UV-blocking sunglasses, even on

cloudy days, and attention to protecting and supplementing the tear

film with artificial tear drops can greatly improve comfort and vision.

Although modern refractive surgeries, such as photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK), are stable at high

altitude, patients who have undergone radial keratotomy should be

cautioned that hypoxemia to the cornea can lead to swelling that shifts

the refraction during ascent.

Psychological/Psychiatric Problems Delirium characterized

by a sudden change in mental status, a short attention span, disorganized thinking, and an agitated state during the period of confusion

has been well described in mountain climbers and trekkers without a

prior history. In addition, anxiety attacks, often triggered at night by

excessive periodic breathing, are well documented. The contribution

of hypoxia to these conditions is unknown. Expedition medical kits

need to include antipsychotic injectable drugs to control psychosis in

patients in remote high-altitude locations.

■ PREEXISTING MEDICAL ISSUES

Because travel to high altitudes is increasingly popular, common conditions such as hypertension, coronary artery disease, and diabetes are

more frequently encountered among high-altitude sojourners. This

situation is of particular concern for the millions of elderly pilgrims

with medical problems who visit high-altitude sacred areas (e.g., in the

Himalayas) each year. In recent years, high-altitude travel has attracted

intrepid trekkers who are taking immunosuppressive medications

(e.g., kidney transplant recipients or patients undergoing chemotherapy). Recommended vaccinations and other precautions (e.g., hand

washing) may be especially important for this group. Although most

of these medical conditions do not appear to influence susceptibility to

altitude illness, they may be exacerbated by ascent to altitude, exertion

in cold conditions, and hypoxemia. Advice regarding the advisability of

high-altitude travel and the impact of high-altitude hypoxia on these

preexisting conditions is becoming increasingly relevant, but there are

no evidence-based guidelines. In addition, recommendations made

for relatively low altitudes (~3000 m) may not hold true for higher

altitudes (>4000 m), where hypoxic stress is greater. Personal risks and

benefits must be clearly thought through before ascent.

Hypertension At high altitudes, enhanced sympathetic activity

may lead to a transient rise in blood pressure. Occasionally, nonhypertensive, healthy, asymptomatic trekkers have pathologically high blood

pressure at high altitude that rapidly normalizes without medicines

on descent. Sojourners should continue to take their antihypertensive

medications at high altitudes. Importantly, hypertensive patients are

not more likely than others to develop altitude illness. Because the

probable mechanism of high-altitude hypertension is α-adrenergic

activity, anti-α-adrenergic drugs such as prazosin have been suggested

for symptomatic patients and those with labile hypertension. It is best

to start taking the drug several weeks before the trip and to carry a

sphygmomanometer if a trekker has labile hypertension. Sustainedrelease nifedipine may also be useful. A recent observational cohort

study of 672 hypertensive and nonhypertensive trekkers in the

Himalayas showed that most travelers, including those with wellcontrolled hypertension, can be reassured that their blood pressure will

remain relatively stable at high altitude. Although blood pressure may

be extremely elevated at high altitude in normotensive and hypertensive people, it is unlikely to cause symptoms.

Coronary Artery Disease Myocardial oxygen demand and maximal heart rate are reduced at high altitudes because the VO2

 max

(maximal oxygen consumption) decreases with increasing altitude.

This effect may explain why signs of cardiac ischemia or dysfunction

usually are not seen in healthy persons at high altitudes. Asymptomatic, fit individuals with no risk factors need not undergo any tests for

coronary artery disease before ascent. For persons with ischemic heart

disease, previous myocardial infarction, angioplasty, and/or bypass

surgery, an exercise treadmill test is indicated. A strongly positive

treadmill test is a contraindication for high-altitude trips. Patients with

poorly controlled arrhythmias should avoid high-altitude travel, but

patients with arrhythmias that are well controlled with antiarrhythmic

medications do not seem to be at increased risk. Sudden cardiac deaths

3622 PART 15 Disorders Associated with Environmental Exposures

are not noted with a greater frequency in the Alps than at lower altitudes; although sudden cardiac deaths are encountered every trekking

season in the higher Himalayan range, accurate documentation is

lacking.

Cerebrovascular Disease Patients with TIAs should avoid travel

to high altitude for at least 3 months. Patients with known cerebral

aneurysm should also avoid high-altitude travel because of possible

rupture of the aneurysm due to increased cerebral blood flow at high

altitude.

Migraine Trekkers with a history of migraine may have an increased

likelihood of suffering from AMS and may also be predisposed to

headaches including altered character of their migraine presenting

with focal neurologic deficits. Oxygen inhalation may reduce AMStriggered headache, whereas a migraine headache usually persists even

after 10–15 min of oxygen inhalation.

Asthma Although cold air and exercise may provoke acute bronchoconstriction, asthmatic patients usually have fewer problems at

high than at low altitudes, possibly because of decreased allergen levels

and increased circulating catecholamine levels. Nevertheless, asthmatic

individuals should carry all their medications, including oral glucocorticoids, with proper instructions for use in case of an exacerbation.

Severely asthmatic persons should be cautioned against ascending to

high altitudes.

Pregnancy In general, low-risk pregnant women ascending to

3000 m are not at special risk except for the relative unavailability of

medical care in many high-altitude locations, especially in developing

countries. Despite the lack of firm data on this point, venturing higher

than 3000 m to altitudes at which oxygen saturation drops steeply

seems unadvisable for pregnant women.

Obesity Although living at a high altitude has been suggested as a

means of controlling obesity, obesity has also been reported to be a risk

factor for AMS, probably because nocturnal hypoxemia is more pronounced in obese individuals. Hypoxemia may also lead to greater pulmonary hypertension, thus possibly predisposing the trekker to HAPE.

Sickle Cell Disease High altitude is one of the rare environmental

exposures that occasionally provokes a crisis in persons with sickle

cell anemia. Even when traversing mountain passes as low as 2500 m,

people with sickle cell anemia have been known to have a vaso-occlusive

crisis. Patients with known sickle cell anemia who need to travel to

high altitudes should use supplemental oxygen and travel with caution.

Thalassemia has not been known to cause problems at high altitude.

Diabetes Mellitus Well-controlled diabetes is not a contraindication for travel to high altitude. Most of the high-altitude diabetes

advice is based on patients with type 1 diabetes and not type 2 diabetic

patients with comorbidities. An eye examination before travel may be

useful. Insulin pumps are increasingly used, but bubble formation in

the system may need to be closely monitored. Diabetic patients need

to carry a reliable glucometer. Ready access to sweets is also essential.

It is important for companions of diabetic trekkers to be fully aware of

potential problems like hypoglycemia. Dexamethasone, as far as possible, should be avoided in the prevention or treatment of altitude illness

in a diabetic patient.

Chronic Lung Disease Depending on disease severity and access

to medical care, preexisting lung disease may not always preclude

high-altitude travel. A proper pretravel evaluation must be conducted.

Supplemental oxygen may be required if the predicted PaO2

 for the altitude is <50–55 mmHg. Preexisting pulmonary hypertension may also

need to be assessed in these patients. If the result is positive, patients

should be discouraged from ascending to high altitudes; if such travel

is necessary, treatment with sustained-release nifedipine (20 mg twice a

day) should be considered. Small-scale studies have revealed that when

patients with bullous disease reach ~5000 m, bullous expansion and

pneumothorax are not noted. Compared with information on chronic

obstructive pulmonary disease, fewer data exist about the safety of

travel to high altitude for people with pulmonary fibrosis, but acute

exacerbation of pulmonary fibrosis has been seen at high altitude. A

handheld pulse oximeter can be useful to check for oxygen saturation.

Chronic Kidney Disease Patients with chronic kidney disease

can tolerate short-term stays at high altitudes, but theoretical concern

persists about progression to end-stage renal disease. Acetazolamide,

the drug most commonly used for altitude sickness, should be avoided

by anyone with preexisting metabolic acidosis, which can be exacerbated by this drug. In addition, the acetazolamide dosage should be

adjusted when the glomerular filtration rate falls to <50 mL/min, and

the drug should not be used at all if this value falls to <10 mL/min.

Cirrhosis Of patients with cirrhosis, 16% may have portopulmonary arterial hypertension, and 32% may have hepatopulmonary

syndrome; these conditions may be detrimental at high altitude as they

may cause exaggerated hypoxemia. Thus, screening for these problems

is important in cirrhotic patients planning a high-altitude trip. In addition, acetazolamide may be inadvisable in these patients as the drug

may increase the risk of hepatic encephalopathy.

Dental Problems Air resulting from decay in the root system

could expand on ascent and lead to increasing pain. A good dental

checkup before a trekking or climbing trip may be prudent.

■ CHRONIC MOUNTAIN SICKNESS AND HIGHALTITUDE PULMONARY HYPERTENSION IN

HIGHLANDERS

The largest populations of highlanders live in the South American

Andes, the Tibetan Plateau, and parts of Ethiopia. Chronic mountain

sickness (Monge’s disease) is a disease in highlanders that is characterized by excessive erythrocytosis with moderate to severe pulmonary

hypertension leading to cor pulmonale. This condition was originally described in South America and has also been documented in

Colorado and in the Han Chinese population in Tibet; it is much less

common in Tibetans or in Ethiopian highlanders. Migration to a low

altitude results in the resolution of chronic mountain illness. Venesection and acetazolamide are helpful.

High-altitude pulmonary hypertension is also a subacute disease

of long-term high-altitude residents. Unlike Monge’s disease, this

syndrome is characterized primarily by pulmonary hypertension

(not erythrocytosis) leading to heart failure. Indian soldiers living at

extreme altitudes for prolonged periods and Han Chinese infants born

in Tibet have presented with the adult and infantile forms, respectively.

High-altitude pulmonary hypertension bears a striking pathophysiologic resemblance to brisket disease in cattle. Descent to a lower

altitude is curative.

■ FURTHER READING

Basnyat B: High altitude pilgrimage medicine. High Alt Med Biol

15:434, 2014.

Basnyat B, Murdoch D: High altitude illness. Lancet 361:1967, 2003.

Hillebrandt D et al: UIAA medical commission recommendations

for mountaineers, hillwalkers, trekkers, and rock and ice climbers

with diabetes. High Alt Med Biol, 2018. [Epub ahead of print]

Keyes LE et al: Blood pressure and altitude: An observational cohort

study of hypertensive and nonhypertensive Himalayan trekkers in

Nepal. High Alt Med Biol 18:267, 2017.

Luks AM et al: Wilderness Medical Society practice guidelines for

the prevention and treatment of acute altitude illness: 2019 update.

Wilderness Environ Med 30:S3, 2019.

Mcintosh SE et al: Reduced acetazolamide dosing in countering altitude illness: A comparison of 62.5 vs 125 mg (the RADICAL Trial).

Wilderness Environ Med 30:12, 2019.

Roach RC et al: Mountain medicine, in Wilderness Medicine, 7th ed.

PS Auerbach et al (eds). Philadelphia, Elsevier, 2017, pp 2–39.

3623Hyperbaric and Diving Medicine CHAPTER 463

WHAT IS HYPERBARIC

AND DIVING MEDICINE?

Hyperbaric medicine is the treatment of health disorders using wholebody exposure to pressures >101.3 kPa (1 atmosphere or 760 mmHg).

In practice, this almost always means the administration of hyperbaric

oxygen therapy (HBO2

T). The Undersea and Hyperbaric Medical

Society (UHMS) defines HBO2

T as: “an intervention in which an

individual breathes near 100% oxygen intermittently while inside

a hyperbaric chamber that is pressurized to greater than sea level

pressure (1 atmosphere absolute, or ATA). For clinical purposes, the

pressure must equal or exceed 1.4 ATA.” The chamber is an airtight

vessel variously called a hyperbaric chamber, recompression chamber,

or decompression chamber, depending on the clinical and historical

context. Such chambers may be capable of compressing a single patient

(a monoplace chamber) or multiple patients and attendants as required

(a multiplace chamber) (Figs. 463-1 and 463-2). Historically, these

compression chambers were first used for the treatment of divers and

compressed air workers suffering decompression sickness (DCS; “the

bends”). Although the prevention and treatment of disorders arising

after decompression in diving, aviation, and space flight have developed into a specialized field of their own, they remain closely linked to

the broader practice of hyperbaric medicine.

Despite an increased understanding of mechanisms and an improving evidence basis, hyperbaric medicine has struggled to achieve

widespread recognition as a “legitimate” therapeutic measure. There

are several contributing factors, but high among them are a poor

grounding in general oxygen physiology and oxygen therapy at medical

schools and a continuing tradition of charlatans advocating hyperbaric

therapy (often using air) as a panacea. Funding for both basic and clinical research has been difficult in an environment where the pharmacologic agent under study is abundant, cheap, and unpatentable. There

are signs of an improved appreciation of the potential importance of

HBO2

T with significant National Institutes of Health (NIH) funding

for mechanisms research, from the U.S. military for clinical investigation, and as evidenced by the recent appreciation of HBO2

T as a

potentially useful tool for improving oxygenation in severe COVID-19

(see “Further Readings”).

MECHANISMS OF HYPERBARIC OXYGEN

Increased hydrostatic pressure will reduce the volume of any bubbles present within the body (see “Diving Medicine”), and this is

partly responsible for the success of prompt recompression in DCS

and arterial gas embolism. Supplemental oxygen breathing has a

463

dose-dependent effect on oxygen transport, ranging from improvement in hemoglobin oxygen saturation when a few liters per minute

are delivered by simple mask at 101.3 kPa (1 ATA) to raising the dissolved plasma oxygen sufficiently to sustain life without the need for

hemoglobin at all when 100% oxygen is breathed at 303.9 kPa (3 ATA).

Most HBO2

T regimens involve oxygen breathing at between 202.6 and

283.6 kPa (2 and 2.8 ATA), and the resultant increase in arterial oxygen

tensions to >133.3 kPa (1000 mmHg) has widespread physiologic and

pharmacologic consequences (Fig. 463-3).

One direct consequence of such high intravascular tension is to

increase greatly the effective capillary-tissue diffusion distance for

oxygen such that oxygen-dependent cellular processes can resume in

hypoxic tissues. Important as this may be, the mechanism of action is

not limited to this restoration of oxygenation in hypoxic tissue. Indeed,

there are pharmacologic effects that are profound and long-lasting.

Although removal from the hyperbaric chamber results in a rapid

return of poorly vascularized tissues to their hypoxic state, even a

single dose of HBO2

T produces changes in fibroblast, leukocyte and

angiogenic functions, and antioxidant defenses that persist many hours

after oxygen tensions are returned to pretreatment levels.

It is widely accepted that oxygen in high doses produces adverse

effects due to the production of reactive oxygen species (ROS) such as

superoxide (O2

–

) and hydrogen peroxide (H2

O2

). It has become increasingly clear over the past decade that both ROS and reactive nitrogen species (RNS) such as nitric oxide (NO) participate in diverse intracellular

signaling pathways involved in the production of a range of cytokines,

growth factors, and other inflammatory and repair modulators. Such

mechanisms are complex and at times apparently paradoxical. For

example, when used to treat chronic hypoxic wounds, HBO2

T has been

shown to enhance the clearance of cellular debris and bacteria by providing the substrate for macrophage phagocytosis; stimulate growth factor

synthesis by increased production and stabilization of hypoxia-inducible

factor 1 (HIF-1); inhibit leukocyte activation and adherence to damaged

endothelium; and mobilize CD34+ pluripotent vasculogenic progenitor

cells from the bone marrow. The interactions between these mechanisms

remain a very active field of investigation. One exciting development

is the concept of hyperoxic preconditioning in which a short exposure

to HBO2

 can induce tissue protection against future hypoxic/ischemic

insult, most likely through an inhibition of mitochondrial permeability

transition pore (MPTP) opening and the release of cytochrome c. By

targeting these mechanisms of cell death during reperfusion events,

HBO2

 has potential applications in a variety of settings including organ

transplantation. One randomized clinical trial suggested that HBO2

T

prior to coronary artery bypass grafting reduces biochemical markers of

ischemic stress and improves neurocognitive outcomes.

ADVERSE EFFECTS OF THERAPY

HBO2

T is generally well tolerated and safe in clinical practice. About

17% of patients experience an adverse event at some time during their

treatment course, and most are mild and self-limiting. Adverse effects

Hyperbaric and Diving

Medicine

Michael H. Bennett, Simon J. Mitchell

FIGURE 463-1 A monoplace chamber. (Prince of Wales Hospital, Sydney.)

FIGURE 463-2 A chamber designed to treat multiple patients. (Karolinska University

Hospital.)

3624 PART 15 Disorders Associated with Environmental Exposures

are associated with both alterations in pressure (barotrauma) and the

administration of oxygen.

■ BAROTRAUMA

Barotrauma occurs when any noncompliant gas-filled space within

the body does not equalize with environmental pressure during compression or decompression. About 10% of patients complain of some

difficulty equalizing middle-ear pressure early in compression, and

although most of these problems are minor and can be overcome with

training, 2–5% of conscious patients require middle-ear ventilation

tubes or formal grommets across the tympanic membrane. Unconscious patients cannot equalize and should have middle-ear ventilation

tubes placed prior to compression if possible. Other less common sites

for barotrauma of compression include the respiratory sinuses and

dental caries. The lungs are potentially vulnerable to barotrauma of

decompression as described below in the section on diving medicine,

but the decompression following HBO2

T is so slow that pulmonary gas

trapping is extremely rare in the absence of an undrained pneumothorax or lesions such as bullae.

■ OXYGEN TOXICITY

The practical limit to the dose of oxygen, either in a single treatment

session or in a series of daily sessions, is oxygen toxicity. The most

common acute manifestation is a seizure, often preceded by anxiety

and agitation, during which time a switch from oxygen to air breathing

may avoid the convulsion. Hyperoxic seizures are typically generalized

tonic-clonic seizures followed by a variable postictal period. The cause

is an overwhelming of the antioxidant defense systems within the

brain. Although clearly dose-dependent, onset is very variable both

between individuals and within the same individual on different days.

In routine clinical hyperbaric practice, the incidence is ~1:1500 to

1:3000 compressions.

Chronic oxygen poisoning most commonly manifests as myopic

shift. This is due to alterations in the refractive index of the lens

following oxidative damage that reduces the solubility of lenticular

proteins in a process similar to that associated with senescent cataract

formation. Up to 75% of patients show deterioration in visual acuity

after a course of 30 treatments at 202.6 kPa (2 ATA). Although most

return to pretreatment values 6–12 weeks after cessation of treatment, a

small proportion do not recover. A more rapid maturation of preexisting cataracts has occasionally been associated with HBO2

T. Although

a theoretical problem, the development of pulmonary oxygen toxicity

over time does not seem to be problematic in practice—probably due

to the intermittent nature of the exposure.

CONTRAINDICATIONS TO

HYPERBARIC OXYGEN

There are few absolute contraindications to HBO2

T. The most commonly encountered is an untreated pneumothorax. A pneumothorax

may expand rapidly on decompression and come under tension. Prior

to any compression, patients with a pneumothorax should have a patent chest drain in place. The presence of other obvious risk factors for

pulmonary gas trapping such as bullae should trigger a very cautious

analysis of the risks of treatment versus benefit. Prior bleomycin treatment deserves special mention because of its association with a partially

dose-dependent pneumonitis in ~20% of people. These individuals

appear to be at particular risk for rapid deterioration of ventilatory

function following exposure to high oxygen tensions. The relationship

between distant bleomycin exposure and subsequent risk of pulmonary oxygen toxicity is uncertain; however, late pulmonary fibrosis is a

potential complication of bleomycin, and any patient with a history of

receiving this drug should be carefully counseled prior to exposure to

HBO2

T. For those recently exposed to doses >300,000 IU (200 mg) and

whose course was complicated by a respiratory reaction to bleomycin,

compression should be avoided except in a life-threatening situation.

INDICATIONS FOR HYPERBARIC OXYGEN

The appropriate indications for HBO2

T are controversial and evolving. Practitioners in this area are in an unusual position. Unlike most

branches of medicine, hyperbaric physicians do not deal with a range

of disorders within a defined organ system, nor are they masters

of a therapy specifically designed for a single category of disorders.

Hyperbaric oxygen

Restoration of

tissue normoxia

Edema

reduction

Hyperoxic

vasoconstriction

↑Wound growth

factors

Stem cell

mobilization

↓β2 integrin

function

Enhanced phagocytosis,

angiogenesis, and

fibroblast activity

Ischemic

preconditioning,

e.g., HIF-1 HO-1

Wound healing,

radiation tissue injury

Threatened grafts/flaps

cadaveric organ preservation

Enhanced inert gas

diffusion gradients between

bubble, tissue, and lungs

High

arterial PO2

Hydrostatic

compression

Bubble

volume

reduction

DCS

CAGE

Enhanced O2 diffusion Osmotic effect Generation of ROS and RNS

Crush injury

FIGURE 463-3 Mechanisms of action of hyperbaric oxygen. There are many consequences of compression and oxygen breathing. The cell-signaling effects of hyperbaric

oxygen therapy (HBO2

T) are the least understood but potentially most important. Examples of indications for use are shown in the shaded boxes. CAGE, cerebral arterial

gas embolism; DCS, decompression sickness; HIF-1, hypoxia-inducible factor-1; HO-1, hemoxygenase 1; RNS, reactive nitrogen species; ROS, reactive oxygen species.

3625Hyperbaric and Diving Medicine CHAPTER 463

Inevitably, the encroachment of hyperbaric physicians into other

medical fields generates suspicion from specialist practitioners in

those fields. At the same time, this relatively benign therapy, the prescription and delivery of which requires no medical license in most

jurisdictions (including the United States), attracts both charlatans

and well-motivated proselytizers who tout the benefits of oxygen for

a plethora of chronic incurable diseases. This battle on two fronts has

meant that mainstream hyperbaric physicians have been particularly

careful to claim effectiveness only for those conditions where there is a

reasonable body of supporting evidence.

In 1977, the UHMS systematically examined claims for the use of

HBO2

T in >100 disorders and found sufficient evidence to support

routine use in only 12. The Hyperbaric Oxygen Therapy Committee

of that organization has continued to update this list periodically with

an increasingly formalized system of appraisal for new indications and

emerging evidence (Table 463-1). Around the world, other relevant

medical organizations have generally taken a similar approach. Indications vary considerably across the globe—particularly those recommended by hyperbaric medical societies in Russia and China where

HBO2

T has gained much wider support than in the United States,

Europe, and Australasia. Nevertheless, there are now 31 Cochrane

reviews summarizing the randomized trial evidence for 27 putative

indications, including attempts to examine the cost-effectiveness of

HBO2

T. Table 463-2 is a synthesis of these two approaches and lists

the estimated cost of attaining health outcomes with the use of HBO2

T.

Any savings associated with alternative treatment strategies avoided as

a result of HBO2

T are not accounted for in these estimates (e.g., the

avoidance of lower leg amputation in diabetic foot ulcers). Following

are short reviews of three important indications currently accepted by

the UHMS.

■ LATE RADIATION TISSUE INJURY

Radiotherapy is a well-established treatment for suitable malignancies. In the United States alone, ~300,000 individuals annually will

become long-term survivors of cancer treated by irradiation. Serious

radiation-related complications developing months or years after

treatment (late radiation tissue injury [LRTI]) will significantly affect

between 5 and 15% of those long-term survivors, although incidence

varies widely with dose, age, and site. LRTI is most common in the

head and neck, chest wall, breast, and pelvis.

Pathology and Clinical Course With time, tissues undergo a

progressive deterioration characterized by a reduction in the density

of small blood vessels (reduced vascularity) and the replacement

of normal tissue with dense fibrous tissue (fibrosis). An alternative

model of pathogenesis suggests that rather than a primary hypoxia, the

principal trigger is an overexpression of inflammatory cytokines that

promote fibrosis, probably through oxidative stress and mitochondrial

dysfunction, and a secondary tissue hypoxia. Ultimately, and often

triggered by a further physical insult such as surgery or infection, there

may be insufficient oxygen to sustain normal function, and the tissue

becomes necrotic (radiation necrosis). LRTI may be life-threatening

and significantly reduce quality of life. Historically, the management of

these injuries has been unsatisfactory. Conservative treatment is usually restricted to symptom management, whereas definitive treatment

traditionally entails surgery to remove the affected part and extensive

repair. Surgical intervention in an irradiated field is often disfiguring

and associated with an increased incidence of delayed healing, breakdown of a surgical wound, or infection. HBO2

T may act by several

mechanisms to improve this situation, including edema reduction,

vasculogenesis, and enhancement of macrophage activity (Fig. 463-3).

The intermittent application of HBO2

 is the only intervention shown to

increase the microvascular density in irradiated tissue.

Clinical Evidence The typical course of HBO2

T consists of 30

once-daily compressions to 202.6–243.1 kPa (2–2.4 ATA) for 1.5–2 h

each session, often bracketed around surgical intervention if required.

Although HBO2

T has been used for LRTI since at least 1975, most

clinical studies have been limited to small case series or individual

case reports. In a review, Feldmeier and Hampson located 71 such

reports involving a total of 1193 patients across eight different tissues.

There were clinically significant improvements in the majority of

patients, and only 7 of 71 reports indicated a generally poor response

to HBO2

T. A Cochrane systematic review with meta-analysis included

14 randomized trials published since 1985 and drew the following

conclusions (see Table 463-2 for numbers needed to treat): HBO2

T

improves healing in radiation proctitis (relative risk [RR] of healing

with HBO2

T, 1.72; 95% confidence interval [CI], 1.0–2.9) and achievement of mucosal cover of bone after hemimandibulectomy and reconstruction of the mandible (RR, 1. 3; 95% CI, 1.1–1.6); HBO2

T prevents

the development of osteoradionecrosis following tooth extraction from

a radiation field (RR, 1.4; 95% CI, 1.08–1.7) and reduces the risk of

wound dehiscence following grafts and flaps in the head and neck (RR,

4.2; 95% CI, 1.1–16.8). Conversely, there was no evidence of benefit in

established radiation brachial plexus lesions or brain injury.

■ SELECTED PROBLEM WOUNDS

A problem wound is any cutaneous ulceration that requires a prolonged time to heal, does not heal, or recurs. In general, wounds

referred to hyperbaric facilities are those where sustained attempts to

heal by other means have failed. Problem wounds are common and

constitute a significant health problem. It has been estimated that 1%

of the population of industrialized countries will experience a leg ulcer

at some time. The global cost of chronic wound care may be as high as

U.S. $25 billion per year.

Pathology and Clinical Course By definition, chronic wounds

are indolent or progressive and resistant to the wide array of treatments applied. Although there are many contributing factors, most

commonly, these wounds arise in association with one or more comorbidities such as diabetes, peripheral venous or arterial disease, or prolonged pressure (decubitus ulcers). First-line treatments are aimed at

correction of the underlying pathology (e.g., vascular reconstruction,

compression bandaging, or normalization of blood glucose level), and

HBO2

T is an adjunctive therapy to good general wound care practice

to maximize the chance of healing.

For most indolent wounds, hypoxia is a major contributor to failure

to heal. Many guidelines to patient selection for HBO2

T include the

interpretation of transcutaneous oxygen tensions around the wound

while breathing air and oxygen at pressure (Fig. 463-4). Wound healing is a complex and incompletely understood process. While it appears

that in acute wounds healing is stimulated by the initial hypoxia, low

pH, and high lactate concentrations found in freshly injured tissue,

some elements of tissue repair are extremely oxygen dependent, for

example, collagen elaboration and deposition by fibroblasts and bacterial killing by macrophages. In this complicated interaction between

TABLE 463-1 Current List of Indications for Hyperbaric Oxygen

Therapy

1. Air or gas embolism (includes diving-related, iatrogenic, and accidental

causes)

2. Carbon monoxide poisoning (including poisoning complicated by cyanide

poisoning)

3. Clostridial myositis and myonecrosis (gas gangrene)

4. Crush injury, compartment syndrome, and acute traumatic ischemias

5. Decompression sickness

6. Arterial insufficiency including central retinal arterial occlusion and problem

wounds

7. Severe anemia

8. Intracranial abscess

9. Necrotizing soft tissue infections (e.g., Fournier’s gangrene)

10. Osteomyelitis (refractory to other therapy)

11. Delayed radiation injury (soft-tissue injury and bony necrosis)

12. Skin grafts and flaps (compromised)

13. Acute thermal burn injury

14. Sudden sensorineural hearing loss

Source: The Undersea and Hyperbaric Medical Society (2021).

3626 PART 15 Disorders Associated with Environmental Exposures

TABLE 463-2 Selected Indications for Which There Is Promising Efficacy for the Application of Hyperbaric Oxygen Therapy

DIAGNOSIS

OUTCOME (NUMBER OF

SESSIONS) NNT AND 95% CI

ESTIMATED COST TO PRODUCE

ONE EXTRA FAVORABLE

OUTCOME AND 95% CI (USD) COMMENTS AND RECOMMENDATIONS

Radiation tissue injury More information is required on the subset of disease severity, the affected tissue type that is most likely to benefit, and the time over

which benefit may persist.

Resolved proctitis (30) 3 22,392 Large ongoing multicenter trial

2–11 14,928–82,104

Healed mandible (30) 4 29,184 Based on one poorly reported study

2–8 14,592–58,368

Mucosal cover in ORN (30) 3 29,888 Based on one poorly reported study

2–4 14,592–29,184

Bony continuity in ORN (30) 4 29,184 Based on one poorly reported study

2–8 14,592–58,368

Prevention of ORN after dental

extraction (30)

4 29,184 Based on a single study

2–13 14,592–94,848

Prevention of dehiscence (30) 5 36,480 Based on one poorly reported study

3–8 21,888–58,368

Chronic wounds More information is required on the subset of disease severity or classification most likely to benefit, the time over which benefit may

persist, and the most appropriate oxygen dose. Economic analysis is required.

Diabetic ulcer healed at

1 year (30)

2 14,928 Based on one small study, more research

required

1–5 7464–37,320

Diabetic ulcer, major

amputation avoided (30)

4 29,856 Three small studies; outcome over a

longer time period required

3–11 22,392–82,104

ISSNHL No evidence of benefit >2 weeks after onset. More research is required to define the role (if any) of HBO2

T in routine therapy.

Improvement of 25% in hearing

loss within 2 weeks of onset

(15)

5 18,240 Some improvement in hearing, but

functional significance unknown

3–20 10,944–72,960

Acute coronary syndrome More information is required on the subset of disease severity and timing of therapy most likely to result in benefit. Given the potential

of HBO2

T in modifying ischemia-reperfusion injury, attention should be given to the combination of HBO2

T and thrombolysis in early

management and in the prevention of restenosis after stent placement.

Episode of MACE (5) 4 4864 Based on a single small study; more

research required

3–10 3648–12,160

Incidence of significant

dysrhythmia (5)

6 7296 Based on a single moderately powered

study in the 1970s

3–24 3648–29,184

Traumatic brain injury Limited evidence that for acute injury HBO2

T reduces mortality but not functional morbidity. Routine use not yet justified.

Mortality (15) 7 34,104 Based on four heterogeneous studies

4–22 19,488–58,464

Enhancement of

radiotherapy

There is some evidence that HBO2

T improves local tumor control, reduces mortality for cancers of the head and neck, and reduces the

chance of local tumor recurrence in cancers of the head, neck, and uterine cervix.

Head and neck cancer: 5-year

mortality (12)

5 14,592 Based on trials performed in the 1970s and

1980s. There may be some confounding by

radiation fractionation schedule.

3–14 8755–40,858

Local recurrence 1 year (12) 5 14,592 May no longer be relevant to therapy

4–8 11,674–23,347

Cancer of uterine cervix: Local

recurrence at 2 years (20)

5 24,320 As above

4–8 19,456–38,912

Decompression illnessa Reasonable evidence for reduced number of HBO2

T sessions but similar outcomes when NSAID added.

Reduction of HBO2

T treatment

requirement by 1

5

3–18

N/R Single appropriately powered randomized

trial

a

Tenoxicam used as an adjunct to recompression on oxygen.

Abbreviations: CI, confidence interval; HBO2

T, hyperbaric oxygen therapy; ISSNHL, idiopathic sudden sensorineural hearing loss; MACE, major adverse cardiac events; NNT,

number needed to treat; N/R, not remarkable; NSAID, nonsteroidal anti-inflammatory drug; ORN, osteoradionecrosis; USD, U.S. dollars.

Source: M Bennett: The evidence-basis of diving and hyperbaric medicine—a synthesis of the high level evidence with meta-analysis. http://unsworks.unsw.edu.au/fapi/

datastream/unsworks:949/SOURCE01?view=true.