Rom, William N.

Rom, William N.

Address: Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, Depts of Medicine and Environmental Med, 550 First Avenue, New York, New York 10016

Country: United States

Phone: 1 212 263 6479

Fax: 1 212 263 8442

Past position(s): Senior Investigator, Pulmonary Branch, NHIBI, National Institutes of Health

Education: MD, 1971, University of Minnesota; MPH, 1973, Harvard School of Public Health

Areas of interest: Occupational lung disease; tuberculosis; lung cancer

The presence of respiratory irritants in the workplace can be unpleasant and distracting, leading to poor morale and decreased productivity. Certain exposures are dangerous, even lethal. In either extreme, the problem of respiratory irritants and inhaled toxic chemicals is common; many workers face a daily threat of exposure. These compounds cause harm by a variety of different mechanisms, and the extent of injury can vary widely, depending on the degree of exposure and on the biochemical properties of the inhalant. However, they all have the characteristic of nonspecificity; that is, above a certain level of exposure virtually all persons experience a threat to their health.

There are other inhaled substances that cause only susceptible individuals to develop respiratory problems; such complaints are most appropriately approached as diseases of allergic and immunological origin. Certain compounds, such as isocyanates, acid anhydrides and epoxy resins, can act not only as non-specific irritants in high concentrations, but can also predispose certain subjects to allergic sensitization. These compounds provoke respiratory symptoms in sensitized individuals at very low concentrations.

Respiratory irritants include substances that cause inflammation of the airways after they are inhaled. Damage may occur in the upper and lower airways. More dangerous is acute inflammation of the pulmonary parenchyma, as in chemical pneumonitis or non-cardiogenic pulmonary oedema. Compounds that can cause parenchymal damage are considered toxic chemicals. Many inhaled toxic chemicals also act as respiratory irritants, warning us of their danger with their noxious odour and symptoms of nose and throat irritation and cough. Most respiratory irritants are also toxic to the lung parenchyma if inhaled in sufficient amount.

Many inhaled substances have systemic toxic effects after being absorbed by inhalation. Inflammatory effects on the lung may be absent, as in the case of lead, carbon monoxide or hydrogen cyanide. Minimal lung inflammation is normally seen in the inhalation fevers (e.g., organic dust toxic syndrome, metal fume fever and polymer fume fever). Severe lung and distal organ damage occurs with significant exposure to toxins such as cadmium and mercury.

The physical properties of inhaled substances predict the site of deposition; irritants will produce symptoms at these sites. Large particles (10 to 20mm) deposit in the nose and upper airways, smaller particles (5 to 10mm) deposit in the trachea and bronchi, and particles less than 5mm in size may reach the alveoli. Particles less than 0.5mm are so small they behave like gases. Toxic gases deposit according to their solubility. A water-soluble gas will be adsorbed by the moist mucosa of the upper airway; less soluble gases will deposit more randomly throughout the respiratory tract.

Respiratory Irritants

Respiratory irritants cause non-specific inflammation of the lung after being inhaled. These substances, their sources of exposure, physical and other properties, and effects on the victim are outlined in Table 1. Irritant gases tend to be more water soluble than gases more toxic to the lung parenchyma. Toxic fumes are more dangerous when they have a high irritant threshold; that is, there is little warning that the fume is being inhaled because there is little irritation.

Table 1. Summary of respiratory irritants

Chemical

Sources of exposure

Important properties

Injury produced

Dangerous exposure level under 15 min 
(PPM)

Acetaldehyde

Plastics, synthetic rubber industry, combustion products

High vapour pressure; high water solubility

Upper airway injury; rarely causes delayed pulmonary oedema

 

Acetic acid, organic 
acids

Chemical industry, electronics, combustion products

Water soluble

Ocular and upper airway injury

 

Acid anhydrides

Chemicals, paints, and plastics 
industries; components of epoxy resins

Water soluble, highly reactive, may cause allergic sensitization

Ocular, upper airway injury, bronchospasm; pulmonary haemorrhage after massive exposure

 

Acrolein

Plastics, textiles, pharmaceutical manufacturing, combustion products

High vapour pressure, intermediate water solubility, extremely irritating

Diffuse airway and parenchymal injury

 

Ammonia

Fertilizers, animal feeds, chemicals, and pharmaceuticals manufacturing

Alkaline gas, very high water solubility

Primarily ocular and upper airway burn; massive exposure may cause bronchiectasis

500

Antimony trichloride, antimony penta-chloride

Alloys, organic catalysts

Poorly soluble, injury likely due to halide ion

Pneumonitis, non-cardiogenic pulmonary oedema

 

Beryllium

Alloys (with copper), ceramics; electronics, aerospace and nuclear reactor equipment

Irritant metal, also acts as an antigen to promote a long-term granulomatous response

Acute upper airway injury, tracheobronchitis, chemical pneumonitis

25 μg/m3

Boranes (diborane)

Aircraft fuel, fungicide manufacturing

Water soluble gas

Upper airway injury, pneumonitis with massive exposure

 

Hydrogen bromide

Petroleum refining

 

Upper airway injury, pneumonitis with massive exposure

 

Methyl bromide

Refrigeration, produce fumigation

Moderately soluble gas

Upper and lower airway injury, pneumonitis, CNS depression and seizures

 

Cadmium

Alloys with Zn and Pb, electroplating, batteries, insecticides

Acute and chronic respiratory effects

Tracheobronchitis, pulmonary oedema (often delayed onset over 24–48 hours); chronic low level exposure leads to inflammatory changes and emphysema

100

Calcium oxide, calcium hydroxide

Lime, photography, tanning, insecticides

Moderately caustic, very high doses required for toxicity

Upper and lower airway inflammation, pneumonitis

 

Chlorine

Bleaching, formation of chlorinated compounds, household cleaners

Intermediate water solubilty

Upper and lower airway inflammation, pneumonitis and non-cardiogenic pulmonary oedema

5–10

Chloroacetophenone

Crowd control agent, “tear gas”

Irritant qualities are used to incapacitate; alkylating agent

Ocular and upper airway inflammation, lower airway and parenchymal injury with masssive exposure

1–10

o-Chlorobenzomalo-
nitrile

Crowd control agent, “tear gas”

Irritant qualities are used to
incapacitate

Ocular and upper airway inflammation, lower airway injury with massive exposure

 

Chloromethyl ethers

Solvents, used in manufacture of other organic compounds

 

Upper and lower airway irritation, also a respiratory tract carcinogen

 

Chloropicrin

Chemical manufacturing, fumigant component

Former First World War gas

Upper and lower airway inflammation

15

Chromic acid (Cr(IV))

Welding, plating

Water soluble irritant, allergic sensitizer

Nasal inflammation and ulceration, rhinitis, pneumonitis with massive exposure

 

Cobalt

High temperature alloys, permanent magnets, hard metal tools (with tungsten carbide)

Non-specific irritant, also allergic sensitizer

Acute bronchospasm and/or pneumonitis; chronic exposure can cause lung fibrosis

 

Formaldehyde

Manufacture of foam insulation, plywood, textiles, paper, fertilizers,
resins; embalming agents; combustion products

Highly water soluble, rapidly metabolized; primarily acts via sensory nerve stimulation; sensitization reported

Ocular and upper airway irritation; bronchospasm in severe exposure; contact dermatitis in sensitized persons

3

Hydrochloric acid

Metal refining, rubber manufacturing, organic compound manufacture, photographic materials

Highly water soluble

Ocular and upper airway inflammation, lower airway inflammation only with massive exposure

100

Hydrofluoric acid

Chemical catalyst, pesticides, bleaching, welding, etching

Highly water soluble, powerful and rapid oxidant, lowers serum calcium in massive exposure

Ocular and upper airway inflammation, tracheobronchitis and pneumonitis with massive exposure

20

Isocyanates

Polyurethane production; paints; herbicide and insecticide products; laminating, furniture, enamelling,
resin work

Low molecular weight organic compounds, irritants, cause sensitization in susceptible persons

Ocular, upper and lower inflammation; asthma, hypersensitivity pneumonitis in sensitized persons

0.1

Lithium hydride

Alloys, ceramics, electronics, chemical catalysts

Low solubility, highly reactive

Pneumonitis, non-cardiogenic pulmonary oedema

 

Mercury

Electrolysis, ore and amalgam extraction, electronics manufacture

No respiratory symptoms with low level, chronic exposure

Ocular and respiratory tract inflammation, pneumonitis, CNS, kidney and systemic effects

1.1 mg/m3

Nickel carbonyl

Nickel refining, electroplating, chemical reagents

Potent toxin

Lower respiratory irritation, pneumonitis, delayed systemic toxic effects

8 μg/m3

Nitrogen dioxide

Silos after new grain storage, fertilizer making, arc welding, combustion products

Low water solubility, brown gas at
high concentration

Ocular and upper airway inflammation, non-cardiogenic pulmonary oedema, delayed onset bronchiolitis

50

Nitrogen mustards;
sulphur mustards

Military gases

Causes severe injury, vesicant
properties

Ocular, upper and lower airway inflammation, pneumonitis

20mg/m3 (N) 
1 mg/m3 (S)

Osmium tetroxide

Copper refining, alloy with iridium, catalyst for steroid synthesis and ammonia formation

Metallic osmium is inert, tetraoxide forms when heated in air

Severe ocular and upper airway irritation; transient renal damage

1 mg/m3

Ozone

Arc welding, copy machines, paper bleaching

Sweet smelling gas, moderate water solubility

Upper and lower airway inflammation; asthmatics more susceptible

1

Phosgene

Pesticide and other chemical manufacture, arc welding, paint removal

Poorly water soluble, does not irritate airways in low doses

Upper airway inflammation and pneumonitis; delayed pulmonary oedema in low doses

2

Phosphoric sulphides

Production of insecticides, ignition compounds, matches

 

Ocular and upper airway inflammation

 

Phosphoric chlorides

Manufacture of chlorinated organic compounds, dyes, gasoline additives

Form phosphoric acid and hydrochloric acid on contact with mucosal surfaces

Ocular and upper airway inflammation

10 mg/m3

Selenium dioxide

Copper or nickel smelting, heating of selenium alloys

Strong vessicant, forms selenious acid (H2SeO3) on mucosal surfaces

Ocular and upper airway inflammation, pulmonary oedema in massive exposure

 

Hydrogen selenide

Copper refining, sulphuric acid production

Water soluble; exposure to selenium compounds gives rise to garlic odour breath

Ocular and upper airway inflammation, delayed pulmonary oedema

 

Styrene

Manufacture of polystyrene and resins, polymers

Highly irritating

Ocular, upper and lower airway inflammation, neurological impairments

600

Sulphur dioxide

Petroleum refining, pulp mills, refrigeration plants, manufacturing of sodium sulphite

Highly water soluble gas

Upper airway inflammation, bronchoconstriction, pneumonitis on massive exposure

100

Titanium tetrachloride

Dyes, pigments, sky writing

Chloride ions form HCl on mucosa

Upper airway injury

 

Uranium hexafluoride

Metal coat removers, floor sealants, spray paints

Toxicity likely from chloride ions

Upper and lower airway injury, bronchospasm, pneumonitis

 

Vanadium pentoxide

Cleaning oil tanks, metallurgy

 

Ocular, upper and lower airway symptoms

70

Zinc chloride

Smoke grenades, artillery

More severe than zinc oxide exposure

Upper and lower airway irritation, fever, delayed onset pneumonitis

200

Zirconium tetrachloride

Pigments, catalysts

Chloride ion toxicity

Upper and lower airway irritation, pneumonitis

 

 

This condition is thought to result from persistent inflammation with reduction of epithelial cell layer permeability or reduced conductance threshold for subepithelial nerve endings.Adapted from Sheppard 1988; Graham 1994; Rom 1992; Blanc and Schwartz 1994; Nemery 1990; Skornik 1988.

The nature and extent of the reaction to an irritant depends on the physical properties of the gas or aerosol, the concentration and time of exposure, and on other variables as well, such as temperature, humidity and the presence of pathogens or other gases (Man and Hulbert 1988). Host factors such as age (Cabral-Anderson, Evans and Freeman 1977; Evans, Cabral-Anderson and Freeman 1977), prior exposure (Tyler, Tyler and Last 1988), level of antioxidants (McMillan and Boyd 1982) and presence of infection may play a role in determining the pathological changes seen. This wide range of factors has made it difficult to study the pathogenic effects of respiratory irritants in a systematic way.

The best understood irritants are those which inflict oxidative injury. The majority of inhaled irritants, including the major pollutants, act by oxidation or give rise to compounds that act in this way. Most metal fumes are actually oxides of the heated metal; these oxides cause oxidative injury. Oxidants damage cells primarily by lipid peroxidation, and there may be other mechanisms. On a cellular level, there is initially a fairly specific loss of ciliated cells of the airway epithelium and of Type I alveolar epithelial cells, with subsequent violation of the tight junction interface between epithelial cells (Man and Hulbert 1988; Gordon, Salano and Kleinerman 1986; Stephens et al. 1974). This leads to subepithelial and submucosal damage, with stimulation of smooth muscle and parasympathetic sensory afferent nerve endings causing bronchoconstriction (Holgate, Beasley and Twentyman 1987; Boucher 1981). An inflammatory response follows (Hogg 1981), and the neutrophils and eosinophils release mediators that cause further oxidative injury (Castleman et al. 1980). Type II pneumocytes and cuboidal cells act as stem cells for repair (Keenan, Combs and McDowell 1982; Keenan, Wilson and McDowell 1983).

Other mechanisms of lung injury eventually involve the oxidative pathway of cellular damage, particularly after damage to the protective epithelial cell layer has occurred and an inflammatory response has been elicited. The most commonly described mechanisms are outlined in table 2.

Table 2. Mechanisms of lung injury by inhaled substances

Mechanism of injury

Example compounds

Damage that occurs

Oxidation

Ozone, nitrogen dioxide, sulphur dioxide, chlorine, oxides

Patchy airway epithelial damage, with increased permeability and exposure of nerve fibre endings; loss of cilia from ciliated cells; necrosis of type I pneumocytes; free radical formation and subsequent protein binding and lipid peroxidation

Acid formation

Sulphur dioxide, chlorine, halides

Gas dissolves in water to form acid that damages epithelial cells via oxidation; action mainly on upper airway

Alkali formation

Ammonia, calcium oxide, hydroxides

Gas dissolves in water to form alkaline solution that may cause tissue liquefaction; predominant upper airway damage, lower airway in heavy exposures

Protein binding

Formaldehyde

Reactions with amino acids lead to toxic intermediates with damage to the epithelial cell layer

Afferent nerve stimulation

Ammonia, formaldehyde

Direct nerve ending stimulation provokes symptoms

Antigenicity

Platinum, acid anhydrides

Low molecular weight molecules serve as haptens in sensitized persons

Stimulation of host inflammatory response

Copper and zinc oxides, lipoproteins

Stimulation of cytokines and inflammatory mediators without apparent direct cellular damage

Free radical formation

Paraquat

Promotion of formation or retardation of clearance of superoxide radicals, leading to lipid peroxidation and oxidative damage

Delayed particle clearance

Any prolonged inhalation of mineral dust

Overwhelming of mucociliary escalators and alveolar macrophage systems with particles, leading to a non-specific inflammatory response

 

Workers exposed to low levels of respiratory irritants may have subclinical symptoms traceable to mucous membrane irritation, such as watery eyes, sore throat, runny nose and cough. With significant exposure, the added feeling of shortness of breath will often prompt medical attention. It is important to secure a good medical history in order to determine the likely composition of the exposure, the quantity of exposure, and the period of time during which the exposure took place. Signs of laryngeal oedema, including hoarseness and stridor, should be sought, and the lungs should be examined for signs of lower airway or parenchymal involvement. Assessment of the airway and lung function, together with chest radiography, are important in short-term management. Laryngoscopy may be indicated to evaluate the airway.

If the airway is threatened, the patient should undergo intubation and supportive care. Patients with signs of laryngeal oedema should be observed for at least 12 hours to insure that the process is self-limited. Bronchospasm should be treated with b-agonists and, if refractory, intravenous corticosteroids. Irritated oral and ocular mucosa should be thoroughly irrigated. Patients with crackles on examination or chest radiograph abnormalities should be hospitalized for observation in view of the possibility of pneumonitis or pulmonary oedema. Such patients are at risk of bacterial superinfection; nevertheless, no benefit has been demonstrated by using prophylactic antibiotics.

The overwhelming majority of patients who survive the initial insult recover fully from irritant exposures. The chances for long-term sequelae are more likely with greater initial injury. The term reactive airway dysfunction syndrome (RADS) has been applied to the persistence of asthma-like symptoms following acute exposure to respiratory irritants (Brooks, Weiss and Bernstein 1985).

High-level exposures to alkalis and acids can cause upper and lower respiratory tract burns that lead to chronic disease. Ammonia is known to cause bronchiectasis (Kass et al. 1972); chlorine gas (which becomes HCl in the mucosa) is reported to cause obstructive lung disease (Donelly and Fitzgerald 1990; Das and Blanc 1993). Chronic low-level exposures to irritants may cause continued ocular and upper airway symptoms (Korn, Dockery and Speizer 1987), but deterioration of lung function has not been conclusively documented. Studies of the effects of chronic low-level irritants on airway function are hampered by a lack of long-term follow-up, confounding by cigarette smoking, the “healthy worker effect,” and the minimal, if any, actual clinical effect (Brooks and Kalica 1987).

After a patient recovers from the initial injury, regular follow-up by a physician is needed. Clearly, there should be an effort to investigate the workplace and evaluate respiratory precautions, ventilation and containment of the culprit irritants.

Toxic Chemicals

Chemicals toxic to the lung include most of the respiratory irritants given enough high exposure, but there are many chemicals that cause significant parenchymal lung injury despite possessing low to moderate irritant properties. These compounds work their effects by mechanisms reviewed in Table 3 and discussed above. Pulmonary toxins tend to be less water soluble than upper airway irritants. Examples of lung toxins and their sources of exposure are reviewed in table 3.

Table 3. Compounds capable of lung toxicity after low to moderate exposure

Compound

Sources of exposure

Toxicity

Acrolein

Plastics, textiles, pharmaceutical manufacturing, combustion products

Diffuse airway and parenchymal injury

Antimony trichloride; antimony
pentachloride

Alloys, organic catalysts

Pneumonitis, non-cardiogenic pulmonary oedema

Cadmium

Alloys with zinc and lead, electroplating, batteries, insecticides

Tracheobronchitis, pulmonary oedema (often delayed onset over 24–48 hours), kidney damage: tubule proteinuria

Chloropicrin

Chemical manufacturing, fumigant components

Upper and lower airway inflammation

Chlorine

Bleaching, formation of chlorinated compounds, household cleaners

Upper and lower airway inflammation, pneumonitis and non-cardiogenic pulmonary oedema

Hydrogen sulphide

Natural gas wells, mines, manure

Ocular, upper and lower airway irritation, delayed pulmonary oedema, asphyxiation from systemic tissue hypoxia

Lithium hydride

Alloys, ceramics, electronics, chemical catalysts

Pneumonitis, non-cardiogenic pulmonary oedema

Methyl isocyanate

Pesticide synthesis

Upper and lower respiratory tract irritation, pulmonary oedema

Mercury

Electrolysis, ore and amalgam extraction, electronics manufacture

Ocular and respiratory tract inflammation, pneumonitis, CNS, kidney and systemic effects

Nickel carbonyl

Nickel refining, electroplating, chemical reagents

Lower respiratory irritation, pneumonitis, delayed systemic toxic effects

Nitrogen dioxide

Silos after new grain storage, fertilizer making, arc welding; combustion products

Ocular and upper airway inflammation, non-cardiogenic pulmonary oedema, delayed onset bronchiolitis

Nitrogen mustards, sulphur
mustards

Military agents, vesicants

Ocular and respiratory tract inflammation, pneumonitis

Paraquat

Herbicides (ingested)

Selective damage to type-2 pneumocytes leading to RADS, pulmonary fibrosis; renal failure, GI irritation

Phosgene

Pesticide and other chemical manufacture, arc welding, paint removal

Upper airway inflammation and pneumonitis; delayed pulmonary oedema in low doses

Zinc chloride

Smoke grenades, artillery

Upper and lower airway irritation, fever, delayed onset pneumonitis

 

One group of inhalable toxins are termed asphyxiants. When present in high enough concentrations, the asphyxiants, carbon dioxide, methane and nitrogen, displace oxygen and in effect suffocate the victim. Hydrogen cyanide, carbon monoxide and hydrogen sulphide act by inhibiting cellular respiration despite adequate delivery of oxygen to the lung. Non-asphyxiant inhaled toxins damage target organs, causing a wide variety of health problems and mortality.

The medical management of inhaled lung toxins is similar to the management of respiratory irritants. These toxins often do not elicit their peak clinical effect for several hours after exposure; overnight monitoring may be indicated for compounds known to cause delayed onset pulmonary oedema. Since the therapy of systemic toxins is beyond the scope of this chapter, the reader is referred to discussions of the individual toxins elsewhere in this Encyclopaedia and in further texts on the subject (Goldfrank et al. 1990; Ellenhorn and Barceloux 1988).

Inhalation Fevers

Certain inhalation exposures occurring in a variety of different occupational settings may result in debilitating flu-like illnesses lasting a few hours. These are collectively referred to as inhalation fevers. Despite the severity of the symptoms, the toxicity seems to be self-limited in most cases, and there are few data to suggest long-term sequelae. Massive exposure to inciting compounds can cause a more severe reaction involving pneumonitis and pulmonary oedema; these uncommon cases are considered more complicated than simple inhalation fever.

The inhalation fevers have in common the feature of nonspecificity: the syndrome can be produced in nearly anyone, given adequate exposure to the inciting agent. Sensitization is not required, and no previous exposure is necessary. Some of the syndromes exhibit the phenomenon of tolerance; that is, with regular repeated exposure the symptoms do not occur. This effect is thought to be related to an increased activity of clearance mechanisms, but has not been adequately studied.

Organic Dust Toxic Syndrome

Organic dust toxic syndrome (ODTS) is a broad term denoting the self-limited flu-like symptoms that occur following heavy exposure to organic dusts. The syndrome encompasses a wide range of acute febrile illnesses that have names derived from the specific tasks that lead to dust exposure. Symptoms occur only after a massive exposure to organic dust, and most individuals so exposed will develop the syndrome.

Organic dust toxic syndrome has previously been called pulmonary mycotoxicosis, owing to its putative aetiology in the action of mould spores and actinomycetes. With some patients, one can culture species of Aspergillus, Penicillium, and mesophilic and thermophilic actinomycetes (Emmanuel, Marx and Ault 1975; Emmanuel, Marx and Ault 1989). More recently, bacterial endotoxins have been proposed to play at least as large a role. The syndrome has been provoked experimentally by inhalation of endotoxin derived from Enterobacter agglomerans, a major component of organic dust (Rylander, Bake and Fischer 1989). Endotoxin levels have been measured in the farm environment, with levels ranging from 0.01 to 100μg/m3. Many samples had a level greater than 0.2μg/m3, which is the level where clinical effects are known to occur (May, Stallones and Darrow 1989). There is speculation that cytokines, such as IL-1, may mediate the systemic effects, given what is already known about the release of IL-1 from alveolar macrophages in the presence of endotoxin (Richerson 1990). Allergic mechanisms are unlikely given the lack of need for sensitization and the requirement for high dust exposure.

Clinically, the patient will usually present symptoms 2 to 8 hours after exposure to (usually mouldy) grain, hay, cotton, flax, hemp or wood chips, or upon manipulation of pigs (Do Pico 1992). Often symptoms begin with eye and mucous membrane irritation with dry cough, progressing to fever, and malaise, chest tightness, myalgias and headache. The patient appears ill but otherwise normal upon physical examination. Leukocytosis frequently occurs, with levels as high as 25,000 white blood corpuscles (WBC)/mm3. The chest radiograph is almost always normal. Spirometry may reveal a modest obstructive defect. In cases where fibre optic bronchoscopy was performed and bronchial washings were obtained, an elevation of leukocytes was found in the lavage fluid. The percentage of neutrophils was significantly higher than normal (Emmanuel, Marx and Ault 1989; Lecours, Laviolette and Cormier 1986). Bronchoscopy 1 to 4 weeks after the event shows a persistently high cellularity, predominantly lymphocytes.

Depending on the nature of the exposure, the differential diagnosis may include toxic gas (such as nitrogen dioxide or ammonia) exposure, particularly if the episode occurred in a silo. Hypersensitivity pneumonitis should be considered, especially if there are significant chest radiograph or pulmonary function test abnormalities. The distinction between hypersensitivity pneumonitis (HP) and ODTS is important: HP will require strict exposure avoidance and has a worse prognosis, whereas ODTS has a benign and self-limited course. ODTS is also distinguished from HP because it occurs more frequently, requires higher levels of dust exposure, does not induce the release of serum precipitating antibodies, and (initially) does not give rise to the lymphocytic alveolitis that is characteristic of HP.

Cases are managed with antipyretics. A role for steroids has not been advocated given the self-limited nature of the illness. Patients should be educated about massive exposure avoidance. The long-term effect of repeated occurrences is thought to be negligible; however, this question has not been adequately studied.

Metal Fume Fever

Metal fume fever (MFF) is another self-limited, flu-like illness that develops after inhalation exposure, in this instance to metal fumes. The syndrome most commonly develops after zinc oxide inhalation, as occurs in brass foundries, and in smelting or welding galvanized metal. Oxides of copper and iron also cause MFF, and vapours of aluminium, arsenic, cadmium, mercury, cobalt, chromium, silver, manganese, selenium and tin have been occasionally implicated (Rose 1992). Workers develop tachyphalaxis; that is, symptoms appear only when the exposure occurs after several days without exposure, not when there are regular repeated exposures. An eight-hour TLV of 5 mg/m3 for zinc oxide has been established by the US Occupational Safety and Health Administration (OSHA), but symptoms have been elicited experimentally after a two-hour exposure at this concentration (Gordon et al. 1992).

The pathogenesis of MFF remains unclear. The reproducible onset of symptoms regardless of the individual exposed argues against a specific immune or allergic sensitization. The lack of symptoms associated with histamine release (flushing, itching, wheezing, hives) also militates against the likelihood of an allergic mechanism. Paul Blanc and co-workers have developed a model implicating cytokine release (Blanc et al. 1991; Blanc et al.1993). They measured the levels of tumour necrosis factor (TNF), and of the interleukins IL-1, IL-4, IL-6 and IL-8 in the fluid lavaged from the lungs of 23 volunteers experimentally exposed to zinc oxide fumes (Blanc et al. 1993). The volunteers developed elevated levels of TNF in their bronchoalveolar lavage (BAL) fluid 3 hours after exposure. Twenty hours later, high BAL fluid levels of IL-8 (a potent neutrophil attractant) and an impressive neutrophilic alveolitis were observed. TNF, a cytokine capable of causing fever and stimulating immune cells, has been shown to be released from monocytes in culture that are exposed to zinc (Scuderi 1990). Accordingly, the presence of increased TNF in the lung accounts for the onset of symptoms observed in MFF. TNF is known to stimulate the release of both IL-6 and IL-8, in a time period that correlated with the peaks of the cytokines in these volunteers’ BAL fluid. The recruitment of these cytokines may account for the ensuing neutrophil alveolitis and flu-like symptoms that characterize MFF. Why the alveolitis resolves so quickly remains a mystery.

Symptoms begin 3 to 10 hours after exposure. Initially, there may be a sweet metallic taste in the mouth, accompanied by a worsening dry cough and shortness of breath. Fever and shaking chills often develop, and the worker feels ill. The physical examination is otherwise unremarkable. Laboratory evaluation shows a leukocytosis and a normal chest radiograph. Pulmonary function studies may show a slightly reduced FEF25-75 and DLCO levels (Nemery 1990; Rose 1992).

With a good history the diagnosis is readily established and the worker can be treated symptomatically with antipyretics. Symptoms and clinical abnormalities resolve within 24 to 48 hours. Otherwise, bacterial and viral aetiologies of the symptoms must be considered. In cases of extreme exposure, or exposures involving contamination by toxins such as zinc chloride, cadmium or mercury, MFF may be a harbinger of a clinical chemical pneumonitis that will evolve over the next 2 days (Blount 1990). Such cases can exhibit diffuse infiltrates on a chest radiograph and signs of pulmonary oedema and respiratory failure. While this possibility should be considered in the initial evaluation of an exposed patient, such a fulminant course is unusual and not characteristic of uncomplicated MFF.

MFF does not require a specific sensitivity of the individual for the metal fumes; rather, it indicates inadequate environmental control. The exposure problem should be addressed to prevent recurrent symptoms. Although the syndrome is considered benign, the long-term effects of repeated bouts of MFF have not been adequately investigated.

Polymer Fume Fever

Polymer fume fever is a self-limited febrile illness similar to MFF, but caused by inhaled pyrolysis products of fluoropolymers, including polytetrafluoroethane (PTFE; trade names Teflon, Fluon, Halon). PTFE is widely used for its lubricant, thermal stability and electrical insulative properties. It is harmless unless heated above 30°C, when it starts to release degradation products (Shusterman 1993). This situation occurs when welding materials coated with PTFE, heating PTFE with a tool edge during high speed machining, operating moulding or extruding machines (Rose 1992) and rarely during endotracheal laser surgery (Rom 1992a).

A common cause of polymer fume fever was elicited after a period of classic public health detective work in the early 1970s (Wegman and Peters 1974; Kuntz and McCord 1974). Textile workers were developing self-limited febrile illnesses with exposures to formaldehyde, ammonia and nylon fibre; they did not have exposure to fluoropolymer fumes but handled crushed polymer. After finding that exposure levels of the other possible aetiological agents were within acceptable limits, the fluoropolymer work was examined more closely. As it turned out, only cigarette smokers working with the fluoropolymer were symptomatic. It was hypothesized that the cigarettes were being contaminated with fluoropolymer on the worker’s hands, then the product was combusted on the cigarette when it was smoked, exposing the worker to toxic fumes. After banning cigarette smoking in the workplace and setting strict handwashing rules, no further illnesses were reported (Wegman and Peters 1974). Since then, this phenomenon has been reported after working with waterproofing compounds, mould-release compounds (Albrecht and Bryant 1987) and after using certain kinds of ski wax (Strom and Alexandersen 1990).

The pathogenesis of polymer fume fever is not known. It is thought to be similar to the other inhalation fevers owing to its similar presentation and apparently non-specific immune response. There have been no human experimental studies; however, rats and birds both develop severe alveolar epithelial damage on exposure to PTFE pyrolysis products (Wells, Slocombe and Trapp 1982; Blandford et al. 1975). Accurate measurement of pulmonary function or BAL fluid changes has not been done.

Symptoms appear several hours after exposure, and a tolerance or tachyphalaxis effect is not there as seen in MFF. Weakness and myalgias are followed by fever and chills. Often there is chest tightness and cough. Physical examination is usually otherwise normal. Leukocytosis is often seen, and the chest radiograph is usually normal. Symptoms resolve spontaneously in 12 to 48 hours. There have been a few cases of persons developing pulmonary oedema after exposure; in general, PTFE fumes are thought to be more toxic than zinc or copper fumes in causing MFF (Shusterman 1993; Brubaker 1977). Chronic airways dysfunction has been reported in persons who have had multiple episodes of polymer fume fever (Williams, Atkinson and Patchefsky 1974).

The diagnosis of polymer fume fever requires a careful history with high clinical suspicion. After ascertaining the source of the PTFE pyrolysis products, efforts must be made to prevent further exposure. Mandatory handwashing rules and the elimination of smoking in the workplace has effectively eliminated cases related to contaminated cigarettes. Workers who have had multiple episodes of polymer fume fever or associated pulmonary oedema should have long-term medical follow-up.

 

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The major effects of high altitude on humans relate to the changes in barometric pressure (PB) and its consequential changes in the ambient pressure of oxygen (O2). Barometric pressure decreases with increasing altitude in a logarithmic fashion and can be estimated by the following equation:

where a = altitude, expressed in metres. In addition, the relationship of barometric pressure to altitude is influenced by other factors such as distance from the equator and season. West and Lahiri (1984) found that direct measurements of barometric pressure near the equator and at the summit of Mt. Everest (8,848 m) were greater than predictions based on the International Civil Aviation Organization Standard Atmosphere. Weather and temperature also affect the relationship between barometric pressure and altitude to the extent that a low-pressure weather system can reduce pressure, making sojourners to high altitude “physiologically higher”. Since the inspired partial pressure of oxygen (PO2) remains constant at approximately 20.93% of barometric pressure, the most important determinant of inspired PO2 at any altitude is the barometric pressure. Thus, inspired oxygen decreases with increasing altitude due to decreased barometric pressure, as shown in figure 1.

Figure 1. Effects of altitude on barometric pressure and inspired PO2

BA1030T1

Temperature and ultraviolet radiation also change at high altitudes. Temperature decreases with increasing altitude at a rate of approximately 6.5 °C per 1,000 m. Ultraviolet radiation increases approximately 4% per 300 m due to decreased cloudiness, dust, and water vapour. In addition, as much as 75% of ultraviolet radiation can be reflected back by snow, further increasing exposure at high altitude. Survival in high altitude environments is dependent on adaptation to and/or protection from each of these elements.

 

 

 

 

 

 

 

 

 

Acclimatization

While rapid ascent to high altitudes often results in death, slow ascent by mountaineers can be successful when accompanied by compensatory physiological adaptation measures. Acclimatization to high altitudes is geared towards maintaining an adequate supply of oxygen to meet metabolic demands despite the decreasing inspired PO2. In order to achieve this goal, changes occur in all organ systems involved with oxygen uptake into the body, distribution of O2 to the necessary organs, and O2 unloading to the tissues.

Discussion of oxygen uptake and distribution requires understanding the determinants of oxygen content in the blood. As air enters the alveolus, the inspired PO2 decreases to a new level (called the alveolar PO2) because of two factors: increased partial pressure of water vapour from humidification of inspired air, and increased partial pressure of carbon dioxide (PCO2) from CO2 excretion. From the alveolus, oxygen diffuses across the alveolar capillary membrane into the blood as a result of a gradient between alveolar PO2 and blood PO2. The majority of oxygen found in blood is bound to haemoglobin (oxyhaemoglobin). Thus, oxygen content is directly related to both the haemoglobin concentration in the blood and the percentage of O2 binding sites on haemoglobin that are saturated with oxygen (oxyhaemoglobin saturation). Therefore, understanding the relationship between arterial PO2 and oxyhaemoglobin saturation is essential for understanding the determinants of oxygen content in the blood. Figure 2 illustrates the oxyhaemoglobin dissociation curve. With increasing altitude, inspired PO2 decreases and, therefore, arterial PO2 and oxyhaemoglobin saturation decreases. In normal subjects, altitudes greater than 3,000 m are associated with sufficiently decreased arterial PO2 that oxyhaemoglobin saturation falls below 90%, on the steep portion of the oxyhaemoglobin dissociation curve. Further increases in altitude will predictably result in significant desaturation in the absence of compensatory mechanisms.

Figure 2. Oxyhaemoglobin dissociation curve

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The ventilatory adaptations that occur in high-altitude environments protect the arterial partial pressure of oxygen against the effects of decreasing ambient oxygen levels, and can be divided into acute, subacute and chronic changes. Acute ascent to high altitude results in a fall in the inspired PO2 which in turn leads to a decrease in the arterial PO2 (hypoxia). In order to minimize the effects of decreased inspired PO2 on arterial oxyhaemoglobin saturation, the hypoxia that occurs at high altitude triggers an increase in ventilation, mediated through the carotid body (hypoxic ventilatory response–HVR). Hyperventilation increases carbon dioxide excretion and subsequently the arterial and then the alveolar partial pressure of carbon dioxide (PCO2) falls. The fall in alveolar PCO2 allows alveolar PO2 to rise, and consequently, arterial PO2 and arterial O2 content increases. However, the increased carbon dioxide excretion also causes a decrease in blood hydrogen ion concentration ([H+]) leading to the development of alkalosis. The ensuing alkalosis inhibits the hypoxic ventilatory response. Thus, on acute ascent to high altitude there is an abrupt increase in ventilation that is modulated by the development of an alkalosis in the blood.

Over the next several days at high altitude, further changes in ventilation occur, commonly referred to as ventilatory acclimatization. Ventilation continues to increase over the next several weeks. This further increase in ventilation occurs as the kidney compensates for the acute alkalosis by excretion of bicarbonate ions, with a resultant rise in blood [H+]. It was initially believed that renal compensation for the alkalosis removed the inhibitory influence of alkalosis on the hypoxic ventilatory response, thereby allowing the full potential of the HVR to be reached. However, measurements of blood pH revealed that the alkalosis persists despite the increase in ventilation. Other postulated mechanisms include: (1) cerebrospinal fluid (CSF) pH surrounding the respiratory control centre in the medulla may have returned to normal despite the persistent serum alkalosis; (2) increased sensitivity of the carotid body to hypoxia; (3) increased response of the respiratory controller to CO2. Once ventilatory acclimatization has occurred, both hyperventilation and the increased HVR persist for several days after return to lower altitudes, despite resolution of hypoxia.

Further ventilatory changes occur after several years of living at high altitude. Measurements in high-altitude natives have shown a decreased HVR when compared to values obtained in acclimatized individuals, although not to levels seen in subjects at sea level. The mechanism for the decreased HVR is unknown, but may be related to hypertrophy of the carotid body and/or development of other adaptive mechanisms for preserving tissue oxygenation such as: increased capillary density; increased gas exchange capacity of the tissues; increased number and density of mitochondria; or increased vital capacity.

In addition to its effect on ventilation, hypoxia also induces constriction of the vascular smooth muscle in the pulmonary arteries (hypoxic vasoconstriction). The ensuing increase in pulmonary vascular resistance and pulmonary artery pressure redirects blood flow away from poorly ventilated alveoli with low alveolar PO2 and towards better ventilated alveoli. In this manner, pulmonary arterial perfusion is matched to lung units that are well ventilated, providing another mechanism for preserving arterial PO2.

Oxygen delivery to the tissues is further enhanced by adaptations in the cardiovascular and haematological systems. On initial ascent to high altitude, heart rate increases, resulting in an increase in cardiac output. Over several days, cardiac output falls due to decreased plasma volume, caused by an increased water loss that occurs at high altitudes. With more time, increased erythropoietin production leads to increased haemoglobin concentration, providing the blood with increased oxygen-carrying capacity. In addition to increasing levels of haemoglobin, changes in the avidity of oxygen binding to haemoglobin may also help maintain tissue oxygenation. A shift of the oxyhaemoglobin dissociation curve to the right may be expected because it would favour release of oxygen to the tissues. However, data obtained from the summit of Mt. Everest and from hypobaric chamber experiments simulating the summit suggest that the curve is shifted to the left (West and Lahiri 1984; West and Wagner 1980; West et al. 1983). Although a left shift would make oxygen unloading to the tissues more difficult, it may be advantageous at extreme altitudes because it would facilitate oxygen uptake in the lungs despite markedly reduced inspired PO2 (43 mmHg on the summit of Mt. Everest versus 149 mmHg at sea level).

The last link in the chain of oxygen supply to the tissues is cellular uptake and utilization of O2. Theoretically, there are two potential adaptations that can occur. First, minimization of the distance that oxygen has to travel on diffusion out of the blood vessel and into the intracellular site responsible for oxidative metabolism, the mitochondria. Second, biochemical alterations can occur that improve mitochondrial function. Minimization of diffusion distance has been suggested by studies that show either increased capillary density or increased mitochondrial density in muscle tissue. It is unclear whether these changes reflect either recruitment or development of capillaries and mitochondria, or are an artefact due to muscle atrophy. In either case, the distance between the capillaries and the mitochondria would be decreased, thereby facilitating oxygen diffusion. Biochemical alterations that may improve mitochondrial function include increased myoglobin levels. Myoglobin is an intracellular protein that binds oxygen at low tissue PO2 levels and facilitates oxygen diffusion into the mitochondria. Myoglobin concentration increases with training and correlates with muscle cell aerobic capacity. Although these adaptations are theoretically beneficial, conclusive evidence is lacking.

Early accounts of high altitude explorers describe changes in cerebral function. Decreased motor, sensory and cognitive abilities, including decreased ability to learn new tasks and difficulty expressing information verbally, have all been described. These deficits may lead to poor judgement and to irritability, further compounding the problems encountered in high-altitude environments. On return to sea level, these deficits improve with a variable time course; reports have indicated impaired memory and concentration lasting from days to months, and decreased finger-tapping speed for one year (Hornbein et al. 1989). Individuals with greater HVR are more susceptible to long-lasting deficits, possibly because the benefit of hyperventilation on arterial oxyhaemoglobin saturation may be offset by hypocapnia (decreased PCO2 in the blood), which causes constriction of the cerebral blood vessels leading to decreased cerebral blood flow.

The preceding discussion has been limited to resting conditions; exercise provides an additional stress as oxygen demand and consumption increases. The fall in ambient oxygen at high altitude causes a fall in maximal oxygen uptake and, therefore, maximal exercise. In addition, the decreased inspired PO2 at high altitudes severely impairs oxygen diffusion into the blood. This is illustrated in figure 3, which plots the time course of oxygen diffusion into the alveolar capillaries. At sea level, there is excess time for equilibration of end-capillary PO2 to alveolar PO2, whereas at the summit of Mt. Everest, full equilibration is not realized. This difference is due to the decreased ambient oxygen level at high altitudes leading to a decreased diffusion gradient between alveolar and venous PO2. With exercise, cardiac output and blood flow increase, thereby reducing transit time of blood cells across the alveolar capillary, further exacerbating the problem. From this discussion, it becomes apparent that the left shift in the O2 and haemoglobin dissociation curve with altitude is necessary as compensation for the decreased diffusion gradient for oxygen in the alveolus.

Figure 3. The calculated time course of oxygen tension in the alveolar capillary

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Disturbed sleep is common among sojourners at high altitude. Periodic (Cheyne-Stokes) breathing is universal and characterized by periods of rapid respiratory rate (hyperpnoea) alternating with periods of absent respirations (apnoea) leading to hypoxia. Periodic breathing tends to be more pronounced in individuals with the greatest hypoxic ventilatory sensitivity. Accordingly, sojourners with lower HVR have less severe periodic breathing. However, sustained periods of hypoventilation are then seen, corresponding with sustained decreases in oxyhaemoglobin saturation. The mechanism for periodic breathing probably relates to increased HVR causing increased ventilation in response to hypoxia. The increased ventilation leads to increased blood pH (alkalosis), which in turn suppresses ventilation. As acclimatization progresses, periodic breathing improves. Treatment with acetazolamide reduces periodic breathing and improves arterial oxyhaemoglobin saturation during sleep. Caution should be used with medications and alcohol that suppress ventilation, as they may exacerbate the hypoxia seen during sleep.

Pathophysiological Effects of Reduced Barometric Pressure

The complexity of human physiological adaptation to high altitude provides numerous potential maladaptive responses. Although each syndrome will be described separately, there is considerable overlap between them. Illnesses such as acute hypoxia, acute mountain sickness, high-altitude pulmonary oedema, and high-altitude cerebral oedema most likely represent a spectrum of abnormalities that share a similar pathophysiology.

Hypoxia

Hypoxia occurs with ascent to high altitudes because of the decreased barometric pressure and the resultant decrease in ambient oxygen. With rapid ascent, hypoxia occurs acutely, and the body does not have time to adjust. Mountaineers have generally been protected from the effects of acute hypoxia because of the time that elapses, and hence the acclimatization that occurs, during the climb. Acute hypoxia is problematic for both aviators and rescue personnel in high-altitude environments. Acute oxyhaemoglobin desaturation to values less than 40 to 60% leads to loss of consciousness. With less severe desaturation, individuals note headache, confusion, drowsiness and loss of coordination. Hypoxia also induces a state of euphoria which Tissandier, during his balloon flight in 1875, described as experiencing “inner joy”. With more severe desaturation, death occurs. Acute hypoxia responds rapidly and completely to either administration of oxygen or descent.

Acute mountain sickness

Acute mountain sickness (AMS) is the most common disorder in high-altitude environments and afflicts up to two-thirds of sojourners. The incidence of acute mountain sickness is dependent on multiple factors, including rate of ascent, length of exposure, degree of activity, and individual susceptibility. Identification of affected individuals is important in order to prevent progression to pulmonary or cerebral oedema. Identification of acute mountain sickness is made through recognition of characteristic signs and symptoms occurring in the appropriate setting. Most often, acute mountain sickness occurs within a few hours of a rapid ascent to altitudes greater than 2,500 m. The most common symptoms include headache that is more pronounced at night, loss of appetite that may be accompanied by nausea and vomiting, disturbed sleep, and fatigue. Individuals with AMS often complain of shortness of breath, cough and neurological symptoms such as memory deficits and auditory or visual disturbances. Findings on physical exam may be lacking, although fluid retention may be an early sign. The pathogenesis of acute mountain illness may relate to relative hypoventilation that would increase cerebral blood flow and intracranial pressure by increasing arterial PCO2 and decreasing arterial PO2. This mechanism may explain why persons with greater HVR are less likely to develop acute mountain sickness. The mechanism for fluid retention is not well understood, but may be related to abnormal plasma levels for proteins and/or hormones that regulate renal excretion of water; these regulators may respond to the increased activity of the sympathetic nervous system noted in patients with acute mountain sickness. The accumulation of water may in turn lead to the development of oedema or swelling of the interstitial spaces in the lungs. More severe cases may go on to develop pulmonary or cerebral oedema.

Prevention of acute mountain sickness can be accomplished through slow, graded ascent, allowing adequate time for acclimatization. This may be especially important for those individuals with greater susceptibility or a prior history of acute mountain sickness. In addition, administration of acetazolamide before or during ascent may help prevent and ameliorate symptoms of acute mountain sickness. Acetazolamide inhibits the action of carbonic anhydrase in the kidneys and leads to increased excretion of bicarbonate ions and water, producing an acidosis in the blood. The acidosis stimulates respiration, leading to increased arterial oxyhaemoglobin saturation and decreased periodic breathing during sleep. Through this mechanism, acetazolamide speeds the natural process of acclimatization.

Treatment of acute mountain sickness can be accomplished most effectively by descent. Further ascent to high altitudes is contra-indicated, as the disease may progress. When descent is not possible, oxygen may be administered. Alternatively, portable lightweight fabric hyperbaric chambers may be brought on expeditions to high-altitude environments. Hyperbaric bags are particularly valuable when oxygen is not available and descent is not possible. Several drugs are available that improve symptoms of acute mountain sickness, including acetazolamide and dexamethasone. The mechanism of action of dexamethasone is unclear, although it may act by decreasing oedema formation.

High-altitude pulmonary oedema

High-altitude pulmonary oedema affects approximately 0.5 to 2.0% of individuals who ascend to altitudes greater than 2,700 m and is the most common cause of death due to illnesses encountered at high altitudes. High-altitude pulmonary oedema develops from 6 to 96 hours after ascent. Risk factors for the development of high-altitude pulmonary oedema are similar to those for acute mountain sickness. Common early signs include symptoms of acute mountain sickness accompanied by decreased exercise tolerance, increased recovery time after exercise, shortness of breath on exertion, and persistent dry cough. As the condition worsens, the patient develops shortness of breath at rest, findings of audible congestion in the lungs, and cyanosis of the nail beds and lips. The pathogenesis of this disorder is uncertain but probably relates to increased microvascular pressure or increased permeability of the microvasculature leading to the development of pulmonary oedema. Although pulmonary hypertension may help explain the pathogenesis, elevation in the pulmonary artery pressure due to hypoxia has been observed in all individuals who ascend to high altitude, including those who do not develop pulmonary oedema. Nevertheless, susceptible individuals may possess uneven hypoxic constriction of the pul-monary arteries, leading to over-perfusion of the microvasculature in localized areas where hypoxic vasoconstriction was absent or diminished. The resulting increase in pressure and shear forces may damage the capillary membrane, leading to oedema formation. This mechanism explains the patchy nature of this disease and its appearance on x-ray examination of the lungs. As with acute mountain sickness, individuals with a lower HVR are more likely to develop high-altitude pulmonary oedema as they have lower oxyhaemoglobin saturations and, therefore, greater hypoxic pulmonary vasoconstriction.

Prevention of high-altitude pulmonary oedema is similar to prevention of acute mountain sickness and includes gradual ascent and use of acetazolamide. Recently, use of the smooth-muscle relaxing agent nifedipine has been shown to be of benefit in preventing disease in individuals with a prior history of high-altitude pulmonary oedema. Additionally, avoidance of exercise may have a preventive role, although it is probably limited to those individuals who already posses a subclinical degree of this disease.

Treatment of high-altitude pulmonary oedema is best accomplished by assisted evacuation to a lower altitude, keeping in mind that the victim needs to limit his or her exertion. After descent, improvement is rapid and additional treatment other than bed rest and oxygen are usually not necessary. When descent is not possible, oxygen therapy may be beneficial. Drug treatment has been attempted with multiple agents, most successfully with the diuretic furosemide and with morphine. Caution must be used with these drugs, as they can lead to dehydration, decreased blood pressure, and respiratory depression. Despite the effectiveness of descent as therapy, mortality remains at approximately 11%. This high mortality rate may reflect failure to diagnose the disease early in its course, or inability to descend coupled with lack of availability of other treatments.

High-altitude cerebral oedema

High-altitude cerebral oedema represents an extreme form of acute mountain sickness that has progressed to include generalized cerebral dysfunction. The incidence of cerebral oedema is unclear because it is difficult to differentiate a severe case of acute mountain sickness from a mild case of cerebral oedema. The pathogenesis of high-altitude cerebral oedema is an extension of the pathogenesis of acute mountain sickness; hypoventilation increases cerebral blood flow and intracranial pressure progressing to cerebral oedema. Early symptoms of cerebral oedema are identical to symptoms of acute mountain sickness. As the disease progresses, additional neurological symptoms are noted, including severe irritability and insomnia, ataxia, hallucinations, paralysis, seizures and eventually coma. Examination of the eyes commonly reveals swelling of the optic disc or papilloedema. Retinal haemorrhages are frequently noted. In addition, many cases of cerebral oedema have concurrent pulmonary oedema.

Treatment of high-altitude cerebral oedema is similar to treatment of other high-altitude disorders, with descent being the preferred therapy. Oxygen should be administered to maintain oxyhaemoglobin saturation greater that 90%. Oedema formation may be decreased with use of corticosteroids such as dexamethasone. Diuretic agents have also been utilized to decrease oedema, with uncertain efficacy. Comatose patients may require additional support with airway management. The response to treatment is variable, with neurological deficits and coma persisting for days to weeks after evacuation to lower altitudes. Preventative measures for cerebral oedema are identical to measures for other high-altitude syndromes.

Retinal haemorrhages

Retinal haemorrhages are extremely common, affecting up to 40% of individuals at 3,700 m and 56% at 5,350 m. Retinal haemorrhages are usually asymptomatic. They are most likely caused by increased retinal blood flow and vascular dilatation due to arterial hypoxia. Retinal haemorrhages are more common in individuals with headaches and can be precipitated by strenuous exercise. Unlike other high-altitude syndromes, retinal haemorrhages are not preventable by acetazolamide or furosemide therapy. Spontaneous resolution is usually seen within two weeks.

Chronic mountain sickness

Chronic mountain sickness (CMS) afflicts residents and long-term inhabitants of high altitude. The first description of chronic mountain sickness reflected Monge’s observations of Andean natives living at altitudes above 4,000 m. Chronic mountain sickness, or Monge’s disease, has since been described in most high-altitude dwellers except Sherpas. Males are more commonly affected than females. Chronic mountain sickness is characterized by plethora, cyanosis and elevated red blood cell mass leading to neurological symptoms that include headache, dizziness, lethargy and impaired memory. Victims of chronic mountain sickness may develop right heart failure, also called cor pulmonale, due to pulmonary hypertension and markedly reduced oxyhaemoglobin saturation. The pathogenesis of chronic mountain sickness is unclear. Measurements from affected individuals have revealed a decreased hypoxic ventilatory response, severe hypoxemia that is exacerbated during sleep, increased haemoglobin concentration and increased pulmonary artery pressure. Although a cause-and-effect relationship seems likely, evidence is lacking and often confusing.

Many symptoms of chronic mountain sickness can be ameliorated by descent to sea level. Relocation to sea level removes the hypoxic stimulus for red blood cell production and pulmonary vasoconstriction. Alternate treatments include: phlebotomy to reduce red blood cell mass, and low-flow oxygen during sleep to improve hypoxia. Therapy with medroxyprogesterone, a respiratory stimulant, has also been found to be effective. In one study, ten weeks of medroxyprogesterone therapy was followed by improved ventilation and hypoxia, and decreased red blood cell counts.

Other conditions

Patients with sickle cell disease are more likely to suffer from painful vaso-occlusive crisis at high altitude. Even moderate altitudes of 1,500 m have been known to precipitate crises, and altitudes of 1,925 m are associated with a 60% risk of crises. Patients with sickle cell disease residing at 3,050 m in Saudi Arabia have twice as many crises as patients residing at sea level. In addition, patients with sickle cell trait may develop splenic infarct syndrome on ascent to high altitude. Likely aetiologies for the increased risk of vaso-occlusive crisis include: dehydration, increased red blood cell count, and immobility. Treatment of vaso-occlusive crisis includes descent to sea level, oxygen and intravenous hydration.

Essentially no data exist describing the risk to pregnant patients on ascent to high altitudes. Although patients residing at high altitude have an increased risk of pregnancy-induced hypertension, no reports of increased foetal demise exist. Severe hypoxia may cause abnormalities in foetal heart rate; however, this occurs only at extreme altitudes or in the presence of high-altitude pulmonary oedema. Therefore, the greatest risk to the pregnant patient may relate to the remoteness of the area rather than to altitude-induced complications.

 

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