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The pathology of high altitude: an introduction to the disease states of high altitude
Current Anaesthesia and Critical Care (2000) 11, 104–112 © 2000 Harcourt Publishers Ltd doi:10.1054/cacc.2000.0243, available online at http://www.idealibrary.com on
Medicine
The pathology of high altitude: an introduction to the disease states of high altitude
N. Mason A number of pathologies specific to high altitude, that are precipitated by exposure to hypobaric hypoxia, may be grouped under the broad heading of altitude illness. These overlapping conditions, acute mountain sickness, high altitude cerebral oedema and high altitude pulmonary oedema are all characterized by marked individual susceptibility, oedema formation and a usually rapid resolution on descent to lower altitude. Possible pathophysiological mechanisms, prevention and treatment are discussed. Sleep disturbance and periodic breathing, high altitude cough and local cold injury, or frostbite, are also reviewed. © 2000 Harcourt Publishers Ltd
Introduction The pathological processes which may be encountered at altitude include trauma, environmental pathologies such as cold injury and a spectrum of infectious diseases. This article will concentrate on those acute pathologies which result directly from the influence of hypobaric hypoxia and are often grouped under the vague term, altitude sickness. Cold-injury will also be discussed as it is greatly exacerbated by the effects of hypobaric hypoxia. While altitude illness in its simplest form as acute mountain sickness may only be regarded as a failure or delay in the acclimatization process, in its most severe forms as high altitude pulmonary and cerebral oedema it presents a life-threatening condition, whose aetiology is
Nicholas P. Mason FRCA, Laboratoire de Physiologie et de Physiopathologie, Faculté de Médecine – Campus Erasme, Bat. E2 niveau 4, Route de Lennik 808 – CP604, B-1070 Bruxelles, Belgium. Correspondence to: N.P.M. e-mail: [email protected]
poorly understood, and requires rapid treatment which may be difficult to achieve in the mountain environment.
The spectrum and nomenclature of altitude illness Dickinson suggested that the acute mountain sickness (AMS) which affects most people ascending to high altitude and which will disappear with acclimatization be termed, ‘Simple AMS’, while the more severe, and if untreated life-threatening, high altitude pulmonary oedema (HAPO) and high altitude cerebral oedema (HACO) be termed, ‘Malignant pulmonary AMS’ and ‘Malignant cerebral AMS’ respectively.1 This nomenclature is helpful in emphasizing both the relative seriousness of the conditions and also their probable common aetiology. AMS shows a continuum of severity ranging from mild symptoms to a severe, incapacitating condition which merges into HACO. In its most severe forms as HAPO and HACO it is not unusual for there to be a degree of overlap between the conditions, with HAPO 104
THE PATHOLOGY OF HIGH ALTITUDE Table 1 Lake Louise consensus score for acute mountain sickness (Ref 2) Each symptom is scored from 0 to 3 and the total calculated. A self assessment score of up to 3 is often seen on arrival at a new altitude and will improve with acclimatisation. A score of greater than 3 should alert the clinician to the possibility of more severe AMS. The clinical and functional assessments are rarely used. a) AMS self assessment Symptom Headache
Gastrointestinal symptoms
Fatigue and/or weakness
Dizziness/light-headedness
Difficulty sleeping (the previous night)
Overall, if you had any of these symptoms, how they affect your activities?
Score 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
None at all Mild headache Moderate headache Severe, incapacitating, headache Good appetite Poor appetite or nausea Moderate nausea or vomiting Severe, incapacitating, nausea and vomiting Not tired or weak Mild fatigue/weakness Moderate fatigue/weakness Severe fatigue/weakness None Mild Moderate Severe, incapacitating Slept as well as usual Did not sleep as well as usual Woke many times, poor night’s sleep Could not sleep at all Not at all Mild reduction Moderate reduction Severe reduction (bedrest)
b) Clinical assessment All responses obtained by interview to the self-assessment questions plus the following Sign Score Change in mental status
Ataxia (heel – toe walking)
Peripheral oedema
0 1 2 3 4 0 1 2 3 4 0 1 2
No change Lethargy/lassitude Disorientated/confused Stupor/semiconcious Coma None Balancing manoeuvres Steps off the line Falls down Unable to stand None One location Two or more locations
c) Functional assessment Assigned by investigator, not self-assessment Grade Assessment 0 1 2 3 4
No symptoms Symptoms, but no change in activity Must reduce activities Reduced to bed rest Life threatening
victims having some signs of cerebral oedema and vice versa.
Acute mountain sickness The symptoms of acute mountain sickness (AMS) are non-specific. In 1992 a consensus statement defined
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AMS as the presence of headache and at least one other symptom from gastrointestinal disturbance, fatigue or weakness, dizziness or lightheadedness, or difficulty in sleeping, in the setting of a recent gain in altitude.2 A scoring system which can be used either for selfassessment or clinical assessment was proposed (Table 1). A score of 3 or less will often be seen on arrival at a new altitude and will improve with acclimatization. A score of greater than 3 should alert the clinician to the possibility of more serious AMS. There is great individual variation in the incidence of AMS. One of the problems in discussing the incidence is that it is dependent upon the altitude, the speed of ascent and the time spent at altitude. A few hours spent at moderate altitude and most subjects will escape symptom free. The lowest altitude at which people are affected is around 2000 m and it is not unheard of for subjects to report mild AMS symptoms during the first days in high ski resorts. At altitudes of between 3500 and 4500 m the reported incidence varies between 30 and 45%.3, 4 Aetiology While those people who develop AMS on their first ascent to altitude will probably do so on subsequent occasions, the aetiology of AMS is complex and poorly understood. The rate of ascent clearly plays an important role and most subjects will develop AMS if their ascent is rapid enough. Men and women are equally susceptible, although the young are probably more susceptible than older subjects. Fitness provides no degree of protection. There is some evidence that those subjects with a brisk hypoxic ventilatory response (HVR) are less susceptible than those with a blunted response. However, this observation is confounded by the fact that high altitude natives, who generally suffer less from AMS than lowlanders, on ascent to higher altitudes, in general have a low HVR. The most characteristic sign of AMS is peripheral oedema resulting from water retention and/or shifts to the extracellular space. The same process occurring at a cerebral level and resulting in cerebral oedema could explain the symptoms of AMS. There is now evidence that on ascent to high altitude there is an increase in cerebral volume, visible on MRI scan, and consistent with diffuse cerebral oedema.5 As the degree of oedema does not correlate with the severity of AMS, other factors, such as individual variation in cranial or spinal canal volumes or compliance, may play a role in dictating whether a given increase in brain volume produces AMS. The observation that it takes between 12 and 24 h at a given altitude before symptoms begin to appear, and that if one spends only a few hours at altitude before descent, one can escape symptom free, provides an insight into the possible aetiology of the condition. It would seem likely that exposure to hypobaric hypoxia, perhaps exacerbated by a blunt HVR, initiates a mechanism which may result in AMS in susceptible individuals. The most likely mechanisms are deranged fluid homeostasis, an inflammatory process, changes in endothelial function
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resulting in increased microvascular permeability, or a combination of these factors. The changes occurring in the renin-angiotensionaldosterone system and in fluid balance were discussed in the previous article on the physiology of high altitude, in the February 2000 issue of the journal. The normal response to exposure at high altitude is mild diuresis and fluid loss, while those subjects with AMS develop antidiuresis.6 In favour of an inflammatory process, Maggiorini reported a mild pyrexia in those subjects with AMS.7 Increased levels of inflammatory mediators have been found in the bronchoalveolar lavage fluid of subjects with HAPO (see below) although not with simple AMS. Richalet reported a marked correlation between the plasma concentration of the eicosanoids thromboxane B2 (TXB2), 6-keto-PGF1α (a stable metabolite of prostacyclin), PGE2, PGF2α, and of leukotriene LTB4, and the symptoms of AMS,8 suggesting that these mediators, by producing a direct increase in capillary permeability could be responsible for the symptoms of AMS. Against an inflammatory process, however, other authors have found no increase in the plasma concentrations of the cytokines interleukin1β, (IL-1β), IL-1ra, IL-8, TNFα, C reactive protein, or the systemic escape of 125I-labelled albumin, on exposure to high altitude.9, 10, 11 Recently, drawing a parallel with the symptoms of severe falciparum malaria, it has been suggested that excessive hypoxia-induced production of inducible nitric oxide synthetase (iNOS) might be responsible for many of the symptoms of AMS.12 The effect of endothelial released mediators such as prostacyclin and inducible nitric oxide (NO) on vascular permeability is complex and controversial.13, 14 Although the effect of altitude on such mediators is not clearly understood, it is feasible that changes in the levels of these mediators may play a role in the development of AMS. Perhaps the major conclusion that can be drawn from all of these studies is that we are, as yet, far from understanding the basic pathophysiological mechanisms involved in AMS. Prevention and treatment of AMS The most reliable way of avoiding AMS is to adopt a slow ascent profile with regular rest days. A typical recommended rate of ascent is, as far as possible, to never sleep more than 300–400 m above the previous night’s altitude and to have a full rest day (i.e. to spend 2 nights at the same altitude) every 1000 m or 3 days. Some climbers believe that it aids acclimatization to ascend high during the day but to sleep within 300–400 m of the previous night’s altitude. Obviously there will be certain situations where it is not possible to maintain a slow ascent and in addition there are those subjects who, despite a sensible ascent profile, still develop AMS. In this situation acetazolamide at a dose of 250 mg twice-daily may be used to aid acclimatization; the treatment being commenced on the evening before the ascent. The mechanism of action of acetazolamide will be discussed later.
In most cases of developed AMS it is sufficient to rest and remain at the same altitude for another day and symptoms will improve. Symptomatic treatment of headache can be given with paracetamol or aspirin although it is not always effective. Non-steroidal antiinflammatories may work better. Should symptoms not improve, or if the subject is severely incapacitated, the only completely effective treatment is descent to a lower altitude. Very often descent of only a few-hundred metres is sufficient to bring about a remarkable improvement in the condition. Oral acetazolamide may be taken (250 mg twice-daily) combined, in severe cases, with dexamethasone (8 mg initially followed by 4 mg four times daily) to aid descent. In such cases and where the distinction with HACO is blurred, rapid descent is imperative regardless of the time of day. Portable hyperbaric chambers There exist a number of types of portable hyperbaric chamber within which a patient can be placed to increase the barometric pressure temporarily. Light, and inflated using a hand pump, one such example, the CERTEC bag, increases the barometric pressure by 220 mbar (165 mmHg), resulting in a significant reduction in altitude (e.g. at 3500 m the altitude is reduced to 1200 m and at 5000 m to 2375 m). While these devices should never be used to avoid descent, they may be useful when descent is impossible due to the weather or clinical condition of the patient and may be used to buy time or improve the patient’s condition sufficiently that he can descend. It must be emphasized, however, that the only reliable treatment remains descent, and neither the use of drugs nor portable hyperbaric chambers should be regarded as a means to avoid this.
Sleep disturbance and periodic breathing at altitude Sleep disturbance is very common at high altitude. There is a delay in the onset of sleep; a decrease in the time spent in deep sleep (stages III and IV) and an increase in the number of arousals.15 Total sleep time tends to increase, probably in an attempt to compensate for the reduced time spent in deep sleep. Periodic breathing is a very common finding during sleep at high altitude and consists of repetitive cycles of hyper- and hypoventilation. Peripheral chemoreceptor induced hyperventilation reduces arterial PCO2 (PaCO2) sufficiently to bring about central chemoreceptor mediated hypoventilation. This produces a fall in arterial PO2 which reactivates the peripheral chemoreceptors, provoking a period of hyperventilation and commencing another cycle of periodic breathing. The hypoventilation is usually associated with periods of apnoea which can last for over 10 s. Time spent in periodic breathing increases with altitude. The periodic breathing cycle is accompanied by heart rate changes of a similar frequency, with the periods of apnoea being associated with bradycardia and the
THE PATHOLOGY OF HIGH ALTITUDE
maximum heart rate occurring shortly after the peak of hyperpnoea. The periods of apnoea are associated with marked desaturation. Susceptibility to periodic breathing at altitude appears to be related to the hypoxic ventilatory response (HVR), whereby the subjects with the briskest response suffer most from periodic breathing. High altitude natives who generally do not have a very strong HVR are less troubled by periodic breathing at altitude.16 The carbonic anhydrase inhibitor acetazolamide decreases the time spent in periodic breathing, increases arterial oxygen saturation and improves sleep quality. Hypnotic agents such as temazepam and zolpidem increase the quality and duration of sleep at altitude without affecting respiratory parameters.17 One possible mechanism for this improvement is a reduction in arousals and an increase in respiratory stability.
Carbonic anhydrase inhibitors The enzyme carbonic anhydrase (CA) which catalyses the conversion of water and CO2 to carbonic acid is distributed throughout the body, including in the kidneys, red blood cells, the cells of the peripheral and central chemoreceptors and in the choroid plexus. It is also found on the endothelial surface of capillaries. The sulphonamide related CA inhibitor (CAI) acetazolamide is now well known to increase ventilation and arterial oxygen saturation and to be effective in both the prophylaxis and treatment of AMS. Ventilation is increased by 10–20% and arterial oxygen saturation by 3–6%.18 Acetazolamide is concentrated in the kidney and urine, and at low doses renal CA inhibition is achieved with little inhibition of CA in other tissues. Thus the increase in ventilation appears to be mediated primarily by inhibition of renal CA, resulting in a decrease in proximal tubular reabsorption of bicarbonate and distal tubular secretion of H+ ions. This results in a urinary bicarbonate loss of around 4–6 mmol within 24 h of commencing the drug.18 As discussed in the previous article, the normal hypoxic ventilatory response on initial exposure to high altitude is blunted by the subsequent respiratory alkalosis resulting from hyperventilation. This respiratory alkalosis reduces the sensitivity of the peripheral chemoreceptors to hypoxia and reduces the tonic output from the central chemoreceptors. Normally the respiratory alkalosis is partly compensated for by a decrease in renal bicarbonate absorption and H+ ion secretion, but maximal compensation, which is probably never complete, takes a number of days. The renal action of CAIs accelerates this effect and if commenced before ascending to altitude effectively reduces the brake on respiration which would otherwise occur upon exposure to altitude. The primary role of renal CA inhibition in the mode of action of acetazolamide is further confirmed by the fact that benzolamide, a CAI which is highly selective for the kidney, is as effective as acetazolamide in reducing the symptoms of AMS and produces a better increase in ventilation, yet is devoid of effects in other tissues. In addi-
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tion, inhibition of peripheral chemoreceptor CA actually blunts HVR.19 Recent work suggests that an isoenzyme of CA, CA IV, which is found on the endothelial surface of most capillaries, and which is inhibited even with low doses of CAIs, may also play an important role in increasing the ventilatory response to hypobaric hypoxia. Inhibition of CA IV will inhibit blood CO2 uptake and release, resulting in a local retention of CO2 of 1–2 mmHg. The central chemoreceptors have a ventilatory response to CO2 of 1–3 l/min/mmHg and thus, this relatively small increase in CO2 is capable of bringing about a large increase in ventilation.18 CAIs also reduce the frequency of periodic breathing at high altitude by between 50 and 80% and improve arterial oxygen saturation . By producing a metabolic acidosis, CAIs may increase the tonic output of the central chemoreceptors, reducing their sensitivity to reductions in CO2. In addition the fact that peripheral chemoreceptor stimulants such as almitrine increase periodic breathing frequency would suggest that the effect on periodic breathing of CAIs is also mediated via the peripheral chemoreceptors, perhaps by reducing their hypoxic sensitivity.20
High altitude cerebral oedema As noted, the symptoms of AMS are probably due to ‘benign’ cerebral oedema, which in a proportion of cases progresses to the life threatening condition, high altitude cerebral oedema (HACO). Initially subjects will have symptoms which are indistinguishable from severe AMS, but the emergence of ataxia at altitude is almost pathognomonic of HACO. Other signs and symptoms are listed in Table 2. The incidence of HACO is not known, although it appears to be less common than HAPO, and possible aetiological factors have been less well studied. HACO is rare below 3500 m but has been reported at altitudes as low as 2500 m. As with the other altitude pathologies rapid ascent would seem to predispose to HACO, but the condition can occur in seemingly well acclimatized individuals.
Table 2
Signs and symptoms of HACO
Ataxia Severe headache Vomiting Hallucinations Impaired short term memory Altered level of consciousness progressing to coma if untreated Blurred vision or visual field defects Focal neurological deficits Urinary incontinence Papilloedema Hypo- or hypertonic reflexes Extensor plantar responses
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Pathophysiology HACO is characterized on MRI by reversible white matter oedema.21 Oedema of white matter is consistent with a capillary leak, or vasogenic aetiology (the alternative explanation would be due to a failure of cell volume regulation or blood–brain barrier (BBB) ion transport — cytotoxic oedema). This is further borne out by the effectiveness of dexamethasone in the treatment of HACO. Vasogenic cerebral oedema responds to corticosteroid therapy while cytotoxic oedema does not. In addition there is no convincing evidence of a significant alteration in cerebral oxygen or glucose metabolism in an animal model of severe AMS-HACO which makes a cytotoxic mechanism further unlikely.22 The physical integrity of the BBB is located in endothelial cell tight junctions. If HACO is due to a vascular leak, then this implies that there must be a disruption of the tight junctions permitting the movement of fluid and macromolecules into the extracellular spaces. One possible explanation would be a simple hydrostatic stress failure of cerebral capillaries as has been postulated in the pulmonary circulation. However, while there is good evidence of increases in cerebral blood flow (CBF) and capillary pressure (Pcap) during sustained hypoxia, not everybody who goes to altitude develops HACO. In addition, sustained elevations of CBF in non-hypoxic circumstances such as hypercapnia or infusion of nitroglycerin fail to elicit HACO or AMS-like symptoms. It would seem, therefore, that the increases in CBF or Pcap which occur at altitude are by themselves insufficient to open the BBB and that another mechanism or mechanisms must be active to precipitate HACO. Little is known of the role played by endothelial mediators such as nitric oxide in HACO. Evidence exists in other pathologies of a leucocyte-mediated inflammatory response which increases microvascular permeability and could open up the BBB, but in HACO increasing interest is being shown towards the possible role for vascular endothelial growth factor (VEGF). VEGF is a dimeric glycoprotein which induces angiogenesis and increases vascular permeability and has essential roles in embryonic vascularization and probably in tumour growth. Xu and Severinghaus demonstrated that after 12 h of hypoxia, levels of VEGF in rat cortex and cerebellum were increased, with the level peaking at 2 day.23 In addition, the expression of mRNA for the VEGF receptor, VEGFR-1 (or Flt-1), increased after 3 days of hypoxia. Further possible proof of a role for VEGF in HACO is that dexamethasone is an effective inhibitor of angiogenesis. In conclusion, it seems likely that HACO is due to an increase in capillary permeability brought about by increases in certain circulating mediators and/or a leukocyte-mediated inflammatory response, and that the increase in CBF and Pcap seen at altitude serve to further enhance fluid loss across the disrupted BBB. Prevention and treatment As with AMS, slow ascent will reduce, although not remove completely, the risk of HACO. Once the condi-
tion has developed the only reliable treatment is rapid descent. Oxygen should be given if available along with dexamethasone, initially 8 mg IM, followed by 4 mg, 6-hourly. Portable hyperbaric chambers should be considered if the patient is incapable of descending or if weather conditions prohibit descent, but descent as soon as possible must remain the first priority.
High altitude pulmonary oedema The first recorded description of high altitude pulmonary oedema (HAPO) is probably to be found in a Chinese Buddhist monk’s account of his remarkable travels through Asia at the end of the 4th century. However it took another 16 centuries before HAPO was clearly defined as a separate disease process in South America in the 1950s,24 although the condition was not widely recognized until the publication of three reports in English between 1960 and 1961.24 Before this, acute respiratory distress at altitude was usually attributed to pneumonia. HAPO can occur at altitudes as low as 2500 m and commences between 12 and 48 h after ascent. The symptoms of AMS are often present. Symptoms specific to HAPO are shown in Table 3. If further tests are available the electrocardiogram may show signs of right heart strain. The chest X-ray reveals prominent pulmonary arteries and bilateral patchy shadowing is often present, becoming confluent with increasing severity. Pulmonary artery pressure (PAP) is elevated compared to normal subjects at the same altitude. It is normally around 60–80 mmHg systolic in HAPO, but values as high as 144 mmHg have been reported.25 Pulmonary capillary occlusion pressure is normal. Aetiology The aetiology of the condition remains unclear although there are a number of well recognized characteristics. Certain individuals exhibit a susceptibility to HAPO, developing the condition repeatedly on ascent to high altitude. Such subjects tend to have an exaggerated pulmonary pressor response to both hypoxia and exercise, Table 3 cases.
Incidence of clinical features of HAPO in a series of 101
Clinical feature
%
Breathlessness Chest pain Headache Nocturnal dyspnoea Dry cough Haemoptysis Nausea Insomnia Dizziness Heart rate > 120/min Respiratory rate > 30/min Cyanosis Pyrexia (≥ 36.8°C ≤ 39°C
83.2 65.3 62.4 58.4 50.5 38.6 25.7 22.8 17.8 69.3 68.3 51.5 70.0
From Menon N D. High altitude pulmonary edema: a clinical study. N Engl J Med 1965; 273: 66–73.
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and a reduced HVR. However this is not exclusively the case, with some HAPO susceptible individuals exhibiting normal responses. Some workers have also reported reduced lung volumes in susceptible individuals. HAPO appears to be precipitated by exercise, cold (both of which increase PAP) and respiratory tract infections. The reason for the brisker hypoxic pulmonary vasoconstrictor response (HPVR) in HAPO susceptible individuals is not known, but possible mechanisms include increased sympathetic activity, as is known to occur at altitude,26 increased endothelin production,27 or decreased NO production.28 A high PAP is clearly necessary, but not sufficient, for the development of HAPO, as demonstrated in one study, where although HAPO susceptible individuals had a significantly higher systolic PAP than the control group, there was no difference in the systolic PAP between those HAPO susceptible individuals who developed HAPO and those who did not.28 Despite an increase in systemic inflammatory mediators on ascent to altitude, there is little evidence that inflammation plays a role in the development of HAPO. In developed cases, however, increased levels of leukotriene LTB4, thromboxane (TX) B4,29 the interleukins IL-1β, IL-1ra, IL-6 and IL-8, and tumour necrosis factor α (TNFα)30 have been found in the bronchoalveolar lavage fluid of subjects with HAPO, along with evidence of complement activation. The most widely accepted explanation of the mechanism of HAPO has been that suggested by Hultgren in the 1970s, that patchy pre-capillary vasoconstriction associated with pulmonary hypertension leads to overperfusion of those capillaries not protected by vasoconstriction.31 Thus one can imagine a reduced HVR, possibly exacerbated by small lung volumes, producing a greater than normal degree of alveolar hypoxia which exacerbates an already brisk HPVR. West demonstrated the presence of capillary rupture in isolated rabbit lung exposed to PAPs of greater than 40 mmHg, and similar lesions in rats rapidly exposed to barometric pressures equivalent to altitudes of between 7000 and almost 9000 m, and coined the term ‘stress failure’ of pulmonary capillaries32 proposing it as the principal mechanism by which HAPO occurs. As attractive as this simple mechanical theory based only on animal data is, it seemed insufficient to explain the rapid recovery which occurs on descent to lower altitude and with certain treatments such as calcium antagonists. However, recent work by Maggiorini and co-workers33 demonstrated a significantly elevated pulmonary capillary pressure, (obtained by analysis of the pressure decay curve after rapid inflation of the balloon of a Swan–Ganz catheter) in HAPO susceptible individuals at 4559 m compared to non-susceptible controls. In addition, pulmonary capillary permeability was assessed using gallium-67 labelled transferring, and showed no difference between the two groups. There would appear to be growing evidence that HAPO is primarily of hydrostatic origin and is not due to increased capillary permeability. Inflammation due to infection may be a separate precipitating factor for
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HAPO, but for those subjects who develop HAPO in whom there is no evidence of infection, current evidence would only favour the development of an inflammatory response after the development of pulmonary oedema. Prevention and treatment The major method of prevention is slow ascent and there is evidence that even those subjects susceptible to developing HAPO may reach altitudes of up to 7000 m if they adopt a slow ascent profile limited to no more than 300–400 m ascent per day. If a slow ascent rate is not possible, then oral nifedipine 20 mg twice-daily is effective as prophylaxis against HAPO in susceptible subjects.34 The prophylactic administration of nifedipine lowers PAP and adds further weight to the important aetiological role of pulmonary hypertension in HAPO. In developed HAPO the most importantant treatment is to lower PAP. This can be achieved most effectively by descent. To aid descent, or if descent is not possible, a number of effective treatments have been used to lower PAP including oxygen, nifedipine, and inhaled nitric oxide. Initial treatment in the mountain environment is with sublingual nifedipine 10 mg, followed by 20 mg orally every 6 h. Portable hyperbaric chambers have also been successfully used in the treatment of the condition. Descent usually brings about a rapid improvement in oxygenation and recovery is usually complete after 2–3 days. However, in rare, severe cases which often show a degree of HACO, prolonged hospitalization is necessary.
High altitude cough Numerous anecdotal reports exist of paroxysmal cough in climbers and travellers to high altitude which can be extremely debilitating and may be severe enough to cause rib fractures. Traditionally the cause has been alttributed to the inspiration of cold, dry air but in a recent hypobaric chamber study that simulated extreme altitude (Operation Everest 3), in which both the temperature and humidity of the chamber were controlled to normal sea level conditions, the subjects remained troubled by cough, particularly at night.35 Mucociliary clearance is reduced at high altitude36 and there is an increase in the incidence of upper respiratory tract infections.37 While this may account for some cough at altitude the vast majority of subjects with coughs exhibit no evidence of respiratory tract infection. Although in the Operation Everest 3 study the subjects continued to cough despite controlled environmental conditions, drying of the respiratory mucosa, which is known to precipitate cough,38 may still play an important aetiological role. The hypoxia mediated increase in ventilation at altitude requires large volumes of air to be warmed and humidified, and it is possible that this increase may exceed the upper respiratory tracts ability to condition inspired air sufficiently to prevent water loss. However it seems unlikely that this is the case at rest, although it may play a role during exercise.
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It is generally considered that pulmonary oedema causes cough, which is one of the recognized symptoms of HAPO, and yet the known anatomical sites which stimulate cough are actually located proximal to the distal airways where early oedema will be present. However, with the probable inflammatory processes and alterations in vascular permeability which occur upon exposure to high altitude, it is possible that if sub-clinical HAPO, or AMS, result from an overall increase in vascular permeability, similar changes occurring around pulmonary rapidly acting receptors could be responsible for cough at altitude. The hypercapnic ventilatory response (HCVR) increases with acclimatization and Banner has demonstrated an inverse relationship between the HCVR and cough threshold, with those subjects with the greatest HCVR having the lowest cough threshold.39 There may, therefore be a role for a putative ‘cough centre’, whose sensitivity changes in a similar manner to the respiratory control centre. This is supported by observational data from high altitude.40 However, for the moment, the cause of this troublesome complaint remains obscure.
Freezing cold injury Cold injury may be divided into non-freezing and freezing types. The former, of which perhaps the best known example is ‘Trench Foot’, occurs after prolonged exposure to temperatures below 15°C and is exacerbated by damp conditions. It often occurs proximal to areas of freezing cold injury and may result in permanent damage to nerves and muscles. Freezing cold injury, or frostbite, occurs in sub-zero conditions. It is a local lesion which has a predilection for the extremities, with the feet being the most affected, followed by the hands and then facial extremities (nose, ears and cheeks). It may be classified into three degrees of severity (Table 4).
Table 4
Classification and clinical features of frostbite
Degree
Features
First (‘frost nip’)
Skin pallor, but skin remains pliable Transitory paraesthesia Erythema on rewarming Superficial skin loss Complete revovery over 1–2 weeks
Second Superficial
Deep
Third
Skin becomes white and frozen Underlying tissues remain pliable Development of clear blisters within 12–24 h Paraesthesia may persist longer Complete recovery over 1–2 weeks Complete anaesthesia Haemorrhagic blisters may form Proximal oedema and swelling Deep second degree progressing to necrosis and auto-amputation
Pathophysiology The pathophysiology of frostbite is complex. The initial freezing insult results in a decrease in perfusion due to vasoconstriction and in local tissue, destruction due to ice crystal fromation. The crystals form initially in the extracellular space, increasing its osmolality and resulting in cellular dehydration by movement of water out of the cells. This initial phase is usually followed by rewarming which is the major phase of tissue destruction. On rewarming, vasodilatation results in hyperaemia which paradoxically decreases capillary perfusion by enhancing fluid loss from the microcirculation and increasing blood viscosity. Neutrophil mediated tissue damage41 is associated with a marked derangement in platelet function42 and an increase in thromboxane A2 (TXA2) release, altering the normal TXA2/prostacyclin balance.43 After 24–48 h, if treatment has not been instituted, irreversible vascular necrosis results. Frostbite at altitude appears to be more common than at sea level for comparable temperatures. Maximum oxygen uptake falls with increasing altitude, reducing the body’s ability to produce heat,44 while dehydration, cold, the fall in plasma volume which occurs at high altitude and increased erythropoietin production all work to increase blood viscosity and reduce peripheral blood flow. A reduction in calorie intake also reduces insulating subcutaneous fat. Treatment The goal of treatment is to counter hyperviscosity, vasospasm and thrombosis and to prevent infection. The patient will usually be dehydrated and hypothermic, so initial resuscitation should consist of rapid rewarming and rehydration using warmed IV fluids. The initial treatment of the frostbitten part should be started as soon as possible by rewarming in warm water at between 37 and 41°C and which contains a mild antiseptic. Ideally this should be carried out in a whirlpool bath to remove necrotic tissue. Treatment in the field should be avoided if there is the slightest risk of refreezing. There is no consensus of opinion on the pharmacological treatment of frostbite and controlled clinical trials are lacking. For first degree and superficial second degree frostbite the patient is given low dose aspirin and IV praxilene. Symptomatic pain relief can be achieved with non-steroidal anti inflammatory agents. For the more severe forms of frostbite recent work suggests that the synthetic PGI2 analogue iloprost, up to 50 mcg/day IV, may be of benefit in combination with low molecular weight heparin and aspirin. There is some experimental evidence that treatment with thrombolytic agents such as streptokinase reduces tissue damage45 but clinical trials in humans are lacking. The reperfusion period can be extremely painful and adequate analgesia should be given with systemic opioids. Antibiotics should not be given routinely and surgical amputation is only indicated in the presence of severe infection, and even then should be delayed for as long as is safely possi-
THE PATHOLOGY OF HIGH ALTITUDE
ble to allow the clearest demarcation of tissue damage. It is normal for far more tissue to survive after frostbite than would be thought from the clinical appearance. In comparison with peripheral vascular disease, tissue loss is generally more superficial. One of the most frustrating problems for both the medical team and the frostbite victim is the delay in waiting for demarcation to occur and to know what tissue will be preserved. As a result of this a number of techniques have been tried to predict tissue survival, the most promising of which is technetium99 isotope scanning. Scanning should be performed at 48 h and 1 week. Where the scan shows normal uptake in the late (bony) phase, amputation will not be necessary. Where, however, there is late phase bony hypofixation, amputation will almost certainly be required.
Acknowledgements The author would like to thank Dr Bernard Marsigny, of the Mountain Medicine and Traumatology Department, Chamonix Hospital, France, for his help in the preparation of the section on local cold injury.
References 1. Dickinson J G. Terminology and classification of acute mountain sickness. Br Med J 1982; 285: 720–721. 2. Hackett P H, Oelz O. The Lake Louise consensus on the definition and quantification of altitude illness. In: Sutton J R, Coates G, Houston C S, eds Hypoxia and Mountain Medicine. Burlington, Vermont: Queen City Printers, 1992; 327–330. 3. Hackett P H, Rennie D. Rales, peripheral oedema, retinal hemorrhages and acute mountain sickness. Am J Med 1979; 67: 214–218. 4. Maggiorini M, Buhler B, Walter M, Oelz O. Prevalance of acute mountain sickness in the Swiss Alps. Br Med J 1990; 301: 853–855. 5. Muza S R, Lyons T P, Rock P B et al. Effect of altitude exposure on brain volume and development of acute mountain sickness (Abstract). 1999 International Hypoxia Symposium, Jasper, Canada. 6. Claybaugh J R, Wade C E, Sato A K et al. Antidiuretic hormone reponsess to eucapnic and hypocapanic hypoxia in humans. J Appl Physiol 1982; 53: 815–823. 7. Maggiorini M, Bartsch P, Oelz O. Association between raised body temperature and acute mountain sickness: cross sectional study. Br Med J 1997; 315: 403–404. 8. Richalet J P, Hornych A, Rathat C, Aumont J, Larmignat P, Rémy P. Plasma prostaglandins, leukotrienes and thromboxane in acute high altitude hypoxia. Respir Physiol 1991; 85: 205–215. 9. Klausen T, Olsen N V, Poulsen T D, Richalet J P, Pedersen B K. Hypoxemia increases serum interleukin-6 in humans. Eur J Appl Physiol 1997; 76: 480–482. 10. Swenson E R, MacDonald A, Vatheuer M et al. Acute mountain sickness is not altered by a high carbohydrate diet nor associated with elevated circulating cytokines. Aviat Space Environ Med 1997; 68: 499–503. 11. Kleger G R, Bartsch P, Vock P, Heilig B, Roberts L J 2nd, Ballmer P E. Evidence against an increase in capillary permeability in subjects exposed to high altitude. J Appl Physiol 1996; 81: 1917–1923. 12. Clark I A, Awburn M, Cowden W B, Rockett K A. Can excessive iNOS induction explain much of the illness of acute mountain sickness? (Abstract). 1999 International Hypoxia Symposium, Jasper, Canada. 13. Kubes P. Nitric oxide and microvascular permeability: a continuing dilemma. Eur Respir J 1997; 10: 4–5. 14. Henderson W R. Eicosanoids and lung inflammation. Am Rev Respir Dis 1987; 135: 1176–1185.
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15. Anholm J D, Powles A C, Downey R 3d, Houston C S, Sutton J R, Bonnet M H, Cymerman A, Operation Everest II: arterial oxygen saturation and sleep at extreme simulated altitude. Am Rev Respir Dis 1992; 145: 817–826. 16. Lahiri S, Maret K, Sherpa M G. Dependence on high altitude sleep apnea on ventilatory sensitivity to hypoxia. Respir Physiol 1983; 52: 281–301. 17. Dubowitz G. Effect of temazepam on oxygen saturation and sleep quality at high altitude: randomised placebo controlled crossover trial. Br Med J 1998; 316: 587–589. 18. Swenson E R. Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression. Eur Respir J 1998; 12: 1242–1247. 19. Swenson E R, Hughes J M B, Differential effects of acute and chronic acetazolamide on ventilation and ventilatory responses in man. J Appl Physiol 1993; 73: 230–237. 20. Hackett P H, Roach R C, Harrison G L, Schoene R B, Mills J W. Respiratory sitmulants and sleep periodic breathing at high altitude. Am Rev Respir Dis 1987; 135: 896–898. 21. Hackett P H, Yarnell P R, Hill R, Reynard K, Heit J, McCormick J. High-altitude cerebral edema evaluated with magnetic resonance imaging: clinical correlation and pathophysiology. JAMA 1998; 280: 1920–1925. 22. Yang S-P, Bergo G W, Krasney E, Krasney J A. Cerebral pressure-flow and metabolic responses to sustained hypoxia: effect of CO. J Appl Physiol 1994; 76: 303–313. 23. Xu F, Severinghaus J W. Rat brain VEGF expression in alveolar hypoxia: possible role in high-altitude cerebral edema. J Appl Physiol 1998; 85: 53–57. 24. Richalet J-P. High altitude pulmonary oedema: still a place for controversy? Thorax 1995; 50: 923–929. 25. Hultgren H N, Lopez C E, Lundberg E, Miller H. Physiologic studies of pulmonary edema at high altitude. Circulation 1964; 29: 393–408. 26. Bartsch P, Shaw S, Franciolli M, Gnadinger M P, Weidman P. Atrial natriuretic peptide in acute mountain sickness. J Appl Physiol 1988; 65: 1929–1937. 27. Droma Y, Hayano T, Takabayashi Y et al. Endothelin-1 and interleukin-8 in high altitude pulmonary oedema. Eur Respir J 1996; 1947–1949. 28. Scherrer U, Vollenweider L, Delabays A et al. Inhaled nitric oxide for high altitude pulmonary edema. N Engl J Med 1996; 334: 624–629. 29. Schoene R B, Hackett P H, Henderson W R et al. High- altitude pulmonary edema. Characteristics of lung lavage fluid. JAMA 1986; 256: 63–69. 30. Kubo K, Hanaoka M, Hayano T et al. Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema. Respir Physiol 1998; 111: 301–310. 31. Hultgren N H. High altitude pulmonary edema. In: Staub N C ed. Lung Water and Solute Exchange. L’Enfant Series. New York: Dekker, 1978, vol 7, 237–269. 32. West J B, Colice G L, Lee Y J et al. Pathogenesis of highaltitude pulmonary oedema: direct evidence of stress failure of pulmonary capillaries. Eur Respir J 1995; 8: 523–529. 33. Maggiorini M, Merlot C, Pierre S et al. High altitude pulmonary edema is an hydrostatic and not a high permeability type of edema. 1999 International Conference of the American Thoracic Society, San Diego, California, April 23–28, 1999. Am J Respir Crit Care Med 1999; 159 (part 2): A355. 34. Bartsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 1991; 325(18): 1284–9. 35. Mason N P, Barry P W, Despiau G, Gardette B, Richalet J-P. Cough frequency and cough receptor sensitivity to citric acid challenge during a simulated ascent to extreme altitude. Eur Respir J 1999; 13: 508–513. 36. Barry P W, Mason N P, O’Callaghan C. Nasal mucociliary transport is impaired at altitude. Eur Respir J 199; 10: 35–37. 37. Murdoch D R. Symptoms of infection and altitude illness among hikers in the Mount Everest region of Nepal. Aviat Space Environ Med 1995; 66: 148–151. 38. Irwin R S, Rosen M J. Cough. A comprehensive review. Arch Intern Med 1977; 137: 1186–1191. 39. Banner A S. Relationship between cough due to hypotonic aerosol and the ventilatory response to CO2 in normal subjects. Am Rev Respir Dis 1988; 137: 647–650. 40. Barry P W, Mason N P, Nickol A et al. Cough receptor sensitivity and dynamic ventilatory response to carbon dioxide in man
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acclimatised to high altitude (Abstract). J Physiol 1996; 497P: 29–30. 41. Mileski W J, Raymond J F, Winn R K, Harlan J M, Rice C L. Inhibition of leukocyte adherence and aggregation for treatment of severe cold injury in rabbits. J Appl Physiol 1993; 74: 1432–1436. 42. Zook N, Hussmann J, Brown R, Russell R, Kucan J, Roth A, Suchy H. Microcirculatory studies of frostbite injury. Ann Plast Surg 1998; 40: 246–255. 43. Ozyazagan I, Tercan M, Melli M, Bekerecioglu M, Ustun H, Gunay G K. Eicosanoids and inflammatory cells in frostbitten
tissue: prostacyclin, thromboxane, polymorphonuclear leukocytes, and mast cells. Plast Reconstr Surg 1998; 101: 1881–1886. 44. Gautier H, Bonora M, Schultz S A, Remmers J E. Hypoxia induced changes in shivering and body temperature. J Appl Physiol 1987; 62: 2577–2581. 45. Salimi Z, Wolverson M K, Herbold D R, Vas W, Salimi A. Treatment of frostbite with i.v. streptokinase: an experimental study in rabbits. Am J Roentgenol 1987; 149: 773–776.
Medicine
The pathology of high altitude: an introduction to the disease states of high altitude
N. Mason A number of pathologies specific to high altitude, that are precipitated by exposure to hypobaric hypoxia, may be grouped under the broad heading of altitude illness. These overlapping conditions, acute mountain sickness, high altitude cerebral oedema and high altitude pulmonary oedema are all characterized by marked individual susceptibility, oedema formation and a usually rapid resolution on descent to lower altitude. Possible pathophysiological mechanisms, prevention and treatment are discussed. Sleep disturbance and periodic breathing, high altitude cough and local cold injury, or frostbite, are also reviewed. © 2000 Harcourt Publishers Ltd
Introduction The pathological processes which may be encountered at altitude include trauma, environmental pathologies such as cold injury and a spectrum of infectious diseases. This article will concentrate on those acute pathologies which result directly from the influence of hypobaric hypoxia and are often grouped under the vague term, altitude sickness. Cold-injury will also be discussed as it is greatly exacerbated by the effects of hypobaric hypoxia. While altitude illness in its simplest form as acute mountain sickness may only be regarded as a failure or delay in the acclimatization process, in its most severe forms as high altitude pulmonary and cerebral oedema it presents a life-threatening condition, whose aetiology is
Nicholas P. Mason FRCA, Laboratoire de Physiologie et de Physiopathologie, Faculté de Médecine – Campus Erasme, Bat. E2 niveau 4, Route de Lennik 808 – CP604, B-1070 Bruxelles, Belgium. Correspondence to: N.P.M. e-mail: [email protected]
poorly understood, and requires rapid treatment which may be difficult to achieve in the mountain environment.
The spectrum and nomenclature of altitude illness Dickinson suggested that the acute mountain sickness (AMS) which affects most people ascending to high altitude and which will disappear with acclimatization be termed, ‘Simple AMS’, while the more severe, and if untreated life-threatening, high altitude pulmonary oedema (HAPO) and high altitude cerebral oedema (HACO) be termed, ‘Malignant pulmonary AMS’ and ‘Malignant cerebral AMS’ respectively.1 This nomenclature is helpful in emphasizing both the relative seriousness of the conditions and also their probable common aetiology. AMS shows a continuum of severity ranging from mild symptoms to a severe, incapacitating condition which merges into HACO. In its most severe forms as HAPO and HACO it is not unusual for there to be a degree of overlap between the conditions, with HAPO 104
THE PATHOLOGY OF HIGH ALTITUDE Table 1 Lake Louise consensus score for acute mountain sickness (Ref 2) Each symptom is scored from 0 to 3 and the total calculated. A self assessment score of up to 3 is often seen on arrival at a new altitude and will improve with acclimatisation. A score of greater than 3 should alert the clinician to the possibility of more severe AMS. The clinical and functional assessments are rarely used. a) AMS self assessment Symptom Headache
Gastrointestinal symptoms
Fatigue and/or weakness
Dizziness/light-headedness
Difficulty sleeping (the previous night)
Overall, if you had any of these symptoms, how they affect your activities?
Score 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
None at all Mild headache Moderate headache Severe, incapacitating, headache Good appetite Poor appetite or nausea Moderate nausea or vomiting Severe, incapacitating, nausea and vomiting Not tired or weak Mild fatigue/weakness Moderate fatigue/weakness Severe fatigue/weakness None Mild Moderate Severe, incapacitating Slept as well as usual Did not sleep as well as usual Woke many times, poor night’s sleep Could not sleep at all Not at all Mild reduction Moderate reduction Severe reduction (bedrest)
b) Clinical assessment All responses obtained by interview to the self-assessment questions plus the following Sign Score Change in mental status
Ataxia (heel – toe walking)
Peripheral oedema
0 1 2 3 4 0 1 2 3 4 0 1 2
No change Lethargy/lassitude Disorientated/confused Stupor/semiconcious Coma None Balancing manoeuvres Steps off the line Falls down Unable to stand None One location Two or more locations
c) Functional assessment Assigned by investigator, not self-assessment Grade Assessment 0 1 2 3 4
No symptoms Symptoms, but no change in activity Must reduce activities Reduced to bed rest Life threatening
victims having some signs of cerebral oedema and vice versa.
Acute mountain sickness The symptoms of acute mountain sickness (AMS) are non-specific. In 1992 a consensus statement defined
105
AMS as the presence of headache and at least one other symptom from gastrointestinal disturbance, fatigue or weakness, dizziness or lightheadedness, or difficulty in sleeping, in the setting of a recent gain in altitude.2 A scoring system which can be used either for selfassessment or clinical assessment was proposed (Table 1). A score of 3 or less will often be seen on arrival at a new altitude and will improve with acclimatization. A score of greater than 3 should alert the clinician to the possibility of more serious AMS. There is great individual variation in the incidence of AMS. One of the problems in discussing the incidence is that it is dependent upon the altitude, the speed of ascent and the time spent at altitude. A few hours spent at moderate altitude and most subjects will escape symptom free. The lowest altitude at which people are affected is around 2000 m and it is not unheard of for subjects to report mild AMS symptoms during the first days in high ski resorts. At altitudes of between 3500 and 4500 m the reported incidence varies between 30 and 45%.3, 4 Aetiology While those people who develop AMS on their first ascent to altitude will probably do so on subsequent occasions, the aetiology of AMS is complex and poorly understood. The rate of ascent clearly plays an important role and most subjects will develop AMS if their ascent is rapid enough. Men and women are equally susceptible, although the young are probably more susceptible than older subjects. Fitness provides no degree of protection. There is some evidence that those subjects with a brisk hypoxic ventilatory response (HVR) are less susceptible than those with a blunted response. However, this observation is confounded by the fact that high altitude natives, who generally suffer less from AMS than lowlanders, on ascent to higher altitudes, in general have a low HVR. The most characteristic sign of AMS is peripheral oedema resulting from water retention and/or shifts to the extracellular space. The same process occurring at a cerebral level and resulting in cerebral oedema could explain the symptoms of AMS. There is now evidence that on ascent to high altitude there is an increase in cerebral volume, visible on MRI scan, and consistent with diffuse cerebral oedema.5 As the degree of oedema does not correlate with the severity of AMS, other factors, such as individual variation in cranial or spinal canal volumes or compliance, may play a role in dictating whether a given increase in brain volume produces AMS. The observation that it takes between 12 and 24 h at a given altitude before symptoms begin to appear, and that if one spends only a few hours at altitude before descent, one can escape symptom free, provides an insight into the possible aetiology of the condition. It would seem likely that exposure to hypobaric hypoxia, perhaps exacerbated by a blunt HVR, initiates a mechanism which may result in AMS in susceptible individuals. The most likely mechanisms are deranged fluid homeostasis, an inflammatory process, changes in endothelial function
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resulting in increased microvascular permeability, or a combination of these factors. The changes occurring in the renin-angiotensionaldosterone system and in fluid balance were discussed in the previous article on the physiology of high altitude, in the February 2000 issue of the journal. The normal response to exposure at high altitude is mild diuresis and fluid loss, while those subjects with AMS develop antidiuresis.6 In favour of an inflammatory process, Maggiorini reported a mild pyrexia in those subjects with AMS.7 Increased levels of inflammatory mediators have been found in the bronchoalveolar lavage fluid of subjects with HAPO (see below) although not with simple AMS. Richalet reported a marked correlation between the plasma concentration of the eicosanoids thromboxane B2 (TXB2), 6-keto-PGF1α (a stable metabolite of prostacyclin), PGE2, PGF2α, and of leukotriene LTB4, and the symptoms of AMS,8 suggesting that these mediators, by producing a direct increase in capillary permeability could be responsible for the symptoms of AMS. Against an inflammatory process, however, other authors have found no increase in the plasma concentrations of the cytokines interleukin1β, (IL-1β), IL-1ra, IL-8, TNFα, C reactive protein, or the systemic escape of 125I-labelled albumin, on exposure to high altitude.9, 10, 11 Recently, drawing a parallel with the symptoms of severe falciparum malaria, it has been suggested that excessive hypoxia-induced production of inducible nitric oxide synthetase (iNOS) might be responsible for many of the symptoms of AMS.12 The effect of endothelial released mediators such as prostacyclin and inducible nitric oxide (NO) on vascular permeability is complex and controversial.13, 14 Although the effect of altitude on such mediators is not clearly understood, it is feasible that changes in the levels of these mediators may play a role in the development of AMS. Perhaps the major conclusion that can be drawn from all of these studies is that we are, as yet, far from understanding the basic pathophysiological mechanisms involved in AMS. Prevention and treatment of AMS The most reliable way of avoiding AMS is to adopt a slow ascent profile with regular rest days. A typical recommended rate of ascent is, as far as possible, to never sleep more than 300–400 m above the previous night’s altitude and to have a full rest day (i.e. to spend 2 nights at the same altitude) every 1000 m or 3 days. Some climbers believe that it aids acclimatization to ascend high during the day but to sleep within 300–400 m of the previous night’s altitude. Obviously there will be certain situations where it is not possible to maintain a slow ascent and in addition there are those subjects who, despite a sensible ascent profile, still develop AMS. In this situation acetazolamide at a dose of 250 mg twice-daily may be used to aid acclimatization; the treatment being commenced on the evening before the ascent. The mechanism of action of acetazolamide will be discussed later.
In most cases of developed AMS it is sufficient to rest and remain at the same altitude for another day and symptoms will improve. Symptomatic treatment of headache can be given with paracetamol or aspirin although it is not always effective. Non-steroidal antiinflammatories may work better. Should symptoms not improve, or if the subject is severely incapacitated, the only completely effective treatment is descent to a lower altitude. Very often descent of only a few-hundred metres is sufficient to bring about a remarkable improvement in the condition. Oral acetazolamide may be taken (250 mg twice-daily) combined, in severe cases, with dexamethasone (8 mg initially followed by 4 mg four times daily) to aid descent. In such cases and where the distinction with HACO is blurred, rapid descent is imperative regardless of the time of day. Portable hyperbaric chambers There exist a number of types of portable hyperbaric chamber within which a patient can be placed to increase the barometric pressure temporarily. Light, and inflated using a hand pump, one such example, the CERTEC bag, increases the barometric pressure by 220 mbar (165 mmHg), resulting in a significant reduction in altitude (e.g. at 3500 m the altitude is reduced to 1200 m and at 5000 m to 2375 m). While these devices should never be used to avoid descent, they may be useful when descent is impossible due to the weather or clinical condition of the patient and may be used to buy time or improve the patient’s condition sufficiently that he can descend. It must be emphasized, however, that the only reliable treatment remains descent, and neither the use of drugs nor portable hyperbaric chambers should be regarded as a means to avoid this.
Sleep disturbance and periodic breathing at altitude Sleep disturbance is very common at high altitude. There is a delay in the onset of sleep; a decrease in the time spent in deep sleep (stages III and IV) and an increase in the number of arousals.15 Total sleep time tends to increase, probably in an attempt to compensate for the reduced time spent in deep sleep. Periodic breathing is a very common finding during sleep at high altitude and consists of repetitive cycles of hyper- and hypoventilation. Peripheral chemoreceptor induced hyperventilation reduces arterial PCO2 (PaCO2) sufficiently to bring about central chemoreceptor mediated hypoventilation. This produces a fall in arterial PO2 which reactivates the peripheral chemoreceptors, provoking a period of hyperventilation and commencing another cycle of periodic breathing. The hypoventilation is usually associated with periods of apnoea which can last for over 10 s. Time spent in periodic breathing increases with altitude. The periodic breathing cycle is accompanied by heart rate changes of a similar frequency, with the periods of apnoea being associated with bradycardia and the
THE PATHOLOGY OF HIGH ALTITUDE
maximum heart rate occurring shortly after the peak of hyperpnoea. The periods of apnoea are associated with marked desaturation. Susceptibility to periodic breathing at altitude appears to be related to the hypoxic ventilatory response (HVR), whereby the subjects with the briskest response suffer most from periodic breathing. High altitude natives who generally do not have a very strong HVR are less troubled by periodic breathing at altitude.16 The carbonic anhydrase inhibitor acetazolamide decreases the time spent in periodic breathing, increases arterial oxygen saturation and improves sleep quality. Hypnotic agents such as temazepam and zolpidem increase the quality and duration of sleep at altitude without affecting respiratory parameters.17 One possible mechanism for this improvement is a reduction in arousals and an increase in respiratory stability.
Carbonic anhydrase inhibitors The enzyme carbonic anhydrase (CA) which catalyses the conversion of water and CO2 to carbonic acid is distributed throughout the body, including in the kidneys, red blood cells, the cells of the peripheral and central chemoreceptors and in the choroid plexus. It is also found on the endothelial surface of capillaries. The sulphonamide related CA inhibitor (CAI) acetazolamide is now well known to increase ventilation and arterial oxygen saturation and to be effective in both the prophylaxis and treatment of AMS. Ventilation is increased by 10–20% and arterial oxygen saturation by 3–6%.18 Acetazolamide is concentrated in the kidney and urine, and at low doses renal CA inhibition is achieved with little inhibition of CA in other tissues. Thus the increase in ventilation appears to be mediated primarily by inhibition of renal CA, resulting in a decrease in proximal tubular reabsorption of bicarbonate and distal tubular secretion of H+ ions. This results in a urinary bicarbonate loss of around 4–6 mmol within 24 h of commencing the drug.18 As discussed in the previous article, the normal hypoxic ventilatory response on initial exposure to high altitude is blunted by the subsequent respiratory alkalosis resulting from hyperventilation. This respiratory alkalosis reduces the sensitivity of the peripheral chemoreceptors to hypoxia and reduces the tonic output from the central chemoreceptors. Normally the respiratory alkalosis is partly compensated for by a decrease in renal bicarbonate absorption and H+ ion secretion, but maximal compensation, which is probably never complete, takes a number of days. The renal action of CAIs accelerates this effect and if commenced before ascending to altitude effectively reduces the brake on respiration which would otherwise occur upon exposure to altitude. The primary role of renal CA inhibition in the mode of action of acetazolamide is further confirmed by the fact that benzolamide, a CAI which is highly selective for the kidney, is as effective as acetazolamide in reducing the symptoms of AMS and produces a better increase in ventilation, yet is devoid of effects in other tissues. In addi-
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tion, inhibition of peripheral chemoreceptor CA actually blunts HVR.19 Recent work suggests that an isoenzyme of CA, CA IV, which is found on the endothelial surface of most capillaries, and which is inhibited even with low doses of CAIs, may also play an important role in increasing the ventilatory response to hypobaric hypoxia. Inhibition of CA IV will inhibit blood CO2 uptake and release, resulting in a local retention of CO2 of 1–2 mmHg. The central chemoreceptors have a ventilatory response to CO2 of 1–3 l/min/mmHg and thus, this relatively small increase in CO2 is capable of bringing about a large increase in ventilation.18 CAIs also reduce the frequency of periodic breathing at high altitude by between 50 and 80% and improve arterial oxygen saturation . By producing a metabolic acidosis, CAIs may increase the tonic output of the central chemoreceptors, reducing their sensitivity to reductions in CO2. In addition the fact that peripheral chemoreceptor stimulants such as almitrine increase periodic breathing frequency would suggest that the effect on periodic breathing of CAIs is also mediated via the peripheral chemoreceptors, perhaps by reducing their hypoxic sensitivity.20
High altitude cerebral oedema As noted, the symptoms of AMS are probably due to ‘benign’ cerebral oedema, which in a proportion of cases progresses to the life threatening condition, high altitude cerebral oedema (HACO). Initially subjects will have symptoms which are indistinguishable from severe AMS, but the emergence of ataxia at altitude is almost pathognomonic of HACO. Other signs and symptoms are listed in Table 2. The incidence of HACO is not known, although it appears to be less common than HAPO, and possible aetiological factors have been less well studied. HACO is rare below 3500 m but has been reported at altitudes as low as 2500 m. As with the other altitude pathologies rapid ascent would seem to predispose to HACO, but the condition can occur in seemingly well acclimatized individuals.
Table 2
Signs and symptoms of HACO
Ataxia Severe headache Vomiting Hallucinations Impaired short term memory Altered level of consciousness progressing to coma if untreated Blurred vision or visual field defects Focal neurological deficits Urinary incontinence Papilloedema Hypo- or hypertonic reflexes Extensor plantar responses
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Pathophysiology HACO is characterized on MRI by reversible white matter oedema.21 Oedema of white matter is consistent with a capillary leak, or vasogenic aetiology (the alternative explanation would be due to a failure of cell volume regulation or blood–brain barrier (BBB) ion transport — cytotoxic oedema). This is further borne out by the effectiveness of dexamethasone in the treatment of HACO. Vasogenic cerebral oedema responds to corticosteroid therapy while cytotoxic oedema does not. In addition there is no convincing evidence of a significant alteration in cerebral oxygen or glucose metabolism in an animal model of severe AMS-HACO which makes a cytotoxic mechanism further unlikely.22 The physical integrity of the BBB is located in endothelial cell tight junctions. If HACO is due to a vascular leak, then this implies that there must be a disruption of the tight junctions permitting the movement of fluid and macromolecules into the extracellular spaces. One possible explanation would be a simple hydrostatic stress failure of cerebral capillaries as has been postulated in the pulmonary circulation. However, while there is good evidence of increases in cerebral blood flow (CBF) and capillary pressure (Pcap) during sustained hypoxia, not everybody who goes to altitude develops HACO. In addition, sustained elevations of CBF in non-hypoxic circumstances such as hypercapnia or infusion of nitroglycerin fail to elicit HACO or AMS-like symptoms. It would seem, therefore, that the increases in CBF or Pcap which occur at altitude are by themselves insufficient to open the BBB and that another mechanism or mechanisms must be active to precipitate HACO. Little is known of the role played by endothelial mediators such as nitric oxide in HACO. Evidence exists in other pathologies of a leucocyte-mediated inflammatory response which increases microvascular permeability and could open up the BBB, but in HACO increasing interest is being shown towards the possible role for vascular endothelial growth factor (VEGF). VEGF is a dimeric glycoprotein which induces angiogenesis and increases vascular permeability and has essential roles in embryonic vascularization and probably in tumour growth. Xu and Severinghaus demonstrated that after 12 h of hypoxia, levels of VEGF in rat cortex and cerebellum were increased, with the level peaking at 2 day.23 In addition, the expression of mRNA for the VEGF receptor, VEGFR-1 (or Flt-1), increased after 3 days of hypoxia. Further possible proof of a role for VEGF in HACO is that dexamethasone is an effective inhibitor of angiogenesis. In conclusion, it seems likely that HACO is due to an increase in capillary permeability brought about by increases in certain circulating mediators and/or a leukocyte-mediated inflammatory response, and that the increase in CBF and Pcap seen at altitude serve to further enhance fluid loss across the disrupted BBB. Prevention and treatment As with AMS, slow ascent will reduce, although not remove completely, the risk of HACO. Once the condi-
tion has developed the only reliable treatment is rapid descent. Oxygen should be given if available along with dexamethasone, initially 8 mg IM, followed by 4 mg, 6-hourly. Portable hyperbaric chambers should be considered if the patient is incapable of descending or if weather conditions prohibit descent, but descent as soon as possible must remain the first priority.
High altitude pulmonary oedema The first recorded description of high altitude pulmonary oedema (HAPO) is probably to be found in a Chinese Buddhist monk’s account of his remarkable travels through Asia at the end of the 4th century. However it took another 16 centuries before HAPO was clearly defined as a separate disease process in South America in the 1950s,24 although the condition was not widely recognized until the publication of three reports in English between 1960 and 1961.24 Before this, acute respiratory distress at altitude was usually attributed to pneumonia. HAPO can occur at altitudes as low as 2500 m and commences between 12 and 48 h after ascent. The symptoms of AMS are often present. Symptoms specific to HAPO are shown in Table 3. If further tests are available the electrocardiogram may show signs of right heart strain. The chest X-ray reveals prominent pulmonary arteries and bilateral patchy shadowing is often present, becoming confluent with increasing severity. Pulmonary artery pressure (PAP) is elevated compared to normal subjects at the same altitude. It is normally around 60–80 mmHg systolic in HAPO, but values as high as 144 mmHg have been reported.25 Pulmonary capillary occlusion pressure is normal. Aetiology The aetiology of the condition remains unclear although there are a number of well recognized characteristics. Certain individuals exhibit a susceptibility to HAPO, developing the condition repeatedly on ascent to high altitude. Such subjects tend to have an exaggerated pulmonary pressor response to both hypoxia and exercise, Table 3 cases.
Incidence of clinical features of HAPO in a series of 101
Clinical feature
%
Breathlessness Chest pain Headache Nocturnal dyspnoea Dry cough Haemoptysis Nausea Insomnia Dizziness Heart rate > 120/min Respiratory rate > 30/min Cyanosis Pyrexia (≥ 36.8°C ≤ 39°C
83.2 65.3 62.4 58.4 50.5 38.6 25.7 22.8 17.8 69.3 68.3 51.5 70.0
From Menon N D. High altitude pulmonary edema: a clinical study. N Engl J Med 1965; 273: 66–73.
THE PATHOLOGY OF HIGH ALTITUDE
and a reduced HVR. However this is not exclusively the case, with some HAPO susceptible individuals exhibiting normal responses. Some workers have also reported reduced lung volumes in susceptible individuals. HAPO appears to be precipitated by exercise, cold (both of which increase PAP) and respiratory tract infections. The reason for the brisker hypoxic pulmonary vasoconstrictor response (HPVR) in HAPO susceptible individuals is not known, but possible mechanisms include increased sympathetic activity, as is known to occur at altitude,26 increased endothelin production,27 or decreased NO production.28 A high PAP is clearly necessary, but not sufficient, for the development of HAPO, as demonstrated in one study, where although HAPO susceptible individuals had a significantly higher systolic PAP than the control group, there was no difference in the systolic PAP between those HAPO susceptible individuals who developed HAPO and those who did not.28 Despite an increase in systemic inflammatory mediators on ascent to altitude, there is little evidence that inflammation plays a role in the development of HAPO. In developed cases, however, increased levels of leukotriene LTB4, thromboxane (TX) B4,29 the interleukins IL-1β, IL-1ra, IL-6 and IL-8, and tumour necrosis factor α (TNFα)30 have been found in the bronchoalveolar lavage fluid of subjects with HAPO, along with evidence of complement activation. The most widely accepted explanation of the mechanism of HAPO has been that suggested by Hultgren in the 1970s, that patchy pre-capillary vasoconstriction associated with pulmonary hypertension leads to overperfusion of those capillaries not protected by vasoconstriction.31 Thus one can imagine a reduced HVR, possibly exacerbated by small lung volumes, producing a greater than normal degree of alveolar hypoxia which exacerbates an already brisk HPVR. West demonstrated the presence of capillary rupture in isolated rabbit lung exposed to PAPs of greater than 40 mmHg, and similar lesions in rats rapidly exposed to barometric pressures equivalent to altitudes of between 7000 and almost 9000 m, and coined the term ‘stress failure’ of pulmonary capillaries32 proposing it as the principal mechanism by which HAPO occurs. As attractive as this simple mechanical theory based only on animal data is, it seemed insufficient to explain the rapid recovery which occurs on descent to lower altitude and with certain treatments such as calcium antagonists. However, recent work by Maggiorini and co-workers33 demonstrated a significantly elevated pulmonary capillary pressure, (obtained by analysis of the pressure decay curve after rapid inflation of the balloon of a Swan–Ganz catheter) in HAPO susceptible individuals at 4559 m compared to non-susceptible controls. In addition, pulmonary capillary permeability was assessed using gallium-67 labelled transferring, and showed no difference between the two groups. There would appear to be growing evidence that HAPO is primarily of hydrostatic origin and is not due to increased capillary permeability. Inflammation due to infection may be a separate precipitating factor for
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HAPO, but for those subjects who develop HAPO in whom there is no evidence of infection, current evidence would only favour the development of an inflammatory response after the development of pulmonary oedema. Prevention and treatment The major method of prevention is slow ascent and there is evidence that even those subjects susceptible to developing HAPO may reach altitudes of up to 7000 m if they adopt a slow ascent profile limited to no more than 300–400 m ascent per day. If a slow ascent rate is not possible, then oral nifedipine 20 mg twice-daily is effective as prophylaxis against HAPO in susceptible subjects.34 The prophylactic administration of nifedipine lowers PAP and adds further weight to the important aetiological role of pulmonary hypertension in HAPO. In developed HAPO the most importantant treatment is to lower PAP. This can be achieved most effectively by descent. To aid descent, or if descent is not possible, a number of effective treatments have been used to lower PAP including oxygen, nifedipine, and inhaled nitric oxide. Initial treatment in the mountain environment is with sublingual nifedipine 10 mg, followed by 20 mg orally every 6 h. Portable hyperbaric chambers have also been successfully used in the treatment of the condition. Descent usually brings about a rapid improvement in oxygenation and recovery is usually complete after 2–3 days. However, in rare, severe cases which often show a degree of HACO, prolonged hospitalization is necessary.
High altitude cough Numerous anecdotal reports exist of paroxysmal cough in climbers and travellers to high altitude which can be extremely debilitating and may be severe enough to cause rib fractures. Traditionally the cause has been alttributed to the inspiration of cold, dry air but in a recent hypobaric chamber study that simulated extreme altitude (Operation Everest 3), in which both the temperature and humidity of the chamber were controlled to normal sea level conditions, the subjects remained troubled by cough, particularly at night.35 Mucociliary clearance is reduced at high altitude36 and there is an increase in the incidence of upper respiratory tract infections.37 While this may account for some cough at altitude the vast majority of subjects with coughs exhibit no evidence of respiratory tract infection. Although in the Operation Everest 3 study the subjects continued to cough despite controlled environmental conditions, drying of the respiratory mucosa, which is known to precipitate cough,38 may still play an important aetiological role. The hypoxia mediated increase in ventilation at altitude requires large volumes of air to be warmed and humidified, and it is possible that this increase may exceed the upper respiratory tracts ability to condition inspired air sufficiently to prevent water loss. However it seems unlikely that this is the case at rest, although it may play a role during exercise.
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It is generally considered that pulmonary oedema causes cough, which is one of the recognized symptoms of HAPO, and yet the known anatomical sites which stimulate cough are actually located proximal to the distal airways where early oedema will be present. However, with the probable inflammatory processes and alterations in vascular permeability which occur upon exposure to high altitude, it is possible that if sub-clinical HAPO, or AMS, result from an overall increase in vascular permeability, similar changes occurring around pulmonary rapidly acting receptors could be responsible for cough at altitude. The hypercapnic ventilatory response (HCVR) increases with acclimatization and Banner has demonstrated an inverse relationship between the HCVR and cough threshold, with those subjects with the greatest HCVR having the lowest cough threshold.39 There may, therefore be a role for a putative ‘cough centre’, whose sensitivity changes in a similar manner to the respiratory control centre. This is supported by observational data from high altitude.40 However, for the moment, the cause of this troublesome complaint remains obscure.
Freezing cold injury Cold injury may be divided into non-freezing and freezing types. The former, of which perhaps the best known example is ‘Trench Foot’, occurs after prolonged exposure to temperatures below 15°C and is exacerbated by damp conditions. It often occurs proximal to areas of freezing cold injury and may result in permanent damage to nerves and muscles. Freezing cold injury, or frostbite, occurs in sub-zero conditions. It is a local lesion which has a predilection for the extremities, with the feet being the most affected, followed by the hands and then facial extremities (nose, ears and cheeks). It may be classified into three degrees of severity (Table 4).
Table 4
Classification and clinical features of frostbite
Degree
Features
First (‘frost nip’)
Skin pallor, but skin remains pliable Transitory paraesthesia Erythema on rewarming Superficial skin loss Complete revovery over 1–2 weeks
Second Superficial
Deep
Third
Skin becomes white and frozen Underlying tissues remain pliable Development of clear blisters within 12–24 h Paraesthesia may persist longer Complete recovery over 1–2 weeks Complete anaesthesia Haemorrhagic blisters may form Proximal oedema and swelling Deep second degree progressing to necrosis and auto-amputation
Pathophysiology The pathophysiology of frostbite is complex. The initial freezing insult results in a decrease in perfusion due to vasoconstriction and in local tissue, destruction due to ice crystal fromation. The crystals form initially in the extracellular space, increasing its osmolality and resulting in cellular dehydration by movement of water out of the cells. This initial phase is usually followed by rewarming which is the major phase of tissue destruction. On rewarming, vasodilatation results in hyperaemia which paradoxically decreases capillary perfusion by enhancing fluid loss from the microcirculation and increasing blood viscosity. Neutrophil mediated tissue damage41 is associated with a marked derangement in platelet function42 and an increase in thromboxane A2 (TXA2) release, altering the normal TXA2/prostacyclin balance.43 After 24–48 h, if treatment has not been instituted, irreversible vascular necrosis results. Frostbite at altitude appears to be more common than at sea level for comparable temperatures. Maximum oxygen uptake falls with increasing altitude, reducing the body’s ability to produce heat,44 while dehydration, cold, the fall in plasma volume which occurs at high altitude and increased erythropoietin production all work to increase blood viscosity and reduce peripheral blood flow. A reduction in calorie intake also reduces insulating subcutaneous fat. Treatment The goal of treatment is to counter hyperviscosity, vasospasm and thrombosis and to prevent infection. The patient will usually be dehydrated and hypothermic, so initial resuscitation should consist of rapid rewarming and rehydration using warmed IV fluids. The initial treatment of the frostbitten part should be started as soon as possible by rewarming in warm water at between 37 and 41°C and which contains a mild antiseptic. Ideally this should be carried out in a whirlpool bath to remove necrotic tissue. Treatment in the field should be avoided if there is the slightest risk of refreezing. There is no consensus of opinion on the pharmacological treatment of frostbite and controlled clinical trials are lacking. For first degree and superficial second degree frostbite the patient is given low dose aspirin and IV praxilene. Symptomatic pain relief can be achieved with non-steroidal anti inflammatory agents. For the more severe forms of frostbite recent work suggests that the synthetic PGI2 analogue iloprost, up to 50 mcg/day IV, may be of benefit in combination with low molecular weight heparin and aspirin. There is some experimental evidence that treatment with thrombolytic agents such as streptokinase reduces tissue damage45 but clinical trials in humans are lacking. The reperfusion period can be extremely painful and adequate analgesia should be given with systemic opioids. Antibiotics should not be given routinely and surgical amputation is only indicated in the presence of severe infection, and even then should be delayed for as long as is safely possi-
THE PATHOLOGY OF HIGH ALTITUDE
ble to allow the clearest demarcation of tissue damage. It is normal for far more tissue to survive after frostbite than would be thought from the clinical appearance. In comparison with peripheral vascular disease, tissue loss is generally more superficial. One of the most frustrating problems for both the medical team and the frostbite victim is the delay in waiting for demarcation to occur and to know what tissue will be preserved. As a result of this a number of techniques have been tried to predict tissue survival, the most promising of which is technetium99 isotope scanning. Scanning should be performed at 48 h and 1 week. Where the scan shows normal uptake in the late (bony) phase, amputation will not be necessary. Where, however, there is late phase bony hypofixation, amputation will almost certainly be required.
Acknowledgements The author would like to thank Dr Bernard Marsigny, of the Mountain Medicine and Traumatology Department, Chamonix Hospital, France, for his help in the preparation of the section on local cold injury.
References 1. Dickinson J G. Terminology and classification of acute mountain sickness. Br Med J 1982; 285: 720–721. 2. Hackett P H, Oelz O. The Lake Louise consensus on the definition and quantification of altitude illness. In: Sutton J R, Coates G, Houston C S, eds Hypoxia and Mountain Medicine. Burlington, Vermont: Queen City Printers, 1992; 327–330. 3. Hackett P H, Rennie D. Rales, peripheral oedema, retinal hemorrhages and acute mountain sickness. Am J Med 1979; 67: 214–218. 4. Maggiorini M, Buhler B, Walter M, Oelz O. Prevalance of acute mountain sickness in the Swiss Alps. Br Med J 1990; 301: 853–855. 5. Muza S R, Lyons T P, Rock P B et al. Effect of altitude exposure on brain volume and development of acute mountain sickness (Abstract). 1999 International Hypoxia Symposium, Jasper, Canada. 6. Claybaugh J R, Wade C E, Sato A K et al. Antidiuretic hormone reponsess to eucapnic and hypocapanic hypoxia in humans. J Appl Physiol 1982; 53: 815–823. 7. Maggiorini M, Bartsch P, Oelz O. Association between raised body temperature and acute mountain sickness: cross sectional study. Br Med J 1997; 315: 403–404. 8. Richalet J P, Hornych A, Rathat C, Aumont J, Larmignat P, Rémy P. Plasma prostaglandins, leukotrienes and thromboxane in acute high altitude hypoxia. Respir Physiol 1991; 85: 205–215. 9. Klausen T, Olsen N V, Poulsen T D, Richalet J P, Pedersen B K. Hypoxemia increases serum interleukin-6 in humans. Eur J Appl Physiol 1997; 76: 480–482. 10. Swenson E R, MacDonald A, Vatheuer M et al. Acute mountain sickness is not altered by a high carbohydrate diet nor associated with elevated circulating cytokines. Aviat Space Environ Med 1997; 68: 499–503. 11. Kleger G R, Bartsch P, Vock P, Heilig B, Roberts L J 2nd, Ballmer P E. Evidence against an increase in capillary permeability in subjects exposed to high altitude. J Appl Physiol 1996; 81: 1917–1923. 12. Clark I A, Awburn M, Cowden W B, Rockett K A. Can excessive iNOS induction explain much of the illness of acute mountain sickness? (Abstract). 1999 International Hypoxia Symposium, Jasper, Canada. 13. Kubes P. Nitric oxide and microvascular permeability: a continuing dilemma. Eur Respir J 1997; 10: 4–5. 14. Henderson W R. Eicosanoids and lung inflammation. Am Rev Respir Dis 1987; 135: 1176–1185.
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15. Anholm J D, Powles A C, Downey R 3d, Houston C S, Sutton J R, Bonnet M H, Cymerman A, Operation Everest II: arterial oxygen saturation and sleep at extreme simulated altitude. Am Rev Respir Dis 1992; 145: 817–826. 16. Lahiri S, Maret K, Sherpa M G. Dependence on high altitude sleep apnea on ventilatory sensitivity to hypoxia. Respir Physiol 1983; 52: 281–301. 17. Dubowitz G. Effect of temazepam on oxygen saturation and sleep quality at high altitude: randomised placebo controlled crossover trial. Br Med J 1998; 316: 587–589. 18. Swenson E R. Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression. Eur Respir J 1998; 12: 1242–1247. 19. Swenson E R, Hughes J M B, Differential effects of acute and chronic acetazolamide on ventilation and ventilatory responses in man. J Appl Physiol 1993; 73: 230–237. 20. Hackett P H, Roach R C, Harrison G L, Schoene R B, Mills J W. Respiratory sitmulants and sleep periodic breathing at high altitude. Am Rev Respir Dis 1987; 135: 896–898. 21. Hackett P H, Yarnell P R, Hill R, Reynard K, Heit J, McCormick J. High-altitude cerebral edema evaluated with magnetic resonance imaging: clinical correlation and pathophysiology. JAMA 1998; 280: 1920–1925. 22. Yang S-P, Bergo G W, Krasney E, Krasney J A. Cerebral pressure-flow and metabolic responses to sustained hypoxia: effect of CO. J Appl Physiol 1994; 76: 303–313. 23. Xu F, Severinghaus J W. Rat brain VEGF expression in alveolar hypoxia: possible role in high-altitude cerebral edema. J Appl Physiol 1998; 85: 53–57. 24. Richalet J-P. High altitude pulmonary oedema: still a place for controversy? Thorax 1995; 50: 923–929. 25. Hultgren H N, Lopez C E, Lundberg E, Miller H. Physiologic studies of pulmonary edema at high altitude. Circulation 1964; 29: 393–408. 26. Bartsch P, Shaw S, Franciolli M, Gnadinger M P, Weidman P. Atrial natriuretic peptide in acute mountain sickness. J Appl Physiol 1988; 65: 1929–1937. 27. Droma Y, Hayano T, Takabayashi Y et al. Endothelin-1 and interleukin-8 in high altitude pulmonary oedema. Eur Respir J 1996; 1947–1949. 28. Scherrer U, Vollenweider L, Delabays A et al. Inhaled nitric oxide for high altitude pulmonary edema. N Engl J Med 1996; 334: 624–629. 29. Schoene R B, Hackett P H, Henderson W R et al. High- altitude pulmonary edema. Characteristics of lung lavage fluid. JAMA 1986; 256: 63–69. 30. Kubo K, Hanaoka M, Hayano T et al. Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema. Respir Physiol 1998; 111: 301–310. 31. Hultgren N H. High altitude pulmonary edema. In: Staub N C ed. Lung Water and Solute Exchange. L’Enfant Series. New York: Dekker, 1978, vol 7, 237–269. 32. West J B, Colice G L, Lee Y J et al. Pathogenesis of highaltitude pulmonary oedema: direct evidence of stress failure of pulmonary capillaries. Eur Respir J 1995; 8: 523–529. 33. Maggiorini M, Merlot C, Pierre S et al. High altitude pulmonary edema is an hydrostatic and not a high permeability type of edema. 1999 International Conference of the American Thoracic Society, San Diego, California, April 23–28, 1999. Am J Respir Crit Care Med 1999; 159 (part 2): A355. 34. Bartsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 1991; 325(18): 1284–9. 35. Mason N P, Barry P W, Despiau G, Gardette B, Richalet J-P. Cough frequency and cough receptor sensitivity to citric acid challenge during a simulated ascent to extreme altitude. Eur Respir J 1999; 13: 508–513. 36. Barry P W, Mason N P, O’Callaghan C. Nasal mucociliary transport is impaired at altitude. Eur Respir J 199; 10: 35–37. 37. Murdoch D R. Symptoms of infection and altitude illness among hikers in the Mount Everest region of Nepal. Aviat Space Environ Med 1995; 66: 148–151. 38. Irwin R S, Rosen M J. Cough. A comprehensive review. Arch Intern Med 1977; 137: 1186–1191. 39. Banner A S. Relationship between cough due to hypotonic aerosol and the ventilatory response to CO2 in normal subjects. Am Rev Respir Dis 1988; 137: 647–650. 40. Barry P W, Mason N P, Nickol A et al. Cough receptor sensitivity and dynamic ventilatory response to carbon dioxide in man
112
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acclimatised to high altitude (Abstract). J Physiol 1996; 497P: 29–30. 41. Mileski W J, Raymond J F, Winn R K, Harlan J M, Rice C L. Inhibition of leukocyte adherence and aggregation for treatment of severe cold injury in rabbits. J Appl Physiol 1993; 74: 1432–1436. 42. Zook N, Hussmann J, Brown R, Russell R, Kucan J, Roth A, Suchy H. Microcirculatory studies of frostbite injury. Ann Plast Surg 1998; 40: 246–255. 43. Ozyazagan I, Tercan M, Melli M, Bekerecioglu M, Ustun H, Gunay G K. Eicosanoids and inflammatory cells in frostbitten
tissue: prostacyclin, thromboxane, polymorphonuclear leukocytes, and mast cells. Plast Reconstr Surg 1998; 101: 1881–1886. 44. Gautier H, Bonora M, Schultz S A, Remmers J E. Hypoxia induced changes in shivering and body temperature. J Appl Physiol 1987; 62: 2577–2581. 45. Salimi Z, Wolverson M K, Herbold D R, Vas W, Salimi A. Treatment of frostbite with i.v. streptokinase: an experimental study in rabbits. Am J Roentgenol 1987; 149: 773–776.