Mechanisms of Altitude-Related Cough

Mechanisms of Altitude-Related Cough

Nicholas Paul Mason

Laboratoire de Physiologie et de Physiopathologie Faculté de Médecine

Thèse présentée en vue de l’obtention du titre académique de Docteur en Sciences Médicales

Année Académique 2011- 2012

Jury de Thèse

Président : Prof. Pierre-Alain GEVENOIS

(Service de Radiologie, Hôpital Erasme, ULB, Bruxelles)

Membres Facultaires : Dr. Guy DECAUX

( Service de Medecine Interne Génerale, Hôpital Erasme, ULB, Bruxelles)

Prof. André De TROYER

( Service de Pneumologie, Hôpital Erasme, ULB, Bruxelles)

Prof. Paul DE VUYST

(Service de Pneumologie, Hôpital Erasme, ULB, Bruxelles)

Prof. Alexandre LEGRAND

(Service de Pneumologue, Hôpital Erasme, ULB, Bruxelles.

Faculté de Médecine Université de Mons)

Experts Extérieurs : Dr. James MILLEDGE

(Honorary Professor, Department of Physiology, University College London)

Prof. Jean-Paul RICHALET

(Laboratoire de Réponses Cellulaires et Fonctionnelles à l'Hypoxie, Université Paris 13. Service de Physiologie, Hôpital Avicenne, Bobigny)

Secrétaire / Promoteur : Prof. Robert NAEIJE

(Laboratoire de Physiologie et de Physiopathologie, ULB, Bruxelles)

Dr. Nicholas P. Mason

CONTENTS

Synopsis of Thesis Chapter 1

Literature Review.

Chapter 2

Cough frequency and cough receptor sensitivity to citric acid challenge during a simulated ascent to extreme altitude.

Chapter 3

Serial changes in spirometry during an ascent to 5300 m in the Nepalese Himalaya.

Chapter 4

Serial changes in nasal potential difference and lung electrical impedance tomography at high altitude.

Chapter 5

Changes in plasma bradykinin concentration and citric acid cough threshold at altitude Chapter 6

The citric acid cough threshold and the ventilatory response to carbon dioxide on ascent to high altitude.

Acknowledgements

SYNOPSIS OF THESIS

The original work presented in this thesis investigates some of the mechanisms that may be responsible for the aetiology of altitude-related cough. Particular attention is paid to its relationship to the long recognised, but poorly understood, changes in lung volumes that occur on ascent to altitude. The literature relevant to this thesis is reviewed in Chapter 1.

Widespread reports have long existed of a debilitating cough affecting visitors to high altitude that can incapacitate the sufferer and, on occasions, be severe enough to cause rib fractures (22, 34, 35).

The prevalence of cough at altitude has been estimated to be between 22 and 42% at between 4200 and 4900 m in the Everest region of Nepal (10, 29). Traditionally the cough was attributed to the inspiration of the cold, dry air characteristic of the high altitude environment (37) but no attempts were made to confirm this aetiology. In the first formal study of cough at high altitude, nocturnal cough frequency was found to increase with increasing altitude during a trek to Everest Base Camp (5300 m) and massively so in 3 climbers on whom recordings were made up to 7000 m on Everest (8). After 9 days at 5300 m the citric acid cough threshold, a measure of the sensitivity of the cough reflex arc, was significantly reduced compared with both sea level and arrival at 5300 m.

During Operation Everest II, a simulated climb of Mount Everest in a hypobaric chamber, the majority of the subjects were troubled above 7000 m by pain and dryness in the throat and an irritating cough despite the chamber being maintained at a relative humidity of between 72 and 82%

and a temperature of 23ºC (18). This argued against the widely held view that altitude-related cough was due to the inspiration of cold, dry air.

In the next major hypobaric chamber study, Operation Everest III, nocturnal cough frequency and

citric acid cough threshold were measured on the 8 subjects in the study. The chamber temperature

was maintained between 18 and 24ºC and relative humidity between 30 and 60% (24). This work is

presented in Chapter 2 and, demonstrated an increase in nocturnal cough frequency with increasing

altitude which immediately returned to control values on descent to sea level. Citric acid cough

threshold was reduced at 8000 m compared to both sea level and 5000 m values. Changes in citric

acid cough threshold at lower altitudes may not have been detected because of the constraints on

subject numbers in the chamber. The study still however demonstrated an increase in clinical cough

and a reduction in the citric acid cough threshold at extreme altitude, despite controlled

environmental conditions, and thus refuted the long held belief that altitude-related cough is solely

due to the inspiration of cold, dry air.

If altitude-related cough is not simply due to the inspiration of cold, dry air, other possible aetiologies are:

• Acute mountain sickness (AMS).

• Sub-clinical high altitude pulmonary oedema.

• Changes in the central control of cough.

• Respiratory tract infections.

• Loss of water from the respiratory tract.

• Bronchoconstriction and asthma.

• Vasomotor-rhinitis and post-nasal drip.

• Gastro-oesophageal reflux.

It is unlikely that cough at altitude is due to AMS. Despite both AMS and cough occurring commonly at high altitude no relationship has ever been demonstrated between them in any study of altitude-related cough (8, 24, 27, 38) and cough has not been reported as a symptom in over 20 papers studying AMS (9).

There is considerable indirect evidence that the majority of subjects ascending to high altitude may develop sub-clinical pulmonary oedema. This evidence includes changes in lung volumes and in particular forced vital capacity (FVC) and changes in the nitrogen washout curve and closing volume. The conflicting literature on this topic, and other possible mechanisms underlying the fall in FVC on ascent to altitude, are reviewed fully in Chapter 1.

Chapter 3 presents a field study investigating the changes in FVC, forced expiratory volume in one second (FEV 1 ) and peak expiratory flow (PEF) in 55 subjects ascending to Everest Base Camp at 5300 m and addressing some of the methodological shortcomings of previous studies (25). Forced vital capacity fell significantly on ascent to 5300 m. Peak expiratory flow increased, as predicted by the fall in gas density with increasing altitude, while FEV 1 was unchanged.

If sub-clinical pulmonary oedema is responsible for the fall in FVC on ascent to altitude then it

might also be an aetiological factor in altitude-related cough. Animal work has demonstrated that

even small changes in left atrial pressure can be sufficient to produce pulmonary venous congestion

sufficient to stimulate airway rapidly adapting receptors (RAR) that form part of the afferent limb

of the cough reflex arc (15-17). It is therefore possible that sub-clinical pulmonary oedema

occurring at altitude could stimulate airway RARs and provoke cough.

Two possible mechanisms could be responsible for sub-clinical pulmonary oedema at high altitude:

pulmonary hypertension secondary to hypoxic pulmonary vasoconstriction or a reduction in respiratory epithelial fluid clearance. Chapter 4 presents a study investigating these two mechanisms during a 14 day stay at 3800 m in 20 lowland volunteers (26). Forced vital capacity fell on ascent to 3800m as did the normalized change in lung electrical impedance tomography suggestive of an increase in extravascular lung water. There was a positive correlation between FVC and the change in lung electrical impedance tomography. Respiratory epithelial ion transport was studied using nasal potential difference measurements. Nasal potential difference hyperpolarised at altitude which would be consistent with either increased transepithelial sodium absorption or anion secretion, or a combination of both. If anion secretion predominated over sodium reabsorption, it would be associated with the secretion of water into the respiratory lumen as occurs in the fetal lung (4) and could cause sub-clinical pulmonary oedema. The increase in pulmonary artery pressure estimated by echo-Doppler was insufficient to cause clinical pulmonary oedema .

Cough is a recognised side effect of angiotensin converting enzyme (ACE) inhibitors and is thought to be due to the sensitisation of airway RARs by increased levels of bradykinin and substance P (21). Bradykinin is degraded by kininases of which the most important in human serum is ACE.

Little or nothing was known about the effects of hypoxia on ACE and bradykinin. Chapter 5 presents further work done on the 20 lowland subjects during their 2 week stay at 3800 m (27).

Citric acid cough threshold was reduced throughout the stay at altitude compared to low altitude baseline measurements. Serum ACE activity was unchanged on ascent to 3800 m, although plasma bradykinin fell significantly making it unlikely that bradykinin plays a role in the change in citric acid cough threshold seen on ascent to altitude.

Respiratory control undergoes profound changes with acclimatisation (39) and the central control of cough is complex and poorly understood (12, 13). A relationship has been demonstrated between the hypercapnic ventilatory response (HCVR) and the cough threshold to hypotonic saline (1).

Those subjects who responded to the hypotonic saline challenge had a higher HCVR than the subjects who did not respond. In addition post-hoc analysis of data from the 1994 British Mount Everest Medical Expedition also demonstrated a relationship between the citric acid cough threshold and the dynamic ventilatory response to CO 2 (5).

Chapter 6 presents work which investigated the relationship between the citric acid cough

threshold and HCVR in 25 healthy subjects during a 9 day stay at 5200 m (38). Citric acid cough

threshold fell significantly on ascent to altitude and the HCVR increased significantly on ascent to

5200 m. There was, however, no demonstrable relationship between the citric acid cough threshold and HCVR, or any change in these parameters on ascent to altitude. These findings argue against altitude-related cough being mediated through changes in central control mechanisms.

Respiratory tract infections are the commonest cause of acute cough at sea level (20, 28, 32) and occur commonly in visitors to altitude (11, 29). There is also evidence of impairment of mucociliary transport, a crucial respiratory defence mechanism, at altitude (6). While there was no clinical evidence of respiratory infection observed in any of the subjects during Operation Everest III (24), cough associated with the production of purulent sputum is, anecdotally, a common finding at altitude, particularly following prolonged vigorous exertion.

It is still possible, despite the controlled environmental conditions during Operation Everest III (24), that water loss from the respiratory tract plays a role in the aetiology of altitude-related cough.

Hyperpnoea with cold air, in subjects susceptible to exercise-induced cough, and at respiratory rates similar to those occurring with strenuous exercise, has been shown to be associated with an increase in cough frequency (2). However increased coughing associated with hypernoea appears to depend upon water loss rather than heat loss. Hypernoea with warm dry air produced more coughing than hypernoea with cold air despite causing less heat loss (3). Hyperpnoea with ambient air also produced an increase in cough frequency because it was associated with water loss. Increased minute ventilation is a feature of the body’s response to hypobaric hypoxia and will increase further with exercise (23). In addition there is evidence of subjective nasal blockage and an increase in nasal resistance at altitude which may result in increased mouth breathing (6, 7) which will increase water loss compared to nasal breathing (36).

Cough may be the only symptom of asthma (28) and bronchoconstriction can occur at altitude and after hyperpnoea with cold air (14). However there was no demonstrable relationship between FEV 1

or PEF and the change in the citric acid cough threshold at 5300 m altitude (8) or FEV 1 and the citric acid threshold during Operation Everest III (24). In addition no evidence of bronchoconstriction could be found in healthy, non-asthmatic, subjects at Mount Everest Base Camp (30).

Nasal blockage could also be a symptom of vasomotor rhinitis and post-nasal drip (recently

redesignated upper airway cough syndrome) and which is reported in some series to be one of the

most common causes of chronic cough at sea level (28, 31). Gastro-oesophageal reflux disease has

been reported in up to 40% of patients with chronic cough at sea level (19, 33). Nothing is known

about the relationship between post-nasal drip and cough, or the prevalence of gastro-oesophageal

reflux, at high altitude.

Conclusions and Future Perspectives

This thesis has investigated some of the potential aetiologies of altitude-related cough and demonstrates that, contrary to the popularly held view, it may not solely be due to the inspiration of the cold, dry air characteristic of the high-altitude environment. Data is presented that confirms the fall in vital capacity on ascent to altitude and possible causes for this reduction are discussed. One possible cause would be sub-clinical pulmonary oedema. This could also be a potential cause for altitude-related cough and data is presented that suggests that this may be the result of changes in respiratory epithelial ion and water transport. Evidence is presented that argues against altitude- related cough being due to changes in bradykinin or in the central control of cough.

While sub-clinical pulmonary oedema may be an aetiological factor in altitude-related cough, and merits further study, it is likely that it is not the only cause and it is probable that cough at altitude is a symptom of a number of unrelated conditions. Future work should focus on the role of water loss from the respiratory tract at altitude, particularly during exercise as well as the association of upper respiratory tract infection with cough and the place of vasomotor rhinitis and gastro-oesophageal reflux in the aetiology of this fascinating condition.

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MECANISMES DE LA TOUX LIEE A L’ALTITUDE

Dr. Nicholas P. Mason

SOMMAIRE

Résumé de la thèse Chapitre 1

Revue de la littérature Chapitre 2

Fréquence de la toux et sensibilité du récepteur de la toux au test de provocation par l’acide citrique au cours d’une ascension simulée vers une altitude extrême.

Chapitre 3

Modifications en série de la spirométrie durant une ascension jusqu’à 5300 m dans l’Himalaya.

Chapitre 4

Modifications en série de la différence de potentiel nasale et de la tomographie électrique par impédance du poumon à haute altitude.

Chapitre 5

Modifications de la concentration plasmatique de bradykinine et du seuil de toux à l’acide citrique en altitude.

Chapitre 6

Seuil de la toux à l’acide citrique et réponse ventilatoire au gaz carbonique lors de l’ascension jusqu’en haute altitude

Remerciements

RESUME DE LA THESE

L’étude d’une partie des mécanismes à l’origine de la toux liée à l’altitude, constitue un travail original, présenté dans cette thèse. La relation entre cette toux et les modifications de volumes pulmonaires survenant lors de la montée en altitude sont connues de longue date mais mal élucidées ; elle fait l’objet d’une attention particulière. Une revue de la littérature pertinente est exposée dans le chapitre 1.

Des rapports largement diffusés évoquent une toux fatigante, possiblement invalidante, qui touche les personnes en haute altitude et qui, quand elle est suffisamment sévère, peut entraîner des fractures de côtes (22, 34, 35). La prévalence de la toux en altitude a été estimée entre 22 et 42 % à une altitude comprise entre 4 200 et 4 900 m dans la région de l’Everest népalais (10, 29).

Traditionnellement, la toux est attribuée à l’inspiration d’air froid et sec, caractéristique de l’environnement à haute altitude (37), mais aucun essai n’a été réalisé pour confirmer cette étiologie. Dans la première étude formelle sur la toux en haute altitude, il a été montré, au cours d’un trek vers le camp de base de l’Everest (5 300 m), que la fréquence de la toux nocturne augmentait avec l’altitude et, de façon massive, pour 3 alpinistes chez lesquels les enregistrements ont été effectués jusqu’à 7 000 m sur l’Everest (8). Après 9 jours à 5 300 m, le seuil de toux à l’acide citrique, mesurant la sensibilité de l’arc réflexe de la toux, était significativement diminué comparé à celui, à la fois, du niveau de la mer et de l’arrivée à 5 300 m.

Au cours de l’Opération Everest II (ascension simulée du Mont Everest réalisée en chambre hypobare), la majorité des sujets ont présenté des troubles à type de douleur et de sécheresse au niveau de la gorge ainsi qu’une toux irritative, malgré une humidité relative comprise entre 72 % et 82 % et une température à 23° C (18). Ce résultat plaide contre l’idée largement répandue que l’air froid et sec serait à l’origine de la toux liée à l’altitude.

Dans l’étude majeure suivante en chambre hypobare, Opération Everest III, la fréquence de la toux nocturne et le seuil de toux à l’acide citrique ont été mesurés chez 8 sujets. La température de la chambre et l’humidité relative ont été maintenues respectivement entre 18 et 24°C et entre 30 et 60% (24). Dans ce travail, présenté au chapitre 2, la fréquence de la toux nocturne s’élève avec l’altitude revenant immédiatement aux valeurs de base en descendant vers le niveau de la mer. Le seuil de toux à l’acide citrique est abaissé à 8 000 m par rapport aux valeurs à la fois au niveau de la mer et à 5 000 m. Les modifications du seuil de toux à l’acide citrique à de plus basses altitudes peuvent ne pas avoir été détectées du fait de la limitation du nombre de sujets dans la chambre.

Néanmoins, l’étude montre un accroissement de la toux clinique et une réduction du seuil de la toux

à l’acide citrique à une altitude extrême, malgré des conditions environnementales contrôlées, et réfute, par conséquence, la vieille croyance selon laquelle la toux liée à l’altitude est uniquement due à l’inspiration d’air froid et sec.

Si la toux liée à l’altitude n’est pas simplement la conséquence de l’inspiration d’air froid et sec, quelles sont les autres étiologies possibles ? Il existe plusieurs mécanismes potentiels comprenant :

• mal aigu des montagnes (MAM)

• sub-œdème pulmonaire de haute altitude

• modifications du contrôle central de la toux

• infections des voies aériennes

• perte d’eau des voies aériennes

• bronchoconstriction et asthme

• rhinite vasomotrice et secrétions post-nasales

• reflux gastro-œsophagien.

Il est peu probable que ce type de toux soit dû au MAM. Bien que toux et MAM surviennent tous deux, à haute altitude, aucune relation n’a jamais été démontrée entre eux, dans quelque étude que soit sur la toux liée à l’altitude (8, 24, 27, 38). Dans plus d’une vingtaine d’articles sur le MAM, la toux n’a jamais été signalée comme un symptôme (9).

Il a largement été prouvé, de façon indirecte, que la majorité des personnes montant en haute altitude peuvent développer un sub-œdème pulmonaire. Cette preuve comporte des modifications des volumes pulmonaires, en particulier de la capacité vitale forcée, de la courbe de rinçage de l’azote et du volume de fermeture. La littérature contradictoire sur le sujet, et d’autres mécanismes possibles à l’origine de la baisse de la capacité vitale forcée lors de la montée en altitude, sont largement examinés au chapitre 1.

Le chapitre 3 présente un travail de terrain étudiant les modifications de la capacité vitale forcée,

du volume expiratoire forcé sur une seconde (VEF 1 ) et du débit expiratoire de pointe (DEP) de 55

sujets en ascension vers le Camp de Base de l’Everest à 5 300 m. Ce travail répond à certaines des

insuffisances méthodologiques des études précédentes (25). La capacité vitale forcée a chuté, de

façon significative, en montant à 5 300 m. Le débit expiratoire de pointe a augmenté, comme

attendu puisque la densité d’un gaz baisse quand l’altitude s’élève, tandis que VEF 1 restait

inchangé.

Si le sub-œdème pulmonaire est responsable de la baisse de capacité vitale forcée en montant en altitude, il pourrait être aussi un facteur étiologique de la toux liée à l’altitude. Des travaux chez l’animal, ont montré que même de faibles modifications de la pression de l’oreillette gauche suffisaient à produire une congestion veineuse pulmonaire entraînant une stimulation des récepteurs ventilatoires à adaptation rapide qui constituent une partie de la branche afférente de l’arc réflexe de la toux (15-17). C’est pourquoi, il est possible que ce sub-œdème pulmonaire survenant en altitude stimule les récepteurs ventilatoires à adaptation rapide et provoque la toux.

Deux mécanismes pourraient être responsables du sub-oedème pulmonaire en haute altitude : l’HTAP secondaire à la vasoconstriction pulmonaire hypoxique ou la diminution de la clairance du liquide alvéolaire. Le travail présenté dans le chapitre 4 analyse ces deux mécanismes pendant un séjour de 14 jours à 3 800 m, chez 20 volontaires venus des plaines (26). En montant à 3 800 m, la capacité vitale forcée a diminué tout comme la modification normalisée de la tomographie pulmonaire d’impédance électrique, évocatrice d’une élévation de liquide pulmonaire extravasculaire. Il existe une corrélation positive entre la capacité vitale forcée et la modification de tomographie d’impédance électrique du poumon. Le transport ionique dans l’épithélium respiratoire a été étudié en utilisant des mesures de différence de potentiel nasale. Cette dernière s’hyperpolarise en altitude, ce qui pourrait être compatible avec soit une absorption sodique transépithéliale augmentée, soit une sécrétion d’anions soit une combinaison des deux. Si la sécrétion d’anions prédominait sur la réabsorption sodique, elle aurait été associée à la sécrétion d’eau dans la lumière respiratoire comme c’est le cas dans le poumon fœtal (4) et pourrait causer un sub-œdème pulmonaire. L’augmentation de pression artérielle pulmonaire estimée par échodoppler, n’a pas été suffisante pour déclencher un sub-œdème pulmonaire.

La toux est un effet secondaire connu des inhibiteurs de l’enzyme de conversion de l’angiotensine

qui serait due à la sensibilisation des récepteurs ventilatoires à adaptation rapide par des taux élevés

de bradykinine et de substance P (21). La bradykinine est dégradée par des kinases dont la plus

importante est l’enzyme de conversion de l’angiotensine dans le sérum humain. Très peu de

données sont disponibles concernant les effets de l’hypoxie sur l’enzyme de conversion de

l’angiotensine et la bradykinine. Dans le chapitre 5, est présenté un autre travail, réalisé sur les 20

sujets venus des plaines, pendant leur séjour de 2 semaines à 3 800 m (27). Le seuil de toux à

l’acide citrique était réduit tout au long du séjour en altitude comparé aux mesures de référence en

basse altitude. L’activité sérique de l’enzyme de conversion de l’angiotensine n’était pas modifiée

en montant à 3 800 m, alors que la bradykinine plasmatique a chuté de façon significative. Il est

donc improbable que la bradykinine joue un rôle dans la modification du seuil de la toux à l’acide citrique relevée lors de la montée en altitude.

Le contrôle respiratoire subit de profonds changements en s’adaptant au climat (39) et le contrôle central de la toux est d’une part complexe, d’autre part mal élucidé (12, 13). On note une relation entre la réponse ventilatoire à l’hypercapnie et le seuil de la toux au sérum hypotonique (1). Ces sujets qui répondent au test de provocation au sérum hypotonique ont une réponse ventilatoire à l’hypercapnie supérieure à ceux qui ne répondent pas. De plus, l’analyse post-hoc des données de l’expédition britannique médicale de 1994 sur le Mont Everest a aussi montré une relation entre le seuil de toux à l’acide citrique et la réponse ventilatoire dynamique au CO 2 (5).

Le travail présenté dans le chapitre 6 analyse la relation entre le seuil de la toux à l’acide citrique et la réponse ventilatoire à l’hypercapnie chez 25 sujets en bonne santé, au cours d’un séjour de 9 jours à 5 200 m (38). Le seuil de toux à l’acide citrique a chuté, de façon significative, lors de la montée en altitude et la réponse ventilatoire à l’hypercapnie a augmenté, de façon significative, lors de l’ascension à 5 200 m. Pourtant, il n’existait aucune relation évidente entre le seuil de la toux à l’acide citrique et la relation ventilatoire hypercapnique ou quelque modification de ces paramètres lors de la montée en altitude. Ces résultats plaident contre la toux liée à l’altitude impliquant des modifications des mécanismes centraux de contrôle.

Les infections des voies aériennes sont la cause la plus fréquente de toux aiguë, au niveau de la mer (20, 28, 32) et survient généralement en altitude chez les touristes (11, 29). Un dysfonctionnement du transport mucociliaire, mécanisme de défense respiratoire crucial, en altitude est prouvé également (6). Bien qu’il n’ait pas été relevé de preuve clinique d’infection respiratoire chez les sujets pendant l’Opération Everest III (24), la toux associée à la production d’expectoration purulente a été fréquemment constatée en altitude, en particulier à la suite d’un effort vigoureux prolongé.

Il est toujours possible, malgré des conditions environnementales contrôlées au cours de l’opération

Everest III (9), que la perte d’eau des voies aériennes joue un rôle dans l’étiologie de la toux liée à

l’altitude. Il a été montré que l’hyperpnée due à l’air froid, à une fréquence ventilatoire similaire de

celle survenant lors d’un effort énergique, était associée à une élévation de la fréquence de la toux

(2). Néanmoins, l’élévation de la toux associée à l’hyperpnée semble plus dépendre de la perte

d’eau que de la perte de chaleur. L’hyperpnée liée à l’air chaud et sec a entraîné plus de toux que

l’hyperpnée liée à l’air froid bien qu’entraînant moins de perte de chaleur (3). L’hyperpnée en air

ambiant a également eu pour conséquence une augmentation de la fréquence de la toux car associée

à une perte d’eau. L’augmentation de la ventilation-minute est une réponse à l’hypoxie hypobare qui augmente un peu plus avec l’exercice (23). De plus, il est démontré un blocage nasal subjectif et une augmentation de la résistance nasale en altitude qui peuvent entraîner une respiration buccale (6, 7) et donc une élévation de la perte d’eau comparé à la respiration nasale (36).

La toux peut être le seul symptôme de l’asthme (28) et la bronchoconstriction peut survenir en altitude et après hyperpnée liée à l’air froid (14). Pourtant, il n’existait pas de relation évidente entre le volume expiratoire forcé en une seconde ou le débit expiratoire de pointe et la modification du seuil de toux à l’acide citrique, à 5 300 m d’altitude (8), ni entre le volume expiratoire forcé en une seconde et le seuil de toux à l’acide citrique au cours de l’Opération Everest III (24). De plus, aucune preuve de bronchoconstriction n’a été retrouvée chez les sujets en bonne santé, non asthmatiques, au camp de base du Mont Everest (30).

Le blocage nasal pourrait être aussi un symptôme de rhinite vasomotrice et de, considéré, dans quelques séries, comme l’une des plus fréquentes causes de toux chronique au niveau de la mer (28, 31). Le reflux gastro-œsophagien est retrouvé chez presque 40 % des patients présentant une toux chronique, au niveau de la mer (19, 33). On ne connait ni la relation entre les secrétions post- nasales et la toux, ni la prévalence du reflux gastro-œsophagien à haute altitude.

Conclusions et perspectives futures

Cette thèse a passé en revue quelques causes potentielles de toux liée à l’altitude et a montré que, contrairement à une idée populaire répandue, elle n’est pas seulement due à l’inspiration d’air froid et sec, caractéristique de l’environnement en haute altitude. Les données présentées confirment la chute de la capacité vitale lors de la montée en altitude et les causes possibles de cette chute sont discutées. Une cause possible pourrait être le sub-œdème pulmonaire. Cela pourrait être aussi une cause potentielle à la toux liée à l’altitude et les données présentées suggèrent qu’il résulte de modifications du transfert ionique et d’eau à travers l’épithélium respiratoire. Il est également prouvé que la toux liée à l’altitude n’est la conséquence des modifications ni des taux de bradykinine ou ni du centre de contrôle de la toux.

Alors que le sub-œdème pulmonaire peut être un facteur étiologique de la toux liée à l’altitude, et

mérite des études complémentaires, il est vraisemblable qu’il ne s’agit pas de la seule cause, la toux

étant un symptôme retrouvé dans bon nombre de situations sans rapport avec l’altitude. Un travail

futur devrait se concentrer sur le rôle de la perte d’eau des voies aériennes en altitude,

particulièrement au cours de l’exercice, mais aussi sur l’association infections des voies aériennes

supérieures et toux, et envisager la place de la rhinite vasomotrice et du reflux gastro-œsophagien dans l’étiologie de cette passionnante situation.

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CHANGES IN LUNG VOLUMES AT ALTITUDE

The first report of a change in lung volume on exposure to hypobaric hypoxia is credited to von Vivenot in 1868 when 2 subjects who were acutely decompressed in a hypobaric chamber to an equivalent altitude of 4650 m had a reduction in vital capacity (VC) of 9 and 13%

(quoted by Bert (51) who demonstrated a reduction of 32% in his own VC on exposure to a barometric pressure of 430 mm Hg, equivalent to an altitude of around 4500m). A number of studies during the first half of the 20 ^th Century seemed to confirm the reduction in VC on exposure to hypobaric hypoxia although the change in volume was extremely variable ranging from 0 to 14% with acute exposure and up to 50% with longer exposure (422). However these studies frequently involved small numbers of subjects and invariably volumes were not corrected to BTPS. As a result the reported changes in VC may simply represent the fall in temperature between the subjects and the spirometer (350). Early studies are here arbitrarily defined as studies performed before the end of the Second World War and are summarised in Table 1.

Table 1: Early chamber and field studies of change in vital capacity (VC) on exposure to hypoxia or high altitude.

Adapted from Rahn & Hammond (350).

Only Durig (1911) and Barcroft (1923) mention that corrections were applied to spirometric measurements to account for the temperature change between the subjects and the spirometer, but the factors are not given.

Author

Barometric pressure

(mm hg) Altitude (m) Reduction in

VC (%) Comments

1) Acute exposure in hypobaric chamber or breathing hypoxic gas mixture

V. Vivenot (1868) 424 4572 10 & 14 2 subjects.

Bert ( 1878) 430 ~ 4500 32 1 subject.

Bohr (1907) Sea level -- Insignificant Hypoxic gas mixtures of FiO

0.8 to 0.12.

Schneider (1932) 350 6096 8 24 subjects.

Hurtado et al (1934) 419 4877 4, 8 & 14 3 subjects.

2) Longer exposure to high altitude

Hewett (1875) 682 914 11 & 12 2 subjects. Returned to baseline values after 3

days.

Bert (1878) 440 4389 50 1 subject. Monte Rosa, Switzerland.

Mosso (1889) 440 4389 3, 6, 9, 10, 13 &

20 6 subjects. Monte Rosa, Switzerland.

Schumburg & Zuntz (1896)

626 480

1524 3658

11 & 8

7 & 3 2 subjects.

Durig (1911) 440 4389 14 to 16 4 subjects. No change over 3 weeks.

Barcroft et al (1923) 460 4023 2, 3, 4 & 13 5 subjects. 1 week Cerro de Pasco, Peru.

Grollman (1930) -- 4298 11.2 1 subject. Pike’s Peak, Colorado.

Schneider (1932) -- 4298 7 to 15 9 subjects. Maximum decrease on first day.

Pike’s Peak, Colorado.

Verzar (1933) 492 3475 2 to 24 5 subjects. Return towards normal after 5 days.

Jungfaujoch, Switzerland.

Verzar (1945) 492 3475 9 to 12 9 subjects. Jungfraujoch, Switzerland.

Subsequently there have been many reports of changes in lung volumes on exposure to hypoxia and hypobaria but the interpretation of this body of literature is again difficult because of the widely varying conditions under which the measurements have been made:

• Hypobaric hypoxia in hypobaric chambers

• Normoxic hypobaria in hypobaric chambers

• Normobaric hypoxia using hypoxic gas mixtures

• Hypobaric hypoxia in field studies at high altitude

In addition interpretation is further complicated by the durations of exposure which range from a few hours to several weeks and even on occasions months to years. These later studies are summarised in Tables 2a and 2b and discussed below.

1) Hypobaric chamber studies

The first study of what may considered the modern era addressing the fall in VC on exposure to hypobaric hypoxia is that of Rahn and Hammond (350). In this complex protocol between 4 and 18 subjects were exposed to a variety of environments for varying durations. In summary the authors showed that VC fell on acute exposure to hypobaric hypoxia in 18 subjects ¹ . Although they claim that there was less of a fall with normobaric hypoxia sufficient to produce an equivalent partial pressure of oxygen (PO 2 ) in 9 subjects, suggesting that hypobaria per se played a role, re-analysis of their data shows it to be underpowered invalidating this claim ² . Approaching the data from this often cited paper critically, the only conclusion that can be drawn is that VC fell on exposure to an altitude equivalent of 4267 m and 5468 m by 2.4 and 3.8% respectively, and at 5468 m this fall in VC was reversed by breathing supplementary oxygen.

In a further experiment on, “an average of 4 subjects,” to investigate the effects of acute extreme hypobaria, with oxygen supplementation to normalise or limit the effects of hypoxia, VC fell only at 9144 and 12192 m. No comment is made as to whether these reductions were statistically significant and at 12192 m, even with supplementary oxygen, the PiO 2 was

1 : Rahn and Hammond (350). Effect of acute hypobaric hypoxia in 18 subjects: 5 min ascents to 3048, 4267, 5486 m (10,

14 and 18 000 ft); 5 mins adjustment at new altitude; 5 mins for measurements before ascent to new altitude. Supplementary

O

given at the end of measurement at 5486m. No information is given on statistical methods. However ANOVA with

Bonferroni t-test for multiple comparisons on data in the paper gives a significant difference between 4267 m and SL and

2 : Rahn and Hammond (350). Effect of acute normobaric hypoxia using O

:N

mixtures to give the equivalent PO

as

acute hypobaric hypoxia for the same duration in 9 subjects. ANOVA shows no significant difference, however the power of

the test with α at 0.05 is 0.408 (i.e. < 0.8).

Authors (ref) Conditions Length of stay Subjects Relevant

Methodology VC or FVC TLC RV FRC

Rahn &

Hammond, 1952 (350)

Chamber 446 & 379 mm Hg

= 4267 & 5486m

5 mins 18 Bell spirometer ↓ 2.4 & 3.8% N / A N / A N / A

Tenney et al, 1953 (422)

4300 m (Mount Evans,

Colorado) 8 days 4 Spirometer ↔ underpowered ↔

underpowered ↑ 22% day 1 N/A Shields et al,

1968 (397) 4298m (Pike's Peak) 65 days 8 Stead-Wells

Spirometer ↓ 3.7% at 7 days. N / A N / A N / A Cruz, 1973

(105)

4350m (Cerro de Pasco,

Peru)

72hrs 8 alt residents

6 SL residents Cournand's method ↓ 3.7% (pooled

data) N / A N / A ↑ 5.2%

(pooled data) Gray et al,

1973 (167)

Chamber

= 4900m 4 hrs 5 Spirometer ↓ 7% N / A N / A N / A

Saunders et al,

1977 (379) Normobaric hypoxia

= 3700 - 4300m 20 mins 7 Plethysmography

Pneumotach ↔ underpowered ↑5% ↑31% ↑9%

Coates et al, 1979 (92)

Chamber

446 mm Hg = 4268m 24hrs 4 Wedge spirometer He dilution

↓ 10% at 20 hrs cf 5hrs

↑ 21% at 5h

NS at 20 hrs ↑ at 5h ↑ 18% at 5h but NS

Goldstein et al, 1979 (160)

Normobaric hypoxia

= 3700 - 4300m 20 mins 6 Wedge spirometer

He & Ar dilution ↔ ↔ N / A N / A

Jaeger et al, 1979 (218)

3000 - 4300m (Pike's Peak,

Colorado)

72hrs up to 25 Dry rolling seal

spirometer ↓ ~1% cf SL ↔

↑ 11.2% at 72hrs cf SL72hrs

N / A Mansell et al,

1980 (274) 5366m (Mt Logan) up to 6 weeks 7 Wedge spirometer

He dilution ↔ underpowered ↑ 18% ↑ 76% ↑ 40%

Gautier et al, 1982 (156)

3457m

(Jungfraujoch) 6 days 9 Pneumotach

Plethysmography

↓ 250ml on D2 &

D3 ↔ ↔ ↓ 280ml on D1 Welsh et al,

1993 (452) Chamber

maximum = 8844m 40 days 6 Water filled

spirometer

↓ ~7.5% at 6096m

↓ ~12% at 7620m

↓13.6% at 8844m N / A N / A N / A

Pollard et al,

1996 (344) 5300m (Everest Base Camp)

12 day trek to EBC.

Measurements up to 5 days after arrival.

51 Micromedical

Turbine ↓ 5.2% N / A N / A N / A

Cogo et al, 1997 (93)

4559 m (Margherita Hut)

5 days to 4559 m and then 4 day stay

5 Micromedical

Turbine

↓ 3.6% D2 3500 m

↓ 4.3% D1 & D2 4559 m

N / A N / A N / A

5050 m (Pyramid Lab, Nepal)

9 days to 5050 m and then 10 day

stay

12 Micromedical

Turbine ↓ 8.6% at 3500m

↓ 11.5 % at 5050m N / A N / A N / A

Table 2a: Post-War chamber and field studies on lung volumes.

↓: decrease; ↔: unchanged. Results are shown without comment if statistically significant.

VC: vital capacity; FVC: forced vital capacity; TLC: total lung capacity; RV: residual volume; FRC: functional residual capacity; D: day;

Forte et al, 1997 (149)

Chamber 460 mm Hg = 4300

m

Maximum of 5 hrs 12 Collins water seal spirometer

↓ 3%

NB: Pooled group mean data

N / A N / A N / A 4300 m

(Pikes Peak, Colorado)

Weekly measurements

over 3 weeks 9 Collins water

seal spirometer

↓ 2.8%

NB: Pooled group mean

data N / A N / A N / A

Mason et al, 2000 (281)

Serial to 5300m

(Everest Base Camp) 12 days to EBC 46 Micromedical Turbine

↓ 4% at 2800m

↓ 8.6% at 5300m N / A N / A N / A

Cremona et al, 2002 (104)

4559 m (Margherita Hut)

Within 1 hr of

arriving 262

Cosmed Spirometer Turbine or Pneumotach

↔ in healthy subjects

↓ ~2% in 39 with HAPE

Mason et al, 2003 (282)

3800m (Tien Shan,

Kyrgyzstan)

Over 15 days 20 Micromedical

Turbine

↓ 4.3% D1; ↓ 5.7% D2;

↓ 5.9% D5; ↓ 6.5% D10;

↓ 4.8% D15

N / A N / A N / A DeBoeck,

2005 (118)

Chamber

451 mm Hg = 4267m Up to 12hrs 15 Micromedical Turbine

↓ 3%(300ml) at 6hrs

↓ 4%(350ml) at 12hrs N / A N / A N / A Senn et al,

2006 (393)

4559 m (Margherita

Hut) 24 hrs 26 SensorMedics

Vmax 2900

↓ 6.4% D1

↓ 7% D2 N / A N / A N / A Fasano et al,

2007 (145)

4559 m (Margherita

Hut) 7 days 8 Micromedical

Spirometer ↓ ~5% (estimated) N / A N / A N / A Dehnert et al,

2010 (120)

4559 m (Margherita

Hut) 48 hrs 34 6 with previous

HAPE

Pneumotach Plethysmography

↔ in non-HAPE subjects underpowered

↔ ?

underpowered N / A N / A

Table 2b: Post-War chamber and field studies on lung volumes.

↓: decrease; ↔: unchanged. Results are shown without comment if statistically significant

VC: vital capacity; FVC: forced vital capacity; TLC: total lung capacity; RV: residual volume; FRC: functional residual capacity; D: day;

equivalent to an altitude of 3353 m. In a further experiment reported in their paper the effect on VC of an 8 day stay at 14200 ft (4328 m) on the summit of Mount Evans in Colorado was studied in 4 subjects. The data is again hevily underpowered and it is not possible to draw any meaningful conclusions from it.

Gray et al (168) studied 5 subjects exposed to a barometric pressure equivalent to 4900 m for 4 hours. Measurements were made 4 times at roughly 1 hour intervals throughout the study.

Vital capacity had fallen by a mean of 11% from control after 1 hour in the chamber and by a mean of 7% after 4 hours.

Coates et al (92) despite studying only 4 subjects decompressed to 446 mm Hg (equivalent to an altitude of 4268 m) found a significant 10% fall in VC at 20 hours compared to the value at 5 hours (p <0.05) although there was no difference between control values and 5 hours. The data at 20 hours is not given but re-analysis of the control and 5 hour data shows them to be underpowered to detect a significant change3. Total lung capacity (TLC) measured by helium dilution increased by a mean of 21% at 5 hours compared to control (p<0.02) but had fallen again so that it was not significantly different from control values at 20 hours. Residual volume (RV) and closing capacity (CC) both showed large increases between control and 5 hours (p < 0.02 and 0.05 respectively. Absolute values are not given but are of the order of 30-40%) and then did not change between 5 and 20 hours. As both RV and CC increased by similar amounts closing volume did not change4. Functional residual capacity (FRC) increased by 19% between control and 5 hours but was not statistically significant because of the underpowered nature of the data. In summary, despite being considerably underpowered, this study demonstrated a 21% increase in TLC and significant increases in RV and CC between control and 5 hours exposure to a barometric pressure of 446 mm Hg. Vital capacity fell by 10% between 5 and 20 hours.

Welsh et al (451) during the hypobaric chamber experiment Operation Everest II, in which 8 subjects underwent a simulated ascent of Mount Everest, demonstrated significant decreases (p<0.05) in forced vital capacity (FVC) at barometric pressures of 347, 282 and 240 mm Hg (equivalent to 6096, 7620 and 8844 m respectively, the last value approximating the summit of Mount Everest). The mean value of FVC on the “summit” was 13.6% less than the control values. Measurements made within 30 minutes of a return to sea level pressures showed that FVC had normalised by approximately 50% and had normalised completely after 19 hours.

3 : Coates et al (92). Comparing control with 5 hours at 4268m using paired t-test, p = 0.37. With α of 0.05 the power of the performed test is 0.059 (i.e. significantly < 0.8).

4 : closing volume (CV) = closing capacity (CC) – residual volume (RV)

Forte et al (149) studied 12 subjects, 3 of whom also participated in the field component of the study at Pikes Peak, Colorado (4300 m), discussed below, who were decompressed to a barometric pressure of 460 mm Hg (equivalent to an altitude of 4300 m). The subjects were studied on 5 occasions at sea level and on 5 occasions at 460 mm Hg. The FVC fell by 2.8%

at 460 mm Hg compared with sea level (p<0.05) which is very similar to the magnitude of the fall observed at Pikes Peak. It is unclear from the paper if the values reported represent the average of the 5 decompressions.

Dillard et al (123), in a study designed to investigate the changes in lung function which occur during commercial airline flights, looked at 18 patients with severe chronic obstructive pulmonary disease (COPD - defined as a forced expiratory volume in 1 second (FEV 1 ) ≤ 50%

predicted; > 15% increase in FEV 1 after bronchodilator therapy and normal TLC) and 9 healthy controls, during 2 hours exposure to a barometric pressure of 565 mm Hg, equivalent to an altitude of 2438 m. In the healthy controls FVC fell by 3% (p<0.05) and by 4.3% in the COPD group but did not reach statistical significance.

During Operation Everest III (COMEX ‘97) which followed a similar design to Operation Everest II, Mason et al (280) demonstrated a 6.8% fall in FVC at a simulated altitude of 8000 m compared with sea level in 8 subjects. There was no change between sea level and 5000 m but because of the limitations of the study (the restriction of subject numbers by chamber size) the data was underpowered.

Deboeck et al (118) reported a significant fall in FVC of 3% after 6 hours and 4% after 12 hours of exposure to a barometric pressure of 451 mm Hg equivalent to an altitude of 4267 m in the Belgian Air Force hypobaric chamber at Evere, Brussels.

2) Normobaric hypoxia

Saunders et al (379) in an attempt to isolate the effects of hypoxia from the concomitant hypocapnia that accompanies it at altitude, studied 7 subjects using a re-breathing method to give an alveolar partial pressure of oxygen (PA _O2 ) of 40-50 mm Hg (5.3-6.4 kPa, equivalent to an altitude of between 3700 and 4300 m) for 20 minutes while maintaining alveolar normocapnia (alveolar partial pressure of CO 2 (PA _CO2 ): 38 to 42 mm Hg (5.1 to 5.6 kPa)).

Measurements using body plethysmography were made before and after hypoxia, and every 5

minutes during hypoxia. There was no change in VC, although analysis of the raw data in the

paper shows it to be underpowered ⁵ , whereas RV, TLC and FRC all increased significantly by 31% (p<0.02), 5% (p<0.005) and 9% (P<0.01) respectively. All volumes had returned to their equivalent to an altitude of 3353 m. In a further experiment reported in their paper the effect on VC of an 8 day stay at 14200 ft (4328 m) on the summit of Mount Evans in Colorado was studied in 4 subjects. The data is again heavily underpowered and it is not possible to draw any meaningful conclusions from it. control values within 3 minutes of re-oxygenation by the addition of 100% O 2 to the breathing circuit.

Goldstein et al (160), using the same re-breathing technique as Saunders et al (379) and identical normobaric isocapnic hypoxic conditions, found no changes in TLC or VC using helium and argon dilution. Unfortunately data for individual subjects are not given and it is not possible to see if the study was adequately powered to demonstrate a significant difference although this is unlikely in view of the small numbers of subjects involved (9 for VC measurements). In their discussion the authors suggest that the discrepancy between their results and those of Saunders are due to artefacts from body plethysmography, although Coates et al (92) in hypobaric hypoxia at a roughly equivalent PA _O2 demonstrated a 21%

increase in TLC using the same technique of helium dilution.

3) Hypobaric normoxia

In an attempt to simulate the conditions of space flight, Ulvedal et al (431) studied the effects of prolonged hypobaria without hypoxia for between 14 and 17 days at simulated altitudes of 5486, 8230 and 10211 m on 2, 4 and 8 subjects respectively. Unfortunately only average summary changes for these simulated altitudes are given and so it is not possible to make any informed comments, The authors report a fall in FVC of 3.1%, 2.9% and 7.6% at 5486, 8230 and 10211 m respectively despite the absence of hypoxia but it is not known if these results were statistically significant.

4) Field studies

Tenney et al (422) studied 4 subjects during a 7 day stay at 4300 m on Mount Evans in Colorado. The authors claim that VC fell over the first 3 days at altitude with the maximum fall on day 3, before increasing back towards sea level values during the rest of the stay at altitude. Reanalysis of the data for VC shows that this change was not statistically significant

5: Saunders et al (379). Using ANOVA on VC data in the paper, p = 0.25. Power of the performed test, with α of 0.05 =

0.121

and, unsurprisingly in view of the small sample size, that the study was markedly underpowered ⁶ . The increase in RV that occurred from day 1 at altitude was claimed by the authors to show a definite trend but no statistical analysis was performed. Reanalysis of the data in the paper shows that the 22% increase in RV was only statistically significant on day 1 at altitude compared with the sea level control ⁷ and not significant on the other days at altitude. Data is not given for TLC, however the authors state that in 3 out of 4 subjects TLC had increased on day 1 at 4300 m but had fallen to well below control values by day 3.

Calculation of TLC from the data for RV and VC in the paper allows statistical analysis of these claimed changes and shows them not to be statistically significant, and also to be underpowered ⁸ . Functional residual capacity was estimated from measures of RV and expiratory reserve volume (ERV). As RV was measured in the sitting position and ERV supine, and as the data is underpowered, it is not possible to draw any conclusions on changes in FRC from this study.

Shields et al (397) studied 8 female subjects during a 65 day stay at Pike’s Peak, Colorado (4298 m). Measurements were made on days 1, 7, 30 and 65 on Pike’s Peak. FVC was significantly reduced compared to sea level controls by 3.7% on day 7. By day 30 FVC although still reduced compared to baseline was no longer statistically different. This study is important because it is one of the longest field studies and shows a return to baseline values of FVC with time at altitude.

In a complicated series of experiments Cruz et al (105) studied 8 Peruvian high altitude natives at Cerro de Pasco (4350 m). Four of these high altitude natives were then studied again after descent to Lima (150 m). Six sea level subjects were also studied first at Lima and then at 4350 m. Vital capacity decreased and FRC increased in the lowlanders on ascent to 4350 m but because of the small group size these changes were not statistically significant ⁹ . In the high altitude natives, descent to Lima produced an increase in VC while FRC decreased. Despite being only 4 subjects the 4.6% increase in VC with descent to Lima was

6: Tenney et al (422). Using one way repeat measure ANOVA on the raw data in the paper the change in VC is not statistically significant (p = 0.582) but is underpowered with a power for α = 0.05 of 0.05 (i.e. well below 0.8). Even using a paired t-test comparing VC for the sea level control with high altitude day 3 when the maximum fall occurred, the data is still not statistically significant (p = 0.343).

7: Tenney et al (422). Using one way repeat measure ANOVA with Bonferroni t-test for multiple comparisons vs sea level control on RV data, the difference between sea level and day 1 at altitude was statistically significant (p = 0.004).

8: Tenney et al (422). Using one way repeat measure ANOVA the power for α = 0.05 is 0.05.

9 : Cruz et al (105). Using a paired t-test, FVC in 6 lowlanders fell by 3.1% on ascent to 4350 m, but p = 0.07 and power for

α = 0.05 is 0.38. FRC increased by 5.3% but p = 0.08 and power for α = 0.05 is 0.349.