Selected Abstracts From the Symposium on the Effects of Chronic Hypoxia on Diseases at High Altitude,October 2005,La Paz,Bolivia

Changes in the Rat Cortex Following Exposure to Moderate Hypoxia

Background.—High energy requirements compared to low energy reserves render the brain vulnerable to hypoxic conditions.

Objective.—To determine the effect of moderate exposure to hypoxia on the rat cerebral cortex.

Methods.—Experimental design—Two groups of age and sex matched, Wistar albino rats raised at 400 m above sea level, were exposed for 6hrs, 12hrs and 24hrs to an altitude equivalent to 3000m above sea level. Sections from the cerebral cortex were analyzed biochemically and histopathologically. Succinate dehydrogenase levels and lactate dehydrogenase levels were measured and changes in enzyme levels at 6, 12, and 24 hours were measured for significance. Morphologically, the following parameters were assessed: edema, neuronal necrosis, glial proliferation, cytoplasmic and nuclear changes, and inflammatory reaction. Edema, necrosis and glial proliferation were further graded as mild, moderate or severe.

Results.—Acute changes in the cortex were seen at 6hrs, which reduced by 12hrs and remained stable at 24hrs. There was glial cell proliferation observed at 12hrs and mild neuronal necrosis by 24hrs. This correlated with the altered levels of lactate dehydogenase and succinate dehydrogenase enzymes compared to control rats.

Conclusions.—An early peak in enzyme changes indicates an adaptive response while irreversible morphological changes take place in the cortex following exposure to hypoxia even at moderate altitudes. With no proven effective primary therapy for post anoxic brain injury, the goals of neurologic care are supportive, to optimize prognosis and prevent further complications. The morphological and ultra structural patterns of changes in the brain especially in the cortex after hypoxia suggest a number of pathogenic mechanisms in post hypoxic encephalopathies and may help to improve therapy in these states. The important issues are to reduce intracellular edema, to control intracellular acidosis and restore the functions of cell membranes, in order to limit necrosis.

Vinod George Thykadavil, PhD

Karuna Rameshkumar, MD, PhD

Vidyasagar Casikar, FRCS, PhD, FRACS

Venkatesh T, PhD, FACBI

Bangalore, India

Recent High-Altitude Medical Studies in Japan

High altitude medical studies in Japan started with the Manaslu Expedition in 1952. Since then, many Himalayan medical research studies have been reported. Among them, medical reports of the Japanese Mt. Everest Expedition in 1970 (JMEE70) and the Kyoto University Medical Research Expedition to Xixabangma in 1990 (KUMREX90) were distinguished, both having been awarded the Prince Chichibu Memorial Prize in Japan.

The Japanese Society of Mountain Medicine (JSMM) was organized by some members of the Japanese Alpine Club Medical Committee in 1981. JSMM holds annual meetings, the Japanese Symposia on Mountain Medicine, and publishes annual journals (Japanese Journal of Mountain Medicine— JJMM) regularly. The 18th Japanese Symposium on Mountain Medicine was held under the joint auspices of the 3rd World Congress on Mountain Medicine and High Altitude Environmental Physiology in Matsumoto, Japan on May 20–24th, 1998. There were about 430 attendees from 32 countries, and 250 thesis and poster presentations.

This presentation reviews some important Japanese works on high altitude medicine from recent issues of JJMM (eg, the works of Dr. M. Hanaoka, Dr. A. Okumura, Dr. S. Masuyama and others).

Michiro Nakashima, MD

Kyoto, Japan

Genetics of Hypoxic Exercise Tolerance

Genetic analysis of complex phenotypes, especially those of medical importance, eg, heart disease, diabetes, and asthma has greatly advanced in consequence of recent successes in genome sequencing. Molecular genetics methods have also been powerfully allied with behavioral, physiological, and other lines of research in the investigation of biological effects of reduced available oxygen. Here we summarize progress made in genetic analysis of hypoxic exercise tolerance, a phenotypically complex behavioral trait that is germane to the themes of this meeting in La Paz.

Mathematical modeling and subsequent confirmatory breeding tests showed that, in mice, heritable differences in tolerance of treadmill exercise (time elapsed to a behavioral endpoint, HET) in 10.5% O₂ after 8 weeks’ exposure to 380 Torr is associated predominantly with the expression of 2 unlinked autosomal loci. A striking feature of the inheritance pattern is the presence in the hypoxia-exposed CByB6F1 (F1) hybrid of inbred mouse strains BALBc/By (C) and C57BL/6 (B), but not in the normoxic control F1 sample, of a very large epistatic (context dependent) interaction between the 2 loci. A preliminary mapping effort exploiting that interaction using 100 DNA microsatellite map markers localized one of the loci to a region of mouse Ch.16 near—and possibly identical to—Sod1 (Cu,Zn superoxide dismutase), but the Ch.14 position of the other locus is problematic. A fuller characterization of genetic contribution to the HET test variable was sought in a microarray experiment, since the magnitude of the genetic effect and its variability decreased somewhat in successive generations formed from backcrosses to the low-performing parental strain, which is indicative of lesser contributions from HET modifying genes. Of the 5000+ genes tested, 300 were significantly differently expressed in hypoxia, and of those, 35 could be attributed to interactions between genotypes and treatments. Specific contrasts built to investigate the difference between hypoxic F1 and all other genotypes and treatments revealed that Sod1 was the most significantly differentially expressed gene. A high resolution molecular genetic mapping effort to both localize unequivocally the chromosomal positions of the HET loci and modifying genes, and critically identify them is underway.

Dale McCall, PhD

Dargan Frierson, PhD

James Blum, PhD

Stephen Kinsey, PhD

Wilmington, NC, USA

Advances in Biological and Clinical Significance of Carotid Body Chemoreceptors

The ability to counteract hypoxic episodes is essential for disease-free functioning. In mammals, this ability is dependent on the hypoxic ventilatory chemoreflex mediated by the carotid body, a bilateral sensory organ. Reductions in the partial pressure of O₂ are sensed by chemoreceptor, or type I, cells in the organ. Hypoxia-stimulated afferent chemoreceptor discharge is relayed to the brainstem respiratory areas that drive the increase in the depth and rate of pulmonary ventilation. This primarily defensive and crucial to survival chemoreflex is aimed at increasing O₂ delivery to tissues to meet metabolic needs. There seems to be a consensus that chemoreceptors respond to hypoxia via a complex transduction cascade that involves closure of various types of O₂-sensitive K⁺ channels, membrane depolarization, and Ca²⁺ entry followed by release of dopamine and other neurotransmitters. Nonetheless, the underlying mechanisms of carotid body function or the nature of an O₂ sensor remain elusive.

Recent work from this laboratory has attempted to draw attention to novel, lipid-soluble compounds whose hydrophilic counterparts are at the core of long-drawn nebulousness and controversies in the carotid body mechanisms. The rationale was that such compounds would perform well in biomembranes, the target sites of chemoreceptor signaling processes and thus would help get a further insight into these mechanisms. Two such compounds tackled in this article are ascorbyl palmitate, a lipophilic ester of ascorbate, and N-oleoyl-dopamine, a condensation product of oleic acid and N-oleoyl-dopamine at its amino terminal.

Recent studies have shown that reactive oxygen species, whose levels are increased in hypoxia, are involved in the processing of the hypoxic stimulus. Reactive oxygen species facilitate the open state of voltage-dependent K⁺ channels, which may dampen chemoreceptor excitability, and which suggests that antioxidants would act to the opposite, i.e., facilitate the chemosensory response. To this end we have recently identified the presence of ascorbate in the carotid body and its elaboration in hypoxia. Ascorbate increases the hypoxic ventilatory response in humans; the effect being particularly pronounced in a state of lowered hypoxic reactivity. We have further shown that the carotid body is a target organ for ascorbate and that ascorbyl palmitate, a stable, pH-independent, and non-toxic compound that retains the antioxidant capacity of ascorbate, is the preferred form of ascorbate transport into the organ. An animal study has shown that ascorbyl palmitate causes a strong augmentation of the respiratory neural output running down to the diaphragm in response to hypoxia and delays the appearance of hypoxic respiratory depression. These results lend support to the notion that antioxidant redox modulation augments hypoxic respiration. Ascorbyl palmitate supplementation, which provides sustained delivery of ascorbate to tissue, seems to offer promise in enhancement of hypoxic reactivity and thus might hold therapeutic potential.

Our other interest focuses on novel bioactive lipids that belong to cannabinoid and vanilloid receptor ligands. Anandamide, a flag endocannabinoid, inhibits TASK-1 background K⁺ current in chemoreceptor cells, the current that is also inhibited by hypoxia. Cannabinoids, which have recently been unraveled in the carotid body, might thus be germane to membrane depolarization and consequent voltage-gated Ca²⁺ entry. A massive Ca²⁺ influx is directly caused by activation of vanilloid receptors, which are cation-permeable channel pores. New research shows that N-oleoyl-dopamine, which shares some biological properties with cannabinoids, is vividly taken up by the carotid body after systemic injection and thus might be a modulator of hypoxia-sensing.

It may be posited that hypoxia-sensing involves the release of endovanilloids, as exemplified by N-oleoyl-dopamine, with subsequent Ca²⁺ entry into chemoreceptor cells. That, in turn, might unleash Ca²⁺ regulatory proteins such as Ca²⁺/calmodulin-dependent protein kinases, present in these cells, to activate the hypoxia-inducible factor or the expression of immediate early genes that are key in the transcriptional modulation of the organ in hypoxia, including intermittent and chronic hypoxia. Although the presence of both cannabinoid and vanilloid receptors has yet to be unequivocally substantiated in the carotid body, their ligands appear to have formed a new class of chemosensory modulators with a potential to be operative in shaping the hypoxic ventilatory response.

The unresolved mechanisms of carotid body function make it difficult to intervene in hypoxic responsiveness. Improvement of the hypoxic ventilatory response seems desirable in conditions that lead to hypoxic episodes, such as breathing disorders during sleep, occurring more often with age. Insofar as the hypoxic ventilatory response serves to increase pulmonary ventilation and consequently the delivery of O₂ to tissues, improving the hypoxic chemoreflex may foster respiratory health and mitigate the progress of aging.

Mieczyslaw Pokorski, MD, PhD, DSc

Warsaw, Poland

Diving at High Altitude: From Theory to Practice

The diving expedition of Jacques Cousteau in Lake Titicaca, published as part of his “underseas discoveries”, ¹ established that diving at such altitude was possible and exciting. Significant field work to set up safety standards for diving at altitude was done in Switzerland, the U.S.A. (Lake Tahoe), and Turkey. Experience of diving at extreme altitude was gained in the Himalayas and Andes, culminating in “Lake” Licancabur (5916m), at the border of Chile and Bolivia. Beyond corrections for altitude, reducing the no-decompression diving depths, ascent rates and depths of compression stops, several adjustments have to be made. The nitrogen load resulting from traveling to high altitude has to be taken into account until a novel equilibrium is reached. Adjustments must be made for suit buoyancy gain at altitude and fresh water buoyancy loss. Medical evaluation should include evaluation for mountain sickness and subacute pulmonary edema that preclude diving. Hypothermia is a major concern: it should be promptly diagnosed and treated. Given the hypoxic environment, the whole diving procedure has to be done at a slower pace than at sea level, and rescue procedures have to be readily available. Although decompression sickness is a threat, it can be prevented by proper dive planning. Therefore, most disorders reported in diving expeditions at extreme high altitude relate to altitude effects, hypothermia, hypoxia, and equipment malfunction. When carefully planned and performed, diving at high altitude can be safe.

Paul Bégin, MD, PhD

Chicoutimi (Québec), Canada

Genetics of the High Pressure Nervous Syndrome (HPNS)

Humans and other mammals, and indeed representatives of other vertebrate classes tested, when exposed to increasing pressure in helium-oxygen (heliox) atmospheres exhibit progressively greater motor disturbances culminating in a spectacular seizure. The seizure and pre-seizure behavior and the constellation of associated central nervous system events collectively constitute the High Pressure Nervous Syndrome (HPNS). While HPNS is a well-characterized syndrome from several perspectives, eg, ontogenetic development, electrophysiological and pharmacologic properties and comparative aspects, one aspect that has never received sustained attention, judging from the published record, is the extent to which the variations in susceptibility to HPNS phenomena are heritable. McCall and Frierson produced a short series of published reports ^{1 –}3 on the inheritance of HPNS seizure susceptibility in a rodent model more than 20 years ago. A part of their largest study that included data on recombinant inbred (RI) strains that suggested predominant influence of 2 quantitative trait loci (QTL), one of them on mouse Ch. 17, was reanalyzed using a different methodology 10 years later by Plomin, et al.(1991). ⁴ Those authors suggested the presence of QTLs affecting HPNS seizure susceptibility on Chs. 1, 2, and 17. Here we report a reanalysis of our original data in the light of recent refinements in mapping made possible by the addition of thousands of mouse map markers and new statistical algorithms—especially those of The GeneNetwork's WebQTL computer website (www.genenetwork.org). We find that our original idea—produced from a mathematical modeling procedure as well as the analysis of RI data—that 2 QTLs (our “major loci”) are primarily responsible for inherited differences in HPNS susceptibility are sustained, but made more specific: one of the QTLs, whose expression is compression-rate sensitive is on a defined region of Ch. 17; and the other whose expression is compression-rate insensitive is on a defined region of Ch. 12. In addition, we present some results of a cost/benefit analysis of diver safety (“benefit”) as a function of diver selection strategies in models with different levels of correlation of onset of HPNS symptoms on second exposure to high pressure when there is knowledge of response to a first exposure.

Dale McCall, PhD

Dargan Frierson, PhD

James Blum, PhD

Wilmington, NC, USA

Equivalent Ocean Depths for Diving in Titicaca and Other Mountain Lakes

Haldane's description of the cause of decompression sickness as being due to too rapid relative pressure changes in the environment of the diver ¹ has been generally accepted since the start of the previous century. Several theories further explained nitrogen solubility in different tissues, approaching a more precise understanding, albeit more complex.

An even higher risk of developing decompression sickness is present when diving in mountain lakes in contrast to the ocean. In order to make ocean level diving tables usable during high altitude diving, a new terminology for comparison purposes is created: the Standardized Equivalent Ocean Depth (SEOD) factor, which makes it possible to convert the actual lake diving depth (ALDD) to an equivalent ocean diving depth. SEOD is defined as the ocean depth in meters (m or msw) for a standardized ocean dive equivalent to a mountain lake dive at any altitude.

$$\begin{array}{l}\text{SEOD}=\text{ALDD}[Nitrogenratio][Waterdensityratio]\\ \text{SEOD}=\text{ALDD}[(760-47)/({\text{P}}_{\text{B}}-47)][1000/1033]\\ \text{SEOD}=\text{ALDD}[\text{SEOD}\text{factor}]\end{array}$$

Therefore a 30 m Titicaca Lake dive is as dangerous as a 47 m ocean dive due to the larger relative pressure exposure. Following calculation of the SEOD, any ocean diving table can be used, and a conservative choice is recommended.

Poul-Erik Paulev, MD, DSc

Gustavo Zubieta-Calleja Jr, MD

Copenhagen, Denmark

La Paz, Bolivia

Hans-Christian Møller Thorsen, MD

Copenhagen, Denmark

The Adaptation of Man to Severe Altitude Hypoxia

Acute exposure of humans to the highest places of the planet Earth, without any kind of adaptation for tissue oxygenation is not possible. Nevertheless, it is possible to perform maximal work at extreme altitudes with adequate adaptation, as evidenced by a soccer match played at 6542 meters, on the summit of Mount Sajama. This was performed by Bolivian Aymara natives on August 2nd 2001, within 24 hours of arrival including ascent and preparation of the field. ¹ Severe high altitude pulmonary edema (HAPE) occurred in a young man within 72 hours at 3600 m (PaO2 of 27 mmHg and a SaO2 of 45%). We have described a syndrome which we called “The Triple Hypoxia Syndrome” (THS)^2,3 where CMS patients with gradual adaptation to hypoxia, with a high hematocrit and a PaO2 of 30 mmHg, for example, can occasionally tolerate severe hypoxic conditions similar to those on the summit of Mount Everest for a week or longer. ⁴ Normal subjects with full capacity for adaptation show that life is possible at any existing altitude on planet Earth, provided that the following conditions are met: adequate environmental temperatures, lodging, food, slow and progressive adaptation. ⁵ This seems possible in only one generation, as the human organism is provided with adequate compensation mechanisms. Furthermore, human embryos develop normally at oxygen tension values equal to the altitude of Mount Everest until delivery.

After the acute phase of exposure to hypoxia where the cardiopulmonary system plays the fundamental role, the increase in oxygen content through the increase in the number of red blood cells is one of the most important progressive mechanisms of adaptation to high altitude.

Gustavo Zubieta-Castillo, MD

Gustavo R. Zubieta-Calleja, MD

Luis Zubieta-Calleja, MD

Nancy Zubieta

La Paz, Bolivia

The Effect of Low Birth Weight on Stillbirth Rate in Peruvian Populations at High Altitude

One third of the Peruvian population lives at altitudes above 2000 meters, ¹ and because of its diverse geography one can find human populations that range from sea level to altitudes above 4500 meters. It is known that birth weight decreases in a rate of 100 g per 1000 m altitude.

The present study's aim was to determine the relation between high altitude residence and birth weight in populations from different altitudes. Also studied was the relationship between low birth weight (LBW) at high altitude and stillbirth on 4 study populations.

This is a secondary analysis of data obtained from the Perinatal Information System between years 1995–2002. The study design was a retrospective cohort study. Data for Lima (150 m above sea level) was obtained from the South II Health Services (DISA, Sur II), for Huancayo (3250 m above sea level) from the El Carmen Hospital, for Cuzco (3430 m above sea level) from Lorena and Regional Hospital and for Juliaca (3850 m above sea level) from Juliaca Hospital. Data were analyzed with the STATA program v8.0, using different regression models to determine the relationship between the variables: low birth weight and late fetal death (LFD).

There is no linear relationship between altitude and birth weight. Birth weight in Juliaca was higher than in Cuzco and Huancayo. Late fetal death was higher in Huancayo (27.7 per 1000) than in Cuzco (12.6 per 1000), Juliaca (12.2 per 1000) and Lima (2.4 per 1000). High altitude residence increases the incidence of LBW and LFD independently from each other, with a relative risk (odds ratio) of 1.95 (1.77–2.00) and 8.85 (7.25–10.82) respectively. The LFD rate of high altitude populations was 21.4 (per 1000 live births), compared to 2.4 (per 1000 live births) for the sea level population. The LFD rate was 12.2 (per 1000 live births) for the high altitude LBW population, in comparison with 1 (per 1000 live births) for the high altitude normal birth weight population. The same finding is seen in sea level populations, showing a decrease in normal birth weight infants in comparison to the LBW populations. However, independent of birth-weight, the LFD rate was higher at high altitude. Higher LFD was observed in Huancayo than in Cuzco or Juliaca.

In conclusion high altitude residence increases the incidence of LBW and the LFD rate (per 1000 live births) in high altitude populations (Huancayo, Cuzco and Juliaca). Highest values for LBW and LFD were observed for Huancayo despite that altitude being lower than Cuzco or Juliaca. The differences among these populations are the antiquity of the peoples living there. It is suggested that populations in Cuzco and Juliaca are better adapted to high altitude than in Huancayo due to antiquity of life in the Peruvian Southern Andes.

Stella Hartinger, MSc

Walter Valdivia, MD

Carlos Carrillo, MD

Gustavo F. Gonzales, DSc, MD

Lima, Peru

Our Experience of Over 50 Years With Chronic Mountain Sickness

Our clinical practice, performing medical evaluations at high altitude in patients with polyerythrocythemia for over 50 years has provided us with extraordinary experience and the opportunity to collect data. Patients with a high hematocrit in the city of La Paz have received a full cardio-respiratory evaluation performed with gradually progressing technology. Arterial blood gases provide information on oxygenation status, showing a decreased oxygen tension compared to normal. Hypoxia must be explained, looking for the fundamental causes which include: hypoventilation, diffusion alteration, shunts and uneven ventilation-perfusion. ¹ Chest radiographs, spirometry, hyperoxic tests, nitrogen washout, flow-volume curves and ventilation studies at rest and during exercise are performed. Cardiac studies include the search for abnormal rhythms, heart block, cardiomegaly, valve anomalies, pulmonary hypertension, sequelae of pneumonia and signs of cardiac insufficiency. Evaluations include electrocardiograms, exercise testing and doppler color echocardiography. Specialized blood studies such as evaluation of the oxygen dissociation curve are likewise run, so as to rule out hemoglobinopathies. Renal function tests looking for renal insufficiency and protein loss are also done. These studies, correlated with the clinical history and close follow up, have shown that chronic mountain sickness (CMS) is always secondary to some type of anomaly in cardio-respiratory or renal function. CMS, once again, is shown to be an adaptation of deficient organic function due to diverse disease in order to maintain normoxia at the cellular level in the hypoxic environment at high altitude.

Gustavo Zubieta-Castillo, MD

Gustavo R. Zubieta-Calleja, MD

Luis Zubieta-Calleja, MD

Nancy Zubieta

La Paz, Bolivia

The Olfactory System Regulates High Altitude Sickness

High altitude sickness is a collective term that includes Acute Mountain Sickness (AMS) and high altitude cerebral and pulmonary oedema. The mechanism of the illness is not fully understood. Between 25–85% of mountaineers suffer from AMS depending on the altitude and rapidity of ascent. ¹ Interestingly, when Indian Himalayan people living in low altitudes (1500 m) migrate to altitudes of approximately 4000 m for meditation and Pranayama (a regulated breathing exercise used in yoga), they do not seem to suffer from AMS. ² Casikar et al., during their expeditions to the Himalayas, observed a significant drop in the carotid blood flow of fellow climbers between the altitudes of 3500–6500 m.^3,4 Basnyat et al. have proposed a mechanism of AMS based on the concept that there is an increase in cerebral blood flow and blood brain barrier damage. ¹ This was based on the observation that at moderate high altitude (3500 m) there is increased pulse rate and systemic arterial pressure. To assume that there is increased cerebral blood flow (CBF) as a result of these changes we feel is inappropriate. The doppler evaluation by Casikar et al. showed a significant reduction in carotid artery lumen diameter and a corresponding drop in flow in spite of increased pulse pressure and systemic arterial pressure.^3,4 The authors hypothesize a hypothalamic deregulation influence by the olfactory system as a primary mechanism of AMS.

The present study aimed to determine the relationship between the olfactory system and high altitude sickness in terms of disturbed metabolic and physiological mechanisms. Albino rats whose olfactory lobes were removed were subjected to high altitude states under laboratory conditions. Blood and urine samples were collected at various stages to measure biochemical parameters. Rats whose olfactory systems were intact were used as controls. The results suggested that the olfactory system regulated the pituitary function and that hypoxic brain damage occurred in rats whose olfactory lobes were removed. High altitude sickness is primarily a neurological dysfunction. The olfactory system regulates physiology at high altitude through its connections with the median fore brain bundle. The hypothalamus-pituitary-adrenal axis is influenced by the olfactory system through this pathway. Albino rats whose olfactory bulbs were destroyed showed evidence of significant endocrine dysfunction when subjected to high altitude conditions.

Vidyasagar Casikar, FRCS, PhD, FRACS

Sydney, Australia

New Acid-Base Correction Factors in Critical Care at High Altitude

The well-known Siggaard-Andersen Chart based on the fundamental Van-Slyke Equation has done a great service to humanity by saving innumerable lives in intensive care units around the world. It allows for identification of the 9 Van-Slyke conditions and the adequate correction of acid-base imbalance establishing the correct amount of bicarbonates to be administered in cases of life threatening acidosis. To date, it has been widely used even at high altitude. However, in this special environment, several factors have been overlooked. With the current sea level chart, a normal subject in the city of La Paz, will have a THID (Titratable Hydrogen Ion Difference, previously known as Base Excess) of −5, instead of the expected 0. The Van-Slyke Equation will compensate the acid-base disorder at altitude to 0, whereby it actually introduces an aggravating factor in the fundamental pH correction for optimal cellular function under critical conditions ¹ .

A modification of the Van-Slyke formula is introduced taking into account the new values for arterial carbon dioxide tensions and the hemoglobin levels for each altitude. Thereby, new charts are developed for 3 different altitudes (2000–2999 m, 3000–3999 m and 4000–4999 m) that allow for the adequate correction of acid-base status during intensive care at high altitude.

Gustavo R. Zubieta-Calleja, MD

Poul-Erik Paulev, MD, DSc

Gustavo Zubieta-Castillo, MD

Luis Zubieta-Calleja, MD

La Paz, Bolivia

Chronic Mountain Sickness on the Qinghai-Tibetan Plateau

Objective.—To better characterize the syndrome of chronic mountain sickness (CMS) and its diagnosis, epidemiology and pathogenesis on the Qinghai-Tibetan plateau.

Methods.—This study was a retrospective review of CMS, and explored questions related to CMS development in residents of the Qinghai-Tibetan plateau, such as: How is CMS diagnosed in China? Does CMS really exist in native Tibetans? What are the epidemiological characteristics of CMS among Tibetan populations? What are the predisposing factors which put persons at risk for CMS? What is the pathogenesis of CMS in Tibet? Based on recent achievements of high altitude medicine attained by Chinese researchers, these and other questions are discussed in this presentation.

Results.—Recently, quantitative diagnostic criteria were established which were accepted by the ISMM (2004) as international criteria of CMS and named “Qinghai criteria.” Both clinical and epidemiological studies suggest that CMS is a common disease on the Qinghai-Tibetan plateau. The overall prevalence of CMS above 2500 m to 5000 m in these highland populations is thought to be as high as 2.8%. Loss of altitude adaptation leading to hypoventilation is the primary pathogenesis and results in severe hypoxemia, excessive polycythemia, and accentuated pulmonary artery hypertension. Reports of CMS from the Qinghai-Tibetan plateau indicate the condition to be prevalent in Han immigrants but rare in the Tibetan natives. Our studies indicated that Tibetans compared to Chinese Han had greater ventilation, increased acute hypoxic ventilatory response, less hypoxic erythropoiesis, blunted hypoxic pulmonary vasoconstriction, and a better quality of sleep with a higher sleeping oxygen saturation. Tibetans may have a genetic adaptation to altitude selected over many generations. Even so, the “true Monge's disease” still occurs in a few Tibetans. As compared with CMS in Andeans, CMS in Tibetans on the Qinghai-Tibetan plateau has similar clinical features, but may have a different pathogenesis.

Conclusion.—With development in the western region of China, as a large number of lowlanders migrate to the Qinghai-Tibetan plateau, no doubt CMS will increase in its prevalence. It is estimated that CMS occurs in approximately 5% of Han immigrants, which amounts to some 250 000 persons on the high plateau. Comparative studies will undoubtedly lead to important findings about possible genetic differences between the Tibetan natives and the Han immigrants. It seems that CMS is a public health problem of the whole world and should be given more research attention.

Tianyi Wu, MD

Qinghai, People's Republic of China

The Increase in Hematocrit During the High Altitude Adaptation Process

Adaptation to high altitude is time and altitude dependent following the equation:

$$\text{Adaptation}=\frac{\text{time}}{\text{altitude}}$$

For a fixed altitude the only variable that changes is time. Immediately upon ascent the organism senses the lowering of the oxygen partial pressure due to a diminished barometric pressure. The initial acute phase usually lasts between 1 and 2 days, varying with the health conditions of the subjects and whether they have previously been exposed to high altitude, and learned how to “handle” it in complex macro-systemic and micro-systemic mechanisms. The first implies cardio-respiratory compensation and the later adaptation processes at the cellular and molecular level. The macro-systemic mechanisms attempt to raise the PaO₂ to “sea level values” through increased ventilation and higher cardiac frequency, never being able to achieve it, thereby reducing the PaCO₂ and producing respiratory alkalosis, a negative action at the cellular level. The micro-systemic mechanisms return the pH to normal, through kidney function, reducing the negative symptoms of acute mountain sickness through adequate cellular function. However a permanent and stable adaptation is only achieved at around 4 weeks when the hematocrit reaches the optimal level for the altitude. CMS subjects increase the hematocrit to levels above that of normal individuals due to cardio-pulmonary deficiencies. As shown before, breath-holding times in stable CMS are prolonged close to twice the capacity of normal. CMS patients with increased hematocrit are well adapted in order to continue their life at high altitude in spite of their underlying disease.

Gustavo R. Zubieta-Calleja, MD

Gustavo Zubieta-Castillo, MD

Luis Zubieta-Calleja, MD

Nancy Zubieta

La Paz, Bolivia

Decompression Sickness Following Seawater Hunting Using Underwater Scooters—A Model Evaluation

Since the 1960s there have been several reports of divers suffering from decompression illness (DCI) after repetitive breath-hold (BH) diving. In the period from 1995 to 2000 John Batle observed apparent decompression sickness in 30 free divers competing with underwater scooters in the sea around Mallorca. ¹ The cases were treated successfully with recompression therapy. Two of the typical diving profiles, described by Batle, have been submitted to calculations with a modified Haldane model: a perfusion limited, symmetrical multi-tissue/multi-level model. The model predicts that the two dive profiles (A and B) will lead to decompression sickness as recorded. A third profile (profile C with the ama pearl divers of Japan), confirmed by reports to avoid decompression sickness, was also accurately predicted. In order to protect free divers John Batle developed a dive table for repeated BH diving. Our calculations predict that the Batle Table does not predict/prevent decompression sickness during prolonged exposures. An alternative table is developed and presented.

Hans-Christian Møller Thorsen, MD

Gustavo R. Zubieta-Calleja Jr, MD

Poul-Erik Paulev, MD, DSc

Copenhagen, Denmark

New Studies on Fluid and Electrolyte Balance in Humans Under Normobaric-Normoxic Conditions During Isolation/Confinement and Their Potential Impact on Studies Performed at High Altitude

Introduction.—Similar to long-term high altitude expeditions during long-term space flights groups of 8–12 humans of different age, sex, nationality etc. have to live and work together for several weeks, months and even years. This isolation and confinement induces medical, physiological and psychological reactions. Therefore the European Space Agency (ESA) has conducted several isolation and confinement studies. During these human studies body mass and composition changes as well as salt-water balance were intensively studied. These studies revealed a new mechanism of non-osmotic sodium storage in the superficial tissues. These results might have an impact on salt-water balance in humans at altitude as well.

Methods.—Data from three different isolation and confinement ESA studies will be presented: ISEMSI’90, duration 28 days, 6 male subjects (age 28 ± 3.0 years, body height 1.82 ± 0.06 m, body mass 78.2 ± 6.6 kg, body mass index [BMI] 23.6 ± 2.7); EXEMSI’92, 60 days, 1 female, 3 males (age 29 ± 3.6 years, body height 1.78 ± 0.05 m, body mass 76.5 ± 9.9 kg, BMI 23.9 ± 2.6); HUBES’94/95, 135 days, 3 males (age 23.5 ± 2.6 years, body height 1.76 ± 0.04 m, body mass 72.2 ± 8.4 kg, BMI 23.1 ± 2.1). The changes in body composition were analysed by body impedance measurements. During the HUBES’94/95 a detailed analysis of the sodium balance was performed in addition.

Results.—Body mass and body composition changed markedly between the different subjects. Fluid intake and urine output showed weekly and monthly rhythms in all three studies. During HUBES’94/95 we observed that the test subjects accumulated sodium without expansion of the extracellular volume.

Conclusions.—It is concluded that during isolation and confinement body mass and body composition changes occurred with a highly individual pattern. Furthermore, subjects of HUBES’94/95 study showed a non-osmotic sodium storage. Recently animal studies have shown that this sodium storage mainly occurs in superficial tissues. ¹ From these results it is hypothesized that the capacity for osmotically inactive storage might also play a role in the salt and fluid balance in humans resulting in peripheral edema during hypobaric-hypoxic exposure.

These studies were supported by BMBF/DLR (Germany).

Hanns-Christian Gunga, MD, PhD

Berlin, Germany

Biochemical Adjustments During Regulated Breathing or Pranayama in Short and Long Term Exposure to High Altitude Conditions

Hypoxia and extreme variations in temperature accompanied by low humidity at high altitude are known to alter physiology in all forms of life. Significant biochemical adjustments during the process of adaptation to these conditions are observed in both high altitude native humans and animals. These changes have shown significant effect on the genetic morphology of highlanders, which have the effect of preventing the development of Chronic Mountain Sickness (CMS). In contrast to this, low landers going to high altitude undergo short term biochemical changes resulting in Acute Mountain Sickness (AMS). Practicing the ancient yogic technique of regulated breathing or pranayama and adopting time-tested oriental nutrition is known to stimulate the olfactory-hypothalamic-pituitary-adrenal axis. Studies by authors have found simple means of combating high altitude illness by reversing biochemical changes during acclimatization.

Vinod George

Savita M

Vidyasagar Casikar, FRCS, PhD, FRACS

Venkatesh Thuppil, PhD, FACBI

Bangalore, India

The Relation Between Subacute Mountain Sickness and Chronic Mountain Sickness

Objective.—The purpose of this study was to evaluate the relation between Subacute Mountain Sickness (SAMS) and Chronic Mountain Sickness (CMS). These 2 altitude illnesses present with similar clinical features and a common pathogenesis, but with different times of onset.

Methods.—This was a longitudinal study. From July 1, 2001 to October 31, 2003, a total of 18 784 workers worked at altitudes between 4547 m (PB431 torr) and 4905 m (PB 417 torr) on Mt. Tanggula while constructing the Qinghai-Tibetan Railroad between the months of April and October. This construction provided a unique opportunity for investigation of altitude illnesses. Before ascent, physical and laboratory examinations were evaluated in all workers and revealed they were healthy at baseline. The diagnosis of SAMS and CMS was based on the “Consensus Statement on Chronic and Subacute High Altitude Diseases.” ¹ Hemoglobin (Hb) concentration ≥ 18 g/dl was considered as erythrocytosis, while Hb ≥ 21 g/dl was diagnosed as excessive polycythemia of high altitude or CMS. The measurement of pulmonary artery pressure (PAP) was done via echocardiography. Mean PAP > 30 mm Hg was diagnosed as hypoxic pulmonary hypertension (HPH). We did a follow-up study to determine the incidence of erythrocytosis, high altitude excessive polycythemia, CMS and HPH in the workers.

Results.—In the year 2001, the incidence of erythrocytosis in workers at 3 months and 7 months was 10.4% and 25.3%, respectively, while 3% had pre-existing excessive polycythemia. In 2002, the incidence of erythrocytosis increased to 17.9% and 29.3%, respectively, during the 3 and 7 months worked on high mountains. Four percent were diagnosed with CMS, and 2.3% presented with HPH and right heart failure. In 2003, the incidence of erythrocytosis was 22.3% and 28.3% during the 3 and 7 months, respectively. Incidence of CMS was found to be 5.6%, and the incidence of HPH rose from 3.6% for 3 months to 4.8% for 7 months on Mt. Tanggula.

Discussion.—The available data ² from the Han infants on the Qinghai-Tibetan plateau, from the Indian and Chinese soldiers garrison on the Himalayas and Karakorams, and from the workers on Mt. Tanggula suggest that higher altitude of residence, shorter exposure to severe hypoxia, and greater physical activity are merged into 1 large stimulus which induces high altitude excessive polycythemia or HPH. Factors regarding the relation between SAMS and CMS are summarized as follows:

Conclusion.—The polycythemic and pulmonary hypertensive responses are dependent upon the magnitude of the hypoxic stimulus and the individual susceptibility to hypoxia. As altitude rises, the syndrome of CMS develops with a shorter residence. There may be a transitional relation between SAMS and CMS.

Tianyi Wu, MD

Shouquan Ding, Jinliang Liu

Jianhou Jia, Baozhu Liang

Jizhui Zhao, Detang Qi

Beijing, People's Republic of China