Post Natal Pulmonary Adaptations

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Respiratory Physiology & Neurobiology 158 (2007) 190203

Postnatal cardiopulmonary adaptations to high altitude

Luis Huicho a,b,c,

a Departamento Acad emico de Pediatra, Universidad Nacional Mayor de San Marcos, Lima, Perub Universidad Peruana Cayetano Heredia, Lima, Peru

cInstituto de Salud del Nino, Lima, Peru

Accepted 1 May 2007

Abstract

Postnatal cardiopulmonary adaptations to high altitude constitute a key component of any set of responses developed to face high altitude

hypoxia. Such responses are required ultimately to meet the energy demands necessary for adequate functioning at cell and organism level.After a brief insight on general and cardiopulmonary comparative studies in growing and adult organisms, differences and possible explanations

for varying cardiopulmonary pathology, pulmonary artery hypertension, persistent right ventricular predominance and subacute high altitude

pulmonary hypertension in different populations of children living at high altitude are discussed. Potential long-term implications of early chronic

hypoxic exposure on later diseases are also presented. It is hoped that this review will help the practicing physician working at high altitude

to make informed decisions concerning individual pediatric patients, specifically with regard to diagnosis and management of altitude-related

cardiopulmonary pathology. Finally, plausibility and the knowledge-base of public health interventions to reduce the risks posed by suboptimal or

inadequate postnatal cardiopulmonary responses to high altitude are discussed.

2007 Elsevier B.V. All rights reserved.

Keywords: Cardiopulmonary adaptations; High altitude; Postnatal

1. Introduction

Animals living in diverse settings but facing hypoxia/anoxia

as a common factor constitute ideal models for studying dif-

ferent response patterns (Hochachka and Lutz, 2001). In brief,

one fundamental lesson learned from comparative studies in

organisms naturally or experimentally exposed to low oxygen

is that there are species able to withstand hypoxia (hypoxia

tolerant) and species that are not equipped to face success-

fully the hypoxic challenge for achieving optimal functioning

and survival (hypoxia sensitive). Hypoxia-tolerant and hypoxia-

sensitive are terms used for referring to these two categories of

animal species (Hochachka and Lutz, 2001). These two cate-

gories of animals are also referred to as genetically adapted

and non-genetically adapted species to high altitude hypoxia

(Monge and Leon-Velarde, 1991). We will use both set of

terms interchangeably throughoutthe review, although the genes

accounting for the different strategies developed by both groups

Correspondence address: Batallon Libres de Trujillo227, LI 33, Lima,Peru.

Tel.: +51 1 93481121; fax: +51 1 3190019.

E-mail address: [email protected].

of species have not been entirely demonstrated and thereforethe first classification is probably more cautious, as it may

include both genetic and functional changes. The responses to

hypoxia assessed in such comparative studies range from the

whole organism to sub-cellular and molecular responses. They

include at least the following levels, as proposed by Hochachka

et al. (1998): regulation of hypoxic ventilatory response (HVR)

by carotid body chemoreceptors, oxygen sensors at pulmonary

vasculature that regulate the hypoxic vasoconstrictor response

and the ventilation-perfusion matching, oxygen sensors in other

tissues involved in the activation of the vascular endothelial

growth factor and thus the angiogenesis especially in the heart

and probably in the brain, and oxygen sensors in the kidney and

liver involved in an enhanced erythropoietin expression. Finally,

there are tissue-specific oxygen sensing and signal transduction

pathways that lead to metabolic reorganization at least in part

by altering the expression rates of hypoxia-sensitive genes for

metabolic enzymes and metabolic transporters.

At the sub-cellular and molecular level, the metabolic effi-

ciency of genetically adapted animals is higher than that of

non-genetically adapted ones. There are several mechanisms by

which hypoxia-tolerant animals resolve the challenges posed

by hypoxic environments, but metabolic arrest and stabilized

1569-9048/$ see front matter 2007 Elsevier B.V. All rights reserved.

doi:10.1016/j.resp.2007.05.004
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L. Huicho / Respiratory Physiology & Neurobiology 158 (2007) 190 203 191

Fig. 1. From the cell to the organism: several fundamental features of cells tolerant to hypoxia and of cells sensitive to hypoxia-implications of programming and of

modifying factors on resulting overall organism-level responses (successful adaptation or non-adaptation). Modified from Hochachka (1986). AMS: acute mountain

sickness; HAPE: high altitude pulmonary edema; HACE: high altitude cerebral edema; CMS: chronic mountain sickness, CSHAPH: chronic symptomatic high

altitude pulmonary hypertension.

membrane functions appear to be the most effective strategies

for extending tolerance to hypoxia (Hochachka, 1986). Depend-

ing on whether the organism is tolerant or sensitive to hypoxia,

early exposure to chronic hypoxia and intervention of risk fac-

tors may alter to a varying degree early programming events at

the cellular level and lead to a final successful or non-successful

pattern of adaptation at the organism level (Fig. 1).A conceptual summary of the relationships between time

and physiological responses to hypoxia and the ancestral phys-

iological phenotype as a phylogenetic adaptation to hypobaric

hypoxia is seen in Fig. 2. This conceptual model of responses

was taken from Hochachka et al., who discussed them in detail

in several reviews (Hochachka, 1986; Hochachka et al., 1998;

Rupert and Hochachka, 2001a, 2001b). We added concepts

most likely present in Hochachkas propositions but not explic-

itly included in his model, namely: (1) the determinant role of

the genetic background, which leads ultimately to an adaptive

or non-adaptive set of responses to hypoxia, (2) the potential

role of important modifying factors (life style, environmen-

tal and indoor pollution, and chronic respiratory diseases), and

(3) the notion of programming, that is, the possible long-term

indirect effects that poverty, malnutrition and other environmen-

tal agents can exert on the responses to hypoxia in the fetal

and early postnatal vulnerable periods of life. Programming

and modifying/risk factors were incorporated in the model as

important modulators of different steps from signal transductiononwards. All such modifying effects can change substantially

the genetic expression of both acute and long-term responses.

Acute responses to hypoxia occur instantaneously with the

hypoxic exposure, whereas adjustments requiring hours to days

are termed acclimatory responses or acclimation. We also

included the concept of long-term responses to imply that they

can take the whole life of an individual. Only acute and acclima-

tory responses are possible within a given generation. However,

all components of the cascade of responses can change through

evolutionary time (genetic adaptation), changes that involve

genetic alterations. Andean, Tibetan and Ethiopian populations

show three different patterns of adaptation to high altitude


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192 L. Huicho / Respiratory Physiology & Neurobiology 158 (2007) 190203

Fig. 2. Relationship between time of exposure to hypoxia and physiological responses. Acute responses are those occurring instantaneously with the hypoxic

exposure. Adjustments requiring some fraction of the life of organisms are termed acclimatory responses and they were extended here to so-called long-term

responses to imply that they can take the whole life of an individual. Only acute and acclimatory responses are possible within a given generation. All components

of the cascade can change through evolutionary time (phylogenetic adaptation or genetic adaptation), changes that involve genetic alterations. Andean, Tibetan and

Ethiopian human populations are includedas examples of differentpatterns of adaptation to highaltitude hypoxia. Besides genetic adaptationas a resultingsuccessful

set of responses, acute and long-term non-adaptive strategies resulting in several conditions are included. Programming and modifying/risk factors were incorporated

as important modulators of different steps from signal transduction onwards. Modified from Hochachka et al. (1998). AMS: acute mountain sickness; HAPE:

high altitude pulmonary edema; HACE: high altitude cerebral edema; CMS: chronic mountain sickness; CSHAPH: chronic symptomatic high altitude pulmonary

hypertension.

hypoxia and therefore show different phenotypes of SaO2 and

eryhtropoiesis. Besides genetic adaptation as a successful set

of responses, we included acute and long-term non-adaptive

strategies resulting in several conditions. The resulting acute

non-adaptive responsesinclude acutemountainsickness(AMS),

high altitude pulmonary edema (HAPE), and high altitude cere-

bral edema (HACE). On the other hand, non-adaptive responses

to long-term exposure may lead to chronic mountain sickness

(CMS)and chronic symptomatic high altitude pulmonary hyper-

tension (CSHAPH).

Studies on Andean, Tibetan andEthiopian high altitude popu-lations have revealed different patterns of adaptation to hypoxia.

Andean natives show erythrocytosis and hypoxemia, and may

also develop pulmonary artery hypertension (Monge, 1978;

Winslow and Monge, 1978). Moreover, CMS may result from

an excessively enhanced erythropoietin response (Monge, 1978;

Winslow and Monge, 1978). Tibetans show consistently low

oxygen saturation and lack of enhanced erythropoiesis (Beall,

2000, 2006). Recently, in Ethiopia, a third successful pattern

of human adaptation to high altitude hypoxia that contrasts with

both the Andean and the Tibetan patterns was described(Beall et

al., 2006). In Ethiopian native residents at 3530 m, 1486 years

of age, without evidence of iron deficiency, hemoglobinopathy,

or chronic inflammatory conditions, they found that hemoglobin

concentration and arterial oxygen saturation were within the

ranges of sea level populations, despite the ambient hypoxia

(Beall et al., 2002). The understanding of the underlying mech-

anisms leading to these differences is not complete. Although

it is plausible that they are due to genetic differences in the

strategies for facing hypoxia, the genes involved, their transmis-

sion patterns and their distribution among and within different

populations are not clear (Beall et al., 2002; Brutsaert, 2001).

The effect of environmental factors other than hypoxia and the

interaction of hypoxia with genetic variables on the patternsof adaptation are aspects also waiting for further clarification

(Moore, 2001; Rupert and Hochachka, 2001a, 2001b).

In the following sections we will discuss whether there

are similar population differences in developmental cardiopul-

monary adaptation patterns to high altitude hypoxia. We will

offer first a brief physiological overview on cardiopulmonary

responses to hypoxia, particularly on the reactivity of the

pulmonary artery. We will then discuss from a comparative

perspective the responses of growing and adult organisms, and

follow this with a discussion of cardiopulmonary responses in

human infants andchildrenliving at high altitude.In thefinal sec-

tions we will comment on the possible long-term effects of early


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hypoxic exposure on the health status in later life and whether

there is a sound knowledge-base for drawing clinical and health

policy recommendations regarding exposure of children to life

at high altitude.

2. Comparative cardiopulmonary responses to high

altitude hypoxia in developing and adult organisms

2.1. Physiological significance of cardiopulmonary

responses to hypoxia

A particular challenge that hypoxic exposure presents to the

lungs is that they should overcome any existing limitation to

gas exchange so as to ensure that blood equilibrate completely

with alveolar oxygen pressure. Three physiological mechanisms

that may act as limiting factors to an efficient gas exchange

have been described: intrapulmonary shunts, diffusion limita-

tions and ventilation to perfusion heterogeneity (Scheid and

Piiper, 1997; Skovgaard and Wang, 2006). Pulmonary vascular

reactivity is fundamental in the reduction of the ventilation toperfusion heterogeneity by means of a constrictive response that

is variable from species to species. Hypoxic pulmonary vaso-

constriction (HPV) is considered a widely conserved adaptive

vasomotor response to alveolar hypoxia, which distributes pul-

monary blood flow to optimally ventilated lung segments by a

process of vasoconstriction whichspecifically involves the small

muscular pulmonaryarteries (Moudgil et al., 2005). Itthusmedi-

ates ventilation-perfusion matching by reducing shunt fraction

optimizing in this waysystemic oxygenpressure (Moudgil et al.,

2005). On exposure to hypoxia, the primary site of vasoconstric-

tion is the precapillary muscular pulmonary and low alveolar

oxygen leads to constriction of the pulmonary vasculature inbirds and mammals which elevates resistance to pulmonary

blood flow and leads to a rise in pulmonary arterial blood pres-

sure (Skovgaard and Wang, 2006; Moudgil et al., 2005). In

the systemic vessels, in contrast, hypoxia dilates most systemic

arteries in both animals and humans. These differing responses

of pulmonary and systemic arteries to hypoxia indicate that HPV,

although modulatedby the endothelial cells, cannot be explained

by endocrine or paracrine vasoconstrictors that have concor-

dant effects on the pulmonary and systemic circulation such as

endothelin and leukotrienes (Moudgil et al., 2005). It is believed

that the restricted occurrence of HPV to intrapulmonary arteries

reflects the localization of the molecular apparatus that mediates

HPV, namely the mitochondrial redox sensor and the effectors(O2-sensitive K

+ channels in pulmonary artery smooth muscle

cells) to the resistance pulmonary arteries (Moudgil et al., 2005).

This seductive hypothesis should be verified through the con-

duction of studies aimed at developing organ-specific designs

for assessing in different species developmental responses to

hypoxia within the framework of an overall, integrative con-

ception of adaptation. Also, the hypothesis paves the way for

focusing the study of hypoxic adaptive responses of animals

and humans exposed chronically to high altitude hypoxia on the

mitochondrial level in pulmonary artery smooth muscle cells,

and also for understanding better the genetic aspects of such

responses. Fig. 3 shows a diagrammatic summary of the cas-

cade of responses elicited at pulmonary vasculature level when

organisms are challenged by hypoxia. The genetic background

provides the basis of the response, although pulmonary vascu-

lar reactivity resulting from hypoxia sensing may be modified

by programming during early intrauterine or extrauterine life

periods. This leads to successful long-term vascular pulmonary

adaptation or to non-adaptive long-term responses that can be

ultimately manifested in chronic and symptomatic high altitude

pulmonary hypertension.

2.2. Cardiopulmonary responses in young organisms

There is a paucity of research performed on cardiopulmonary

responses to high altitude hypoxia in growing animals. A com-

prehensive review made on physiological adaptations to high

altitudein1991(Mongeand Leon-Velarde, 1991) concludedthat

animals tolerant to hypoxia such as guinea-pigs, when studied

during growth, show a lower degree of ventricular hypertrophy

and pulmonary artery hypertension than growing rats, consid-

ered hypoxia-sensitive animals. Unfortunately, the prenatal andpostnatal time-course of such responses in humans is fundamen-

tally unknown, though there are critical periods during prenatal

and early postnatal growth. If growing organisms are exposed

to certain factors such as under-feeding during these critical

periods, they may be programmed for later development of dis-

eases such as ischemic heart disease, diabetes, hypertension, and

stroke (Barker, 2002).

As for the more general problem of early exposure to diverse

agentsduring critical periods of lung developmentand thesubse-

quent risk of developing cardiorespiratory diseases later in life,

as well as the underlying molecular mechanisms, this is a largely

neglected area and more uncertainties than definitive answersstill prevail (Massaro and DeCarlo Masaro, 2004). Fig. 4 depicts

the different stages of human lung development and shows pre-

sumably vulnerable periods that may be affected by exposure to

several agents including hypoxia. There are clearly compelling

examples of late consequences of early events, such as intrauter-

ine and postnatal exposure to parental tobacco smoking and

later risk in adulthood for more respiratory symptoms, poorer

lung function, and increased risk for obstructive pulmonary dis-

ease (Hafstrom et al., 2005; Harding et al., 2000; Maritz et al.,

2005; Svanes et al., 2004). A recent publication by Le Cras et al.

(2004) synthesized divergent studies about transforming growth

factor-alpha (TGF-) pointing to its overexpression in important

developmental and adult pulmonary diseases and showed thatbrief overexpression of TGF- by the lung, if produced when

the gas-exchange saccules of the architecturally immature lung

are beingsubdivided (septated)to form alveoli, permanently dis-

rupts septation. Their results support the existence of a critical

period for septation and for the formation of the pulmonary vas-

culature and provide additional evidence that early events can

influence laterlung anatomy, lung function,and the development

of lung disease. Importantly, this work also points to the impact

early events have on the subsequent development of lung disease

and adds to our still poor understanding of the molecular basis

of this effect (Svanes et al., 2004). Of interest, in all species

studied so far septation, whether prenatal or postnatal, occurs


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Fig. 3. Pulmonary vasculature set of responses in conditions of chronic exposure to hypoxia. A hierarchical approach is proposed where the genetic endowment is

determinant in the way organisms respondto hypoxia at the pulmonary vasculature level. Earlyexposure to chronic hypoxiaand participationof modifying/risk factors

may significantly alter the responses, which may therefore lead to increased or normal pulmonary vasculature resistance and pressure, successful or inadequate blood

flow redistribution to optimally ventilated lung regions, reduction or inadequately persistent shunt fractions, improvement or not in ventilation-perfusion matching,

and eventually to maintenance or not of optimum systemic oxygen pressure. The global resulting responses may signify a successful long-term pulmonary adaptation

or a non-adaptive set of responses leading to chronic symptomatic high altitude hypertension. NO: nitric oxide; ET-1: endothelin-1; LKs: leukotrienes; CSHAPH:

chronic symptomatic high altitude pulmonary hypertension; PAP: pulmonary artery pressure.

during a period when the organisms blood concentration of its

major glucocorticosteroid hormone is low; septation ends as the

glucocorticosteroid concentration rises (Massaro and DeCarlo

Masaro, 2004). Administration of a glucocorticosteroid to ratsor mice during the period of septation, when the concentration of

corticosteroids in the bloodis normally low, impairs spontaneous

septation and the development of the pulmonary vasculature,

resulting in pulmonary hypertension (LeCras et al., 2000). Peri-

natal exposure to hypoxia may also affect septation and pave the

way for later development of pulmonary hypertension (Blanco

et al., 1991; Massaro et al., 1990). However, most experimen-

tal evidence on vulnerable periods comes currently from animal

studies, and we should therefore be cautious in extrapolating

those results to human lung development, as the critical peri-

ods seem to vary from species to species and in addition there

are gender differences. Moreover, the time-period of vulnera-

bility is still nebulous for several specific phases of human lung

development and more research is needed before we can derive

sound recommendations on early preventive interventions. We

will be back with this issue later in the review describingmore evidence pointing to possible associations between events

occurring early in life and the risk of developing specific lung

disorders.

It would be particularly illuminating to have comparative

studies on the ontogenetic characteristics of cardiopulmonary

responses to chronic high altitude hypoxia in hypoxia-sensitive

and hypoxia-tolerant species. They offer the potential to reveal

possible critical periods during early phases of cardiopul-

monary growth and development in conditions of hypoxia and

their relationship with adult fitness to hypoxia in general and

with the risk of developing later persistent cardiopulmonary

pathology including symptomatic high altitude pulmonary


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Fig. 4. Prenatal and postnatal periods of lung development and the notion of critical periods. Rectangles with black areas denote greater vulnerability (critical

periods) whereas those with grey areas denote lower vulnerability. Programming is more likely to occur during critical periods leading thus to various diseases later

during infancy, childhood or adulthood. Proposed period times of vulnerability of specific stages of lung development to diverse agents are only approximations

and some of them may not be fully applicable to human beings. Gender variations also occur. Critical periods may include prenatal phase, postnatal phase or both

intrauterine and extrauterine phases. Vertical and oblique arrows on different developmental lung stages indicate modulatory effects of diverse molecules, such as

growth factors. AB: antibiotics; IGF: insulin-like growth factor; EGF: epidermal growth factor; TGF-: transforming growth factor .

hypertension. Such studies may also identify potential targets

for proving therapeutic options and for implementing preventive

interventions.

2.3. Cardiopulmonary response in adult organisms

In contrast, studies on cardiopulmonary responses to hypoxia

in adult animals are numerous. For a detailed discussion of

the issue we refer the reader to a comprehensive review pub-

lished in 2001 (Tucker and Rhodes, 2001). In that review, the

authors distinguish the findings in animals indigenous to low

altitude from those in animals native to high altitude. Two

patterns of cardiopulmonary response have been consistently

shown in low altitude animals. Species such as sheep and goat

show a hypo-responsive pattern characterized by low thick-ness of the pulmonary vessels, absent or mild pulmonary artery

hypertension, and mild to moderate right ventricular hypertro-

phy. Hyper-responder animals such as cows show comparatively

higher thickness of pulmonary arteries, moderate to severe pul-

monary hypertension and marked rightventricular hypertension.

In addition,animals native to high altitude such as yaks, camelids

(llamas, alpacas, guanacos) and rodents and lagomorphs (guinea

pigs, viscachas, pikas) show consistently less variable, attenu-

ated pulmonary hypertensive responses with little pulmonary

vascular hypertrophy and right ventricular hypertrophy. This

attenuated response is also apparent among human high alti-

tude populations, particularly in Tibetan populations. In brief, it

seems that medial pulmonary artery thickness predicts the pul-

monary vascular response to high altitude (Tucker and Rhodes,

2001).

These findings strongly suggest that the cardiopulmonary

responses to high altitude hypoxia are genetically driven. This

does not deny at all the influence of geneenvironment inter-

actions or the role of developmental adaptation, whose relative

importance in the context of a successful adaptation as compared

to the purely genetic influence needs to be studied.

3. Humans: cardiopulmonary changes in high altitude

infants and children

A basic auxiologic concept universally accepted is that chil-

dren need an adequate environment to reach an optimum,unrestricted growth and development. Accordingly, there is a

justified concern on the potential influence of high altitude

hypoxia on growth and development of children living in such

settings. Ultimately, oxygen availability to tissues should be the

minimal needed for matching the metabolic demands of a grow-

ing organism. Alternatively, an increased metabolic efficiency

in face of limited oxygen availability is a plausible overcoming

strategy. Since cardiovascular and respiratory systems constitute

key steps in the oxygen cascade they deserve a particular con-

sideration in a review on their responses in children living under

hypoxic conditions. We will focus here on studies performed in

children with long-term exposure to high altitude.


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From a more specific perspective,we examine howcardiopul-

monary development occurs in children resident at high altitude

andhow this mayinfluencethe risk of persistence of fetal circula-

tory patterns (patent foramen ovale and patent ductus arteriosus),

as well as of symptomatic pulmonary hypertension with con-

sequent right-heart failure. These concerns are reflected in the

published literature (Alzamora Castro et al., 1960; Khoury and

Hawes, 1963; Hurtado Gomez and Calderon, 1965; Lin and Wu,

1974; Miao et al., 1988; Sui et al., 1988).

3.1. Cardiopulmonary transitional changes in the high

altitude infant

In a comprehensive review of early postnatal transitional

cardiopulmonary changes in infants living at high altitude it

was emphasized there that the immediate postnatal period is a

dynamic one, with continuous developmental changes in virtu-

ally every aspect of the cardiopulmonary system (Niermeyer,

2003). Such changes involve alveolar structure, pulmonary

blood flow, circulatory patterns, central nervous system controlof breathing, regulation by peripheral chemoreceptors, inputs

from metabolic rate and thermoregulation, hemoglobin synthe-

sis, and modulators of oxyhemoglobin binding. Within seconds

after birth,the lungs fillwith air, pulmonarybloodflow increases,

and fetal shunts through the foramen ovale and ductus arteriosus

close. The respiratory system is challenged by a rapid increase

in metabolic rate and by the gradual resetting of the carotid

chemoreceptors from fetal to postnatal PaO2 values, while the

final steps in structural maturation of the alveolar gas exchange

units take place. Oxygen is crucial in modulating this series of

events and, subsequently, birth into a hypoxic high altitude envi-

ronment has not only short-term impact but also implicationsthat may extend throughout the life-span.

The availability of oxygen influences profoundly the nature

and intensity of the developmental cardiopulmonary changes

that occur in the perinatal period from fetus to newborn infant.

Such changes are clearly different at high altitude from those

occurring at sea level and include differences in oxygen arterial

saturation, breathing patterns and maturation of respiratory con-

trol reflexes, and velocity of regression of fetal characteristics

of the pulmonary vasculature. Various differences in transitional

changes vary not only with postnatal age and altitude, but also

among populations living in different high altitude settings, sug-

gesting an important influence of genetic adaptation on perinatal

physiology. Exposure to chronic high altitude hypoxia during theperinatal transition also results in apparent lifelong alterations in

respiratory reflex responses and pulmonary vasoreactivity. Dis-

ruption of the normal process of cardiopulmonary transition can

result in symptomatic high altitude pulmonary hypertension. It

is also very likely that the high altitude hypoxia may interact

synergistically with hypoxemia due to acute respiratory infec-

tions in young infants still undergoing transition, contributing in

this way to infant mortality at high altitude (Lozano, 2001).

3.1.1. Arterial oxygen saturation

Arterial oxygen saturation (SaO2) decreases with increasing

altitude, but this decrease is not linear. The SaO2 of infants at

high altitude depends on several variables, including the ambient

oxygen pressure, age of infants, state of awakening, feeding,

respiratory rate and pattern, oxygen hemoglobin affinity, and

reactivity of the pulmonary vessels. In addition, SaO2 shows

population variations that may be reflecting differing genetic

adaptation to high altitude.

At 3100 m, saturation in awakening infants is significantly

higher than those in active or quiet sleep. It is variable with

feeding, tending to be intermediate between wakefulness and

sleep. This pattern is similar with further altitude increase, and at

3658 m in Lhasa, the highest saturations occur in the first 2 days

after birth, followed by a decline in the first week (Niermeyer

et al., 1995). Tibetan newborn infants show consistently higher

oxygen saturations than Han infants, although they reside at the

same altitude in Lhasa. In the first 2 days after birth, SaO 2 aver-

ages 90% to 94% in the Tibetans and 86% to 92% in the Han.

During infancy, Tibetan infants maintain fairly constant values

in all states, while Han infants show a progressive decline during

sleep through 4 months (Niermeyer et al., 1995). Andean infants

between 2 and 5 months show at a similar altitude (3750 m) val-uesroughly lowerthan Tibetaninfants, with averagesof 88 3%

(Reuland et al., 1991). In El Alto, Bolivia (4018 m) infants have

a mean SaO2 of 86.9% overall and a mean of 87.8% during the

awake state (Gamponia et al., 1998). At 4540m in Peru, SaO2values range from 57% to 75% in infants from 30 min to 72 h

of age (Gamboa and Marticorena, 1971) and from 74% to 81%

during infancy and childhood (Sime et al., 1963). These values

show a wide range, and thus some caution is warranted before

deriving conclusions on normal values in different high altitude

settings.

As remarked previously, in addition to altitude and post-

natal age, SaO2 variations are related to other factors such asbehavioral state or activity and population group. Moreover,

oxygen hemoglobin affinity also influences SaO2 values, and

oxygen hemoglobin affinity in turn depends on proportion of

fetal hemoglobin, 2,3 DPG, PCO2, pH and temperature. It has

been reported that the proportion of fetal hemoglobin (HbF) in

high altitude newborn infants is higher than that of their sea

level counterparts (Ballew and Haas, 1986). When differences

were assessed between different populations living at high alti-

tude on the Andean plateau, lower proportions of HbF were

demonstrated among high altitude residents of native Aymara

andQuechua versus mestizo background, andover25% of native

infants showed a predominance of adult hemoglobin (HgbA)

in cord blood (Galarza Guzman, 1988). The advantage of HbFin high altitude newborns may depend on how adequate is the

delivery of oxygen to the tissues during fetal life.

Differences in adult SaO2 values found among different adult

populations native to high altitude have also been shown among

Tibetan and Han neonates born to women resident at high alti-

tude.Tibetan infants displayedhigher SaO2 andbirth weight and

lower hemoglobinconcentrationthan Hannewborns(Niermeyer

et al., 1995). These findings reflect likely genetic differences in

the degree of adaptation to high altitude hypoxia of Tibetan

and Han populations. Hypoxia may have operated distinctly

in these populations through genetic modification of regula-

tors of pulmonary vascular reactivity and blood flow such as


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nitric oxide production, which is known to be under genetic

control (Marsden et al., 1993; Pearson et al., 2001). Pulmonary

vascular reactivity may in turn modify the SaO2. Alternatively,

direct effects on genes accounting for oxygen saturation may

have operated distinctly in different populations (Beall, 2006).

It seems that oxygen saturation has no heritability in the Andean

natives, but does among Tibetans where an autosomal domi-

nant major gene for higher oxygen saturation has been detected

(Weiss, 1993). Women estimated with high probability to have

high oxygen saturation genotypes have more surviving chil-

dren than those estimated with high probability to have the low

oxygen saturation genotype. These findings suggest that ongo-

ing natural selection favoring greater reproductive success is

increasing thefrequency of thehigh saturation alleleat this major

gene locus (Beall et al., 1994, 1997, 2004). This is interesting

given the amount of mobility and cross-breeding that occurs

nowadays.

3.1.2. Ventilation and pulmonary function

For a detailed discussion on the development of ventilatorycontrol in infants, the reader is referred to a recently pub-

lished review (Cohen and Katz-Salamon, 2005). The ventilation

control is related to the function of the peripheral chemorecep-

tors, which are the bodys principle O2 (hypoxia) sensors. The

HVR of newborn infants is well known. It consists of an ini-

tial and transient peripherally mediated increase in ventilation,

which quickly returns to baseline or even below (Cohen et al.,

1997). The fall in ventilation during sustained hypoxia, is due

to hypoxic depression of chemoreception, which has peripheral

and central components. With advancing age, the initial tran-

sient increase in ventilation becomes sustained for longer and

the hypoxic depression becomes less dramatic, although devel-opment is slow and the biphasic response persists in some form

into adulthood (Easton et al., 1988; Cohen et al., 1997). Of note,

hypometabolism is known to occur on exposure to hypoxia in

newborns, but infants at high altitude maintain metabolic rate

with no major alterations in ventilation (Mortola et al., 1992).

Neonates gestated and born at high altitude (3850m) show

a similar biphasic HVR as neonates born at a lower altitude

(800 m), that is, initial increase in ventilation, followed by a sus-

tained decrease that may persist beyond the termination of the

hypoxic stimulus (Lahiriet al., 1978). Of note, when infants born

at high altitude experienced a prolonged exposure to 3850 m,

resting ventilation did not increase or decrease as compared

with sea level infants. Developmental control of ventilation isalso influenced by early exposure to hypoxia. Thus it has been

shown that the mature hyperbolic curve of the HVR is delayed

in rats raised at high altitude as compared with rats growing at

sea level (Joseph et al., 2000). Interestingly, infants native to

La Paz (4000 m), showed deeper and slower respiratory pattern

and greater oxygen extraction than infants native to Santa Cruz

(500m)(Mortola et al., 1992). However, in this study, there were

no differences in pulmonary ventilation, oxygen consumption,

or carbon dioxide production between the two groups.

Pulmonary development at the level of gas exchange units is

also influenced by perinatal exposure to hypoxia. In rat models,

the velocity of lung volume increase is slower, there is a delayed

septation of gas exchange saccules, the gas exchange surface

area is blunted, and there is an accelerated thinning of the alve-

olar walls (Massaro et al., 1989). These changes may constitute

the underlying mechanisms of pulmonary anatomic and func-

tional changes observed in infants and children living at high

altitude and exposed to hypoxia in early periods of development.

3.1.3. Pulmonary artery pressure

Infants born at high altitude display in general a constric-

tive arterial pulmonary response to ambient hypoxia which

is related to an increased thickness of the muscular layer

in the pulmonary vessels. This vasoconstriction leads in turn

to right ventricular hypertrophy. These characteristics have

been studied through electrocardiographic, echocardiographic,

hemodynamic and histopathologic studies in children gestated,

born and resident at high altitude settings. How long the

increased pulmonary artery and the right ventricular pattern

predominate has been shown to vary at different altitudes.

Infants studied in Mexico (2240 m) through echocardiog-

raphy showed slightly elevated pulmonary artery pressures at1530 days (Victoria-Oliva et al., 1996). In Leadville, Colorado

(3100m), echocardiography showed that pulmonary artery pres-

sure showed normal to moderately elevated values during the

neonatal period that normalized completely by 24 months of

age (Niermeyer et al., 1993). All these infants had received

supplementary oxygen immediately after birth that may have

modified the pulmonary artery pressure response verified later

in infancy. Healthy infants in La Paz (37004000 m) showed a

gradual decrease of pulmonary artery pressure as determined

by echocardiography (Niermeyer et al., 2002). An echocar-

diographic comparative study revealed that right ventricular

anterior wall of infants native to La Paz (3600 m) was greaterthan that of infants native to Santa Cruz (300 m), difference

that persisted through the first year of extrauterine life; by con-

trast, low altitude infants showed a significant decrease of wall

thickness by the end of the first month of life ( Aparicio et al.,

1991).

Heart catheterization has also been performed for assess-

ing the pulmonary artery pressure response. Neonates born in

Morococha, Peru (4540 m), showed pulmonary artery pressure

values close to systemic blood pressures when alveolar PO2was about 50 mm Hg, values that persisted for 72 h after birth.

Interestingly, the pulmonary artery pressure showed an inverse

correlation with SaO2 and administration of 100% oxygen to

some infants led to a fall of pressure to values near normal forsea level (Gamboa and Marticorena, 1971).

The electrocardiographic findings also point to similar pat-

terns of persistence of increased pulmonary artery pressure and

right ventricular preponderance, again being the time-course of

such changes dependent on the age of infants and on the altitude

of residence (Marticorena, 1983).

Another avenue of evidence for developmental artery pul-

monary pressure response came from histopathologic studies

performed in Peruvian infants. The histologic pattern of the

pulmonary artery trunk at various altitudes ranging from sea

level to 4540 m showed a delayed changed from the aortic to

adult structure. Infants born at sea level display a transitional


9/14


pattern by 6 months and an adult pattern by 2 years of age,

whereas residents above 3440 m may show persistence of an

aortic (high-pressure) pattern into the preschool years (Saldana

and Arias-Stella, 1963a, 1963b).

As for high altitude-related structural heart abnormalities,

echocardiography measurements performed in infants aged

from 2 weeks to 6 months in La Paz (37004000 m) revealed

persistence of an anatomically patent foramen ovale in 75%

through 3 months and 44% through 6 months ( Niermeyer et

al., 2002). None of these infants showed a clinically significant

shunting. However, other studies in school-age children in Tibet

(Miao et al., 1988) and Peru (Alzamora Castro et al., 1960) have

identified an increased prevalence of symptomatic patent ductus

arteriosus and patent foramen ovale with increasing altitude of

residence.

Finally, there is evidence that high altitude interacts with

acute respiratory infections, particularly in young infants and

children, aggravating the hypoxemia and increasing thus the risk

of death (Reuland et al., 1991; Onyango et al., 1993; Lozano

et al., 1994; Dyke et al., 1995; Duke et al., 2001; Lozano,2001). Consequently, it has been proposed that SaO2 moni-

toring through an extensive use of pulse oximetry should be

investigated and implemented for avoiding severe hypoxemia

and death in high altitude infants and children with acute respi-

ratory infections (Duke et al., 2002; Huicho, 2003). The use of

pulse oximetry monitoring would also be a more efficient strat-

egy for detecting hypoxemia and risk of death at high altitude

than clinical signs (Reuland et al., 1991; Duke et al., 2002).

In summary, increased pulmonary arterial pressure and right

ventricular preponderance persist at altitudes above 4000 m well

beyond infancy in Andean populations. Because these find-

ings have not been related to clinical signs, they have beenconsidered as adaptive responses to high altitude hypoxia. How-

ever, these changes have also been described in infants in La

Paz, Leadville and Lhasa who developed symptomatic acute or

subacute pulmonary hypertension (Khoury and Hawes, 1963;

Hurtado Gomez and Calderon, 1965; Sui et al., 1988; Niermeyer

et al., 1998). Thus, caution should be exercised before con-

sidering asymptomatic pulmonary hypertension as a universal

adaptive response.

3.2. Later cardiopulmonary changes in high altitude

children and adolescents

In Peruvian children living at the same altitude in Tintaya,Marquiri, and Nunoa (4100 m), but having different degrees

of genetic admixture and different nutritional and socioeco-

nomic conditions, we showed substantially higher height and

weight in those with better nutrition and socioeconomic con-

dition (Pawson et al., 2001). This finding is suggestive of a

relatively minor influence of high altitude hypoxia on physical

growth in face of relatively advantageous socioeconomic condi-

tions (Pawson et al., 2001). Interestingly, Nunoa children, with

predominant Quechua ancestry, showed higher arterial oxygen

saturation values and lower heart rate than the other two groups,

predominantly mestizo, findings suggestive of a better degree

of adaptation in Nunoa children (Huicho et al., 2001). Fur-

ther studies are needed that compare SaO2 in Andean, Tibetan

and Ethiopian children. They should carefully assess potential

modifying factors such as migration patterns to lower altitudes,

frequency of early respiratory conditions, indoor pollution, and

nutritional and socioeconomic status.

Physical growth and functional development of the respira-

tory system seem to follow a pattern different from that in sea

level children and adolescents. Anatomic and functional studies

showedthat thethorax andrespiratorysystem display an acceler-

ated growth and maturation in high-altitude children (Frisancho,

1976; Frisancho, 1969; Mueller et al., 1978). Also, children with

a genetic ancestry suggestive of long-term exposure to high alti-

tude seem to have higher chest dimensions relative to stature

and higher respiratory functional measurements than children of

European ancestry living at high altitude (Greksa, 1986, 1988;

Greksa et al., 1987, 1988; Stinson, 1985).

As it has been shown in infants, several electrocardiographic,

vectorcardiographic, hemodynamic and histopathologic studies

in children and adolescents living at high altitude have shown

persistent hypertrophy of the pulmonary artery muscular layer,asymptomatic pulmonary artery hypertension and a related right

ventricular hypertrophy. As we already mentioned above, these

characteristics persist well beyond infancy and extend into late

childhood, particularly in children living at extreme altitudes

(Marticorena, 1983; Penaloza et al., 1960, 1961, 1964). A recent

study in healthy Tibetan and Han children aged 712 years

also showed a high prevalence of ECG abnormalities consis-

tent with right heart strain in both groups, with no difference

between the two ethnic groups or sexes. Children were studied

at two altitudes at 3500 and 4500m. These results contrast with

other reports showing higher rates of chronic altitude sickness in

Han Chinese children. The authors conclude that other studiesshowing higher observed rates of symptomatic chronic altitude

sickness in Han Chinese children suggest that extracardiologic

factors play a role in the pathogenesis of the disease. They nev-

ertheless acknowledge limitations of their study, including small

sample size and the low sensitivity of the electrocardiogram in

the detection of right ventricular strain (Hulme et al., 2003).

Overall, all the above research on developmental cardiopul-

monary responses in children living at high altitude show

consistently a prolonged right ventricular predominance beyond

infancy and a concomitant persistence of asymptomatic pul-

monary artery hypertension, characteristics that seem to reflect

an adaptive set of strategies in Andean and Tibetan children liv-

ing at high altitude. However, the description of symptomatichigh altitude pulmonary hypertension and of altitude-related

structural heart abnormalities in different populations of chil-

dren living in Bolivia, Leadville and Lhasa (Hurtado Gomez

and Calderon, 1965; Khoury and Hawes, 1963; Niermeyer et

al., 1998; Sui et al., 1988; Niermeyer et al., 2002; Miao et al.,

1988; Alzamora Castro et al., 1960) strongly suggest the exis-

tence of differing pulmonary artery pressure response patterns

to high altitude hypoxia among different populations. This is

similar to the erythropoietic and SaO2 responses, which show

different patterns in Andean, Tibetan and Ethiopian populations.

In some populations the absence of a delayed regression of

an increased pulmonary artery pressure and right ventricular


10/14


preponderance may be indicating a better adaptation to high

altitude, whereas in those populations with a slower change to

adult patterns or even absence of such transition, the responses

may be indicating a lower degree of adaptation. We can advance

the hypothesis that, similarly to what has been described in adult

populations, different patterns of adaptation to high altitude are

probably present in relation to the pulmonary artery response

in Andean, Tibetan and Ethiopian children. We need further

research to confirm this hypothesis and also to identify the

time-period of the occurring changes. Furthermore, factors such

as genetic admixture, patterns of migration to lower altitudes,

outdoor and indoor pollution, nutritional and socioeconomic

conditions were not adequately addressed or they were com-

pletely absent in most of the above cited studies. Thus there

is a legitimate concern on whether the pattern of cardiopul-

monary responsesis consistently similar whensuch factors differ

among different study populations of children. These factors

may act to modify the pulmonary artery pressure response to

hypoxia. Further studies aimed at assessing the possible influ-

ence of these conditions on developmental cardiopulmonaryresponses of different high altitude children populations are

warranted.

In this regard, we recently studied preschool and school-

aged children resident at 4100 m in Tintaya, Peru (Huicho et al.,

2005; Huicho and Niermeyer, 2006, 2007). Our broad objective

was to correlate clinical assessments with anatomic and physio-

logic cardiovascular findings. Other specific objectives included

the determination of prevalence of pathologic cardiopulmonary

findings and of prevalence of symptomatic high altitude pul-

monary hypertension. We took advantage of an existing mining

settlement that comprised 150 families, with 336 children. The

study population also facilitated exploration of genetic and envi-ronmental factors such as admixture, patterns of exposure to

altitude, and duration of residence at high altitude. We admin-

istered a structured questionnaire to every selected family for

obtaining information on surnames of children, parents, and

grandparents and on language(s) spoken in the household as

indicators of ethnic origin. Questions also covered the alti-

tude of birth for each child and altitude of residence prior to

arrival at Tintaya, duration of residence in Tintaya, and typi-

cal annual pattern of movement. Problems during the perinatal

period were sought, as were childhood health problems, with

particular emphasis on cardiorespiratory ailments and chronic

conditions. The responses to altitude change, level of activ-

ity at high altitude, and environmental smoke exposure werealso assessed. Subsequently, all children underwent a complete

physical examination, anthropometry, oxygen saturation mea-

surements, hemoglobin determination, electrocardiography and

echocardiography. We found that most children showed at least

some degree of high altitude ancestry, based on analysis of

maternal and paternal surnames and the surnames of maternal

and paternal grandparents. Our schoolchildren showed also a

high mobility pattern to lower altitudes, most of them traveled

to lower altitude during summer vacation and winter break each

year. They enjoyed furthermore a good nutritional status and

lived in favorable housing conditions. In those children, we did

not find evidence of pulmonary artery hypertension out of the

context of heart structural abnormalities. The prevalence of such

abnormalities was also similar to that of sea level. Controlling

for potential confounding factors that may influence echocardio-

graphic and electrocardiographic measurements including sex,

nutritional status, chest dimensions, pulse oximetry, hemoglobin

concentration, ethnicity, length of residence at high altitude, or

parental history of exposure to high altitude, did not reveal a

consistent influence of such variables.

Our findings clearly differ from previous studies. Several

explanations may be offered for these discrepant results. Most

children showed at least some degree of high altitude genetic

pattern through patronymic evaluation. This trait may have con-

ferred them a genetic adaptive advantage, although this cannot

explain completely the absence of pulmonary hypertension. In

addition, other factors such as the frequent descent to lower

altitudesmay have attenuated theeffectsof hypoxia on thedevel-

opment of cardiopulmonary system. Although we were not able

to assess completely whether the outdoor and indoor pollution

influences developmental pattern, it is plausible that pollution

can affect important periods of the cardiopulmonary develop-ment process. It is known that indoor pollution is a risk factor

for respiratoryinfections, and thuswe can speculatethat frequent

presentation of such illnesses may impair the setting of adaptive

cardiopulmonary responses in early life. Our study population

enjoyed unusually good outdoor andindoor conditions for a high

altitude mining settlement. Finally, we acknowledge the need to

perform studies that adequately assess the real role of pollution

and of the prevalence of respiratory infections on the patterns

of cardiopulmonary development through comparative observa-

tion of high altitude children living under different degrees of

exposure to pollutants.

4. Symptomatic high altitude pulmonary hypertension

The previous findings on cardiopulmonary responses to high

altitude in infants and children are clearly relevant to the risk of

development of high altitude-related cardiopulmonary pathol-

ogy in general and more specifically of a clinical condition

called high altitude pulmonary hypertension. There are several

reports of the latter in the literature and all have been described

in infants, children and adults resident at altitude (Grover et al.,

1966; Hurtado Gomez and Calderon, 1965; Khoury and Hawes,

1963; Lin and Wu, 1974; Sui et al., 1988; Wu et al., 1998; Wu

and Miao, 2002; Wu et al., 2003). The hallmark of the condition

is the presence of pulmonary artery hypertension and it is associ-ated with several clinical features. A recent consensus statement

on high altitude diseases defines high altitude pulmonary hyper-

tension as a clinical condition occurring in children and adults

resident above 2500m and characterized by a mean pulmonary

artery pressure above 30 mm Hg or a systolic pulmonary artery

pressure above 50 mm Hg, right ventricular hypertrophy, heart

failure, moderate hypoxemia and the absence of excessive ery-

throcytosis (Leon-Velarde et al., 2005). There has been some

confusion in the literature and several terms have been histori-

cally used, including chronic mountain sickness of the vascular

type, high altitude heart disease, hypoxic cor pulmonale, infant

subacute mountain sickness, pediatric high altitude heart dis-


11/14


ease, and adult subacute mountain sickness (Leon-Velarde et

al., 2005).

The consensus statement did not provide information on the

prevalence of high altitude disease and listed some risk fac-

tors, includingprevious pulmonaryarterial hypertension, history

of persistent excessive pulmonary vasoconstriction in response

to hypoxia, and hypoxemia during sleep (Leon-Velarde et al.,

2005). An adequate assessment of prevalence requires the study

of samples with known denominator. Unfortunately, most stud-

ies referring to high altitude disease in children did not provide

this substantial information. Similarly, the determination of risk

factors ideally needs cohort studies or casecontrol studies ade-

quately controlled for bias, and we have not found such studies

in the reviewed literature.

It seems from the above discussed studies that symptomatic

high altitude pulmonary hypertension is (1) a potentially life-

threatening condition presenting in infants, children and even

adults with risk factors and(2) that subjects without high altitude

genetic ancestry may be more susceptible. Among populations

with some degree of genetic admixture, the pre-existence ofpulmonary artery hypertension may be an important risk factor.

The role of other factors such as indoor pollution, pre-existing

respiratory conditions such as asthma, particularly if not con-

trolled, and migration patterns to low altitudes, requires further

study.

5. Possible long-term implications of early

cardiopulmonary patterns of growth and development

at high altitude

A series of papers on the pediatric origins of adult lung

diseases has recently been published that include general devel-opmental issues and specific lung problems arising in infancy,

childhood and adulthood, which are associated with early pre-

natal or postnatal exposure to different agents (Eber and Zach,

2000; Holt and Sly, 2000; Le Souef, 2000; Robinson, 2000; Sly,

2000; Stick, 2000; von Mutius, 2000). Additional epidemiolog-

ical studies showed that exposure to factors that restrict fetal

growth, lead to low birth weight, or interfere with early postna-

tal growth, can alter lung development and have later adverse

effects on lung function and respiratory health. Major causal

factors include reduced nutrient and oxygen availability, nico-

tine exposure via maternal tobacco smoking and preterm birth,

each of which can affect critical stages of lung development

(Hafstrom et al., 2005; Harding et al., 2000; Maritz et al., 2005;Svanes et al., 2004).

Similarly, experimental studies have demonstrated that these

environmental insults can permanently alter lung structure and

hence lung functions, increasing the risk of respiratory illness

and accelerating the rate of lung aging (Harding et al., 2000;

Maritz et al., 2005). A fetus is able to mount a proliferative

response to a common allergic trigger (beta-lactoglobulin, house

dustmite, etc.) asearly as22 weeks of pregnancy (Fig.4). Mater-

nal exposure to allergens influences self-IgG production which

modulates the allergen exposure of the fetus resulting in either

primary sensitization of T cells or tolerance to the allergen.

Atopic mothers create a more Th2-orientated environment for

the developing fetus than non-atopic mothers (Warner, 1999).

Thus early manipulation of the maternal immune response

during pregnancy, either by reducing self-exposure to environ-

mental allergens or controlling her allergic reactions, may be a

method of preventing later development of allergic disease in

infants (Warner, 1999) (Fig. 4). Early postnatal antibiotic use in

the first 6 months of life preceded the manifestation of wheeze

but not eczema or allergic sensitization during the first 2 years

of life (Kummeling et al., 2007) (Fig. 4). However, there is still

incomplete understanding of the molecular and cellular mecha-

nisms by which these factors adversely affect lung development

and whether such effects can be blocked or reversed (Maritz

et al., 2005). The role of early postnatal respiratory infections

such as bronchiolitis and pneumonia in the later development

of chronic respiratory diseases including asthma and chronic

obstructive pulmonary disease is somewhat contradictory and

needs further investigation (Stick, 2000).

Chronic hypoxia is an attractive model that can be used in

animals for performing comparative studies on whether hypoxia

modifies the programming events in the fetus and the newbornand whether it influences on the risk of developing cardiopul-

monary conditions in later periods of life. In fact, cohort and/or

casecontrol studies in humans may also reveal the ways by

which chronic hypoxia operates on early periods of lifefor deter-

mining later cardiopulmonary clinical conditions in human high

altitude populations, as well as the underlying molecular mech-

anisms. Demonstration of critical periods of cardiopulmonary

growth and development that are vulnerable to chronic hypoxia

may lay the basis for developing early preventive interventions

related to lifelong permanence at high altitude.

6. Clinical and public health implications: is the

evidence strong enough?

Thestrength of the available evidence is currently not enough

for implementing sound clinical and health policy recom-

mendations for preventing and managing high altitude-related

conditions in children going to or already living at high alti-

tude. However, the implication is that newcomers, particularly

those of non-high altitude ancestry, may be at more risk of

developing symptomatic high altitude pulmonary hypertension.

Also, it seems that those infants and children with pre-existing

pulmonary artery hypertension and those with an acute respi-

ratory infection should be cautioned against traveling to highaltitude, particularly against a rapid ascent. In addition, it seems

advisable to recommend supplementary oxygen to infants and

children living at high altitude and suffering from an acute respi-

ratory infection, particularly pneumonia, when values of SaO2are lower than those considered normal for the altitude of res-

idence. Pneumonia is known to lead to hypoxemia and it very

likely aggravates any pre-existing high altitude hypoxia. Normal

SaO2 values published for infants and children living at sea level

are clearly not applicable to children living at different altitudes

and thus further investigation is warranted for identifying cut-

off SaO2 values below which supplementary oxygen should be

mandatory (Duke et al., 2002; Huicho, 2003).


12/14


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