Physiology of High-Altitude Acclimatization Sonam Chawla and Shweta Saxena (left) Sonam Chawla is an MTech in Biotechnology. Currently she is pursuing her doctoral studies in Defence Institute of Physiology and Allied Sciences, Delhi as a CSIR Research Fellow. (right) Shweta Saxena is a research scientist at Defence Institute of Physiology and Allied Sciences, Delhi. She is involved in designing pharmacological strategies for rapid acclimatization to high altitude with an aim to improve performance of Indian soldiers during high-altitude deputations. Keywords High altitude, hypobaric hypoxia, acclimatization, HIF-1 Travel to high altitude exposes the human body to a variety of stresses, the most prominent being reduced available oxygen with increase in altitude due to reduced partial pressure of oxygen. Several physiological responses are initiated in the human body to promote faster acclimatization to these adverse environmental conditions. These physiological and molecular readjustments encompassing acclimatization, namely, hypoxic ventilatory response, diuresis, increased cardiac output, improved oxygen carrying capacity and cerebral blood flow, Hypoxia inducible factor 1 stabilization, etc., converge to a single outcome, ensuring optimal bioavailability of oxygen. In this article, we describe the basic acclimatization framework mentioned above. Introduction Human movements in extremely hostile environments such as scorching heat of deserts, humid coastal areas and frigid high altitude lead to detrimental physiological effects, yet it is unavoidable due to military, sports, pilgrimages and tourism activities. Of these harsh climatic adversities, high altitude is one of the most extreme environments posing challenges to human survival and performance. Extremely low ambient temperatures, high velocity winds, low humidity, high intensity solar radiation and reduced atmospheric pressure are variety of stresses being faced during travel to high altitude. High altitude (above 9000 feet) has decreased atmospheric pressure which decreases the oxygen partial pressure in the ambient air. This means that although the relative percentage of oxygen is unaltered, the number of molecules of present per breath decreases. The state of sub-optimal availability due to decreased ambient barometric pressure is termed as hypobaric 538 RESONANCE June 2014
hypoxia. Since is a primal requirement for life processes, its inadequate bio-availability to tissues or organs leads to deficiencies in biological processes such as energy production, biosynthesis and breakdown of cellular/tissue components, cognition, mental coherence, etc [1]. Hypobaric Hypoxia: The Mathematics Behind It AccordingtotheIdealGasLaw, the partial pressure of a gas in the air mixture is determined as, The state of suboptimal availability due to decreased ambient barometric pressure is termed as hypobaric hypoxia. P=Fi B, where Fi is the mole fraction of the gas in air mixture and B is the ambient barometric pressure. Thus, at sea level, the partial pressure of,p = 20.93% 760 mmhg = 159 mmhg. But as the altitude increases and the barometric pressure falls, the partial pressure of the ambient air concomitantly decreases, along with that of the component gases. For ease of understanding, the following example of partial pressure calculation is given: The altitude of Siachen glacier is 18000 feet which is equivalent to 395 mmhg. Thus the partial pressure of at Siachen glacier would be = 20.93 395 = 82.67 mm Hg, which is nearly half of the sea-level partial pressure [2]. Biological Responses to Hypobaric Hypoxia The molecular and physiological adjustments to compensate for reduction in bio-available is termed as acclimatization which is of utmost importance since a successful stay at high altitude depends largely on timely and effective acclimatization responses. However, in a biological system, acclimatization can never be absolute and thus is never able to completely abolish the ill-effect of hypoxia exposure leading to high altitude pathologies. Environmental hypoxia ultimately affects the oxygen delivery to tissues. This is a cumulative outcome of physiological transport RESONANCE June 2014 539
Figure 1. Physiological adjustments to improve acclimatization to hypobaric hypoxia. system to hold oxygen, its flow rate and the partial pressure gradient between blood and the tissues that drives oxygen diffusion. For instance, the driving force for gas-exchange at the alveolar-capillary junction is driven by partial pressure gradient of and C in the alveolar air and in the blood. At high altitude, due to the fall in ambient partial pressure, the alveolar partial pressure of falls; this further reduces its gradient against the partial pressure of in deoxygenated blood leading to reduced diffusion of into the arterial blood. Similarly, as the pressure differential between venous C and alveolar C decreases, the driving force for the removal of C diminishes and thus a higher amount is retained in the arterial blood at high altitude. This lower oxygen partial pressure (hypoxia) and raised C partial pressure (hypercapnia) in the arterial blood trigger a series of compensatory adjustments by the various organ systems, as discussed below [3] (Figure 1): Respiratory Changes The immediate effect of exposure to high altitude hypoxia is faster respiration rate, i.e., pulmonary hyperventilation, which is merely 540 RESONANCE June 2014
a first visible symptom of deep-seated respiratory imbalances, acid base imbalance and other complex metabolic disturbances. Hyperventilation at high altitude is controlled by the stimulus of peripheral chemoreceptor organs along the aorta and the carotid sinus. The carotid body is a highly vascularized cluster of neuronlike glomus cells (type-i) surrounded by sustentacular type-ii cells located at the bifurcation of the common carotid arteries. The glomus cells are sensitive to changes in arterial partial pressure and the raised C partial pressure, and signal to the respiratory centres in the central nervous system to increase the rate and depth of ventilation or Hypoxic Ventilator Response (HVR) [4]. In response to peripheral chemoreceptors, the respiratory centre is triggered in cerebral pons and medulla and the signals are relayed to the diaphragm, intercostal muscles and stretch receptors of the lungs to facilitate HVR. This ventilatory response sets in within a few hours of hypoxic exposure reinstating the driving force of diffusion by raising alveolar ventilation by 25 30% leading to an increased partial pressure of oxygen in the alveolar spaces. Partial pressure of oxygen in alveoli (P A )is calculated as: Aortic and carotid body are the organs which sense ambient hypoxia and trigger the primary adaptive response hypoxic ventilatory response (HVR). P A = P I (P A C )/R, where P I is the partial pressure of oxygen in the inspired air, P A C is the partial pressure of C in the alveoli, and R is the respiratory quotient determined by the type of substrate used for respiration. Thus, if the rate and depth of breathing is raised, it also increases the clearance of C in the alveoli, decreasing the partial pressure of C. As evident from the above equation, higher the ventilation, lower the P A C and higher the P A. Increased clearance of C from the blood leads to increased ph, i.e., alkalosis, which is corrected by the kidneys via renal compensation mechanism (refer to fluid balance section of this article) [3, 5]. Other components of respiratory acclimatisation are the increased pulmonary arterial pressure (PAP) and hypoxic pulmonary vasoconstriction (HPV). The compression of pulmonary artery, i.e., RESONANCE June 2014 541
Box 1. Pathological Symptoms due to Mal-Acclimatization to Hypobaric Hypoxia. Lungs: Cheyne Stokes breathing, compromised integrity of alveolar-endothelial surface, muscularization of pulmonary vasculature, HAPE. Heart: Extended duration of increased PAP, hypertrophy of right ventricle and left ventricle. Brain: Brain swelling, increased intracranial pressure, decreased cognitive performance, blood-brain barrier integrity compromised, HACE. Blood: Polycythemia, hypercoagulable state. Kidneys: Proteinuria, excessive loss of fluid from body dehydration. raised PAP, aids in increased flow of deoxygenated blood to the lungs to improve oxygenation of larger volume of blood in short duration. Further, to improve blood oxygenation, HPV occurs which is an interesting phenomenon where against the vasodilation observed in the general body, the pulmonary vasculature constricts in response to hypoxia. Let us recollect the basics of respiratory physiology that disproportionate oxygen content occurs in lungs due to the complex structure of the respiratory tree. To improve blood oxygenation during hypoxia, HPV occurs to direct the blood supply to selective alveoli with higher oxygen content to further enrich the ventilation/perfusion ratio. But the drawback of this increased PAP and HPV is endothelial dysfunction in pulmonary vasculature and over a long period the pulmonary vasculature integrity is compromised leading to inflammation and plasma leakage in the alveolar spaces. This condition is termed as High Altitude Pulmonary Edema (HAPE) (Box 1) [6]. Cardiovascular Changes Hypoxia-induced respiratory adjustments are closely associated with cardio-vascular changes as well. Hypoxia-induced respiratory adjustments are closely associated with cardio-vascular changes as well. Heart is the primary organ responsible for pumping blood to the entire body and ensuring optimal oxygen delivery to each organ system. Oxygen delivery (D ) is defined as: D =Q A, where Q is cardiac output which further depends on heartbeat rate and stroke volume (volume of blood pumped by left ventricle in 542 RESONANCE June 2014
each heartbeat). A is arterial oxygen content determined by oxygen saturation in the blood and is boosted by haematological adaptive measure discussed in the respective section. As the altitude increases, in order to restore D, increased cardiac output is observed along with increased velocity of blood flow, greater fall in venous pressure, rise in pulse rate, fall in peripheral blood volume of the cerebral flow within the first twelve to thirtysix hours. The raised Q is maintained only in the initial period of stay at high altitude, and is normalized within a few weeks of stay at altitude. However, due to continued pulmonary vasoconstriction, the right ventricle has to exert more force, leading to marked increase in PAP and right ventricular hypertrophy. Left ventricle hypertrophy is also observed, due to the same reason of excessive pumping action (Box 1) [7, 8]. Cardiac adaptive responses include increased heart rate and stroke volume. Haematological Changes Since arterial blood is the principal oxygen carrier in the body, raising the arterial oxygen content is the most important physiological adjustment to mitigate tissue hypoxia. Improvement in arterial oxygen content occurs by increase in haematocrit, haemoglobin and erythrocyte levels during hypoxia exposure. This boost in oxygen-carrying capacity is a direct outcome of erythropoietin (Epo) secretion from the kidneys into the blood stream within 2 3 hours of hypoxic exposure. Epo triggers erythropoiesis, i.e., red blood synthesis, in the bone marrow over the period of stay at high altitude. Acute acclimatization is associated with diuresis, i.e., increased urine excretion. This facilitates loss of body water leading to reduced plasma volume thereby effectively increasing the proportion of red blood cells (RBCs) per unit volume of blood, a phenomenon called haemoconcentration. Haemoconcentration is an efficient way to increase oxygen carrying capacity of a given volume of blood [9]. Although erythropoiesis and diminished plasma volume due to haemo-concentration are adaptive responses to facilitate optimal oxygen supply to body cells and tissues, they are associated with a risk of hyperviscosity and thrombosis. Haematological adaptations to hypoxia include erythropoiesis, haemoconcentration and increased levels of 2, 3-DPG. RESONANCE June 2014 543
Just as oxygen binding and carrying mechanisms, oxygen delivery to tissues is equally important in vascular acclimatization to high altitude. The oxygen binding and carrying is increased by elevated Hb (haemoglobin), but the dissociation of the bound oxygen from Hb and its delivery to the tissue needs to be enhanced further. This is achieved by increasing the concentration of 2, 3-diphosphoglycerate (2,3-DPG) in the RBCs. 2,3-DPG is a structural analog of the glycolytic intermediate 1,3-diphosphoglycerate and is an allosteric regulator of Hb affinity to oxygen. Its binding at an allosteric site leads to lower affinity of Hb for oxygen and hence a higher deliverability in the tissues [10]. Central Nervous System HVR also regulates cerebral blood flow to ensure optimal oxygen delivery to the brain. The brain accounts for nearly 20% of the total oxygen consumption by the body. Compromised oxygen availability at high altitude is known to affect cognition, arithmetic ability, memory and decision-making. The molecular bases for these mental impairments are yet being unravelled in neurotransmitter metabolism and intracellular calcium flux. Ventilatory adaptation-induced changes in the partial pressures of arterial carbon dioxide (P a C ) and oxygen (P a ) also regulate cerebral blood flow (CBF). Although P a C elevation is known to cause vasodilation and increase in CBF, while reduced P a C causes vasoconstriction and decreased CBF, a fall in P a below a certain threshold (< 40 45 mmhg) also produces cerebral vasodilatation. Owing to this, upon initial exposure to hypoxia, CBF is elevated due to hypoxia instead of responding to hypocapnia, attenuating after 2 3 days, since ventilatory acclimatization increases P a and reduces P a C at this time. Maleficent changes in the vasculature environment and compromised blood-brain barrier integrity lead to cerebral edema, pathologically classified as Acute Mountain Sickness (AMS) or the more extreme form High Altitude Cerebral Edema (HACE) (Box 1) [11, 12]. Fluid Balance and Hormonal Response As mentioned earlier, diuresis is an important acclimatisation 544 RESONANCE June 2014
response facilitating haemoconcentration before the actual red blood synthesis takes place, which starts within the first week of high altitude exposure. Hypoxia diuresis response (HDR) is significantly associated with acclimatisation and failure of HDR to set in is associated with risk for acute mountain sickness. HDR also contributes to regulation of body ph, as the respiratory alkalosis due to HVR is offset by increased excretion of sodium and bicarbonate ions in the urine and retention of hydrogen ions (shifting towards acidosis). Renal acclimatisation via diuresis leads to haemoconcentration and facilitates higher oxygen carrying capacity in the organism. Hormonal responses play very important regulatory functions during high altitude exposure. Under this, the role of renin angiotensin aldosterone axis as an important regulator of diuretic response has been studied in great detail. At sea level, renin secreted from kidneys converts plasma angiotensinogen to angiotensin I, and subsequently angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II. This angiotensin II then stimulates secretion of aldosterone from the adrenal glands and vasopressin from the pituitary gland as well as raises the vascular resistance leading to raised blood pressure. The HDR is noted to be an outcome of reduced circulatory aldosterone concentration as well as renin activity, since aldosterone is an anti-diuretic hormone that facilitates retention of sodium and water. A more important determinant is the raised ratio of renin activity to aldosterone concentration indicative of diminished responsiveness of aldosterone to renin as a consequence of reduced ACE activity [13]. On the flip side, a prolonged and pronounced HDR is also associated with a risk of dehydration due to insensible loss of fluids and reduced fluid intake due to decreased thirst at high altitude (Box 1). Molecular Response Hypoxia Inducible Factors Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor regulating the induction/repression of hypoxia responsive genes involved in glucose uptake, glycolysis, metabolism, ph balance, angiogenesis, erythropoiesis, and other transcription factors which preserve biological function and confer defence against hypoxia. RESONANCE June 2014 545
It is composed of a constitutively expressed HIF-1 subunit present in the cytoplasm and an oxygen sensitive subunit HIF- 1. During normoxic conditions, the HIF-1 subunit is rapidly degraded, due to the hydroxylation of proline residues at 402 and 564 positions by prolyl hydroxylases (PHD), marking it for ubiquitination by the Von Hippel Lindau E3 ubiquitin ligase. The hydroxylation reaction by PHD is oxygen dependent, and hence in a hypoxic situation the PHD action is limited and HIF-1 is preserved from proteasomal degradation. Hereafter, HIF-1 and form a dimer and translocate to the nucleus. Here they bind the hypoxia response elements (HREs) in the promotor regions of the target genes [14, 15]. Simulating Hypobaric Hypoxia for Research Physiological responses to hypoxia being an interesting and challenging area of research, facilities have been developed to simulate the field conditions in research laboratories since conducting field experiments exposes the researchers to harsh high altitude conditions. Nowadays, most high-altitude research is being conducted on walk-in human and animal decompression chambers which nearly simulate the high-altitude environment and are equipped with real-time physiological monitoring equipments as well. The chamber essentially contains an airtight enclosure which is depressurised at a constant rate using a vacuum pump. Here the rate of depressurising is regulated to simulate the rate of ascent to high altitude and similarly the release of vacuum is regulated to simulate the rate of descent to high altitude. These chambers have proven to be a valuable tool in studying real-time physiological responses to high altitude exposure and have helped immensely to study the efficacy of several pharmacological interventions to improve acclimatization. For adventurous readers of this article, who intend to sojourn to high altitudes, basic guidelines to facilitate acclimatisation have been described in Box 2. 546 RESONANCE June 2014
Box 2. Do s and Don ts During Ascent and High-Altitude Stay Do s Ascend slowly Rest sufficiently for the initial 72 hours Take plenty of fluids to avoid dehydration, and high fibre & low salt nutritious food Use snow goggles, wear layered clothing Don ts Avoid physical exertion: do not walk too fast or exercise Refrain from alcohol consumption, and using sleeping pills Do not continue climbing higher altitude if signs of mountain sickness appear Do not hesitate to take medical help or descend if physical and cognitive health deteriorates Suggested Reading [1] S S Purkayastha, U S Ray, BSArora, PCChhabra, LThakur, P Bandopadhyay and W Selvamurthy, Acclimatization at high altitude in gradual and acute induction, Journal of Applied Physiology, Vol.79, No.2, pp.487 492, 1995. [2] R N Pittman, Regulation of Tissue Oxygenation, Eds. DNGranger, J P Granger, Morgan and Claypool Life Sciences, California, p.19, 2011. [3] J P R Brown and M P W Grocott, Humans at altitude: physiology and pathophysiology, Continuing Education in Anaesthesia, Critical Care & Pain, doi: 10.1093/bjaceaccp/mks047, 2012. [4] N R Prabhakar, sensing at the mammalian carotid body: why multiple sensors and multiple transmitters?, Experimental Physiology, Vol.91, No.1, pp.17 23, 2006. [5] M V Singh, A K Salhan, S B Rawal, A K Tyagi,NKumar,SSVerma and W Selvamurthy, Bloodgases, hematology, and renal blood flow during prolonged mountain sojourns at 3500 and 5800 m, Aviation, Space and Environmental Medicine, Vol.74, No.5, pp.533 536, 2003. [6] J T Berg, S Ramanathan and E R Swenson, Inhibitors of hypoxic pulmonary vasoconstriction prevent high-altitude pulmonary edema in rats, Wilderness & Environmental Medicine, Vol.15, No.1, pp.32 37, 2004. [7] R Naeije, Physiological adaptation of the cardiovascular system to high altitude, Progress in Cardiovascular Diseases, Vol.52, No.6, pp.456 466, 2010. [8] D Martin and J Windsor, From mountain to bedside: understanding the clinical relevance of human acclimatisation to high-altitude hypoxia, Postgraduate Medical Journal, Vol.84, pp.622 627, 2008. RESONANCE June 2014 547
Address for Correspondence Shweta Saxena Experimental Biology Division Defence Institute of Physiology and Allied Sciences Defence Research and Development Organisation Lucknow Road, Timarpur Delhi 110054 Email: shweta.dipas@gmail.com [9] J S Windsor and G W Rodway, Heights and haematology: thestory of haemoglobin at altitude. Postgraduate Medical Journal, Vol.83, No.977, pp.148 151, 2007. [10] P D Wagner, H E Wagner, B M Groves, A Cymermanand C S Houston, Hemoglobin P(50) during a simulated ascent of Mt. Everest, Operation Everest II. High Altitude Medicine & Biology, Vol.8,No.1,pp.32 42, 2007. [11] S J Lucas, K R Burgess, K N Thomas, J Donnelly, K C Peebles, R A Lucas, J L Fan, J D Cotter, R Basnyat and P N Ainslie, Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m, Journal of Physiology, Vol.589, (Pt 3), pp.741 753, 2011. [12] J B West, The Physiologic Basis of High-Altitude Diseases, Annals of Internal Medicine, Vol.141, pp.789 800, 2004. [13] D R Woods, M Stacey, N Hill and N de Alwis, Endocrine aspects of high altitude acclimatization and acute mountain sickness, Journal of the Royal Army Medical Corps., Vol.157, No.1, pp.33 37, 2011. [14] G Höpfl, O Ogunshola andm Gassmann,Hypoxia and high altitude. The molecular response, Advances in Experimental Medicine & Biology, Vol.543, pp.89 115, 2003. [15] S Sarkar, P K Banerjee and W Selvamurthy, High altitude hypoxia: an intricate interplay ofoxygen responsivemacroevents and micromolecules. Molecular and Cellular Biochemistry, Vol.253, Nos.1 2, pp.287 305, 2003. 548 RESONANCE June 2014