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Hypoxia – An Overview

“In the life of aerobic organisms, oxygen is an essential element. The central role of oxygen is due to the fact that it is the final acceptor of electrons in the mitochondrial respiratory chain. This allows the ultimate process of oxidative phosphorylation and the generation of cellular energy, in the form of adenosine triphosphate (ATP). ATP is used in most reactions that are necessary to maintain cellular viability. Under normoxia a cell continuously maintains a high and constant ratio of cellular ATP/ADP (adenosine diphosphate) ratio in order to survive. The dependence of cells on a high constant ATP/ADP ratio means a dependence on oxygen. Therefore, a reduction of the normal oxygen supply (hypoxia) will have consequences on the cell viability.”1

It is our red blood cells that are responsible for carrying oxygen to our tissues. We constantly use this oxygen as our main source of energy. A molecule within the erythrocytes (red blood cells) called hemoglobin, causes oxygen molecules to adhere to it, which are then carried throughout our bodies and distributed by the circulating blood. Therefore, when there is shortage of blood or shortage of hemoglobin (anemia) structures to ‘capture’ the surrounding oxygen, we are deprived of the ability to distribute oxygen inhaled by our lungs, to all our tissues. This occurs for instance in atherosclerotic processes in the coronary artery, where due to buildup of plaque within the artery lumen, there is insufficient blood being supplied to the cardiac muscle, resulting in infarction. This scenario, where a particular organ is not receiving adequate amounts of blood/oxygen, is called ischemia. When our organs are denied oxygen, they are said to be in a hypoxic state.

“The term hypoxia is quantitatively related to the organ, tissue, and even cell type. A hypoxic state indicates that an imbalance of oxygen is present and baseline function is compromised as a result of this imbalance. The imbalance of oxygen could result from a lack of oxygen or an excessive demand for oxygen. Baseline function in this context means carrying out normal bodily or cellular functions such as heart muscle beating or a neuron firing an action potential, also known as homeostasis. Hypoxia can be transient, acute, or chronic. Hypoxic conditions occur with a persistent lack of oxygen. Individual tissues have differing oxygen tensions and oxygen demands; on average, tissues at rest utilize 5–6 mL of O2 per deciliter of blood delivered. Hypoxia could be fairly defined as a scenario when tissue fails to receive this amount of oxygen. However, hypoxia is better understood as a component of the pathology of many disease states, such as ischemia.”2

“Hypoxia orchestrates a multitude of processes of molecular pathway responses. However, in the higher organisms, the cellular oxygen sensor itself is unknown. Several mechanisms have been proposed as to how a cell senses the lack of oxygen.  The traditional mechanism of hypoxia sensing involves a heme protein. This protein has been suggested because most proteins capable of binding O2 contain iron, which usually is in the center of a heme moiety.  Hypoxia could be detected by a reversible binding of O2 at the heme site, which causes an allosteric shift in the hemoprotein, inactive (oxyform) to active (deoxy) form. There are many kinds of heme containing oxygen binding proteins, but no real candidate has been found yet. Another mechanism, better known as the “membrane hypothesis” or “membrane model”, involves ion channels. It is reported that the ionic currents/conductance are inhibited during hypoxia in the O2-sensitive channels, K+- selective, Ca2+ and Na+ channels.”3

How do we adapt?

Our bodies have mechanisms to attempt to normalize oxygen levels. We have all experienced some of these forms of compensation: deep breaths for greater oxygen intake, an increase in inhalation/exhalation frequency, a rise in systolic pressure to pump more oxygen carrying erythrocytes into circulation. Vasodilation helps make the ‘highways’ through which blood circulates broader for more blood cells to fit as it passes through and into tissue. These changes occur within the body quite rapidly and are a very important defense mechanism against hypoxia.

“During hypoxia resulting from an inadequate airway, tissue perfusion may still be present with the resulting transport of other substrates (e.g. glucose) to the tissue, and removal of metabolites (i.e. carbon dioxide (Co2) and hydrogen ions (H+)) from it. While the availability of glucose provides the potential for continued production of adenosine triphosphate (ATP) through anaerobic metabolism, hyperglycaemia may be detrimental during hypoxaemia, perhaps due to intracellular acidosis. There exist both immediate adaptations to severe hypoxia that may provide protection over a longer period of time (e.g. ischaemic preconditioning) and longer‐term adaptations (e.g. altitude acclimatisation). There is considerable variation in hypoxia tolerance across vertebrates, but even humans manifest a remarkable adaptation to hypoxia when given enough time. It has been estimated that the arterial Po2 in climbers at the top of Mt Everest is ∼28 mmHg, clearly a level that would cause significant brain injury or death if imposed acutely.”4

If oxygen is manageably low, brain stem chemoreceptors send a signal to the brain causing a reflexive reaction that causes a rise in the number of breaths we take. This action becomes even more dramatic when carbon dioxide levels rise as oxygen levels diminish, if breathing becomes too rapid it is known as hyperventilation. The important takeaway here is how chemoreceptors located in the brain measure levels of oxygen versus carbon dioxide and how they signal to our brain to make necessary adjustments to ensure proper breathing, adequate oxygen saturation along with the synchronized expulsion of carbon dioxide as we exhale.

“Under chronic moderate hypoxia multicellular organisms trigger a multitude of cellular responses in order to survive and maintain the oxygen homeostasis in function of time. Here the most important responses will be described:”5

 

Cellular responses needed to survive and maintain oxygen homeostasis
Fig. 1. Cellular responses needed to survive and maintain oxygen homeostasis

 

If mild hypoxia persists chronically, the body will compensate via hematopoiesis in the bone marrow. Hematopoiesis is the process by which we produce more blood elements. Therefore, it is not uncommon for chronically hypoxic patients to have polycythemia which is an increase in the number of red blood cells and a higher concentration of hemoglobin, resulting in a   denser or thicker blood. The drawback of this reaction to hypoxia is that it forces the cardiac muscle to pump harder since thick blood is more difficult to circulate.

“To meet the increased oxygen demands, the body undergoes physiologic processes that involve the lungs, heart, and vasculature. Cardiac output is increased as needed by increases in stroke volume and heart rate, delivering more blood, and hence, more oxygen to the capillary beds per unit of time. Pulmonary vessels constrict shunting blood from areas of low oxygen tension in the lungs to areas with higher oxygen tension, thereby maximizing the exchange of oxygen in the hemoglobin and plasma. This allows for the maintenance of the reservoir of oxygen stored by hemoglobin in red blood cells. Systemic vessels dilate to perfuse tissues with higher oxygen demand, which also aids in blood delivery, and hence, oxygen delivery.”6

All self-activating mechanisms are obviously extremely important to maintain proper gas saturation levels. In extreme or poorly managed hypoxia however, the body is unable to adequately compensate and blood pressure dips, respiratory failure ensues and cardiac arrest is imminent.

Consequences of hypoxia

“The most evident factor linking metabolic consequences and IH is sympathetic overactivity that increases catecholamine levels, which produces hyperglycemia and hyperinsulinemia and promotes insulin resistance. Moreover, activation of the sympathetic system may stimulate the release of adipocyte-derived inflammatory mediators such as interleukin-6, tumor necrosis factor-α, and leptin, factors which can induce lipolysis and release of free fatty acids from adipose tissue; with the latter impairing glucose uptake by the tissues contributing to hyperglycemia and hyperinsulinemia.”7

“Systemic inflammation, oxidative stress, endothelial dysfunction, and increased sympathetic activity induce hemorheologic alterations with increased cell adhesion molecules, endothelial cell dysfunction, thrombotic factor activation, procoagulant activity, and vascular remodeling, all factors contributing to atherosclerotic risk and consequent cardiovascular morbidity and mortality. Animal studies suggest that reduction of endothelial-dependent vasodilatation is the most important precursor for atherosclerosis, related to increased oxidative stress with reduced levels of nitric oxide (NO). Rats exposed to CIH (Intermittent chronic hypoxia) exhibit a reduced vasodilatation in response to infusion of acetylcholine and reduced vasoconstriction following NO (nitric oxide) synthase inhibition. Thus, increased vascular inflammation and lipid peroxidation in response to oxidative stress play a key role on such endothelial dysfunction.” 8

“Chronic severe hypoxemia is associated with a number of diseases, including congenital heart disease, chronic obstructive pulmonary disease, severe asthma, pulmonary fibrosis, hepatopulmonary syndrome and central hypoventilation syndromes from brain tumors, amyotrophic lateral sclerosis, and others. Chronic hypoxia in these conditions causes nutrient malabsorption in the gut, weight loss, sleep disturbance, and cognitive dysfunction, as well as right heart failure from pulmonary hypertension. Acute respiratory distress syndrome leads to cognitive dysfunction, although it is not clear whether the cognitive impact is a result of the hypoxemia per se or from the other stresses of critical illness and critical care. Long-term use of supplemental oxygen in patients with chronic obstructive pulmonary disease is associated with improvements in outcomes, including cardiovascular and cognitive benefits.”9

“Exposure to experimentally induced IH (Intermittent hypoxia) in rodent models is associated with time-related neurodegenerative changes, including alteration in brain regions and in neurotransmitter systems involved in learning, attention, and memory. There are several rodent IH (Intermittent hypoxia) models showing cellular damage of the CA1 area of the hippocampus that is important in learning and memory, and which are considered as hippocampal-dependent. The mechanisms by which IH (Intermittent hypoxia) induces hippocampus dysfunction are multiple, involving glutamate release, growth-tropic factors, chronic excitotoxity, diminished apolipoprotein E, and NO (nitric oxide) reduction. The most evident proposed explanation is oxidative stress inducing inflammation and apoptosis.”10

“Individuals with coexisting cardiovascular or pulmonary disease are undoubtedly at greater risk for circulatory compromise caused by hypoxemia. This is for several important reasons. First, oxygen delivery to the myocardium may already be marginal in individuals with coronary artery disease, leading to myocardial stress during decreases in the arterial oxygen content. The decrease in oxygen delivery can result in depressed myocardial function, wall motion abnormalities, electrocardiogram changes similar to ischemia, and arrhythmias. The sympathetic nervous system is activated by systemic hypoxia, resulting in increased heart rate, pulmonary vascular resistance, and systemic vascular resistance. These are additional stresses for the already compromised myocardium. Another risk factor for hypoxia-induced depression of the myocardium is anemia, because this will reduce oxygen delivery to the heart tissue. The compensatory increased blood flow in response to reduced oxygen availability is impaired with coronary artery disease. Similarly, coexisting pulmonary disease increases the risk of reaching critical oxygen delivery to tissues because of impaired gas exchange.”11

 

 

References

(1, 3, 5) Hypoxia: a review. Gilany, K. & Vafakhah, M. Journal of Paramedical Sciences. 2010. https://www.academia.edu/2361757/Hypoxia_a_Review

(2, 6) Hypoxia and hyperbaric oxygen therapy: a review. Choudhury, R. International Journal of General Medicine. 2018. https://www.dovepress.com/hypoxia-and-hyperbaric-oxygen-therapy-a-review-peer-reviewed-fulltext-article-IJGM

(4) Hypoxia: developments in basic science, physiology and clinical studies. Ward, D.S., Karan, S.B. & Pandit, J.J. Anaesthesia. 2011. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2044.2011.06930.x

(7, 8, 9, 10) Chronic intermittent hypoxia and obstructive sleep apnea: an experimental and clinical approach. Sforza E. & Roche, F. Dovepress. 2015. https://www.dovepress.com/the-role-of-hypoxia-in-cancer-progression-angiogenesis-metastasis-and–peer-reviewed-article-HP 

(11) Effects of Acute, Profound Hypoxia on Healthy Humans: Implications for Safety of Tests Evaluating Pulse Oximetry or Tissue Oximetry Performance. Bickler, P.E., Feiner, J.R., Lipnick, M.S., Batchelder, P.B., MacLeod, D,B. & Severinghaus, J.W. Anesthesia & Analgesia. 2017. https://journals.lww.com/anesthesia-analgesia/fulltext/2017/01000/Effects_of_Acute,_Profound_Hypoxia_on_Healthy.20.aspx

 

María Laura Márquez
13 October, 2018

Written by

María Laura Márquez, general doctor graduated from The University of Oriente in 2018, Venezuela. My interests in the world of medicine and science, are focused on surgery and its breakthroughs. Nowadays I practice my profession...read more:

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