Hypoxia – An Overview

Red blood cells carry oxygen to the tissues, and the body uses this oxygen as the main source of energy. A molecule within the erythrocytes (red blood cells) called hemoglobin, causes oxygen molecules to adhere to it and carries them throughout the body and the circulating blood distributes them. Hypoxia is a physiological state that causes oxygen deprivation to the brain and may provoke serious consequences, including death.

“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 dependence on oxygen. Therefore, a reduction of the normal oxygen supply (hypoxia) will have consequences on cell viability.”¹ 

Due to a shortage of blood or hemoglobin structures (anemia) to ‘capture’ the surrounding oxygen, the body loses the ability to distribute it to all our tissues. This occurs in atherosclerotic processes in the coronary artery where plaque accumulates within the artery lumen, and the cardiac muscle does not obtain sufficient blood, resulting in infarction. The scenario where a particular organ is not receiving adequate amounts of blood/oxygen is called ischemia. 

The Hypoxic State

A hypoxic state occurs when organs do not receive oxygen.

“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 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

The mechanism of Hypoxia

“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 Does the Body Adapt? 

The body has mechanisms to normalize oxygen levels. These forms of compensation are: deep breaths for greater oxygen intake, an increase in inhalation/exhalation frequency, and a rise in systolic pressure to pump more oxygen-carrying erythrocytes into circulation. Vasodilation helps expand the vessels for improved circulation of blood cells into the tissue. These changes occur rapidly and work as a 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, hyperglycemia may be detrimental during hypoxemia, 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. ischemic preconditioning) and longer‐term adaptations (e.g. altitude acclimatization). 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 low, brain stem chemoreceptors send a signal to the brain causing a reflexive reaction that increases the number of breaths patients take. This situation aggravates when carbon dioxide levels rise as oxygen levels diminish, causing fast breathing, also known as hyperventilation. 

In other words, chemoreceptors located in the brain measure levels of oxygen versus carbon dioxide and order the brain to adjust and ensure proper breathing, adequate oxygen saturation and the synchronized expulsion of carbon dioxide while exhaling.

“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 

If mild hypoxia persists, the body will compensate via hematopoiesis in the bone marrow. Hematopoiesis is the process that produces blood cells. Therefore, chronically hypoxic patients commonly have polycythemia, or an increased number of red blood cells and a higher concentration of hemoglobin, resulting in denser or thicker blood. The drawback of this reaction is that it forces the cardiac muscle to pump harder to circulate thicker blood.

“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 crucial to maintain proper gas saturation levels. In extreme or poorly managed hypoxia, the body is unable to compensate and blood pressure drops, producing respiratory failure and imminent cardiac arrest.

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

Chronic Hypoxia

“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.”⁸

Studies in rodents

“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.”⁹ 

Other Risk Factors

“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.”¹⁰ 

Hypoxia is a physiological state that causes oxygen deprivation to the brain, which requires an adequate and constant oxygen supply to function properly. Consider that blood carries oxygen to the brain and the rest of the body, but if this process is compromised, it could cause hypoxia, permanent brain damage, and death. Affected patients who survive after chronic hypoxia may suffer lifelong repercussions. Visit your nearest health facility for routine checkups to prevent Hypoxia.

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) 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  

(10) 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