Hypoxia Part II

 Physiological responses

All vertebrates must maintain oxygen homeostasis to survive, and have evolved physiological systems to ensure adequate oxygenation of all tissues. In air breathing vertebrates this is based on lungs to acquire the oxygen, hemoglobin in red corpuscles to transport it, a vasculature to distribute, and a heart to deliver. Short term variations in the levels of oxygenation are sensed by chemoreceptor cells which respond by activating existing proteins and over longer terms by regulation of gene transcription. Hypoxia is also involved in the pathogenesis of some common and severe pathology.

The most common causes of death in an aging population include myocardial infarction, stroke and cancer. These diseases share a common feature that limitation of oxygen availability contributes to the development of the pathology. Cells and organisms are also able to respond adaptively to hypoxic conditions, in ways that help them to cope with these adverse conditions. Several systems can sense oxygen concentration and may respond with adaptations to acute and long-term hypoxia. The systems activated by hypoxia usually help cells to survive and overcome the hypoxic conditions. Erythropoietin, which is produced in larger quantities by the kidneys under hypoxic conditions, is an essential hormone that stimulates production of red blood cells, which are the primary transporter of blood oxygen, and glycolytic enzymes are involved in anaerobic ATP formation.

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. The HIF signaling cascade mediates the effects of hypoxia on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos and tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium. It is therefore not surprising that HIF-1 modulation was identified as a promising treatment paradigm in wound healing.

Exposure of a tissue to repeated short periods of hypoxia, between periods of normal oxygen levels, influences the tissue's later response to prolonged ischaemic exposure. Thus is known as ischemic preconditioning, and it is known to occur in many tissues.

Acute

If oxygen delivery to cells is insufficient for the demand (hypoxia), electrons will be shifted to pyruvic acid in the process of lactic acid fermentation. This temporary measure (anaerobic metabolism) allows small amounts of energy to be released. Lactic acid build up (in tissues and blood) is a sign of inadequate mitochondrial oxygenation, which may be due to hypoxemia, poor blood flow (e.g., shock) or a combination of both. If severe or prolonged it could lead to cell death.

In humans, hypoxia is detected by the peripheral chemoreceptors in the carotid body and aortic body, with the carotid body chemoreceptors being the major mediators of reflex responses to hypoxia. This response does not control ventilation rate at normal PO2, but below normal the activity of neurons innervating these receptors increases dramatically, so much as to override the signals from central chemoreceptors in the hypothalamus, increasing PO2 despite a falling PCO2.

In most tissues of the body, the response to hypoxia is vasodilation. By widening the blood vessels, the tissue allows greater perfusion.

By contrast, in the lungs, the response to hypoxia is vasoconstriction. This is known as hypoxic pulmonary vasoconstriction, or "HPV", and has the effect of redirecting blood away from poorly ventilated regions, which helps match perfusion to ventilation, giving a more even oxygenation of blood from different parts of the lungs. In conditions of hypoxic breathing gas, such as at high altitude, HPV is generalized over the entire lung, but with sustained exposure to generalized hypoxia, HPV is suppressed. Hypoxic ventilatory response (HVR) is the increase in ventilation induced by hypoxia that allows the body to take in and transport lower concentrations of oxygen at higher rates. It is initially elevated in lowlanders who travel to high altitude, but reduces significantly over time as people acclimatize.

Chronic

When the pulmonary capillary pressure remains elevated chronically (for at least 2 weeks), the lungs become even more resistant to pulmonary edema because the lymph vessels expand greatly, increasing their capability of carrying fluid away from the interstitial spaces perhaps as much as 10-fold. Therefore, in patients with chronic mitral stenosis, pulmonary capillary pressures of 40 to 45 mm Hg have been measured without the development of lethal pulmonary edema.

There are several potential physiologic mechanisms for hypoxemia, but in patients with chronic obstructive pulmonary disease (COPD), ventilation/perfusion (V/Q) mismatching is most common, with or without alveolar hypoventilation, as indicated by arterial carbon dioxide concentration. Hypoxemia caused by V/Q mismatching in COPD is relatively easy to correct, and relatively small flow rates of supplemental oxygen (less than 3 L/min for the majority of patients) are required for long term oxygen therapy (LTOT). Hypoxemia normally stimulates ventilation and produces dyspnea, but these and the other signs and symptoms of hypoxia are sufficiently variable in COPD to limit their value in patient assessment. Chronic alveolar hypoxia is the main factor leading to development of cor pulmonale — right ventricular hypertrophy with or without overt right ventricular failure — in patients with COPD. Pulmonary hypertension adversely affects survival in COPD, proportional to resting mean pulmonary artery pressure elevation. Although the severity of airflow obstruction as measured by forced expiratory volume tests FEV1 correlates best with overall prognosis in COPD, chronic hypoxemia increases mortality and morbidity for any severity of disease. Large-scale studies of long term oxygen therapy in patients with COPD show a dose–response relationship between daily hours of supplemental oxygen use and survival. Continuous, 24-hours-per-day oxygen use in appropriately selected patients may produce a significant survival benefit.

Pathological responses

Cerebral ischemia

The brain has relatively high energy requirements, using about 20% of the oxygen under resting conditions, but low reserves, which make it especially vulnerable to hypoxia. In normal conditions, an increased demand for oxygen is easily compensated by an increased cerebral blood flow. But under conditions when there is insufficient oxygen available, increased blood flow may not be sufficient to compensate, and hypoxia can result in brain injury. A longer duration of cerebral hypoxia will generally result in larger areas of the brain being affected. The brainstem, hippocampus and cerebral cortex seem to be the most vulnerable regions. Injury becomes irreversible if oxygenation is not soon restored. Most cell death is by necrosis but delayed apoptosis also occurs. In addition, presynaptic neurons release large amounts of glutamate which further increases Ca2+ influx and causes catastrophic collapse in postsynaptic cells. Although it is the only way to save the tissue, reperfusion also produces reactive oxygen species and inflammatory cell infiltration, which induces further cell death. If the hypoxia is not too severe, cells can suppress some of their functions, such as protein synthesis and spontaneous electrical activity, in a process called penumbra, which is reversible if the oxygen supply is resumed soon enough.

Myocardial ischemia

Parts of the heart are exposed to ischemic hypoxia in the event of occlusion of a coronary artery. Short periods of ischemia are reversible if reperfused within about 20 minutes, without development of necrosis, but the phenomenon known as stunning is generally evident. If hypoxia continues beyond this period, necrosis propagates through the myocardial tissue. Energy metabolism in the affected area shifts from mitochondrial respiration to anaerobic glycolysis almost immediately, with concurrent reduction of effectiveness of contractions, which soon cease. Anaerobic products accumulate in the muscle cells, which develop acidosis and osmotic load leading to cellular edema. Intracellular Ca2+ increases and eventually leads to cell necrosis. Arterial flow must be restored to return to aerobic metabolism and prevent necrosis of the affected muscle cells, but this also causes further damage by reperfusion injury. Myocadial stunning has been described as "prolonged post-ischaemic dysfunction of viable tissue salvaged by reperfusion", which manifests as temporary contractile failure in oxygenated muscle tissue. This may be caused by a release of reactive oxygen species during the early stages of reperfusion.

Tumor angiogenesis

As tumors grow, regions of relative hypoxia develop as the oxygen supply is unevenly utilized by the tumor cells. The formation of new blood vessels is necessary for continued tumor growth, and is also an important factor in metastasis, as the route by which cancerous cells are transported to other sites.

Diagnosis

Physical examination and history

Hypoxia can present as acute or chronic.

Acute presentation may include dyspnea (shortness of breath) and tachypnea (rapid, often shallow, breathing). Severity of symptom presentation is commonly an indication of severity of hypoxia. Tachycardia (rapid pulse) may develop to compensate for low arterial oxygen tension. Stridor may be heard in upper airway obstruction, and cyanosis may indicate severe hypoxia. Neurological symptoms and organ function deterioration occur when the oxygen delivery is severely compromised. In moderate hypoxia, restlessness, headache and confusion may occur, with coma and eventual death possible in severe cases.

In chronic presentation, dyspnea following exertion is most commonly mentioned. Symptoms of the underlying condition that caused the hypoxia may be apparent, and can help with differential diagnosis. A productive cough and fever may be present with lung infection, and leg edema may suggest heart failure.

Lung auscultation can provide useful information.

Tests

An arterial blood gas test (ABG) may be done, which usually includes measurements of oxygen content, hemoglobin, oxygen saturation (how much of the hemoglobin is carrying oxygen), arterial partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), blood pH level, and bicarbonate (HCO3).

An arterial oxygen tension (PaO2) less than 80 mmHg is considered abnormal, but must be considered in context of the clinical situation.

In addition to diagnosis of hypoxemia, the ABG may provide additional information, such as PCO2, which can help identify the etiology. The arterial partial pressure of carbon dioxide is an indirect measure of exchange of carbon dioxide with the air in the lungs, and is related to minute ventilation. PCO2 is raised in hypoventilation.

The normal range of PaO2:FiO2 ratio is 300 to 500 mmHg, if this ratio is lower than 300 it may indicate a deficit in gas exchange, which is particularly relevant for identifying acute respiratory distress syndrome (ARDS). A ratio of less than 200 indicates severe hypoxemia.

The alveolar–arterial gradient (A-aO2, or A–a gradient), is the difference between the alveolar (A) concentration of oxygen and the arterial (a) concentration of oxygen. It is a useful parameter for narrowing the differential diagnosis of hypoxemia. The A–a gradient helps to assess the integrity of the alveolar capillary unit. For example, at high altitude, the arterial oxygen PaO2 is low, but only because the alveolar oxygen PAO2 is also low. However, in states of ventilation perfusion mismatch, such as pulmonary embolism or right-to-left shunt, oxygen is not effectively transferred from the alveoli to the blood which results in an elevated A-a gradient. PaO2 can be obtained from the arterial blood gas analysis and PAO2 is calculated using the alveolar gas equation.

An abnormally low hematocrit (volume percentage of red blood cells) may indicate anemia.

X-rays or CT scans of the chest and airways can reveal abnormalities that may affect ventilation or perfusion.

A ventilation/perfusion scan, also called a V/Q lung scan, is a type of medical imaging using scintigraphy and medical isotopes to evaluate the circulation of air and blood within a patient's lungs, in order to determine the ventilation/perfusion ratio. The ventilation part of the test looks at the ability of air to reach all parts of the lungs, while the perfusion part evaluates how well blood circulates within the lungs.

Pulmonary function testing may include:

Tests that measure oxygen levels during the night

The six-minute walk test, which measures how far a person can walk on a flat surface in six minutes to test exercise capacity by measuring oxygen levels in response to exercise

Diagnostic measurements that may be relevant include: Lung volumes, including lung capacity, airway resistance, respiratory muscle strength, diffusing capacity

Other pulmonary function tests which may be relevant include: Spirometry, body plethysmography, forced oscillation technique for calculating the volume, pressure, and air flow in the lungs, bronchodilator responsiveness, carbon monoxide diffusion test (DLCO), oxygen titration studies, cardiopulmonary stress test, bronchoscopy, and thoracentesis

Differential diagnosis

Treatment will depend on severity and may also depend on the cause, as some cases are due to external causes and removing them and treating acute symptoms may be sufficient, but where the symptoms are due to underlying pathology, treatment of the obvious symptoms may only provide temporary or partial relief, so differential diagnosis can be important in selecting definitive treatment.

Hypoxemic hypoxia: Low oxygen tension in the arterial blood (PaO2) is generally an indication of inability of the lungs to properly oxygenate the blood. Internal causes include hypoventilation, impaired alveolar diffusion, and pulmonary shunting. External causes include hypoxic environment, which could be caused by low ambient pressure or unsuitable breathing gas. Both acute and chronic hypoxia and hypercapnia caused by respiratory dysfunction can produce neurological symptoms such as encephalopathy, seizures, headache, papilledema, and asterixis. Obstructive sleep apnea syndrome may cause morning headaches

Circulatory Hypoxia: Caused by insufficient perfusion of the affected tissues by blood which is adequately oxygenated? This may be generalized, due to cardiac failure or hypovolemia, or localized, due to infarction or localized injury.

Anemic Hypoxia is caused by a deficit in oxygen-carrying capacity, usually due to low hemoglobin levels, leading to generalized inadequate oxygen delivery.

Histotoxic Hypoxia (Dysoxia) is a consequence of cells being unable to utilize oxygen effectively. A classic example is cyanide poisoning which inhibits the enzyme cytochrome C oxidase in the mitochondria, blocking the use of oxygen to make ATP.

Critical illness polyneuropathy or myopathy should be considered in the intensive care unit when patients have difficulty coming off the ventilator.

Prevention

Prevention can be as simple as risk management of occupational exposure to hypoxic environments, and commonly involves the use of environmental monitoring and personal protective equipment. Prevention of hypoxia as a predictable consequence of medical conditions requires prevention of those conditions. Screening of demographics known to be at risk for specific disorders may be useful.

Prevention of altitude induced hypoxia

To counter the effects of high-altitude diseases, the body must return arterial PaO2 toward normal. Acclimatization, the means by which the body adapts to higher altitudes, only partially restores PO2 to standard levels. Hyperventilation, the body's most common response to high-altitude conditions, increases alveolar PO2 by raising the depth and rate of breathing. However, while PO2 does improve with hyperventilation, it does not return to normal. Studies of miners and astronomers working at 3000 meters and above show improved alveolar PO2 with full acclimatization, yet the PO2 level remains equal to or even below the threshold for continuous oxygen therapy for patients with chronic obstructive pulmonary disease (COPD). In addition, there are complications involved with acclimatization. Polycythemia, in which the body increases the number of red blood cells in circulation, thickens the blood, raising the risk of blood clots.

In high-altitude situations, only oxygen enrichment or compartment pressurization can counteract the effects of hypoxia. Pressurization is practicable in vehicles, and for emergencies in ground installations. By increasing the concentration of oxygen in the at ambient pressure, the effects of lower barometric pressure are countered and the level of arterial PO2 is restored toward normal capacity. A small amount of supplemental oxygen reduces the equivalent altitude in climate-controlled rooms. At 4000 m, raising the oxygen concentration level by 5% via an oxygen concentrator and an existing ventilation system provides an altitude equivalent of 3000 m, which is much more tolerable for the increasing number of low-landers who work in high altitude. In a study of astronomers working in Chile at 5050 m, oxygen concentrators increased the level of oxygen concentration by almost 30 percent (that is, from 21 percent to 27 percent). This resulted in increased worker productivity, less fatigue, and improved sleep.

Oxygen concentrators are suited for high altitude oxygen enrichment of climate-controlled environments. They require little maintenance and electricity, utilize a locally available source of oxygen, and eliminate the expensive task of transporting oxygen cylinders to remote areas. Offices and housing often already have climate-controlled rooms, in which temperature and humidity are kept at a constant level.

Treatment and management

Treatment and management depend on circumstances. For most high altitude situations the risk is known, and prevention is appropriate. At low altitudes hypoxia is more likely to be associated with a medical problem or an unexpected contingency, and treatment is more likely to be provided to suit the specific case. It is necessary to identify persons who need oxygen therapy, as supplemental oxygen is required to treat most causes of hypoxia, but different oxygen concentrations may be appropriate.

Treatment of acute and chronic cases

Treatment will depend on the cause of hypoxia. If it is determined that there is an external cause, and it can be removed, then treatment may be limited to support and returning the system to normal oxygenation. In other cases a longer course of treatment may be necessary, and this may require supplemental oxygen over a fairly long term or indefinitely.

There are three main aspects of oxygenation treatment: maintaining patent airways, providing sufficient oxygen content of the inspired air, and improving the diffusion in the lungs. In some cases treatment may extend to improving oxygen capacity of the blood, which may include volumetric and circulatory intervention and support, hyperbaric oxygen therapy and treatment of intoxication.

Invasive ventilation may be necessary or an elective option in surgery. This generally involves a positive pressure ventilator connected to an endotracheal tube, and allows precise delivery of ventilation, accurate monitoring of FiO2, and positive end-expiratory pressure, and can be combined with anesthetic gas delivery. In some cases a tracheotomy may be necessary. Decreasing metabolic rate by reducing body temperature lowers oxygen demand and consumption, and can minimise the effects of tissue hypoxia, especially in the brain, and therapeutic hypothermia based on this principle may be useful.

Where the problem is due to respiratory failure. It is desirable to treat the underlying cause. In cases of pulmonary edema, diuretics can be used to reduce the eodem. Steroids may be effective in some cases of interstitial lung disease, and in extreme cases, extracorporeal membrane oxygenation (ECMO) can be used.

Hyperbaric oxygen has been found useful for treating some forms of localized hypoxia, including poorly perfused trauma injuries such as Crush injury, compartment syndrome, and other acute traumatic ischemias. It is the definitive treatment for severe decompression sickness, which is largely a condition involving localized hypoxia initially caused by inert gas embolism and inflammatory reactions to extravascular bubble growth. It is also effective in carbon monoxide poisoning and diabetic foot.

A prescription renewal for home oxygen following hospitalization requires an assessment of the patient for ongoing hypoxemia.

Outcomes

Prognosis is strongly affected by cause, severity, treatment, and underlying pathology.

Hypoxia leading to reduced capacity to respond appropriately, or to loss of consciousness, has been implicated in incidents where the direct cause of death was not hypoxia. This is recorded in underwater diving incidents, where drowning has often been given as cause of death, high altitude mountaineering, where exposure, hypothermia and falls have been consequences, flying in unpressurized aircraft, and aerobatic maneuvers, where loss of control leading to a crash is possible.

Epidemiology

Hypoxia is a common disorder but there are many possible causes. Prevalence is variable. Some of the causes are very common, like pneumonia or chronic obstructive pulmonary disease; some are quite rare like hypoxia due to cyanide poisoning. Others, like reduced oxygen tension at high altitude, may be regionally distributed or associated with a specific demographic.

Generalized hypoxia is an occupational hazard in several high-risk occupations, including firefighting, professional diving, mining and underground rescue, and flying at high altitudes in unpressurised aircraft.

Potentially life-threatening hypoxemia is common in critically ill patients.

Localized hypoxia may be a complication of diabetes, decompression sickness, and of trauma that affects blood supply to the extremities.

Hypoxia due to underdeveloped lung function is a common complication of premature birth. In the United States, intrauterine hypoxia and birth asphyxia were listed together as the tenth leading cause of neonatal death.

Silent hypoxia

Silent hypoxia (also known as happy hypoxia) is generalized hypoxia that does not coincide with shortness of breath. This presentation is known to be a complication of COVID-19, and is also known in atypical pneumonia, altitude sickness, and rebreather malfunction accidents.

History

The 2019 Nobel Prize in Physiology or Medicine was awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza in recognition of their discovery of cellular mechanisms to sense and adapt to different oxygen concentrations, establishing a basis for how oxygen levels affect physiological function.

The use of the term hypoxia appears to be relatively recent, with the first recorded use in scientific publication from 1945. Previous to this the term anoxia was extensively used for all levels of oxygen deprivation. Investigation into the effects of lack of oxygen date from the mid-19th century.

Etymology

Hypoxia is formed from the Greek roots υπo (hypo), meaning under, below, and less than, and oξυ (oxy), meaning acute or acid, which is the root for oxygen.