Hypoxia is a state in which oxygen is not available in sufficient amounts at tissue level to maintain adequate homeostasis; this can result from inadequate oxygen delivery to the tissues either due to low blood supply or low oxygen content in blood (hypoxemia).
Hypoxia can vary in intensity from mild to severe and can present in acute, chronic, or acute and chronic forms. The response to hypoxia is variable; while some tissues can tolerate some forms of hypoxia/ischemia for a longer duration, other tissues are severely damaged by low oxygen levels.
There are 2 major causes of hypoxia at the tissue level, low blood flow to the tissue, or low oxygen content in blood (hypoxemia).
In order to understand the mechanism of hypoxia, we have to know that in order to have the oxygen carried by hemoglobin, direct interaction between red blood cells in pulmonary capillaries and the air in the alveoli is needed. This process can be compromised at any 1 of the following 3 points: blood flow to the lung (perfusion), airflow to the alveoli (ventilation), and the gas exchange through the interstitial tissue (diffusion).
Reduced Oxygen Tension
As in cases of high altitude.
Ventilation-perfusion Mismatch (V/Q Mismatch)
Right to Left Shunt
The blood crosses from the right to the left side of the heart without being oxygenated. Causes include:
Impaired Diffusion of Oxygen
Oxygen diffusion is impaired between the alveolus and the pulmonary capillaries. Causes are usually interstitial edema, interstitial inflammation or fibrosis. Clinical examples include pulmonary edema and interstitial lung disease.
Hypoxia is a common disorder that we encounter every day in the hospital. However, the causes of hypoxia are multiple, and its prevalence is variable. Some of these causes are very common like pneumonia or chronic obstructive pulmonary disease (COPD); others are quite rare like the hypoxia due to reduced oxygen tension as in high altitude or due to cyanide poisoning.
This includes the factors that decrease the percentage of oxygen in the alveoli, either due to obstruction of the airways or increase in partial pressure of alveolar gases other than oxygen. Carbon dioxide is one of the examples. Hypoventilation can also occur due to impaired respiratory drive as in cases of deep sedation or because of restricted movement of chest wall as in obesity hypoventilation syndrome or ankylosing spondylitis. In this setting, the A-a gradient will be normal as the oxygen is deficient in both alveoli and bloodstream.
In alveoli, increase in partial pressure of one gas will be on the cost of the other gases composing the air, e.g., increase in carbon dioxide partial pressure results in a decrease of partial pressure of oxygen, both at alveolar as well as the arterial level. This type of hypoxemia is easily corrected with supplemental oxygen.
Ventilation-Perfusion Mismatch (V/Q Mismatch)
In which there is an imbalance between lung ventilation and blood flow. Even in the normal lung, there is V/Q mismatch. In an upright individual, V/Q ratio is higher in the apices than at the lung base. This difference is responsible for the normal A-a gradient. V/Q mismatch increases in pulmonary vascular disease, thromboembolic disease or atelectasis to name a few. Such process ultimately results in hypoxemia which is more difficult to correct with supplemental oxygen.
Right to Left Shunt
Occurs when blood passes from the right to the left side of the heart without being oxygenated. Anatomic abnormalities, such as atrial or ventricular septal defects as well as pulmonary arteriovenous malformations can cause hypoxemia that is notoriously difficult to correct with supplemental oxygen. Similar physiology is observed in hepato-pulmonary syndrome. Physiologic right to left shunt exists when the blood passes through non-ventilated alveoli in cases of atelectasis, pneumonia, and acute respiratory distress syndrome (ARDS).
Impaired Diffusion of Oxygen Across the Alveoli into Blood
The usual causes are interstitial edema, lung tissue inflammation or fibrosis. Depending on disease extent, moderate to a large amount of supplemental oxygen may be required to correct this type of hypoxemia. Exercise can worsen hypoxemia resulting from impaired diffusion. Increase in cardiac output with exercise results in accelerated blood flow through alveoli, reducing the time available for gas exchange. In case of the abnormal pulmonary interstitium, gas exchange time becomes insufficient, and hypoxemia ensues.
Hypoxia presentation can be acute or chronic; acutely the hypoxia may present with dyspnea and tachypnea. Symptom severity usually depends on the severity of hypoxia. Sufficiently severe hypoxia can result in tachycardia to provide sufficient oxygen to the tissues. Some of the signs are very evident on physical exam; stridor can be heard once the patient arrives in cases of upper airway obstruction. Skin can be cyanotic, which might indicate severe hypoxia.
When oxygen delivery is severely compromised, organ function will start to deteriorate. Neurologic manifestations include restlessness, headache, and confusion with moderate hypoxia. In severe cases, altered mentation and coma can occur, and if not corrected quickly may lead to death.
The chronic presentation is usually less dramatic, with dyspnea on exertion as the most common complaint. Symptoms of the underlying condition that induced the hypoxia can help in narrowing the differential diagnosis. For instance, productive cough and fever will be seen in cases of lung infection, leg edema, and orthopnea in cases of heart failure, and chest pain and unilateral leg swelling may point to pulmonary embolism as a cause of hypoxia.
The physical exam may show tachycardia, tachypnea, and low oxygen saturation. Fever may point to infection as the cause of hypoxia.
Lung auscultation can yield a lot of useful information. Bilateral basilar crackles may indicate pulmonary edema or volume overload, other signs of that includes jugular venous distention and lower limb edema. Wheezing and rhonchi can be found in obstructive lung disease. Absent unilateral air entry can be caused by either massive pleural effusion or pneumothorax. Chest percussion can help differentiate the two and will reveal dullness in cases of pleural effusion and hyper-resonance in cases of pneumothorax. Clear lung fields in a setting of hypoxia should raise suspicion of pulmonary embolism, especially if the patient is tachycardic and has evidence of deep vein thrombosis (DVT).
Evaluation of Acute Hypoxia
Pulse oximetry to evaluate arterial oxygen saturation (SaO2)
The arterial oxygen saturation (SaO2) refers to the amount of oxygen bound to hemoglobin in arterial blood. The measurement is given as a percentage. Resting SaO2 less than or equal to 95% or exercise desaturation greater than or equal to 5% is considered abnormal. However, clinical correlation is always necessary as exact cutoff below which tissue hypoxia ensues has not been defined.
Arterial Blood Gas
It is a useful tool to evaluate hypoxemia. Aside from diagnosis of hypoxemia, additional information obtained, such as PCO2, can shed light on etiology of the process.
N.B. PaO2: FiO2 ratio (Normal ratio is 300 to 500), if this ratio drops this may indicate deterioration in gas exchange, this is particularly important in defining ARDS.
Imaging studies of the chest, such as chest x-rays or CT help in identifying the cause of the hypoxia, e.g., pneumonia, pulmonary edema, hyperinflated lungs in COPD and other conditions. CT chest can give more detailed images that outline the exact pathology, CT angiogram of the chest is of particular importance in detecting the pulmonary embolism. Another modality is the VQ scan which can detect the ventilation-perfusion mismatch, which is helpful in diagnostics of acute or chronic pulmonary embolism. VQ scan can be particularly useful when renal failure or allergy to iodinated contrast increases risks of CT angiography.
The first step in evaluating the hypoxia is to calculate the A-a gradient of oxygen. This is the difference in the amount of oxygen between the Alveoli “A” and the amount of oxygen in the blood “a." In other terms, the A-a oxygen gradient = PAO2 - PaO2.
PaO2 can be obtained from the arterial blood gas; however, PAO2 is calculated using the alveolar gas equation:
PAO2 = (FiO2 x [760-47]) - PaCO2/0.8)
N.B.1: 760 is the atmospheric pressure at the sea level in mm Hg, 47 is the partial pressure of water at a temperature of 37 C, and 0.8 is the steady-state respiratory quotient.
N.B.2: the A-a gradient changes with age, and thus it is corrected for age using this equation; A-a gradient = (age/4+4).
If the A-a gradient is normal, then the cause of hypoxia is low oxygen content in the alveoli, either due to low O2 content in the air (low FiO2, as in the high altitude) or more commonly due to hypoventilation like central nervous system (CNS) depression, OHS, or obstructed airways as in COPD exacerbation.
If the gradient is height then the cause of hypoxia is either due to diffusion defect or perfusion defect (VQ mismatch), alternative explanation is shunting of blood flow around the alveolar circulation, administering 1.0 FiO2 may help differentiate the 2, as the oxygenation will improve in VQ mismatch, however, barely will when shunt physiology is present.
PaO2: FiO2 Ratio
This ratio is another way to measure the degree of hypoxia. A normal PaO2/FiO2 ratio is about 300 to 500 mm Hg. If the ration is less than 300, this indicates abnormal gas exchange, and values less than 200 mm Hg indicates severe hypoxemia. The PaO2/FiO2 ratio is used mostly as a definition of acute respiratory distress syndrome severity.
Evaluation of Chronic Hypoxia
Pulmonary Function Test
Provide a direct measure of the lung volumes, bronchodilator response and diffusion capacity, which can help in establishing the diagnosis and guiding the treatment of the lung disorders. Aiding history and physical exam, PFTs can be used to differentiate between the obstructive (bronchial asthma, COPD, upper airway obstruction) versus restrictive lung diseases (interstitial lung diseases, chest wall abnormalities). PFTs play a role in the assessment of airway obstruction severity as well as response to therapy. One has to keep in mind that PFTs are effort dependent and require patient ability to cooperate and understand instructions.
Nocturnal (overnight) Trend Oximetry
Provides information about oxyhemoglobin saturation over a period (usually overnight). This test is primarily used to assess adequacy or need for oxygen supplementation at night. Use of overnight trend oximetry as a surrogate for a diagnostic sleep study is possible, however, is discouraged. A formal sleep study should be used whenever possible.
Six-Minute Walk Test
Provides information on oxyhemoglobin saturation response to exercise as well as the total distance a patient can walk in 6 minutes on a ground level. This information can be used to titrate oxygen supplementation as well as evaluate the response to therapy. The 6-minutes walk test is frequently used in the preoperative pulmonary evaluation, pulmonary hypertension treatment and assessment of supplemental oxygen need with exercise.
Secondary polycythemia can be an indicator of chronic hypoxia.
Management of hypoxia falls under 3 categories: maintaining patent airways, increasing the oxygen content of the inspired air, and improving the diffusion capacity.
Maintaining Patent Airways
Ensure patency of the upper airways with good suctioning, maneuvers that prevent occlusion of the throat (head tilt and jaw trust if necessary), sometimes the placement of an endotracheal tube or tracheostomy is necessary.
In chronic conditions like OSA, maintaining patent airways can be achieved with positive pressure ventilation like CPAP or BiPAP.
Bronchodilators and aggressive pulmonary hygiene, such as chest physiotherapy, flutter valve, and incentive spirometry can be used to maintain patency of the lower airways.
Increase Fraction of the Inspired O2 (FiO2)
This is indicated for low PaO2 less than 60 or SaO2 less than 90, and this can be achieved by increasing the percentage of oxygen in the inspired air that reach the alveoli.
Usually, this requires oxygen blender, humidifier, and heated tubing.
Positive Pressure Ventilation
Allows for accurate delivery of any necessary FiO2
Non-Invasive Ventilation usually used as the last resort to avoid the intubation
Improve the Diffusion of Oxygen through the Alveolar Interstitial Tissue
The overall idea s to treat the underlying cause of respiratory failure:
Low oxygen tension in the arterial blood (PaO2); due to the inability of the lungs to properly oxygenate the blood. Causes include hypoventilation, impaired alveolar diffusion, and pulmonary shunting.
Due to pump failure (heart is unable to pump enough blood, and therefore oxygen delivery is impaired).
Decrease in oxygen carrying capacity due to low hemoglobin leading to inadequate oxygen delivery.
Histotoxic Hypoxia (Dysoxia)
Cells are unable to utilize oxygen effectively, the best example for this is Cyanide poisoning; which inhibits the enzyme cytochrome C oxidase in the mitochondria, blocking the use of oxygen to make ATP.