Hypoxia

Etiology

At the tissue level, 2 primary causes of hypoxia arise—low blood flow to the tissue or low oxygen content in the blood (hypoxemia).[4][5][6] Hypoxemia should be differentiated as a cause of hypoxia. Oxygen is transported by hemoglobin within red blood cells, and efficient ventilation relies on the direct contact between red blood cells and alveoli, facilitating diffusion. This process may be compromised at any of the following 3 points—blood flow to the lung (perfusion), airflow to the alveoli (ventilation), and gas exchange through the interstitial tissue (diffusion).

As mentioned below, hypoxia can arise from various underlying causes, each with distinct etiologies and mechanisms.

Reduced oxygen tension: As in cases of high altitude.

Hypoventilation: Hypoventilation can result from various factors, including:

• Proximal airway obstruction, such as laryngeal edema or foreign body inhalation.

• Distal airway obstruction, as seen in bronchial asthma or chronic obstructive pulmonary disease (COPD).

• Impaired respiratory drive, as observed in cases of deep sedation or coma.

• Restricted chest wall movement, which is evident in conditions such as obesity hypoventilation syndrome, circumferential burns, massive ascites, or ankylosing spondylitis.

• Neuromuscular diseases include myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, or phrenic nerve injuries.

V/Q mismatch: This imbalance also leads to hypoxia in 2 ways, as mentioned below.

• Decreased V/Q ratio: Decreased V/Q ratio, caused by impaired ventilation or high perfusion, as seen in conditions such as chronic bronchitis, obstructive airway disease, mucus plugs, and pulmonary edema, results in compromised ventilation and a reduction in the V/Q ratio.

• Increased V/Q ratio: In cases of increased V/Q ratio, characterized by impaired perfusion as seen in conditions such as pulmonary embolism, or increased ventilation such as in emphysema with large bullae in the lungs, the available surface area for gas exchange diminishes. This results in higher ventilation than perfusion, leading to a high V/Q ratio.

Right-to-left shunt: Right-to-left shunt occurs when blood bypasses the lungs without oxygenation by crossing from the right to the left side of the heart. Causes include:

• Anatomic shunts: Blood bypasses the alveoli, as seen in intracardiac shunts such as atrial septal defect (ASD), a ventricular septal defect (VSD), or a patent ductus arteriosus (PDA), pulmonary arteriovenous malformations, fistulas, and hepato-pulmonary syndrome.

• Physiologic shunts: Blood passes through non-ventilated alveoli, such as pneumonia, atelectasis, and acute respiratory distress syndrome (ARDS).

Impaired diffusion of oxygen: Oxygen diffusion between the alveolus and the pulmonary capillaries is hindered, typically due to interstitial edema, inflammation, or fibrosis. Clinical examples encompass conditions like pulmonary edema and interstitial lung disease.

Epidemiology

Hypoxia is a common feature across numerous medical conditions, with multiple underlying causes and variable prevalence. Although some causes, such as pneumonia or COPD, are widespread, others, such as hypoxia due to reduced oxygen tension at high altitudes or cyanide poisoning, are relatively rare.

Pathophysiology

Hypoventilation

Hypoventilation involves factors that decrease the oxygen percentage in the alveoli, either through airway obstruction or an increase in the partial pressure of alveolar gases other than oxygen, such as carbon dioxide. This condition can also result from impaired respiratory drive, as seen in cases of deep sedation, or restricted chest wall movement, as seen in obesity hypoventilation syndrome or ankylosing spondylitis. In this scenario, the alveolar-arterial oxygen gradient (A-a gradient) remains normal as oxygen deficiency occurs in both the alveoli and the bloodstream.

In the alveoli, an increase in the partial pressure of one gas occurs at the expense of other gases in the air; for example, an increase in carbon dioxide partial pressure leads to a decrease in the partial pressure of oxygen, both at the alveolar and arterial levels. This type of hypoxemia can be readily corrected with supplemental oxygen.

V/Q Mismatch

This condition arises from an imbalance between lung ventilation and blood flow. Even in a healthy lung, a V/Q mismatch can occur, with the V/Q ratio being higher in the apices than at the lung base in an upright individual. This difference contributes to the normal A-a gradient. However, V/Q mismatch escalates in conditions such as pulmonary vascular disease, thromboembolic disease, or atelectasis. Ultimately, this leads to hypoxemia, which proves challenging to correct with supplemental oxygen.

Right-to-Left Shunt

This condition arises when blood moves from the right to the left side of the heart without undergoing oxygenation. Anatomical abnormalities, such as atrial or ventricular septal defects, along with pulmonary arteriovenous malformations, can cause hypoxemia that proves notably resistant to correction with supplemental oxygen. Comparable physiology is evident in hepato-pulmonary syndrome. Furthermore, a physiological right-to-left shunt occurs when blood traverses non-ventilated alveoli in conditions such as atelectasis, pneumonia, and ARDS.

Impaired Diffusion of Oxygen Across the Alveoli Into Blood

The usual causes include interstitial edema, inflammation of lung tissue, or fibrosis. Depending on the severity of the condition, moderate-to-substantial supplemental oxygen may be necessary to address this form of hypoxemia. Exercise can exacerbate hypoxemia due to impaired diffusion. Increased cardiac output during exercise leads to faster blood flow through alveoli, diminishing the duration available for gas exchange. When the pulmonary interstitium is abnormal, inadequate time for gas exchange results in hypoxemia.

History and Physical

The presentation of hypoxia 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. Several signs are discernible during physical examination; for instance, the presence of a stridor upon the patient's arrival signals upper airway obstruction. Additionally, cyanosis of the skin may be observed, potentially indicating 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 are 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 useful information. Bilateral basilar crackles may indicate pulmonary edema or volume overload. Additional signs include 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 massive pleural effusion or pneumothorax. Chest percussion can help differentiate the two, revealing dullness in pleural effusion cases and hyper-resonance in pneumothorax cases. 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.

Evaluation

Evaluation of Acute Hypoxia

Pulse oximetry to evaluate arterial oxygen saturation (SaO₂): Pulse oximetry assesses arterial oxygen saturation (SaO₂), which represents the oxygen bound to hemoglobin in arterial blood, typically measured as a percentage. A resting SaO₂ of less than or equal to 95%, or exercise-induced desaturation of 5% or more, is deemed abnormal. However, clinical correlation remains essential, given the absence of a precisely defined cutoff indicating tissue hypoxia onset.[7][8][9]

Arterial blood gas analysis: This is a valuable tool for evaluating hypoxemia. In addition to diagnosing hypoxemia, it provides additional insights into the underlying etiology, such as through the measurement of PCO₂.

• Arterial oxygen tension (PaO₂): This reflects the amount of oxygen dissolved in the plasma. A PaO₂ below 80 mm Hg is typically considered abnormal, although this assessment should always be contextualized within the clinical scenario.

• The partial pressure of CO₂ (PCO₂): This indirectly reflects the exchange of CO₂ in the alveoli with the air and is influenced by minute ventilation. Elevated PCO₂ levels are observed in hypoventilation, as seen in conditions like obesity hypoventilation or deep sedation. Additionally, acute hypoxia secondary to tachypnea can result in elevated PCO₂ due to CO₂ washout.

• Normal PaO₂:FiO₂ ratio: The normal PaO₂:FiO₂ ratio typically ranges from 300 to 500 mm Hg. A decrease in this ratio may signify a deterioration in gas exchange, which is particularly significant in defining. FiO₂ is the fraction of inspired O_2.

Imaging: Imaging studies of the chest, such as chest x-rays or computed tomography (CT), are instrumental in identifying the underlying cause of hypoxia, including conditions such as pneumonia, pulmonary edema, and hyperinflated lungs in COPD, among others. CT scans provide more detailed images, offering precise delineation of the pathology. A CT angiogram of the chest plays a crucial role in detecting pulmonary embolism. Additionally, the VQ scan is valuable for detecting V/Q mismatch and aids in diagnosing acute or chronic pulmonary embolism. VQ scans are particularly advantageous in cases where renal failure or iodinated contrast allergy increases the risks associated with CT angiography.

The initial step in assessing hypoxia involves calculating the A-a oxygen gradient. This gradient represents the difference in oxygen levels between the alveoli (A) and arterial blood (a). In simpler terms, the "A-a" oxygen gradient is calculated as "A-a oxygen gradient = PAO₂ - PaO₂."

PaO₂ can be measured directly from arterial blood gas samples; however, PAO₂ is derived using the alveolar gas equation:

PAO₂ = (FiO₂ x [760-47]) - PaCO₂/0.8).

Here, "760" represents the atmospheric pressure at sea level in mmHg; "47" is the partial pressure of water at 37 °C; and "0.8" is the steady-state respiratory quotient. The A-a gradient is subject to age-related changes and is corrected accordingly using the equation: A-a gradient = ([age/4] + 4)

If the A-a gradient is normal, hypoxia is likely due to low oxygen content in the alveoli, stemming from factors such as reduced oxygen levels in the air (low FiO₂), as in high-altitude environments, or more commonly due to hypoventilation. Hypoventilation can arise from the central nervous system, depression, obesity hypoventilation syndrome, or airway obstruction, such as in COPD exacerbation. However, if the gradient is elevated, hypoxia may result from a diffusion or perfusion defect (V/Q mismatch). Another alternative explanation is the shunting of blood flow around the alveolar circulation. Administering 1.0 FiO₂ may help differentiate between V/Q mismatch and shunt physiology, as oxygenation typically improves in V/Q mismatch but not in cases of shunt physiology.

PaO₂:FiO₂ ratio: The PaO₂:FiO₂ ratio is another method to assess the extent of hypoxia. A normal ratio falls within the range of approximately 300 to 500 mm Hg. Ratios below 300 indicate abnormal gas exchange, with values below 200 mm Hg indicative of severe hypoxemia. Primarily utilized to gauge the severity of ARDS, the PaO₂:FiO₂ ratio provides valuable insight into respiratory dysfunction.

Evaluation of Chronic Hypoxia

Pulmonary function test: Pulmonary function tests (PFTs) offer a direct assessment of lung volumes, bronchodilator response, and diffusion capacity, aiding in both diagnosis and treatment guidance for various lung disorders. Complementing history-taking and physical examination, PFTs help differentiate between obstructive conditions, such as bronchial asthma, COPD, and upper airway obstruction, and restrictive lung diseases, such as interstitial lung diseases and chest wall abnormalities. They also assist in assessing the severity of airway obstruction and monitoring response to therapy. Notably, PFTs rely on patient effort and cooperation, as they require comprehension and adherence to instructions.

Nocturnal (overnight) trend oximetry: Nocturnal (overnight) trend oximetry offers insight into oxyhemoglobin saturation levels over an extended period, typically throughout the night. The primary objective is to evaluate the necessity or sufficiency of oxygen supplementation during nighttime. Although it can be a substitute for diagnostic sleep studies, this practice is not recommended. A formal sleep study should be conducted for comprehensive assessment and diagnosis whenever feasible.

The 6-minute walk test: The 6-minute walk test offers valuable insights into the oxyhemoglobin saturation response to exercise and the total distance a patient can cover in 6 minutes on level ground. This information aids in titrating oxygen supplementation and assessing the efficacy of therapy. Widely employed in preoperative pulmonary assessment, pulmonary hypertension management, and determining supplemental oxygen requirements during exercise, the 6-minute walk test serves as a valuable tool in various clinical contexts.

Hemoglobin: Hemoglobin levels can indicate secondary polycythemia, which often serves as an indicator of chronic hypoxia.

Treatment / Management

Management of hypoxia entails 3 key approaches—ensuring airway patency, increasing the oxygen content of inspired air, and improving diffusion capacity.[10][11][12]

Maintaining Patent Airways

The healthcare team ensures upper airway patency by employing effective suctioning techniques and maneuvers to prevent throat occlusion, including head tilt and jaw thrust, as needed. In certain cases, an endotracheal tube or tracheostomy placement may be warranted. For chronic conditions, such as obesity hypoventilation syndrome, maintaining patent airways often involves using positive pressure ventilation methods such as continuous positive airways pressure mask (CPAP) or bilevel positive airways pressure (BiPAP). Lower airway patency is maintained through administering bronchodilators and implementing aggressive pulmonary hygiene measures such as chest physiotherapy, flutter valve, and incentive spirometry.

FiO₂: FiO₂ is administered when PaO₂ is less than 60 mm Hg, or SaO₂ is less than 90%, and involves increasing the percentage of oxygen in the inspired air to ensure adequate oxygen reaches the alveoli.

Low-Flow Devices

Nasal cannula: 

• Usage: Suitable for mild hypoxia (with FiO₂ approximately 92%).
• Flow rate: Adjustable up to 6 L/min.
• Delivered FiO₂: Up to 45% (0.45).
• Advantages: Easy to use and offers increased patient convenience (usable during eating, drinking, and speaking)
• Disadvantages: May lead to dry nasal mucosa (requires humidification if the flow exceeds or equals 4 L/min), variability in delivered FiO₂, and reduced efficacy for mouth-breathing.

A predictive formula can approximate FiO₂ percentage: FiO₂ = (0.2 + ([4 times oxygen flow liters]). For example, an oxygen flow of 2 L/min would deliver approximately FiO₂ of 0.3, while 6 L/min would deliver approximately FiO₂ of 0.45 (commonly known as 45%). However, this predictive formula may be inaccurate in low O₂ flow rates (<5 L/min). Recent in vitro studies suggest a more accurate formula, which is 0.21 + (1/[4 x minute ventilation]) x L/min of O₂. For low flow rates and an inspiratory:expiratory time ratio of 0.5, a more accurate equation is suggested, which is 0.21 + (1/[2.5 x minute ventilation]) x L/min of O₂.[13]

Simple face mask: 

• Usage: Suitable for moderate-to-severe hypoxia as an initial treatment.
• Flow rate: Adjustable up to 10 L/min.
• Delivered FiO₂: Ranges from 35% to 50%.
• Advantages: Offers higher FiO₂ levels without imposing pressure; generally well-tolerated by patients.
• Disadvantages: May lead to dry oral mucosa (requires humidification); a minimum flow of 5 L/min is necessary to flush out CO₂ but should not be excessively high. Additionally, the mask may interfere with daily activities.

 Reservoir cannulas (Oxymizer):

• Usage: The device uses a reservoir space, which stores O₂ during expiration and makes it available as a bolus during the next inspiration. This way, the patient gets a higher oxygen delivery without increasing flow. 
• Flow rate: Adjustable up to 16 L/min.
• Delivered FiO₂: Up to 90% (0.9).
• Reservoir cannulas are available in 2 configurations: Mustache (Oxymizer) and pendant (Oxymizer Pendant). In the mustache configuration, the reservoir is positioned directly beneath the nose, while in the pendant configuration, it is connected to a plastic reservoir located on the anterior chest.

Partial-rebreather mask

• Features a 300- to 500-mL reservoir bag and 2 one-way valves to prevent exhalation into the reservoir.
• Usage: Suitable for moderate-to-severe hypoxia.
• Flow rate: Typically set between 6 and 10 L/min, ensuring adequate flow to prevent reservoir bag collapse during inspiration.
• Delivered FiO₂: Ranges from 50% to 70%.
• Advantages: Capable of delivering higher FiO₂ levels.
• Disadvantages: May interfere with activities of daily living.

Non-rebreather mask

• Features a 300- to 500-mL reservoir bag and 2 one-way valves.
• Usage: Effective for moderate-to-severe acute hypoxia.
• Flow rate: Typically set between 10 and 15 L/min, ensuring at least 10 L/min to prevent bag collapse during inspiration).
• Delivered FiO₂: Ranges from 85% to 90%.
• Advantages: higher FiO₂ can be achieved.
• Disadvantages: May interfere with activities of daily living.

Double trunk mask [14][15][16](A1)

• Can be used with either low or high-flow nasal cannula.
• Usage: Designed to elevate FiO₂ levels in patients with elevated inspiratory flow demand.
• Flow rate: Same as low- or high-flow nasal cannula.
• Delivered FiO₂: Up 100%
• Advantages: Has the potential to enhance PaO₂ levels in patients compared to nasal cannula alone.
• Disadvantages: Assembly is required despite its simple construction, which can be cumbersome for the patient.

High-Flow Devices 

High-flow devices typically necessitate an oxygen blender, humidifier, and heated tubing for optimal functionality.

Venturi mask:

• This mask is attached to an air entrainment valve.
• Usage: Effective for moderate-to-severe hypoxia.
• The flow rate and FiO₂ (depending on the color): Blue (2 to 4 L/min) = 24% O₂; white (4 to 6 L/min) = 28% O₂; yellow (8 to 10 L/min) = 35% O₂; red (10 to 12 L/min) = 40% O₂; and green (12 to 15 L/min) = 60% O₂.
• Advantages: Offers precise oxygen delivery and high flow rates.
• Disadvantage: Inconvenient for eating; less accurate at higher flow rates. The mask does not ensure total flow with O₂ percentages above 35% in patients with high inspiratory flow demands. The challenge with air entrainment systems is that as the flow is increased, the air-to-oxygen ratio decreases.

High-flow nasal cannula:

• High-flow oxygen consists of a heated, humidified O₂.
• Flow rate: Ranges from 10 to 60 L/min.
• Delivered FiO₂: Up to 100%
• Advantages: Offers convenience; capable of delivering up to 100% heated and humidified oxygen at a maximum flow of 60 L.
• Disadvantages: Relatively large cannula size may cause discomfort, although typically minimal.

Air/oxygen blender:

• Facilitates precise oxygen delivery regardless of the patient’s inspiratory flow demands.
• Capable of generating positive end-expiratory pressure (PEEP).
• Approximately 1 cm/H₂O of positive pressure is generated for every 10 L flow delivered.

Positive Pressure Ventilation

This ventilation enables precise delivery of required FiO₂ and includes the below-mentioned approaches.

Non-invasive ventilation: This is usually used as the last resort to avoid intubation.

Continuous positive airway pressure mask:

• Primarily utilized for patients with obstructive sleep apnea or acute pulmonary edema.
• Delivers oxygen (or air) at a predetermined high pressure via a tightly fitting face mask.
• Sustains continuous positive pressure to keep the airways open (split them).

Bilevel positive airway pressure:

• Primarily used in patients experiencing acute hypercarbia, such as those with COPD exacerbation or ARDS.
• Delivers high positive pressure during inspiration and lower positive pressure during expiration.
• Pressure delivery varies throughout the respiratory cycle, maintaining high positive pressure during inspiration and lower positive pressure during expiration.

Invasive ventilation:

• Utilizes a positive pressure ventilator connected to an endotracheal tube. 
• Allows for accurate delivery of predetermined minute ventilation, FiO₂, and PEEP.
• Commonly used electively during surgery.

Improving Oxygen Diffusion Through the Alveolar Interstitial Tissues

The primary approach involves addressing the root cause of respiratory failure:

• Diuretics may be administered for pulmonary edema.
• In certain cases of interstitial lung disease, steroids may be prescribed.
• Extracorporeal membrane oxygenation serves as an advanced method for augmenting oxygenation when necessary.

Differential Diagnosis

Understanding the differential diagnoses of hypoxia is crucial in identifying the underlying mechanisms contributing to inadequate oxygen delivery or utilization in the body, including the conditions below.

Hypoxemic hypoxia: Low arterial oxygen tension (PaO₂) resulting from ineffective oxygenation of blood in the lungs. Causes include hypoventilation, impaired alveolar diffusion, and pulmonary shunting.

Circulatory hypoxia: Occurs due to inadequate oxygen delivery caused by pump failure, where the heart fails to pump sufficient blood.

Anemic hypoxia: Caused by a reduction in oxygen-carrying capacity due to low hemoglobin levels, resulting in insufficient oxygen delivery.

Histotoxic hypoxia (dysoxia): Cells are unable to utilize oxygen efficiently. Cyanide poisoning is a classic example, where the inhibition of cytochrome C oxidase in mitochondria prevents oxygen utilization for ATP production.