Oxygenation Status and Pulse Oximeter Analysis

Function

Definitions Generally Used

• Oxygen saturation: The proportion of hemoglobin inside red blood cells that can bind oxygen. This generally means functional hemoglobin or functional arterial oxygen saturation.
• SaO₂ is arterial saturation measured by ABG. This entity excludes certain dyshemoglobinemia and only includes effective hemoglobins. SaO₂ is expressed as 100% X (O2Hb)/(O2Hb + Hb). 
• SpO₂ is oxygen saturation measured by pulse oximetry using light wavelength. Commercially available oximeters use 2 light-emitting diodes (LEDs) that emit light at the 660 nm (red) and the 940 nm (infrared) wavelengths.[1]
• The pressure of any inspired gas (P gas) is equal to the partial pressure of the gas times the barometric pressure. The normal partial pressure of oxygen at sea level is simply the fractional inspired of oxygen (FiO₂) (0.21) times the barometric pressure (760 mm Hg at sea level), which is 160 mm Hg or 159 (if one uses 0.2093 as the FiO₂).
• The A-a gradient (or difference) is defined as the alveolar oxygen content minus the arterial oxygen content obtained from an arterial blood gas (ABG). Theoretically, there should be no gradient, but in reality, there is at least a 5 mm Hg or more gradient. The alveolar oxygen content comes from at least 300 to 400 million or more alveoli present at birth and tends to be a calculated value.[2]

Alveolar oxygen tension (PAO2)

It is essential to understand how the alveolar oxygen equation is developed. 

PAO₂ = (Patm – PH20) FiO2 – PaCO₂/RQ where Patm is atmospheric pressure and RQ is the respiratory quotient. 

Patm is equal to 760 torrs at sea level, and the PH₂O is the partial pressure of water vapor pressure in humans of 47 mmHg at body temperature (37 degrees Celcius). The room air FiO₂ is 0.21. The respiratory quotient (RQ) varies from 0.707 to 1.0 and is usually estimated as 0.80 for an average diet (that includes carbohydrates, protein, and fat). 

Based on these assumptions, the following calculation is made:

PAO₂ = (760 mm Hg – 47 mm Hg) 0.21 – 40 mm Hg/0.8 = 150 mm Hg – 50 mm Hg = 100 mm Hg. Therefore at sea level on room air, the only variables that should change to get the PAO₂ or alveolar oxygen are the arterial PaCO2 and the RQ. Assuming an RQ of 0.8 (volume of CO₂ released/volume of O₂ consumed) means the PaCO₂ is the only variable that changes. The common exceptions would be at high altitudes and hypoventilation, where the PA0₂ decreases.

Arterial Oxygen Tension (PaO2)

PaO₂ refers to the small amount of oxygen dissolved in the plasma after it diffuses from the alveolar spaces in the lung. PaO₂ is usually obtained from an arterial blood sample. The PaO2 measurement is useful, especially when false values of SpO₂ are suspected (such as in dark skin, dyshemoglobinemia, or severe anemia).

 Alveolar-Arterial Oxygen Gradient or (A-a) Gradient

The difference between the PA0₂ and PaO₂ is known as the alveolar-arterial oxygen gradient. This varies from about 5 to 25 mm Hg. It is calculated as the PAO₂ (100 mm Hg) – PaO₂ (approximately 95 mm Hg in a healthy young and nonsmoking person) equals 5 mm Hg. Therefore, the A – a difference (or A-a gradient) on room air last sea level is calculated as follows:

PAO₂ [(760 mm Hg– 47 mm Hg) 0.21 – 40 mm Hg/0.8 = 150 mm Hg – 50 mm Hg] – PaO₂ (95 mmHg) = 5 mm Hg (or more with age). 

For older individuals, there are formulas to adjust for age to calculate the A-a difference, such as [A-a difference adjusted for age= A-a difference (age/4) + 4].[3]

A normal PA0₂ is about 100 mm Hg, with the arterial Pa0₂ varying from about 95 mm Hg to as low as 75 mm Hg (or lower, depending on who one talks to). It is well known that the arterial PaO₂ in mm Hg on room air decreases with age.[4] A crucial point to remember is that an ABG saturation is about 100% when the ABG partial pressure of oxygen is approximately 97 mm Hg or more (depends a little on the oxygen dissociation curve). This means that once the ABG saturation is 100%, the partial pressure of oxygen could be 100, 200, 300, 400, 500 mm Hg or more.

If on room air, the difference is probably closer to 100 mmHg. Also, once the saturation is 100%, all 4 oxygens on each hemoglobin molecule have one oxygen and are full. Therefore, the only way to further increase oxygen transport is to increase hemoglobin. 

Also, if the A-a gradient is calculated with inspired oxygen greater than room air, the alveolar PA0₂ will increase faster than the arterial PaO₂ resulting in an increasing A-a gradient. This is normal. Another point is that the A-a gradient on room air can increase faster with disease (and not just age). This is important to remember. 

Arterial Hyperoxia

Arterial hyperoxemia refers to a high PaO2 in arterial blood.[5] This is defined as a PaO2 of 100 to 300 mm Hg or a PaO₂ of >300 mm Hg post-cardiopulmonary arrest.[5] A high PaO₂ is now considered risky in acute myocardial infarction, as noted in the DETOX-AMI trial (Hofmann et al) and others.[6][7] Treating patients without hypoxemia (a pulse oximeter saturation <90%) during acute ischemia and a possible myocardial infarction is now considered reasonable.[6][7]

Arterial Hypoxia

Hypoxia is where oxygen at the tissue and organ level is unavailable to provide adequate homeostasis.[8][9] Arterial hypoxemia refers to a decrease in the PaO₂ in arterial blood. An actual value is a PaO2 <60 mm Hg on pulse oximetry or an ABG saturation <90%. The ABG is still the gold standard because pulse oximeters can read up to 2 mm Hg above or below the true value.

Arterial hypoxia symptoms include anxiety, confusion, tachypnea, and dyspnea. Chronic low oxygen, particularly with cancer, results in hypoxia-inducible factor (HIF) cell synthesis, which allows oxygen-deprived cells to survive and proliferate. When there is no hypoxia, von Hippel-Lindau (VHL) changes and binds to HIF, which is degraded.

VHL does not change when hypoxia is present, and HIF is not changed. Hypoxia treatment includes exogenous oxygen to return to normal levels, then treating the underlying disease. All causes of hypoxia can cause cell death, or there can be recovery. There are at least 4 common causes of hypoxia which are:

• Hypoxemic hypoxia: Hypoxemia is present and may cause weakness and fatigue; it is the most common cause of hypoxia. Oxygen therapy and treatment of the underlying disease are the treatments of choice.

• Anemic hypoxia: This is due to either low hemoglobin or deshemoglobminemia (methemoglobinemia, sulfhemoglobinemia, and carboxyhemoglobinemia) (functional anemia).[10] One needs to fix the dyshemoglobinemia or transfuse blood to resolve the problem. 

• Histotoxic hypoxia (reduced oxygen-carrying capacity): The inability to use available oxygen due to cyanide toxicity.[11] Cyanide toxicity is often due to fires in the U.S. Toxic levels of cyanide were seen in the past from sodium nitroprusside used intravenously for hypertensive emergencies. Sodium nitroprusside has 5 cyanide groups per molecule, halting cellular respiration by blocking oxygen from going to water. Cyanide toxicity can lead to the failure of the tissue to use oxygen; however, despite that, the pulse oximeter reading is usually within normal due to the standard binding capacity of oxygen to hemoglobin.[11]

• Circulatory hypoxia (stagnant hypoxia) or ischemic hypoxia: Heart failure is often a problem. In this instance, one needs to treat the underlying cause of heart failure.[8][9]

• Other mechanisms of hypoxia: Increased O₂ extraction or pseudo hypoxemia (due to hyperleukocytosis in patients with hematological malignancies who are susceptible to acquired infections).[12][13] 

Oxyhemoglobin Dissociation Curve (ODC) and Oxygen-Myoglobin Dissociation Curve and Binding

Oxygen in blood is transported primarily by hemoglobin; only about 2% is dissolved and follows Henry’s Law. Usually, 4 oxygen molecules are bound to each hemoglobin tetramer when the molecule is completely saturated. A sigmoid shape occurs when plotting oxygen tension on the x-axis and oxygen saturation on the y-axis.

The curve tends to be flat at high oxygen tensions in the pulmonary circuit because oxygen saturations are close to 100% or 100%. The curve goes from flat to much steeper at low oxygen tensions as oxygen is added to hemoglobin. With the addition of each new oxygen molecule to hemoglobin, the conformation of hemoglobin changes, which facilitates the binding of the next oxygen molecule. This property is called binding cooperativity. The p50 is when 50% of the hemoglobin molecules are bound with oxygen.

A normal p50 is from 26 to 27 mm Hg. A high p50 indicates a low oxygen affinity for hemoglobin and vice versa. The high p50 also means easy delivery of oxygen to the tissues. This is seen with acidosis, elevated temperature (exercise), increased 2,3 BPG (stays high in stored blood for at least one week), and increased temperature. (see table). The converse is also true. A low p50 (high oxygen affinity for hemoglobin) is seen with CO poisoning, methemoglobin, and fetal hemoglobin. The high oxygen affinity with fetal hemoglobin allows it to take oxygen from the mother for its own use.

Table. Left versus Right Shift in the Sigmoid Oxyhemoglobin Dissociation Curve

Myoglobin is found in skeletal muscle and has a higher affinity for oxygen than other adult hemoglobin. This entity becomes saturated at lower oxygen levels and holds onto oxygen until oxygen in the muscles is very low. The delayed release of oxygen slows the start of anaerobic metabolism and lactic acidosis. The myoglobin molecule is a single polypeptide chain, and the oxygen-myoglobin dissociation curve is logarithmic and not sigmoidal. Myoglobin is not capable of cooperative binding.

CO-oximetry is also useful in rare congenital or acquired conditions responsible for dyshemoglobinemias, such as methemoglobinemia and Sulfhemoglobinemia.[14][15][16][17] Many co-oximeters have only recently become capable of detecting sulfhemoglobin because it resembles methemoglobinemia and is frequently overlooked. Sulfhemoglobin is a green-pigmented molecule that often results in cyanosis. Despite physiologic anemia, sulfhemoglobinemia is generally well tolerated, possibly because it causes a right shift in the hemoglobin oxygenation dissociation curve (in contrast to the other types of dyshemoglobinemias).

Issues of Concern

Clinical Presentation of Hypoxia

Hypoxia symptoms are nonspecific and vary depending on severity, cause, and which parts of the body are affected. When oxygen is low, the patient might feel dyspneic. However, hypoxia may be asymptomatic. Hence patients with advanced chronic respiratory conditions, such as chronic obstructive pulmonary disease (COPD), may experience symptoms with resting, exertional, and nocturnal hypoxemia which include:

1. Headache
2. Restlessness
3. Confusion
4. Anxiety
5. Tachycardia
6. Tachypnea
7. Dyspnea

Goal-directed Oxygen Therapy

Based on current evidence, it is recommended to avoid PaO₂ levels exceeding 300 mm Hg to mitigate potential adverse effects, including neurotoxicity and reperfusion injuries.[18] Recent studies suggested that using oxygen to correct hypoxia should be gaol targeted to avoid deleterious consequences.[19][20] 

A recent study by Girardis et al demonstrated that in critically ill patients (with an ICU length of more than 72 h), a conservative protocol for oxygen therapy (to maintain SpO₂ between 94 and 97% and median PaO₂, 87mm Hg) versus conventional therapy (SpO₂ between 97 and 100% and PaO₂, 102 mm Hg) resulted in lower ICU mortality. In addition, there has been growing evidence that hyperoxemia could be harmful such as in patients with acute coronary syndromes and following cardio-respiratory arrests.

Likewise, in patients with ARDS, oxygen administration above goal (defined as PaO₂ >80 mm Hg and FiO₂ >0.5) was reported to lead to worse clinical outcomes at different levels of ARDS severity.[21]

Accuracy of SpO₂ in screening for eligibility for long-term O₂ therapy (LTOT)

Oxygen therapy is recommended for eligible patients with evidence of chronic hypoxia, such as COPD, who have moderate-to-severe hypoxia (SpO₂ <88% at rest).[22] However, less severe hypoxia (resting SpO₂ 89-93% or isolated exertional desaturation not exceeding 90%) did not improve all-cause mortality or hospitalization in patients with COPD.[23]

The ability of SpO₂ to provide accurate values f oxygenation is limited to mild degrees of hypoxia as the correlation between it and PaO2 is not linear and becomes more variable with more severe hypoxia (SaO₂ <88%).[24] Furthermore, SpO₂ can lead to significant misclassification in certain conditions, such as in individuals with dark skin (non-white races such as black and Asian).[25] The lacking precision of SpO₂ has been reported to fail to accurately identify PaO₂  values in the hypoxia ranges (<55 mm Hg) and hence the inability to adequately detect LTOT eligibility.[26]

Clinical Significance

Pulse Oximeter Analysis

This is a quick, inexpensive, portable, lightweight, noninvasive method for measuring a person’s continuous oxygenation status and is sometimes called the fifth vital sign. In 95% of cases, this method is accurate within 4% and usually uses transmissive pulse oximetry. These instruments are 2-wavelength devices that measure only two hemoglobin types. These hemoglobin types are oxyhemoglobin and hemoglobin not bound to oxygen. These are two equations with 2 unknowns. The device uses 2 light-emitting diodes emitting light at 660 nm (red) and 940 nm (infrared).[1] 

These 2 wavelengths pass through a finger, earlobe, or foot to a photodetector. The red region or oxyhemoglobin (O2Hb) absorbs less light than hemoglobin (Hb), while the reverse is true with infrared. A ratio of these two absorbances at these wavelengths is calibrated against arterial blood gas saturations from a co-oximeter in normal volunteers and is stored as a calibration algorithm. This algorithm within the device is then called up when needed, and the pulse oximeter estimates the saturation.

One problem is that the normal volunteers tend to be white, and it has been shown that pulse oximeters may tend to be under-read in dark-skinned subjects.[27] This is partly related to proprietary issues. This same procedure needs to be researched in dark-skinned individuals. Thus, this technique still needs validation in other populations and conditions.[28]

The advantage of pulse oximetry is that despite being quick and noninvasive, no study has yet noted a difference in mortality.[29] Hypoxemia, (defined here as pulse oximeter saturation <90%) was 7.9% with pulse oximetry and 0.4% in those without pulse oximetry.[29] 

Eleven years later, 100% of patients undergoing bariatric surgery had hypoxemia (hypoxemia defined as a sat <90% for at least 30 s in this study).[30] The average nadir saturation was 75 + 8 mm Hg, and the pCO₂ was 37 + 3 mm Hg (no hypercarbia).[30] Another pulse oximeter advantage is that fewer blood gases are needed when oxygenation status is known. At the same time, pulse oximeter accuracy is known to be decreased with saturations below 80, hypotension, and nail polish on fingernails.[31] 

The gold standard is still the ABG which gives the best saturations. In addition, ABGs provide more information related to pH, pCO₂, and acid-base status and are often needed. Despite its pros and cons, pulse oximetry has taken the nation by storm in the last 25 years and is here to stay. There are more benefits than negatives. When using pulse oximetry and co-oximetry, it is important for healthcare providers to consider the presence of certain dyshemoglobinemias, which are conditions where oxygen-binding moieties are unable to effectively bind oxygen. The 3 notable dyshemoglobinemias that need to be considered in this context are CO poisoning, methemoglobinemia, and, although rare, sulfhemoglobinemia.

Fractional SaO₂ = Sometime called FO₂Hb; it is the same as SaO₂ (functional arterial saturation) when there is no dyshemoglobinemia.

When there is a dyshemoglobinemia, fractional saturation measures all hemoglobin, and the formula is 100% X (02Hb)/(02Hb + Hb + COHb + MetHb + Sulfhemoglobinemia).

The partial pressure of oxygen (PaO₂): The pressure of oxygen in mm Hg in the blood can be obtained with an ABG with normal values from 75 to at least 95 mm Hg.

CO-oximetry requires arterial blood gas and is divided into functional and fractional oxygen saturations (SaO₂). Functional SaO₂ includes hemoglobins that bind to oxygen.[32]

• Functional SaO₂ = (O2Hb)/(O2Hb + Hb) X 100%. Normal Value: 95 – 100%.

Fractional SaO₂ is important because it includes all hemoglobin, ie, those that don’t bind oxygen (methemoglobin, carboxyhemoglobin, and sulfhemoglobinemia) and those that do (02Hb and Hb) and require one equation for each hemoglobin (wavelength).[32]

• Fractional SaO₂ = (02Hb)/(02Hb + Hb + COHb + MetHb) X 100%.
• Normal Value: 94 – 98%.
• Example 2: O2Hb = 10.0 mg/dL, Hb: 0.5 mg/dL. Methemoglobin: 2.0 mg/dL. COHb: 5 mg/dL.
• Answer: 10 mg/dL/17.5 mg/dL = 57%.
• FO₂Hb = Fractional SaO₂; it is lower than the regular SaO₂ in dyshemoglobinemia. 

Theoretically, functional and fractional hemoglobins are identical when only O2Hb and Hb are present. When the oxygen saturation level is below or higher than expected by pulse oximetry using a 2-wavelength system, consider co-oximetry to ensure no dyshemoglobinemia is present.

Oxygen Content (CtO₂) = SaO₂ X CtHb mg/dL X (1-FCOHb-FmetHg) +

Pa0₂ X 0.003 ml 0₂ per gm Hg/dL

Normal CtO₂ = 18.8 to 22.3 ml/dL -generally 2% dissolved oxygen and 98% on Hb.

Normal SaO₂ = ct0₂2Hb/ct (0₂Hb + HHb) X 100% = 95 – 100%.

One can increase Oxygen Content by transfusions, reducing dyshemoglobinemias, or giving oxygen.

Sa0₂ = percent of oxygenated hemoglobin relative to the amount of hemoglobin capable of carrying oxygen. Reference value = 95% to 100%.

Using 2 wavelengths, simple co-oximeters will give similar functional and fractional values in healthy young white individuals. Pulse oximetry estimates the saturation of hemoglobin and does not give estimates of actual Pa0₂ or other bound gazes, such as carbon monoxide (CO), which require different oximeters. The co-oximeter is a special spectrophotometer used to measure different oxygen saturations. This type of spectrophotometer is used to determine whether a dyshemoglobinemia is present.[15][33]  

Arterial Hypoxemia - 5 Common Causes

1. Diffusion abnormality[34][35][36]

Carbon monoxide is the tracer of choice to measure diffusion since it is diffusion limited. Nitrous oxide (NO) and oxygen are perfusion limited. Oxygen can become diffusion limited if the membrane becomes thickened, particularly if the 0.75-second normal capillary time drops with exercise (can drop to as low as 0.20 seconds with exercise). One can demonstrate that the thickening of the alveolar membrane results in a diffusion capacity for oxygen of less than ¾ of a second. The normal diffusion (DLCO) in the 2017 guidelines is no longer specified, but a value of 0.75 predicted or greater per an older guideline would probably be considered normal.[35][36]

     2. Right to Left Shunt (normal shunt <5%, from Thebesian and bronchial veins). 

The 5 common mechanisms of hypoxemia: order listed from common to rare.

All but a high right-to-left shunt respond well to oxygen. In addition, if there is a shunt with relative hypoxemia, increasing oxygen to the area can increase oxygen carrying capacity of blood that passes it. A shunt will not respond at all to oxygen, only when ventilation is close to zero or zero.

   3. V/Q abnormality

The most common abnormality seen overall and in obstructive lung diseases. The most important point is that, in general, high V/Q areas (V/Q as high as 3) cannot make up for low V/Q areas.[34] High V/Q areas already carry as much oxygen as possible. The difference must come from low V/Q areas. Low V/Q areas like the base of the lung (V/Q less than 0.7) in upright humans do not make up the difference, which is where the problem lies. Here, high V/Q areas cannot respond to any more oxygen, and low V/Q areas tend to respond less to oxygen. Overall, these diseases respond well to oxygen.

  4. Hypoventilation

Hypoventilation presents with an elevated arterial PaC0₂ and a normal A-a gradient that responds well to oxygen. Neurologic disease and drug overdoses are two common causes. 

   5. Altitude

Both barometric pressure and the A-a gradient decrease with an increase in altitude. Therefore, there will be no negative effect with increasing elevation. Increasing altitude responds well to oxygen. High altitude is the rare 5th leading cause of hypoxemia.     

Generally, the alveolar oxygen stays constant at about 100 mm Hg, and the arterial oxygen starts at about 95 mm Hg or less and goes down with age (time). This reduction is partly due to normal shunting and to a slight reduction in the A-a gradient that occurs when standing upright since the normal V/Q ratio is about 0.80 and not one. These are at least two reasons why the A-a gradient can never be zero.

Carbon Monoxide (CO) Poisoning

CO poisoning is one of the most common dyshemoglobinemia that can cause errors in conventional pulse oximetry using two-wavelength techniques. In CO intoxication, the pulse oximeter Sp0₂ is within normal limits, but the actual saturation of oxygenated hemoglobin is much lower.[32] Due to the high  CO affinity to hemoglobin than oxygen (200 times more affinity), there is a much lower level of oxyhemoglobin. In addition, CO absorbs as much light as oxyhemoglobin (0₂Hb) at 660 nm. This means that carboxyhemoglobin can falsely elevate the Sp0₂ measurements.[15] 

Therefore, with CO poisoning the pulse oximeter saturation is elevated to normal due to the elevated CO binding to hemoglobin and not due to oxygen binding to hemoglobin. Therefore not measuring the carboxyhemoglobin level makes the diagnosis of CO poisoning challenging and requires a high level of suspicion, especially since the symptoms are vague and the saturation levels on the pulse oximeter seem normal.  

Evaluation with Co-oximetry

A complete work-up is necessary, including electrolytes, blood count, BUN, creatinine, urine toxicology and urinalysis, troponin, and electrocardiogram (ECG). A prolonged Q-T interval or ischemia is sometimes seen on the ECG. A chest radiograph and brain CT should also be done since sometimes the globus pallidus or other areas of the brain can be affected. An ABG with co-oximetry needs to be done on an arterial or venous blood sample to make the diagnosis. Arterial ABGs give more information about low oxygen in the blood with CO poisoning.[37]

Hyperbaric Oxygen Therapy

If indicated, co-oximetry can be considered. Overall, mortality with hyperbaric oxygen has been equivocal. Late neurologic findings are common. In one well-done randomized controlled trial, the result shows that three hyperbaric oxygen treatments done within 24 hours reduce cognitive sequelae at 6 and 12 months.[38] This suggests that at least neurologic damage can be minimized with hyperbaric oxygen treatment in some cases.

Other Issues

Detecting CO poisoning is challenging without a high index of suspicion because the symptoms are so nonspecific.[39]

Signs and symptoms of CO poisoning can include:

• Headache
• Dizziness
• Weakness
• Nausea and vomiting
• Shortness of breath
• Confusion
• Blurred vision
• Loss of consciousness

CO poisoning can be dangerous for people who are intoxicated or sleeping and can be lethal. 

Studies have shown that pulse oximeters may underestimate saturation in individuals with dark skin.[27][40] Due to this racial disparity in pulse oximetry technology, validation of the accuracy of these devices should be mandated by regulatory agencies, and caution is recommended in this group of patients who may be encountering hypoxia during their critical illness.[41] 

Pseudohypoxia: This condition is commonly seen as a complication of hyperglycemia due to uncontrolled diabetes.[42] The uncontrolled hyperglycemia can lead to overproduction of NADH and lower nicotinamide adenine dinucleotide (NAD), causing redox imbalance and cellular pseudohypoxia.[43] Pseudohypoxemia, however, is a reduction of oxygen in blood in vitro reported in hematological malignancy, such as in a patient with chronic lymphocytic leukemia.[44]

Enhancing Healthcare Team Outcomes

Pulmonary, critical care, anesthesiologist, and respiratory therapists should possess a certain level of understanding regarding the A-a gradient, including its calculation and the potential implications of its levels (normal, low, or elevated).[3][34] [Level 4] Additionally, supplemental oxygen should be administered conservatively (to maintain the Sp0₂ range between 94-96%) to avoid increased mortality and adverse outcomes.[19]

Pulse oximeters are readily available in different clinical settings. All healthcare workers, including physicians, mid-level practitioners, and nurses, should learn to use these devices and interpret the information they provide.[32] [Level 5]

Race correction for dark skin should be a factor, particularly in intensive care units.[27][40] [Level 5] This includes knowing how co-oximetry might be helpful and understanding dyshemoglobinemia. Carbon monoxide poisoning is the most common dyshemoglobinemia that healthcare workers can encounter. Carbon monoxide poisoning may or may not be recognized and sometimes causes neurologic symptoms when diagnosed.[39][38] [Level 1]