Before the era of rapid blood gas analysis, clinicians often assessed hypoxemia on clinical grounds alone, primarily by looking for cyanosis in the perioral area and fingers. Clinical assessment of hypoxemia is now known to be notoriously unreliable.
A host of factors, from natural skin pigment to room lighting, can affect detection of cyanosis. As with many other physical examination findings, significant interobserver variation occurs in detecting cyanosis.  Physicians may diagnose cyanosis as an indicator of hypoxemia when the patient has normal oxygen saturation; alternatively, physicians may miss cyanosis when it should be present (the patient has very low oxygen saturation with normal hemoglobin).
Approximately 5 g/dL of unoxygenated hemoglobin in the capillaries generates the dark blue color appreciated clinically as cyanosis. For this reason, patients who are anemic may be hypoxemic without showing any cyanosis.
Ancillary signs and symptoms of hypoxemia (eg, tachycardia, tachypnea, mental status changes) are nonspecific and of no value in reliably detecting hypoxemia. For example, patients may be dyspneic at rest for reasons other than hypoxemia (ie, they have normal PaO2 and SaO2). Conversely, many patients who are chronically hypoxemic (low PaO2 and/or low SaO2) are perfectly lucid and without any obvious physical signs of their low oxygen state (at least while at rest).
Generation of Cyanosis
The requirement of 5 g/dL of reduced (ie, deoxygenated) hemoglobin in the capillaries translates into a reduced hemoglobin content of 3.4 g/dL in arterial blood.  For this reason, patients with normal hemoglobin manifest cyanosis at higher SaO2 values than patients with anemia. Refer to the image below and consider the following examples:
- A patient whose hemoglobin content is 15 g/dL (hematocrit approximately 45%) would not generate 5 g/dL of reduced (ie, deoxygenated) hemoglobin in the capillaries until his/her SaO 2 level reached about 79% (PaO 2 47 mm Hg).
- When hemoglobin content is 9 g/dL (hematocrit approximately 27%), the threshold SaO 2 level for manifesting cyanosis is lowered to about 65% (PaO 235 mm Hg). At this level of hypoxemia, the patient would certainly have other manifestations of hypoxemia (eg, respiratory symptoms, mental status changes) apart from cyanosis.
- With a hemoglobin content of less than 9 g/dL, the patient would likely succumb from hypoxemia before cyanosis became evident.
- If hypoxemia is suspected for any reason, some measurement of the oxygen level is necessary (eg, arterial blood gas determination, pulse oximetry). No reliable alternative is available to measurement of PaO2 or SaO2 when diagnosing hypoxemia or assessing the need for supplemental oxygen therapy.  At the same time, one should not rely on the absence of cyanosis as reassurance that hypoxemia is not present.
Other Causes of Cyanosis
Normal hemoglobin unbound to oxygen is called reduced hemoglobin and is symbolized HbFe+2. Methemoglobin (metHb), the oxidized form of hemoglobin, is HbFe+3. Normally, as much as 2% of hemoglobin is in the form of metHb. Because metHb is unable to bind with oxygen, arterial oxygen saturation is reduced by the same amount that metHb is increased.
MetHb imparts an intense bluish tinge to the skin; therefore, the cyanosis that comes with methemoglobinemia is not related to reduced hemoglobin but to oxidized hemoglobin. [8, 9] Methemoglobinemia usually occurs as a drug reaction, especially to nitrite or nitrate-containing compounds (eg, nitroglycerin) and to some topical anesthetics. Dahshan and Donovan report a case of severe methemoglobinemia from topical benzocaine in a toddler.  Dapsone, a drug used in HIV and non-HIV conditions, can also cause methemoglobinemia.
Although excess metHb reduces the measured SaO2, PaO2 is not affected; this is because metHb does not affect transfer of oxygen from the atmosphere to the lungs. A low PaO2 in a patient with excess metHb suggests a concomitant pulmonary problem. MetHb can be measured in a co-oximeter, a companion to the blood gas machine available in most hospital blood gas laboratories. The co-oximeter also measures carboxyhemoglobin, hemoglobin content, and SaO2. Note that standard pulse oximeters, which measure SaO2 using 2 wavelengths of light, do not measure metHb (or carboxyhemoglobin). However, a new generation of pulse oximeters that uses 8 wavelengths of light does have the ability to measure carboxyhemoglobin and metHb (Barker 2006).of light does have the ability to measure COHb and metHb. 
Sulfhemoglobinemia is a rare condition caused by sulfur binding with hemoglobin so that oxygen cannot be bound. Unlike metHb, the iron moiety remains in the reduced state (HbFe+2). Sulfhemoglobin is similar to metHb in causing low SaO2 but not affecting PaO2 and in imparting an intense bluish color to the skin.
Peripheral cyanosis is a dusky or bluish tinge to the fingers and toes and may occur with or without central cyanosis (ie, with or without hypoxemia). When unaccompanied by hypoxemia, as determined by blood gas analysis, peripheral cyanosis is caused by peripheral vasoconstriction.
Pseudocyanosis is a bluish tinge to the skin and/or mucous membranes that is not associated with either hypoxemia or peripheral vasoconstriction. Most causes are related to metals (eg, silver nitrate, silver iodide, silver, lead) or drugs (eg, phenothiazines, amiodarone, chloroquine hydrochloride). One report describes blue-gray discoloration in a man who for years ingested colloidal silver for a urinary tract infection  ; his oxygen levels were normal.
One report describes a girl with intensely blue skin from food coloring.  Consider pseudocyanosis when the patient has no cardiopulmonary symptoms and the skin does not blanch under pressure. To be sure of the diagnosis, obtain a pulse oximetry or arterial blood gas measurement.