Hypoxemia and Hypercapnea

Also known as


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Related conditions





Shortness of breath



Respiratory distress

Respiratory acidosis

Respiratory failure



Acute respiratory distress syndrome (ARDS)

Acute lung injury (ALI)

1. Description of the problem

What every clinician needs to know

Hypoxemia and hypercapnea are the key gas exchange abnormalities associated with respiratory disease. “Hypoxemia” denotes a blood oxygen concentration or partial pressure of oxygen (PaO2) below normal. “Hypoxia” also signifies low oxygen levels, but is not restricted to the blood. “Hypercapnea” denotes a high partial pressure of carbon dioxide (PaCO2).

Both pulmonary and extrapulmonary disorders cause hypoxemia. Examples include pneumonia, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome/acute lung injury (ARDS/ALI) and congestive heart failure (CHF). Untreated hypoxemia jeopardizes the heart and brain. Cardiac manifestations include arrhythmias, congestive heart failure, and myocardial infarction. Central nervous system manifestations include altered consciousness and seizures. Complications are more common with severe hypoxemia.

Oxygen supplementation is generally needed when the PaO2 is below 55-60 mmHg or the oxygen saturation (SaO2) is below 88-90%. Oxygen can be supplemented noninvasively, for example by nasal cannulae or face mask. For severe hypoxemia, high flow and non-rebreather systems may be used. The most hypoxemic patients may require oxygen delivery under positive pressure, either noninvasively with a face or nasal mask or invasively via an endotracheal tube. Close monitoring is needed to ensure treatment response.

Acute hypercapnea signifies increased risk or presence of respiratory failure. The normal PaCO2 is 40 mmHg. Slight increases in the PaCO2 rapidly stimulate ventilation, returning the PaCO2 to normal. Causes of hypercapnea include primary ventilatory failure, manifested by a decreased alveolar ventilation (VA), or an inadequate ventilatory response to stresses such as increased CO2production (VCO2) or increased dead space (VD).

Acute hypercapnea causes a respiratory acidosis, manifested by a decreased blood pH. When hypercapnea is chronic, the kidneys retain HCO3, raising the serum HCO3 concentration and mitigating the pH drop.

An arterial blood gas (ABG) is the most common test used to diagnose hypercapnea. High clinical suspicion is necessary. Clinical manifestations that should raise suspicion include dyspnea, abnormal breathing patterns (e.g. accessory respiratory muscle use, rapid shallow breathing) and altered mental status.

Ventilatory support may be needed if acute hypercapnea is not corrected promptly. Worsening symptoms, lack of therapeutic response and a pH persistently below 7.30, signal the need for ventilatory support. Both noninvasive and invasive mechanical ventilation can be used to treat hypercapnea. Several factors influence the decision to initiate support, including the severity of hypercapnea, pH, clinical trajectory and clinician judgment.

Clinical features

Almost any pulmonary or cardiac disease can cause hypoxemia and hypercapnea. Signs and symptoms tend to reflect the underlying disease. Prominent lung disorders include pneumonia, ARDS/ALI, asthma, chest trauma, aspiration and pulmonary embolism. Nonpulmonary examples include congestive heart failure (CHF), strokes (e.g. involving the brain stem respiratory centers), drug overdoses (e.g. respiratory depressants such as narcotics) and intra-abdominal disasters which may impede diaphragm function (such as abdominal compartment syndrome).

Hypoxemia is difficult to detect without tools such as arterial blood gases (ABGs) and pulse oximetry. Cyanosis may be evident in patients with relatively severe hypoxemia, for example those with an SaO2 in the low to mid 80s or less. Cyanosis is difficult to appreciate in patients with less severe hypoxemia. Pulse oximetry is useful for the detection of hypoxemia, although hemodynamic instability may preclude accurate measurement. ABG testing is an alternative and more precise way to measure hypoxemia and is essential to detecting hypercapnea.

Both hypoxemia and hypercapnea cause a variety of non-specific physiological responses that vary from patient to patient. Autonomic stress responses include tachypnea, tachycardia, hypertension and diaphoresis. Bradycardia and hypotension are ominous signs that occur as respiratory failure progresses.

Signs of respiratory distress include orthopnea and accessory respiratory muscle use. Respiratory paradox – a pattern characterized by inward movement of the abdomen during inspiration – strongly suggests diaphragm fatigue or failure. With complete respiratory failure, the respiratory rate slows and becomes irregular before ceasing.

Physical exam findings offer clues to the underlying disease. Key pulmonary signs include dullness to percussion, wheezes, rhonchi, and crackles. The brain and heart are particularly vulnerable to hypoxemia and hypercapnea. Neurological manifestations include anxiety, agitation, delirium, confusion, headache (particularly with hypercapnea), visual alterations, seizures and altered consciousness (ranging from hypervigilance to somnolence and coma).

Cardiac manifestations include CHF, arrhythmias and myocardial infarction. Inadequate oxygen delivery can lead to anaerobic metabolism and lactic acidosis, resulting in dysfunction and failure of several organs, including the brain, heart, kidney and liver. Basic diagnostic tests such as chest radiographs and computed tomography (CT) scans may provide crucial information necessary to diagnose the cause of hypoxemia and hypercapnea.

Key management points

Key features of the management of hypoxemia and hypercapnea include providing supplemental oxygen, ventilatory support and treating the precipitating disorder.

Treatment of hypoxemia

The method chosen to supplement oxygen depends on the severity of hypoxemia. Low flow nasal cannulae suffice for mild hypoxemia. Anywhere from 0.5 to 6 L/M can be used, although nasal mucosal irritation limits tolerance of higher flows.

Nasal cannulae are comfortable and easy to use. Each L/M has been estimated to provide 2-3% more oxygen. However, in practice, the fraction of inspired oxygen (FiO2) is difficult to regulate because the amount of oxygen supplied is fixed while total ventilation is not. When patients hypoventilate, relatively less ambient air is inhaled compared to oxygen, increasing the FiO2. With hyperventilation, more ambient air is inhaled, decreasing the FiO2.

The inability to control the FiO2 can cause problems in patients predisposed to hypercapnea. For example, some patients with advanced COPD develop severe CO2retention when given too much oxygen. A variety of mechanisms contribute to hypercapnea, including a depressed respiratory drive, increased dead space and increased dissolved CO2(i.e. the Haldane effect).

Venturi mask oxygen delivery systems control the FiO2more effectively by mixing fixed ratios of ambient air and oxygen before inhalation. Theoretically, high flow systems allow an FiO2 up to 100%; in practice, however, entrainment of ambient air limits the FiO2 to 60-70%. Disadvantages of face mask systems include patient discomfort; difficulty with talking, eating, and drinking, and difficulty clearing secretions.

High-flow humidified nasal oxygen is a recent innovation used to treat severe hypoxemia and is a reasonable alternative to face mask approaches. Flows as high as 50 L/M, along with a relatively tight seal around the nose, allow high FiO2delivery. Because oxygen enters through the nose, patients may be able to talk, drink and eat. High flows may also create modest positive pressure within the respiratory system, with advantages similar to those associated with low continuous positive airway pressure (CPAP).

Positive pressure plays a key role in the treatment of severe hypoxemia and can be delivered noninvasively by nasal or face mask or invasively through an endotracheal tube (ETT). Noninvasive approaches are especially useful for treating diseases subject to quick reversal, such as CHF. Appropriate candidates must be hemodynamically stable and able to maintain a patent airway. Positive pressure can be delivered as a single pressure (CPAP) or with pressures that alternate during inhalation and exhalation (i.e. noninvasive positive pressure ventilation or NIPPV).

CPAP and NIPPV employ a relatively snug mask applied over the nose or nose and mouth. Those covering both the nose and mouth are generally more reliable and preferred in emergencies. A snug (not tight) fit limits the amount of ambient air entrained, allowing a higher FiO2. For patients with CHF, positive pressure decreases preload and afterload. Positive pressure also optimizes oxygen transfer across edematous alveoli and reverses or ameliorates atelectasis. For CHF patients without hypercapnea, CPAP is generally as effective as NIPPV.

Patients who are not candidates for noninvasive ventilation should be intubated. An ETT provides the means to deliver positive pressure ventilation and easy access to remove airway secretions. Because the system is closed, the FiO2can be titrated precisely from 21-100%. Higher levels of positive pressure can be provided compared to noninvasive systems. As with noninvasive ventilation, positive pressure can be provided in both inhalation and exhalation and has similar benefits.

Positive pressure provided during exhalation (positive end-expiratory pressure or PEEP) is especially important in ARDS/ALI. Common PEEP levels range from 5 to more than 20 cm H2O in those with severe hypoxemia. PEEP generally allows a decrease in the FiO2, mitigating the risk of oxygen toxicity, which is a particular concern when the FiO2 is greater than 60%. A variety of algorithms have been used to guide management in hypoxemic respiratory failure. A prominent example is that employed by the ARDSnet investigators, which titrates FiO2and PEEP based on the patient’s PaO2or SaO2.

Patients with severe hypoxemia may require additional interventions to support oxygenation. Sedation and occasionally neuromuscular blockade may decrease the amount of oxygen required. Diuresis may improve gas exchange in those with pulmonary edema. Prone positioning may improve ventilation and perfusion matching and prove helpful in centers with appropriate expertise. Recruitment maneuvers, which temporarily employ higher distending pressures and tidal volumes, may recruit atelectatic lung and improve oxygenation.

Inhaled vasodilators such as nitric oxide may improve oxygenation and play a temporizing role in those who cannot be oxygenated otherwise. Alternative mechanical ventilation approaches may be tried in refractory patients. Examples include prolonging inspiratory time and employing modes such as airway pressure release ventilation (APRV) and high frequency oscillation ventilation (HFOV).

Thus far, none of these approaches have proven superior to traditional modalities. Finally, there is growing interest in the use of extracorporeal membrane oxygenation (ECMO) in refractory patients, although data supporting this approach remain controversial.

Treatment of hypercapnea

Addressing the underlying cause of hypercapnea is fundamental to successful treatment. For example, patients with asthma and COPD require systemic corticosteroids and bronchodilators. Those who have overdosed on narcotics may need naloxone.

Patients with persistent or worsening acute hypercapnea need positive pressure ventilation. Noninvasive approaches are optimal for patients who are awake, hemodynamically stable and able to clear and protect their airways. Others, including those nearing respiratory arrest, require intubation.

Noninvasive ventilation

NIPPV has become first line therapy in patients with COPD presenting with acute or acute on chronic hypercapnea. Appropriate candidates must be awake, hemodynamically stable, and able to clear secretions and protect their airway. In comparison to invasive approaches, NIPPV improves survival, decreases duration of mechanical ventilation, and is associated with fewer complications such as ventilator associated pneumonia.

A face mask fit over the mouth and nose is the most commonly employed noninvasive interface. Nasal masks can be used too, but face masks are more reliable and should generally be used first. When the patient stabilizes, a switch to nasal ventilation may improve comfort. Masks should be snug but not tight. Those that are too tight are uncomfortable and can cause pressure ulcerations. Masks can be removed intermittently in stable patients, allowing talking, eating, and administration of medications.

Invasive Ventilation

Not all hypercapneic patients are appropriate for NIPPV. Indications for intubation include hemodynamic instability, poor mental status, inability to protect the airway, copious secretions, a weak cough, and apnea or near-apnea. Patients unable to tolerate even brief periods off the ventilator and those who deteriorate on therapy should generally be intubated. Finally, patients requiring particularly high pressures are likely to be uncomfortable and experience unacceptable leaks, necessitating intubation.

When indicated, intubation should be performed promptly to minimize the risk of respiratory arrest. Waiting until the last moment exposes patients to an unnecessary risk of clinical deterioration and complications associated with emergency airway placement. Most patients should be intubated with an oral endotracheal tube (ETT), typically an 8.0 mm ETT in men and a 7.5 mm ETT in women. Intubation should be performed by clinicians with appropriate training in airway management.

The principles of ventilatory support are similar to those used in NIPPV, the exception being that an ETT is used as an interface. The ETT allows effective control of the patient’s secretions. In general, higher driving pressures can be provided through an ETT than a face mask.

Ventilator support

A variety of mechanical ventilators can be used for both noninvasive and invasive ventilation. Regardless of the device chosen, settings need to be adjusted carefully to meet the needs of individual patients. Factors to consider include minute ventilation (VE) requirements, the patient’s gender and height, the presence or absence of a respiratory drive, the target PaCO2and the nature of the underlying disease.

Noninvasive approaches

Patients are generally managed noninvasively by setting inspiratory and expiratory pressures titrated to support spontaneous efforts.

In patients with obstructive lung disease, expiratory pressure may prevent airway closure and mitigate the effects of intrinsic PEEP. Inspiratory pressure supports the patient’s inspiratory efforts. In patients at risk for hyperinflation, pressures that are too high must be avoided. In contrast, higher pressures may be necessary in patients with poor respiratory system compliance, for example those with morbid obesity.

A spontaneous mode of ventilation, without a set respiratory rate, is appropriate for most patients with an intact respiratory drive. In spontaneous modes, breaths are initiated in response to patient effort. In contrast, intermittent timed breaths may be required if the patient’s drive is impaired. The pressures tolerated by individual patients vary and may be limited by leaks between the patient and mask. Ongoing clinical assessment is mandatory to ensure the patient is stable and does not need intubation. Serial ABGs may be needed to titrate ventilator settings and to help identify failing patients who need intubation.

Invasive approaches

Patients requiring intubation are generally sicker and may require sedatives that impair the respiratory drive. When complete rest is desired, or the patient’s drive or ability to initate breaths is in doubt, a minimum VEshould be set, using the “assist-control” (A/C) mode. In A/C, a set tidal volume and backup respiratory rate are used.

Tidal volumes can be set directly using the “volume cycle” approach or indirectly using “pressure control.” A VEof 5-6 liters per minute is considered normal in those without lung disease. Taller patients and men generally require larger tidal volumes than shorter females.

VErequirements may rise with increased CO2production (reflecting the patient’s metabolic rate) and increased dead space (VD) (reflecting ventilatory efficiency). Fever and overfeeding can increase CO2 production; VDcan increase in the setting of several diseases, such as COPD, pneumonia, and pulmonary embolism. A higher VEmay be necessary to achieve a normal PaCO2in patients with increased CO2production or increased VD.

In many patients, attempts to decrease the PaCO2 to “normal” (40 mmHg) may be unnecessary, unsafe or both. In patients with chronic hypercapnea, excessively aggressive attempts to lower the PaCO2 will result in a metabolic alkalosis (termed a post hypercapneic metabolic alkalosis) due to residual HCO3retention. As a rule, aiming to bring the PaCO2 down to a level which allows a pH greater than 7.30 should suffice.

In particularly severe cases of obstructive lung disease, it may be necessary to tolerate significant hypercapnea (i.e. “permissive hypercapnea”) to avoid dynamic hyperinflation, which can cause barotrauma and hemodynamic instability.

Hypercapnea is generally well tolerated by most patients as long as oxygenation is adequate, with the possible exception of those with heart failure and those at risk of increased intracranial pressure. Because hypercapnea imposes a significant respiratory drive in most patients, heavy sedation and even neuromuscular blockade may be required to suppress ventilatory efforts.

Patients with obstructive lung disease should be carefully monitored for signs of dynamic hyperinflation. Although no single parameter can be relied upon entirely, measurements of plateau pressures and intrinsic PEEP are often useful. The plateau pressure – measured with the expiratory port closed during a brief breath hold at end inhalation – correlates well with the elastic recoil pressure of the respiratory system. In most patients, keeping the plateau pressure below 30 cm H2O, which can often be achieved by decreasing the respiratory rate and/or tidal volume, mitigates the risk of barotrauma and hemodynamic collapse.

Intrinsic PEEP (PEEPi) can be identified by showing that expiration is incomplete before the next breath begins (termed expiratory flow limitation). The presence of PEEPi is suggested by the finding of incomplete exhalation on either physical exam (audible exhalation continues until inhalation begins), or by inspection of the expiratory waveform on the ventilator (seeing expiratory flow at end-expiration). These findings suggest dynamic hyperinflation, but only when active exhalation is excluded, which can be detected easily by visual or palpable findings on abdominal exam.

PEEPi is difficult to measure precisely in spontaneously breathing patients and those with mucus plugging. To quantify the actual PEEPi pressure present in the lung at end exhalation, airway pressure is measured under no flow conditions at end exhalation. This requires – and can be measured accurately by – using the expiratory pause button on the mechanical ventilator.

This occludes the exhalation valve exactly at inhalation onset, and since inhalation is prevented, the downstream alveolar pressure quickly equilibrates with the proximal airway (displayed on the pressure vs time curve). Like the expiratory flow assessment, this also can only be measured reliably when the patient is passively ventilated, since any spontaneous efforts will effect the pressure and flow measurements.

If PEEPi is identified and clinically important (e.g. associated with shock or elevated plateau pressures), this should prompt efforts to lengthen exhalation time. This can be achieved by decreasing the VEby lowering the set respiratory rate and tidal volume. Decreasing the rate allows more exhalation time between breaths; decreasing the tidal volume lowers the amount of air to be exhaled. Finally, increasing inspiratory flow rates may allow more time for exhalation, although the impact on hyperinflation may not be as effective as approaches that decrease the VE. As the patient improves, more aggressive ventilation – if needed – would likely be better tolerated.

2. Emergency Management

Emergency management steps

Acute hypoxemia and hypercapnea are life-threatening and demand prompt management. The first priority is to recognize their presence. All patients with acute lung disease or disease affecting the lung (e.g. CHF) require assessment of gas exchange. An evaluation is also essential in patients with findings associated with gas exchange abnormalities, particularly abnormal vital signs and altered mental status.

Pulse oximetry is non-invasive and should be performed routinely in those at risk for hypoxemia. Patients who are unstable, for example those in intensive care units, merit continuous oximetry. Patients with poor perfusion may not generate a useful signal. Dark skinned and jaundiced patients may have falsely elevated pulse oximetry readings. ABGs are necessary to more precisely define the severity of hypoxemia and to detect hypercapnea. An ABG also should be checked when patients are critically ill or when there is reason to doubt the accuracy of pulse oximetry.

Oxygen supplementation is necessary for patients with an oxygen saturation less than 88-90% or a PaO2 less than 55-60 mmHg on ambient air. In some patients, for example those who are pregnant and those with heart disease, strokes, and pulmonary hypertension, it may be helpful to initiate oxygen supplementation for more mild hypoxemia.

For mild hypoxemia, a low flow nasal cannula may be sufficient to achieve adequate blood oxygen concentrations. A venturi mask should be used for patients requiring more precise oxygen titration, particularly when hyperoxia-induced hypercapnea is a concern, for example in patients with severe COPD. Patients with more severe hypoxemia require alternative approaches, including high flow face masks, non-rebreather masks, or high flow nasal cannulae.

NIPPV or CPAP are reasonable approaches in patients with readily reversible disorders such as CHF. Intubation should be performed in patients who are hemodynamically unstable or unable to protect their airways and those whose hypoxemia remains uncorrected with noninvasive management.

The detection of acute hypercapnea suggests the need for ventilatory support. As a rule, assistance is needed when hypercapnea is persistent or worsens despite treatment. However, not all patients with hypercapnea require ventilatory support. For example, patients with acute asthma may present with hypercapnea that responds promptly to steroids and bronchodilators. Moreover, some patients with severe respiratory distress may present with a normal or low PaCO2 and need support if their disease process is not readily reversible.

NIPPV is first line therapy in patients who are alert, hemodynamically stable, and able to protect their airways. Unstable patients, those unable to clear or protect their airways, those with depressed mental status, and those with apnea or near apnea, require intubation. Ventilatory support should be provided to meet the patient’s VE requirements.

However, patients with particularly severe lung disease, particularly those with severe obstructive disease, may need a lower minute ventilation to avoid ventilator-induced lung damage. Fortunately, hypercapnea that persists following intubation is generally well tolerated if patients are well oxygenated.

Patients with mild hypoxemia often can be managed outside the ICU. Patients with more severe hypoxemia and those requiring any form of ventilatory support are best served in an ICU or an equivalent site that can provide close observation and prompt interventions if needed.

Management points not to be missed


  • Patients requiring monitoring of their gas exchange include those with lung disease and respiratory symptoms as well as patients with unexplained, nonspecific findings, including change in mental status, severe vital sign abnormalities and lactic acidosis.

  • Pulse oximetry should be used for screening and monitoring in patients at risk of hypoxemia.

  • Continuous oximetry should be used in unstable patients; in general, continuous oximetry is standard in patients admitted to the ICU.

  • An ABG should be performed in patients at risk for hypercapnea and in any patient in whom pulse oximetry may be unreliable.


  • Oxygen supplementation should be provided to all patients with an SaO2 less than 88-90% or a PaO2 less than 55-60 mmHg on ambient air.

  • A low flow of oxygen by nasal cannula, generally in the range of 1-4 liters per minute, is sufficient for most patients with mild hypoxemia.

  • Oxygen by Venturi mask should be provided to patients requiring more precise titration of oxygen than can be provided by low flow nasal cannulae.

  • High flow oxygen by face mask or high flow nasal cannulae should be provided for more severe hypoxemia.

  • Noninvasive positive pressure, using CPAP or NIPPV, can be used to treat hypoxemia and hypercapnea in appropriately selected patients with more severe hypoxemia, as long as they are hemodynamically stable, alert, and able to protect their airway, assuming the underlying disease is readily reversible.

  • Intubation is required for patients with severe hypoxemia and hypercapnea who are not candidates for or who fail attempts to use noninvasive approaches.

  • Intubation should always be performed in a timely manner to avoid emergencies.

  • Hypercapnea may have to be tolerated in some intubated patients with severe obstructive lung disease because excessive efforts to ventilate may subject patients to ventilator induced lung injury and hemodynamic instability.

  • For both hypoxemia and hypercapnea, treatment of the underlying disease process is crucial.


  • Patients with mild hypoxemia requiring low flow oxygen supplementation can be managed on an acute care ward.

  • ICU admission is needed for all patients requiring intubation and is advisable for many or most requiring NIPPV.

3. Diagnosis

Diagnosis and assessment of severity of hypoxemia

Non-specific symptoms and signs may be the first clue to hypoxemia. An evaluation is warranted in any patient complaining of dyspnea and should be considered in patients with wide ranging symptoms, including anxiety, headache, cough, and chest pain. Screening for hypoxemia is indicated in any patient with abnormal vital signs (i.e. heart rate, respiratory rate, blood pressure) and findings suggesting impaired gas exchange, including altered mental status, orthopnea, accessory muscle use and inability to speak in full sentences.

Hypoxemia is difficult to detect on exam unless severe. Central cyanosis is generally not detectable unless the SaO2 is below the mid to low 80s. Peripheral cyanosis is a common manifestation of vasoconstriction and an unreliable sign of hypoxemia.

Pulse oximetry is a widely available, useful tool for detecting hypoxemia. Probes can be applied over finger tips, the nose, ears and forehead. The SaO2 is derived by the wavelength of light reflected transcutaneously. The “pulse ox” (SpO2) generally correlates well with the SaO2 as long as perfusion is adequate to detect a pulse.

Certain conditions decrease the reliability of pulse oximetry. The pulse of patients in shock and those with peripheral vascular disease may be too weak to generate a reliable signal. The relationship between the SpO2 and the SaO2 can vary from patient to patient, making it prudent to check an ABG to confirm correlation, particularly in seriously ill patients. In dark skinned and jaundiced patients, the SpO2 tends to be slightly higher – for example, an average of four percentage points in Black patients – for any given PaO2 or SaO2, potentially creating a false sense of security.

Certain toxic and metabolic abnormalities can shift the oxygen desaturation curve, altering the relationship between the oxygen saturation and PaO2. Thus, even if the SpO2 reliably reflects the SaO2, the correlation with the PaO2 may be altered. For example, carbon monoxide poisoning increases hemoglobin’s avidity for oxygen, which can lead to a high SpO2 and SaO2 even when the PaO2 is low.

Alkalemia also increases hemoglobin oxygen avidity, similarly leading to a high oxygen saturation for any given PaO2. In contrast, in the setting of acidosis, hemoglobin becomes less avid, decreasing the SaO2 for any given PaO2.

The definitive diagnosis of hypoxemia requires an arterial blood gas, which directly measures the PaO2 and SaO2. For critically ill patients requiring frequent ABGs, it may be helpful to insert an arterial catheter (“a-line”), usually placed into the radial, axillary or femoral arteries.

The severity of hypoxemia can be quantified by several techniques. The measured PaO2 and SaO2 should always be assessed in the context of the amount of supplemental oxygen given. A PaO2 or SaO2 reported without knowing how much supplemental oxygen was given is largely meaningless. The most commonly used indices of severity are the A-a O2 gradient, PaO2/FiO2 ratio and oxygenation index.

The A-a O2 gradient

The “A-a O2 gradient” or “A-a O2 difference” is the most time honored approach to describing the severity of hypoxemia, with a higher gradient denoting more severe hypoxemia. The A-a O2 gradient describes the difference between the partial pressure of oxygen in the alveoli (PAO2) and partial pressure of oxygen in the arterial blood (PaO2). The alveolar gas equation is used to calculate the PAO2:

PAO2 = FiO2 (PB – PH2O) – PaCO2/R

where PB equals the barometric pressure (760 mmHg at sea level), the PH20 the water vapor pressure (47 mmHg at 37oC), and the R the respiratory quotient, typically 0.8. The PB should be adjusted to reflect local barometric pressure, a significant issue for patients managed at higher altitudes.

The A-a O2 gradient equals the difference between the PaO2 obtained by the ABG subtracted from the calculated PAO2 (PAO2 – PaO2). The gradient rises normally with age according to the following formula:

A-a O2 gradient = 2.5 + 0.21 x age in years

The gradient also tends to increase when higher levels of oxygen supplementation is given, particularly in the setting of shunt. In patients managed noninvasively, uncertainty about the true FiO2 adds imprecision to the calculation of the A-a O2 gradient.

The PaO2/FiO2 ratio

The PaO2/FiO2 ratio (P/F ratio) is commonly used to describe severity of hypoxemia, particularly in the setting of suspected ARDS/ALI. The ratio is calculated by dividing the PaO2 by the FiO2.

Normal individuals with a PaO2 of 100 mmHg on ambient air (FiO2 approximately 21%) have a P/F ratio of (100/0.21) or 476. A patient with a PaO2 of 60 mmHg on an FiO2 of 100% would have a P/F ratio of 60, indicating severe hypoxemia. An acutely ill patient with bilateral infiltrates on chest radiograph in the absence of CHF and a P/F ratio less than or equal to 200 meets the diagnostic criteria for ARDS. A similar patient with a P/F ratio less than or equal to 300 meets the criteria for ALI.

As with the A-a O2 gradient, uncertainty about the FiO2 undermines the reliability of the P/F ratio. If an ABG is unavailable, the SaO2/FiO2 may substitute for the P/F ratio.

The oxygenation index

The P/F ratio and A-a O2 gradient share an important limitation by failing to account for the impact positive pressure ventilation has on the PaO2. To illustrate this, consider a patient with a PaO2 of 100 mmHg on an FiO2 of 50% and 5 cmH2O of PEEP and another patient with the same PaO2 on the same FiO2 and 20 cmH2O of PEEP. Both patients have the same P/F ratio (200) even though the second patient’s hypoxemia is clearly more severe.

The oxygenation index (OI) provides an alternate approach to describing the severity of hypoxemia, taking positive pressure into account as follows:

OI = (mean airway pressure x FiO2)/PaO2 x 100

The mean airway pressure is easily measured on modern ventilators and correlates directly with 1) the amount of PEEP applied and 2) the amount of pressure applied and time spent during inspiration. A higher OI denotes more severe hypoxemia. Although used less commonly in adults than the P/F ratio, the OI provides a useful comparison between mechanically ventilated patients requiring different amounts of positive pressure. The OI is sometimes used to identify patients with particularly severe hypoxemia who may need special treatment, such as extracorporeal membrane oxygenation (ECMO).

Diagnosis and assessment of severity of hypercapnea

There is no simple, reliable way to measure PaCO2 noninvasively. Transcutaneous CO2 monitoring is uncommonly used and not validated for use in acute respiratory failure. An increase in the serum HCO3 may suggest the presence of hypercapnea and chronic respiratory acidosis. However, only an ABG can confirm hypercapnea and distinguish between a chronic respiratory acidosis and metabolic alkalosis.

As a rule, acute hypercapnea should raise concern that a patient has developed or is at risk of developing ventilatory failure. However, the PaCO2 needs to be interpreted in the context of the patient’s underlying condition. A normal or low PaCO2 may be seen in many of the same conditions associated with hypercapnea, particularly when respiratory distress stimulates hyperventilation, for example in status asthmaticus.

Patients may progress to hypercapnea if the underlying disorder persists or worsens; a single normal or low PaCO2 may warrant follow up in patients who fail to improve. In contrast, a single high PaCO2 does not necessarily indicate a need for ventilatory assistance if definitive treatment has not been started. A follow up ABG is strongly suggested to document improvement.

In patients with severe respiratory distress, it is reasonable to make a presumptive clinical diagnosis of ventilatory failure if an ABG is not available. Signs suggesting hypercapnea include alterations in mental status (particularly somnolence); inability to speak in full sentences; and shallow, ineffective respiratory efforts. While an ABG may be useful to identify or confirm hypercapnea, initiation of ventilatory support should not be delayed just because hypercapnea has not been documented, particularly if suspicion is high.

Similarly, it may be reasonable to forgo an ABG if it will not change the decision to initiate ventilatory support. In contrast, some patients may be at risk for hypercapnea and not manifest any signs of respiratory distress. This is particularly common among patients with impaired respiratory drives, including obesity hypoventilation disorder, brain stem strokes, narcotic use or abuse, and when supplemental oxygen is given to patients with COPD flares. In these patients, hypercapnea revealed on the ABG may be the only evidence available that the patient has respiratory failure.

The implications of hypercapnea depend on severity and acuity. Hypercapnea causes a respiratory acidosis which is buffered by the serum HCO3 concentration. Acute elevations in the PaCO2 cause a more significant drop in serum pH than chronic elevations. When hypercapnea is chronic, the kidneys retain HCO3, mitigating the drop in pH.

When respiratory acidosis is acute, the serum HCO3 rises by approximately 1 meq/L for every 10 mmHg rise in the PaCO2. When the respiratory acidosis is chronic, the HCO3 rises by approximately 3.5 meq/L for every 10 mmHg rise in the PaCO2. In complex disorders, for example when patients have concurrent metabolic acidoses or alkaloses, or acute on chronic respiratory failure, the relationship between the PaCO2 and HCO3 is less predictable.

Diagnostic approach

The diagnostic approach to hypoxemia and hypercapnea includes 1) documenting the presence of gas exchange abnormalities and 2) identifying the cause. Hypoxemia and hypercapnea should be suspected in all patients with diseases and conditions affecting the lungs, either directly or indirectly. Gas exchange abnormalities should also be suspected in any patient with a dangerous or life threatening condition who presents with worrisome signs and symptoms, including shortness of breath, hypertension or hypotension, tachycardia or bradycardia, and tachypnea or bradypnea.

Physical exam findings that should raise suspicion for hypoxemia and hypercapnea include central cyanosis, inability to speak in full sentences, orthopnea, alterations in mental status, heart murmurs and gallops, distended neck veins, peripheral edema, and abnormalities on lung exam such as dullness to percussion, wheezes, rhonchi and rales.

Pulse oximetry and ABGs are the two most important tests used to identify hypoxemia and hypercapnea. Pulse oximetry should be performed on all patients at risk for hypoxemia, assuming equipment is available. If there is reason to believe that the oxygen saturation identified on the pulse oximeter (SpO2) is inaccurate, an ABG should be performed.

Reasons for inaccuracy include poor perfusion (e.g. due to shock or peripheral vascular disease), dark pigment or jaundice, exposure to carbon monoxide and the presence of acid-base disorders. ABGs are helpful to document the severity of hypoxemia, allowing calculation of the A-a O2 gradient, the PaO2/FiO2 ratio and the oxygenation index. ABGs are essential to diagnose the presence of hypercapnea and to define the nature of acid-base disorders.

An organized approach is needed to diagnose the underlying cause of hypoxemia and hypercapnea. A thorough history as well as a physical exam looking for evidence of both acute and chronic cardiac and pulmonary disorders are essential. The components of the physical exam required varies by patient and should be directed by a differential diagnosis built on the basis of the patient’s presentation. Key physical exam findings include:

  • Vital signs: looking for abnormal temperature, heart rate, respiratory rate, blood pressure.

  • Skin: assessing for cyanosis.

  • HEENT: looking for jugular venous distention, papilledema.

  • Respiratory: evaluating ability to speak in full sentences, presence of orthopnea, use of accessory muscles, respiratory pattern (e.g. shallow or irregular breathing); visualizing the chest; percussing (listening for dullness or hyperresonance); and auscultating (listening for adventitial lung sounds such as wheezes, rhonchi and crackles).

  • Cardiac: listening for murmurs, a loud P2 and gallops.

  • Abdomen: looking for respiratory paradox, underlying liver disease and evidence of abdominal compartment syndrome.

  • Extremities: looking for evidence of edema, signs of deep venous thrombosis and clubbing (note peripheral cyanosis is not a reliable sign of hypoxemia in the absence of central cyanosis).

  • Neurological: Evaluating for altered mental status and focal deficits.

Diagnostic tests

Directed laboratory testing hinges on the differential diagnosis generated by the history and physical exam. In addition to pulse oximetry and ABGs, common laboratory and imaging tests include the following:

  • Complete blood count: looking for evidence of infection and anemia.

  • Chemistries: looking for abnormalities in the serum HCO3.

  • Microbiology: sputum and blood cultures.

  • Chest radiograph: PA and lateral if possible, although a portable AP may be necessary in patients too sick to travel to the radiology department.

  • Chest CT: a standard CT may help identify subtle findings such as faint infiltrates, small pneumothoraces and pleural effusions not visible on routine chest radiographs. CT pulmonary angiograms are used to diagnose pulmonary embolism. High resolution chest CTs are useful for characterizing many lung disorders, such as interstitial lung disease and bronchiectasis.

  • Ultrasound:thoracic ultrasound is useful to identify pleural effusions and is increasingly being used to identify parenchymal consolidation.

  • Doppler ultrasound: helpful for identifying deep venous thromboses in the extremities.

  • Echocardiogram: when CHF, tamponade or right ventricular dysfunction is a concern.

  • Bronchoscopy: may be necessary acutely to diagnose and treat acute airway obstruction, for example due to mucous plugs, tumors or foreign body aspirations. A bronchoscopy can also be useful to obtain cultures and biopsy material.

  • Surgical lung biopsy: useful to diagnose lung infections, malignancies and interstitial lung disease.

  • V/Q scanning: used to diagnose pulmonary embolism but employed less frequently than CT pulmonary angiograms; may still be useful when there is a contraindication to intravenous contrast. Can also provide evidence for anatomic shunt when organs other than the lungs accumulate tracer on perfusion scan.

Normal lab values

PaCO2: 40 mmHg

PaO2: 100 mmHg (may vary with altitude and by patient age)


(Figure 1 and Figure 2)

Figure 1.

Chest radiograph of a patient with ARDS.

Figure 2.

CT scan of patient with ARDS



Hypoxemia is caused by six mechanisms occurring alone or together: shunt, ventilation-perfusion (V/Q) mismatch, diffusion impairment, hypoventilation, low mixed venous oxygen saturation (SvO2) and inadequate oxygen availability.


Shunting occurs when deoxygenated blood returns to the systemic circulation without being exposed to oxygen. Shunt is identified by the failure to normalize the PaO2 with 100% oxygen, a feature not shared by other causes of hypoxemia. The following equation describes the severity of shunting:

QS/QT = (CcO2 – CaO2) ÷ (CcO2 – CvO2)

where QS/QT represents the shunt fraction, CcO2 the oxygen content of the end-capillary blood, CaO2 the oxygen content of the systemic arterial blood and CvO2 the oxygen content of the mixed venous blood. The PAO2, calculated by the alveolar gas equation, is used to estimate the CcO2. The CaO2 and CvO2 are calculated using measurements of the oxygen content of the arterial and mixed venous blood respectively.

There are two types of shunt: physiologic and anatomic. Physiological shunts occur when alveolar units are so diseased that oxygen cannot be transported into the pulmonary capillaries. Causes include filling of the alveoli with edema or debris or collapse of an entire lobe or lung. Prominent examples include ARDS and atelectasis caused by a central mucous plug.

Anatomic shunts imply that deoxygenated blood returns to the systemic circulation without passing through the alveolar-capillary unit. Anatomic shunts are cardiac or pulmonary in nature. With cardiac shunts, deoxygenated blood passes immediately from the right to the left side of the heart without passing through the lungs. Examples include a patent foramen ovale and atrial or ventricular septal defects.

With pulmonary shunts, deoxygenated blood passes through the lung without exposure to the alveolar-capillary gas exchange units. An example is a pulmonary arteriovenous malformation, as seen in hereditary hemorrhagic telangiectasia.

Anatomic shunts can be identified with imaging modalities. The most commonly used is an echocardiogram using intravenous injections of agitated saline which employs tiny air bubbles to provide contrast. In patients without anatomic shunts, contrast is seen on the right but does not pass to the left side of the heart.

In patients with cardiac shunts, contrast passes immediately from the right to the left side of the heart through anatomic defects. In patients with pulmonary anatomic shunts, passage from the right side to the left is delayed by several heart beats as contrast passes through the pulmonary circulation. In patients with physiologic shunts, contrast fails to pass from the right to the left side because the bubbles are trapped in the pulmonary microvasculature.

V/Q mismatch

V/Q mismatch is one of the most common causes of hypoxemia and occurs when deoxygenated blood passes through lung units with low ventilation relative to perfusion. Alveolar-capillary units with low V/Q ratios have insufficient oxygen to saturate the deoxygenated blood passing through. As a result, poorly oxygenated blood returns to the systemic circulation. Unlike shunt, oxygen supplementation can override low V/Q by repleting oxygen in poorly ventilated units, reversing hypoxemia.

V/Q mismatch is associated with many lung diseases, including pneumonia, COPD, and asthma. Even in patients with diseases dominated by physiological shunts, such as ARDS/ALI, at least some lung regions may be characterized by low V/Q and respond to oxygen supplementation. However, in the most diseased areas, the V/Q ratio approaches zero, resulting in physiological shunt, unresponsive to oxygen.

Diffusion Impairment

Diffusion impairment results from an impediment of oxygen transfer from the alveolus to the pulmonary capillary. When diffusion is normal, deoxygenated blood quickly acquires oxygen during transit through the pulmonary capillary. When diffusion is impaired, transport of oxygen into the blood is delayed, so that additional time is needed for oxygenation. Delayed oxygen transfer may not be physiologically important as long as blood is saturated before leaving the pulmonary capillary.

However, problems arise when transit time through the pulmonary capillary decreases because there may be insufficient time available to oxygenate the blood. This may happen, for example, when cardiac output increases with exercise. Disorders which can impair diffusion include interstitial lung disease, CHF and pneumocystis pneumonia.


Hypoventilation causes hypoxemia as a result of hypercapnea. According to the aveolar gas equation, the PAO2 is inversely proportional to the PaCO2, falling as the PaCO2 rises:

PAO2 = FiO2 (PB – PH2O) – PaCO2/R

No increase in the A-a O2 gradient occurs with hypoventilation, because the PAO2 and PaO2 fall in parallel. If an increased A-a O2 gradient occurs in the setting of hypercapnea, another mechanism in addition to hypoventilation must be contributing to hypoxemia. Causes of hypercapnea-induced hypoxemia include narcotic overdose and diseases associated with neuromuscular weakness, such as myasthenia gravis, acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome) and spinal cord injury.

Low oxygen mixed venous oxygen saturation (low SvO2)

Decreases in the SvO2 are associated with increased oxygen utilization, depressed cardiac output and anemia. A low SvO2 rarely causes hypoxemia by itself. However, a low SvO2 can can exacerbate other causes of hypoxemia. For example, in the setting of shunt, a lower SvO2 means that the deoxygenated blood returning to the systemic circulation will be even more poorly oxygenated, worsening systemic hypoxemia.

Hypoxemia may respond at least partially to interventions that address the low SvO2. Examples include decreasing oxygen utilization (e.g. by controlling fever), increasing cardiac output (e.g. giving inotropes to patients with systolic dysfunction) and transfusing for anemia.

Inadequate oxygen availability

Although not really a pathophysiological mechanism per se, it is helpful to consider inadequate oxygen availability as a factor that may contribute to hypoxemia. The alveolar gas equation indicates that a low PB or low FiO2 can cause a low PAO2. High altitudes are associated with a lower PB and consequently, a lower PAO2, all else being equal.

A low FiO2 can occur when patients are not getting sufficient oxygen, for example in the setting of equipment malfunction or entrainment of ambient air into noninvasive supplementation systems. Inadequate FiO2 should always be considered in patients with unexplained hypoxemia and in those who remain hypoxemic despite supplementation.


The PaCO2 is determined by CO2 production and ventilation:

PaCO2 = K x VCO2/VA

where K is a constant, VCO2 represents CO2 production and VA alveolar ventilation. VA cannot be readily measured and can be substituted as follows:

PaCO2 = K x VCO2/(VE – VD)

where VE represents the exhaled minute ventilation and VD the dead space ventilation (regions of the lung that are ventilated but not perfused). Hypercapnea can result from increased VCO2, increased VD, or decreased VE. In patients who can increase their VE to compensate, an increased VCO2 or increased VD should not cause hypercapnea. Hypercapnea can often be attributed to a failure to increase the VE sufficiently to compensate for other stresses.

In normal individuals, the VCO2 is determined by the basal metabolic rate. Factors which increase the VCO2 include fever, hyperthyroidism, overfeeding and increased muscle activity. In normal individuals, the VD is largely fixed and accounted for by the anatomic dead space, made up of portions of the airways that do not participate in gas exchange, such as the trachea and bronchi.

In the setting of shallow breathing, often seen with respiratory muscle fatigue, the VD may become a larger fraction of the patient’s tidal volume (VD/VT), making ventilation less efficient. In the context of pulmonary disease, VD is increased by a physiological component consisting of alveolar-capillary units with insufficient or no perfusion despite ventilation (i.e. areas of high V/Q or wasted ventilation). Many diseases increase physiological VD, the classic being pulmonary embolism.

Two factors contributing to hypercapnea include 1) a primary decrease in the VE, or 2) the failure of the VE to increase sufficiently to meet the demands imposed by an elevated VCO2 or increased VD. This can best be thought of as a state of imbalance between respiratory sytem load and respiratory muscle capacity. Causes of an inadequate VE can be divided into three categories: 1) disorders that result in depressed neuromuscular capability; 2) disorders associated with an increased ventilatory load; and 3) disorders associated with impaired gas exchange at the level of the alveoli (see Table I).

Table I.
Depressed ventilatory capacity Depressed respiratory drive Narcotics, brain stem stroke
Spinal cord disease Quadriplegia, amyotrophic lateral sclerosis
Peripheral nerve disease Guillain-Barre syndrome, phrenic nerve injury
Disease of neuromuscular junction Myasthenia gravis, neuromuscular blocking agents
Muscle Weakness Steroid myopathy, polymyositis, sepsis, electrolyte imbalance (e.g. hypokalemia, hypophosphatemia), fatigue, diaphragm dysfunction associated with hyperinflation
Increased ventilatory load Increased VCO
Fever, hyperthyroidism, overfeeding, increased work of breathing
Increased VD Pulmonary embolism, emphysema
Increased airway resistance (R
Asthma, COPD, bronchiolitis
Decreased respiratory system compliance (C
Chest wall deformity, scoliosis, abdominal compartment syndrome, pleural effusions, pulmonary edema, pneumonia, ARDS/ALI
Impaired alveolar gas exchange Low V/Q COPD, asthma, pneumonia

Problems on several levels can undermine ventilatory capacity. Central nervous system disorders can depress respiratory drive. Spinal cord injury and disease, damage to peripheral nerves and disease of the neuromuscular junction can undermine signaling to the respiratory muscles. Several diseases can cause primary muscle weakness and predispose patients to muscle fatigue. Finally, hypoventilation may occur due to inadequate ventilation at the level of the lungs, for example due to airway obstruction.

The two factors that contribute most significantly to the respiratory workload are the airway resistance (RAW) and respiratory system elastance (ERS). Factors that increase the work load compromise the ventilatory response and can predispose patients to hypercapnea. The RAW is determined by the force (denoted as pressure generated in cmH2O) divided by flow (measured in liters per second). The normal RAW is low and contributes little to the work of breathing. However, a substantial increase in RAW increases the force needed to generate flow, which can significantly increase work of breathing in patients with diseases such as asthma and COPD.

Respiratory system compliance (CRS) is the inverse of the elastic recoil pressure, or ERS:


Respiratory system compliance (CRS) is determined by the change in lung volume (i.e. the tidal volume or VT) divided by the change in elastic recoil pressure of the respiratory system (i.e. the end inspiratory pressure minus the end expiratory pressure):

CRS = VT/(End-inspiratory pressure – End-expiratory pressure)

The CRS is determined by two components, the lung compliance (CL) and the chest wall compliance (CCW):

1/CRS = 1/CL + 1/CCW

It is generally difficult to isolate the contribution of CL from that of CCW, which would require measurement of pleural pressures, something that is not done routinely. However, features of the patient’s clinical presentation should help distinguish between the two.

CRS is denoted in mL/cmH2O. The normal CRS is approximately 50 ml/cmH2O. Normally, relatively little force is needed to overcome elastic recoil pressure and inflate the lungs. A variety of processes can decrease the CL (e.g. pulmonary edema, ARDS/ALI, pneumonia) and CCW (e.g. abdominal compartment syndrome, large pleural effusions). Either can decrease the CRS and increase the work of breathing and risk of hypercapnea.

In summary, ventilatory failure and hypercapnea are largely the result of imbalance between ventilatory capacity and ventilatory load, with some contribution from inadequate alveolar ventilation. Prevention or treatment of hypercapnea requires interventions to increase ventilatory capacity and to decrease the ventilatory load.

Examples of interventions to improve ventilatory capacity include reversing the respiratory depressant effects of narcotics, repleting phosphate in patients with hypophosphatemia, and providing ventilatory support to rest patients with respiratory muscle fatigue. Interventions which can decrease ventilatory load include diuretics to improve CRS in patients with CHF and bronchodilators to decrease RAW in asthma.


The epidemiology of hypoxemia and hypercapnea parallel the epidemiology of disorders of the lungs, heart and other organ systems which lead to gas exchange abnormalities. Readers are referred to chapters on those topics for further information.

What's the evidence?

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Martin, J, Tobin. “Principles and Practice of Mechanical Ventilation”. 2006. (This comprehensive textbook provides a detailed, encyclopedic approach to the science and theory as well as the nuts and bolts of mechanical ventilation.)

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Bateman, NT, Leach, RM. “ABC of Oxygen”. Acute oxygen therapy. BMJ. vol. 317. 1998. pp. 798-801. (An excellent review which considers the use of basic systems used to deliver supplemental oxygen.)

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Pipeling, MR, Fan, E. “Therapies for Refractory Hypoxemia in Acute Respiratory Distress Syndrome”. JAMA. vol. 304. 2010. pp. 2521-7. (A comprehensive review of innovative techniques available to treat patients with refractory hypoxemia.)

Papazian, L, Forel, J-M, Gacouin, A, Penot-Ragon, C, Perrin, G, Loundou, A. “Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome”. N Engl J Med. vol. 362. 2010. pp. 1107-16. (A recently published study which suggested that early use of neuromuscular blockade in severe ARDS was associated with improved oxygenation and survival.)

Peek, GJ, Mugford, M, Tiruvoipati, R, Wilson, A, Allen, E. “Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial”. The Lancet. vol. 374. 2009. pp. 1351-63. (A recent study suggesting that ECMO may be useful for patients with severe hypoxemic respiratory failure. Of note is that transfer of patients to a medical center able to provide ECMO, rather than use of ECMO itself, correlated with improved survival without disability.)