Refractory Hypoxemia

What Is Refractory Hypoxemia?

Refractory Hypoxemia is a condition in which a patient is unable to maintain partial pressure of oxygen in arterial blood (PaO2) more than 60mmHg despite providing a FiO2 of 1.0

If the PaO2 / FiO2 ratio is less than 100mmHg, it indicates refractory hypoxemia.
An oxygenation index of more than 30 also indicates refractory hypoxemia. The oxygenation index is calculated by using the formula:

OI = \frac {FiO2 \times MAP \times 100} {PaO2}

Fio2 – Fraction of inspired oxygen
MAP – Mean arterial pressure
PaO2 – Partial pressure of oxygen

Causes Of Refractory Hypoxemia

  • Refractory hypoxemia is caused due to severe oxygenation impairment in patients with acute respiratory distress syndrome (ARDS), acute lung injury (ALI).
  • It is also caused due to Ventilator-induced lung injury (VILI) like Pulmonary barotrauma.
  • Cardiac diseases due to right to left shunting of blood

Diagnosis Of Refractory Hypoxemia

  • The measure of oxygen saturation using a pulse oximeter and assessment of signs of hypoxemia is the first way to recognize refractory hypoxemia.
  • Arterial blood gas analysis (ABG) and chest x-ray results are the best way for interpretation.


The prognosis depends on factors like age and severity of the disease. The patients associated with refractory hypoxemia has a high mortality rate. Approximately 16% of deaths result from refractory hypoxemia in patients with acute respiratory distress syndrome (ARDS).

Management Of Refractory Hypoxemia

The prevention of refractory hypoxemia should be the foremost focus rather than reversing it. The standard treatment with a mechanical ventilator using small tidal volumes with sufficient levels of positive end-expiratory pressure (PEEP) and carefully monitoring the fluid status and ventilator synchrony with the patient can prevent the need for reverse therapy in many cases.
If the maximal ventilation support fails to prevent refractive hypoxemia, the rescue therapies or salvage therapies are used to reverse the refractive hypoxemia.
The rescue therapies or salvage therapies can be categorized into ventilatory and non-ventilatory interventions.

The non-ventilatory interventions include:

  • Prone positioning
  • Neuromuscular blocking agents (NMBA)
  • Inhaled vasodilator therapy
  • Extracorporeal membrane oxygenation (ECMO)

The ventilatory interventions include:

  • Recruitment maneuvers
  • Airway pressure release ventilation (APRV)
  • High-frequency oscillatory ventilation (HFOV)

Prone positioning

  • Prone position ventilation is incorporating the patient to prone (face down) position to provide mechanical ventilation.
  • The prone position improves alveolar recruitment, optimizes ventilation-perfusion matching, increases functional and residual capacity, helps to clear secretions, and reduces ventilator-induced lung injury (VILI).
  • Studies suggest prone ventilation for 12 to 18 consecutive hours per day for maximum benefit in patients with refractory hypoxemia.
  • An increase in PaO2 by 10mmHg usually predicts an improvement in oxygenation. If there is no improvement in oxygenation after 24 hours, the prone position should be abandoned.
  • Elevation of the head side of the bed to 30-45 degrees helps to minimize facial and ocular edema and also improves gastric emptying.
  • Complications of prone ventilation depend on the duration and sessions. It includes dislodgement of the endotracheal tube, vomiting, increased abdominal pressure, hepatic and renal dysfunction, pressure sores. However many of these complications occur during the initial turning of the patient. a proper protocol and experienced team supervision can prevent the complications.
  • An increased intracranial pressure, spinal instability, hemoptysis, facial, and neck trauma are the contraindications for prone positioning.

Neuromuscular blocking agents (NMBA)

  • Hypoxemic patients, breathing spontaneously usually have a high respiratory drive which generates a larger tidal volume than the targeted volumes per breath. This makes the patient more susceptible to the risk of ventilator-induced lung injury (VILI).
  • Neuromuscular blocking agents (NMBA) are used to eliminate the muscle activity thus ceasing the inspiratory and expiratory efforts of the patients which reduce the oxygen consumption and improve patient-ventilator synchrony.
  • Neuromuscular blocking agents should be considered to administer within the first 48 hours in patients with refractory hypoxemia. It is necessary to limit the usage of NMBA to the shortest possible time due to an increased risk of ICU acquired weakness, critical illness polyneuropathy, and posttraumatic stress disorder.

Inhaled vasodilator therapy

  • inhaled vasodilators such as an inhaled nitric oxide (INO) will selectively dilate the pulmonary vasculature in well-ventilated lung units. This improves the oxygenation and optimizes the ventilation-perfusion ratio. They also reduce hypoxemia and pulmonary hypertension.
  • Inhaled vasodilator medications have short lives, thus there are minimal systemic side effects.
  • It requires special equipment to administer inhaled nitric oxide (INO). It is costly and, is rapidly inactivated by hemoglobin which can result in methemoglobinemia (usually if the dose is above 40ppm. Dose range is 2 – 80 ppm). The therapeutic effects can be generally achieved with the dosage of less than 20 ppm. Studies suggest discontinuing the administration of INO if there is no significant improvement of oxygenation within the first hour of initiation of INO, particularly due to its high cost. If the administration of INO is withdrawn too quickly, it may result in rebound pulmonary hypertension (associated with elevation of pulmonary artery pressure, difficulty in ventilation, and in some cases severe hypoxia and cardiovascular instability). Although INO improves oxygenation, no survival benefits have found in patients
  • An alternative to INO is inhaled prostacyclin. Prostaglandin I‑2 (epoprostenol) is a commonly used prostacyclin. It is easy to administer as it does not require any special equipment and is of low cost compared to INO.

Extracorporeal membrane oxygenation (ECMO)

  • Extracorporeal membrane oxygenation (ECMO) is a technique in which blood is removed from the patient at high flow and pumped through an artificial lung, then returned to the patient again. The gas exchange occurs by diffusion in the circuit membrane. This provides oxygenation and minimizes ventilator-induced lung injury (VILI). This life support machine has been successfully used in neonatal and pediatric diseases. But there are only a few pieces of evidence about the potential usage of ECMO in severe adult respiratory failure.
  • ECMO is difficult to introduce and expensive. It can be either venovenous or venoarterial. The venovenous approach can be used in isolated respiratory failure. If there is any associated hemodynamic instability venoarterial approach is used.
  • Complications of ECMO include bleeding, thrombus formation, thromboembolism.

Recruitment maneuvers (RM)

  • A recruitment maneuver (RM) is the process in which transpulmonary pressure is transiently increased to open the collapsed alveoli. This increases the lung compliance and gas exchange.
  • The most commonly used recruitment maneuvers are sigh and sustained inflation. The other methods include intermittent PEEP increase and pressure control with PEEP.
  • In the sigh method, the tidal volume or PEEP is increased to a predetermined plateau pressure for a few breaths per minute. In the sustained inflation method, airways are pressurized to a particular level and maintained for a specific duration (30 – 40cmH2O applied for 30 – 40 s).
  • After recruiting the collapsed alveoli, it should be maintained by applying PEEP at a pressure above the de-recruitment point to prevent further collapse.
  • Complications of recruitment maneuvers include hemodynamic instability, ventilator-induced lung injury (VILI), arrhythmias, and patient‑ventilator synchrony. RM should be immediately terminated if hemodynamic instability develops.
  • Adequate sedation maximizes the benefits of the recruitment maneuver.

Airway pressure release ventilation (APRV)

  • Airway pressure release ventilation (APRV) is a pressure controlled type of ventilation in which there is intermittent mandatory ventilation with unrestrained spontaneous breathing. It is time-triggered, time cycled with a combination of low pressure and high pressure.
  • The duration of high pressure (inspiration) is maintained for a longer time than low pressure (expiration). `This corresponds to an inverse I:E ratio which is termed as Inverse ratio ventilation (IRV).
  • APRV is associated with spontaneous breathing. The patient is permitted to breathe spontaneously in the complete breathing cycle (at both pressures). Hence this method does not require deep sedation and neuromuscular blockade.
  • The benefits of APRV include improvement of ventilation and perfusion and better patient-ventilator synchrony. The low-pressure phase solves hemodynamic problems and improves cardiac performances.
  • It is relatively contraindicated in patients with chronic obstructive lung disorders (COPD) due to its short expiratory time and due to the development of PEEP.
  • Studies have reported an increase in patient survival with the application of this technique.

High-frequency oscillatory ventilation (HFOV)

  • High-frequency oscillatory ventilation (HFOV) is a technique of ventilation which is characterized by the application of small tidal volumes (1-4ml/kg) combined with a high respiratory rate (at a frequency of 3 – 15 Hz, 100-900 breaths per minute).
  • Types of HFOV include high-frequency percussive ventilation and high-frequency jet ventilation.
  • HFOV maintains oxygenation by inflating the lungs at high pressure and clears carbon dioxide in small volumes at high frequencies thus facilitating alveolar recruitment. This homogenous distribution reduces the risk of hyperinflation and ventilator-induced lung injury (VILI).
  • Sedation and neuromuscular blockers must be used to avoid patient-ventilator asynchrony.
  • This technique is contraindicated in patients with chronic obstructive lung disorders (COPD).
  • Although it showed improvement in oxygenation, the mortality benefit of this technique is unknown.


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