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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 42-47

Hypoxemia and oxygen therapy


National Allergy Asthma Bronchitis Institute, Kolkata, West Bengal, India

Date of Submission02-Jul-2020
Date of Acceptance02-Jul-2020
Date of Web Publication10-Sep-2020

Correspondence Address:
Prof. A. G Ghoshal
Medical Director, 11/3, Dr. Biresh Guha Street, 2nd Floor, IMA House, Park Circus, Kolkata, 700017, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jacp.jacp_44_20

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  Abstract 


Oxygen is a drug prescribed and administered for specific indications with different pathophysiological mechanism. Oxygen is administered to treat hypoxia not dyspnea. Furthermore, the management of hypoxia in patients with COVID-19 demands separate attention.

Keywords: Hypoventilation, hypoxaemia, PaCO2


How to cite this article:
Ghoshal AG. Hypoxemia and oxygen therapy. J Assoc Chest Physicians 2020;8:42-7

How to cite this URL:
Ghoshal AG. Hypoxemia and oxygen therapy. J Assoc Chest Physicians [serial online] 2020 [cited 2020 Oct 30];8:42-7. Available from: https://www.jacpjournal.org/text.asp?2020/8/2/42/294593




  Introduction Top


Oxygenation is the process of oxygen diffusing passively from the alveolus to the pulmonary capillary, where it binds to haemoglobin in red blood cells or dissolves into the plasma. Oxygen delivery is the rate of oxygen transport from the lungs to the peripheral tissues. Oxygen consumption is the rate at which oxygen is removed from the blood for use by the tissues.

Oxygen delivery from the alveolar capillaries to the tissue depends on two factors: O2 content of blood and cardiac output. Mathematically, this is expressed as: DO2 = CaO2 × Q̇T, where DO2 is oxygen delivery, CaO2 is blood O2 content, and Q̇T is cardiac output. Body has regulatory mechanisms to redistribute regional blood flow to the sites where oxygen delivery is required most and away from regions that are less active. Oxygen extraction too differs according to the site and activity status.

Hypoxemia is a decrease in the partial pressure of oxygen in the blood. Hypoxia is reduced oxygenation at the tissues due to impaired delivery of oxygen to the tissues or defective utilization of oxygen by the tissues. Hypoxemia and hypoxia need not coexist. There may be hypoxemia without hypoxia due to increased haemoglobin level and cardiac output as compensatory measures. There can be tissue hypoxia (histotoxic hypoxia) without hypoxemia in cyanide poisoning where cells are unable to utilize oxygen despite having normal blood and tissue oxygen level.[1]

Clinically hypoxia is accepted as oxygen saturation of arterial blood less than 90% on air at sea level which corresponds to partial pressure of oxygen PaO2 less than 60 mm Hg or Kpa. However, the arterial blood saturation or partial pressure of oxygen does not necessarily correlate oxygenation at the tissue level.

Nature keeps a steep gradient of the partial pressure of oxygen from air (150 mmHg) to alveolus (100 mmHg) to tissues for quick transport. But oxygen transport is subject to multiple weak links in the chain as well. Nature keeps a stricter vigil on CO2elimination. CO2 is about 24 times more soluble than oxygen in blood. The shape of the oxyhemoglobin and carboxyhaemoglobin curves dictate that for carbon dioxide, hypoventilation in one region of the lungs can be compensated by hyperventilation at other site which does not happen for oxygen.[2]

Nature also has ways to mitigate the effects of hypoxia − both acute and chronic. Instantaneous response to hypoxia results into regional pulmonary vasoconstriction (to improve V̇/Q̇ match), hyperventilation to improve PAO2, pH-related right shifting of the oxyhemoglobin dissociation curve to facilitate O2 unloading, and increases in cardiac output. Long-term measures include increased red blood cell production and an increase in red blood cell 2,3-diphosphoglycerate to facilitate O2 unloading in the tissues. Adaptations also occur at the cellular level to enhance cellular tolerance to hypoxia. However, resulting polycythemia also increases blood viscosity and may impair blood flow and tissue oxygen delivery through capillaries.[3]

Pathogenesis

There are five major pathophysiologic mechanisms for hypoxia: decreased inspired PO2, ventilation-perfusion (V/Q) mismatch, right to left shunt, impaired diffusion and hypoventilation. While hypoxia may be caused by all these, hypercarbia is associated primarily with alveolar hypoventilation [Table 1].
Table 1 Pathophysiologic mechanism of hypoxia

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Alveolar-arterial oxygen gradient P(A-a)O2

Alveolar to arterial (A-a) oxygen gradient = PAO2–PaO2 is the difference between alveolar oxygen level (PAO2) and arterial oxygen level (PaO2). P(A-a)O2 may be used to narrow the differential diagnosis of hypoxia further into intrinsic and extrinsic causes of hypoxia. The A-a oxygen gradient was assumed to indicate the effectiveness of gas exchange across the alveolocapillary membrane, but other factors like surface area and transit time also modify it. The A-a oxygen difference is <10 mmHg in young healthy adults.[4]

Low inspired oxygen [PI O2]

A decrease in barometric pressure [e.g. breathing at high altitude] or an accidental decrease in FIO2 (anesthesia) maybe the cause.

PaO2 is decreased. Peripheral chemoreceptors sense the low arterial PaO2 and initiate an increase in ventilation through their input to the medullary respiratory centre. Resulting hyperventilation reduces PaCO2. P(A-a)O2 normal.

Ventilation perfusion mismatch

The commonest cause of hypoxia is anatomical/physiological imbalance between ventilation and perfusion − the ventilation perfusion (V/Q) mismatch. Gravity and anatomical inhomogeneity make some degree of V/Q mismatch physiological. Body has ample reserve and compensatory mechanisms to restrict V/Q within the physiological range. Lack of ventilation (the cause of hypoxia) is compensated by pulmonary vasoconstriction at the site and vice versa.[5] V/Q imbalance out of the physiological range occurs in diverse disease states. P(A-a)O2 is elevated, PaCO2 is normal. One common clinical scenario is treating acute severe asthma with bronchodilator nebulisers. The existing hypoxemia worsens slightly due to resulting V/Q mismatch. Hypoxemia due to V/Q mismatch can be corrected with supplemental oxygen therapy and generally have a steep increase in PaO2 when supplemental oxygen is administered.[6]

Right to left shunt

Shunt refers to the entry of deoxygenated blood into the systemic arterial system without going through the ventilated areas of lung. Shunt may be anatomical or physiological. In healthy individuals a portion of the bronchial circulation drains into the pulmonary vein and a portion of the coronary circulation drains through the thebesian veins into the left ventricle. In disease states shunt results with filling of the alveolar spaces with fluid or from collapse of airspaces, thus a part of the cardiac output bypassing the alveolar air. Causes include pneumonia, pulmonary edema, alveolar collapse, pulmonary arteriovenous communication and acute respiratory distress syndrome (ARDS). In congenital cyanotic heart diseases right heart blood flows straight to left side bypassing the lungs. P(A-a)O2 is elevated. PaCO2 is normal. (Hypercapnia is uncommon until the shunt fraction reaches near 50% due to stimulation of the respiratory center by chemoreceptor as the PaCO2 in the arterial blood leaving the shunt unit is high.) Arterial PaO2 cannot rise to the normal level even if the patient is given 100% oxygen to breathe.

Diffusion limitation

Oxygen and carbon dioxide cross the blood-gas barrier by simple passive diffusion. Historically it was assumed that diffusion reflects the integrity of the alveolocapillary membrane and the prototype was accepted as diffuse interstitial pulmonary fibrosis. However, multiple factors may affect diffusion including decrease in surface area for diffusion (loss of alveolar walls and/ or capillaries), inflammation and fibrosis of the alveolocapillary membrane, low alveolar oxygen and extremely short capillary transit time. Loss of functioning lung tissue like pneumonectomy also reduces diffusion. P(A-a)O2 is elevated. PaCO2 is normal.

Hypoxemia may not manifest early due to ample lung reserve and compensatory measures into play like recruitment and distension of capillaries, and rise in alveolar oxygen. Diffusion limitation may be unmasked by the development or worsening of hypoxemia during exercise as the capillary transit time is further shortened.

Hypoventilation

Hypoventilation means abnormally low alveolar ventilation in relation to oxygen uptake or carbon dioxide output. The alveolar PAO2 reaches a lower level than normal. Alveolar PACO2, and therefore arterial PaCO2, are raised (hypercapnia). P(A-a)O2 is normal. Increasing the fraction of inspired oxygen (FIO2) can alleviate the hypoxemia. But hypercapnia can only be corrected by elimination of CO2 through increased ventilation. Commonest causes of hypoventilation include:
  1. Neuromuscular − Lack of stimulus from the respiratory center to the brain stem, spinal cord, myoneural junction (myasthenia gravis) and diseases of the respiratory muscles themselves.
  2. Airway obstruction − upper or lower
  3. Hypoventilation associated with extreme obesity (pickwickian syndrome).[7],[8],[9],[10]


Principles of oxygen therapy

  1. Hypoxaemia is an independent risk factor of poor outcome apart from that due to the severity of the underlying disease(s).
  2. Oxygen is a drug prescribed and administered for specific indications, with a documented target oxygen saturation range (avoiding both hypoxaemia and hyperoxaemia) and with regular monitoring of the patient’s response.
  3. Oxygen is prescribed for the relief of hypoxaemia, not breathlessness.
  4. Pulse oximetry should be available in all clinical situations in which oxygen is used inspite of its variable accuracy in the estimation of arterial oxygen saturation (SaO2) during worsening hypoxemia. Pulse oximetry is inaccurate in patients with carbon monoxide poisoning.
  5. Arterial blood gas (ABG) measurement should be considered in the following situations.
    1. Critically ill patients with cardiorespiratory or metabolic dysfunction
    2. In patients with an SpO2 of <92%
    3. Deteriorating SpO2 requiring increased FiO2
    4. Patients at risk of hypercapnia
    5. Breathless patients in whom a reliable oximetry signal cannot be obtained.
      1. Peripheral venous blood gas analysis has been promoted as a less invasive test; however, it does not provide an accurate estimate of arterial partial pressure of carbon dioxide (PaCO2) or PaO2.
      2. A detailed oxygen prescription should be documented in the patient records and the drug chart with the target SpO2 range, the delivery system and interface and the range of flow rates for each delivery system.



  Delivery system Top


  1. Standard nasal cannulae are still the preferred method of oxygen delivery, with the flow rate varied to achieve the target oxygen saturation.
  2. The FiO2 levels delivered by the different delivery systems may vary considerably between patients and be influenced by a number of factors, including respiratory rate and whether the patient’s mouth is open or closed.

    Nasal canula /1–6 litres per min/28-35% FiO2. Variable flow.

    Simple face mask/ 6–10 litres per min/ 35-60% FiO2. Flow rates of <5 L/min should be avoided due to the potential risk of carbon dioxide rebreathing.

    Venturi mask/4–8 litres per min/ 24–60% FiO2. Precise flow.

    Non-rebreathing mask/10–15 litres per min/60%–85% FiO2. Short-term measure.

    Oxygen mask with a filter on the exhalation port capable of filtering exhaled particles is now a recommended practice for infection prevention.[11],[12],[13],[14]



  Oxygen administration Top


Treatment algorithm for oxygen therapy is based on degree of hypoxemia, acuteness of the condition and risk of hypercapnia. In the acute setting, oxygen saturations should be measured by oximetry, pending the availability of blood gas results if required.

In the presence of hypoxaemia in other acute medical conditions, oxygen should be administered to achieve a target SpO2 range of 92–96%.

Most non-hypoxaemic breathless patients do not need oxygen therapy, but a sudden reduction of ≥3% in a patient’s oxygen saturation within the target saturation range warrants fuller assessment of the patient.

Conscious hypoxaemic patients should be encouraged to maintain the most upright posture possible as oxygenation is reduced in the supine position.

In the presence of COPD or conditions associated with chronic respiratory failure:
  1. If SpO2 ≥ 88%, oxygen therapy is not initially required.
  2. If SpO2 < 88%, oxygen can be administered at 1–2 L/min via nasal cannulae or 2–4 L/min via 24% or 28% Venturi mask, and titrated to achieve target SpO2.


In the absence of COPD or known chronic respiratory failure:
  1. If SpO2 ≥ 92%, oxygen therapy is not routinely required.
  2. If SpO2 is 85–91%, oxygen can be initially instituted at 2–4 L/min via nasal cannulae or other suitable oxygen delivery method, and titrated to achieve target SpO2.
  3. If SpO2 < 85%, oxygen can be initiated at 4 L/min via nasal cannulae, through a simple face mask at 5–10 L/min, a 100% non-rebreather reservoir mask at 15 L/min, or humidified high flow nasal cannulae (FiO2 > 0.35). The choice of delivery system will depend on the SpO2 level (higher FiO2 will be required with greater reductions in SpO2), and titrated to achieve the target SpO2 as soon as practically possible.


If oximetry is not available, or reliable SpO2 cannot be determined and hypoxaemia is suspected, oxygen can be delivered at:
  1. 1–2 L/min via nasal cannulae or 2–4 L/min via 24% or 28% Venturi mask in patients with acute exacerbations of COPD or conditions known to be associated with chronic respiratory failure.
  2. 2–4 L/min oxygen via nasal cannulae in patients who are not critically ill and life-threatening hypoxaemia is not suspected.
  3. 5–10 L/min via simple face mask, 15 L/min through a 100% non-rebreather reservoir mask or high flow nasal cannulae (FiO2 > 0.35) in patients in whom life-threatening hypoxaemia is suspected.


Approach to hypoxemia

The practical approach to management of hypoxemia is shown in [Figure 1].[15],[16],[17]
Figure 1 Flow chart showing practical approach to oxygen therapy

Click here to view


High flow nasal oxygen[18],[19],[20]

HFNO was initially developed for use in neonates to maintain the benefit of high oxygen flows without compromising blood flow to skin areas susceptible to pressure sores. The issue in adult patients, however, was primarily clearance of airway secretions rather than tolerability of a close-fitting mask. The concept of providing NIV with little discomfort to the patient has been the key attraction though the efficacy in different subsets is still a matter of concern. HFNO work on two variables − the percentage of oxygen being delivered and the rate of gas flow. Thus they can deliver a mix of air and oxygen with an inspired oxygen fraction (FiO2) ranging between 0.21–1.0 and gas flows to the range of 1–60 l/min. The gas undergoes 100% humidification and is heated to approximately normal body temperature.

Mechanism of action

How does HFNO work? The possible mechanisms are: maintenance of a constant FiO2, generation of a positive end-expiratory pressure (PEEP), reduction of the anatomical dead space, improvement of mucociliary clearance and reduction in the work of breathing.

Maintenance of constant FiO2

Regular nasal cannulas may allow delivery of gas flows up to 15 l/min. In a dyspneic patient with tachypnea the rapid inspiratory flow rate may exceed the flow of delivered oxygen, with the additional flow recruited from the surrounding air (FiO2 of 0.21). So, as the respiratory rate of the patient increases, the actual FiO2 being delivered decreases. The HFNO overcomes this issue by its delivery of oxygen at particularly high flows facilitating maintenance of a constant delivered FiO2.

Generation of a positive end-expiratory pressure

Study performed in animal models and human volunteers have confirmed generation of positive airway pressures in the nasopharynx.[5] Though relatively low in magnitude, these pressures are translated to increased intra-alveolar volumes and could potentially suffice to prevent alveolar closure. Increased HFNO flows generated a greater increase in pressure with a closed mouth, a proportionate increase was observed with the mouth open as well.[6]

Decrease in anatomical dead space

The hypothesis is that the constant high flow oxygen washes out the inspiratory dead-space and expired volume of carbon dioxide (CO2) from the airway. This results in observed increase in PaO2 and significantly lower PaCO2.

Decreased work of breathing

Studies suggest that HFNO by its effect on increasing the end-expiratory lung volume, may reduce the respiratory rate, increase the tidal volume and decrease the work of breathing.


  Clinical Uses of HFNO Top


HFNO has gained wide acceptance because of its user-friendly application even in low-monitoring conditions. The applications mostly cover respiratory support of patients with acute hypoxemic respiratory failure or respiratory distress syndrome (ARDS), respiratory compromise in heart failure, post-extubation respiratory distress, as an adjunct during airway instrumentation and for immunocompromised patients. Extreme hypoxia is still a source of caution and concern.

Acute hypoxemic respiratory failure/ARDS

HFNO has been compared to conventional oxygen therapy and NIV in patients with acute hypoxemic respiratory failure. Compared to O2 therapy, HFNO reduces the risk of intubation, particularly in the patients with mild hypoxemia (PaO2 /FIO2 > 200 mm Hg). Data for HFNO versus NIV as the initial respiratory support for patients with acute hypoxemic respiratory failure is limited. HFNO seems more effective than conventional oxygen therapy and non-inferior to NIV in most studies and is consistently better tolerated by patients than NIV. In cases of mild to moderate hypoxemia, noninvasive ventilation (NIV) and high flow-nasal oxygen (combined with prone position) have shown to be acceptable alternatives before making the decision to intubate. Frequent reevaluation is mandatory.

In post-extubation respiratory failure, HFNO is better tolerated than NIV and non-inferior to NIV with regards to intubation and mortality. HFNO after abdominal surgery remains controversial.

COPD

Initially HFNO was supposed to improve oxygenation and NIV to improve ventilation and oxygenation. Multiple studies later confirmed the physiological effect of HFNO in COPD patients with reduction of CO2 due to the effects of washing out dead space and a reduction in the work of breathing. HFNO has been tried in 3 aspects of COPD care: use for treatment of COPD exacerbations, long-term use in stable COPD patients, and use during exercise therapy in COPD. Use during COPD Exacerbations has been the acid test for HFNO.

HFNO has been shown in some studies to be as efficient as NIV in improving blood gas parameters in a mixed population of acidotic and nonacidotic AECOPD patients. However, NIV remains the primary choice. HFNO may be an alternative therapy in those group of patients who do not tolerate NIV. HFNO is preferred over standard oxygen during intervals of NIV interruption in patients recovering from AECOPD.

COVID19

Hypoxia in COVID19 infection is likely of multifactorial origin. The pathophysiologic mechanisms comprise all of the following: relatively preserved lung compliance/lack of excessive dead space/intra-pulmonary shunting/ dysfunctional hypoxemic vasoconstriction. Patients initially do not complain of dyspnea as there is no elevation in CO2 and/or work of breathing. Silent hypoxia, frequently termed happy hypoxia, is not a new concept. The PaO2/FiO2 ratio remains low in COVID-19 until critical respiratory insufficiency occurs. The pathological shift to typical ARDS occurs as pulmonary circulation is impaired due to thromboembolic phenomena and hyperferritinemia progressively affects alveolar-capillary cell membrane integrity producing inflammation, edema and lung cell necrosis.

Management of hypoxia is a tricky affair with COVID19. The different stages from mild illness to severe respiratory distress are not clear-cut. Oxygenation is based on PaO2 /FiO2 ratio (if PaO2 is not available, SpO2) with frequent monitoring. The defining clinical assessment parameters are respiratory rate of more than or equal to 24 and oxygen saturation (SpO2) of less than 94% on room air (range 90-94%). Oxygen therapy is initiated at 5 L/min and flow titrated to reach target SpO2 ≥ 90% in non-pregnant adults and SpO2 ≥ 92-96% in pregnant patients. Children should receive oxygen therapy to target SpO2≥94%.

Worsening respiratory distress or hypoxemia inspite of oxygen delivered via a face mask with reservoir bag (flow rates of 10-15 L/min; FiO2 0.60-0.95) is a warning. High-flow nasal oxygen is recommended over noninvasive positive pressure ventilation (NIV)). Compared to standard oxygen therapy, HFNO reduces the need for intubation. Standard airborne precautions when performing an aerosol generating procedure is to be strictly followed. Recent publications suggest that newer HFNO and NIV systems with good interface fitting do not create widespread dispersion of exhaled air and therefore should be associated with low risk of airborne transmission.

Prone positioning improves oxygenation and patient outcomes in patients with moderate-to-severe acute respiratory distress by improving ventilation-perfusion matching and recruiting collapsed alveoli in the dorsal lungs. Awake proning has been tried in the context of COVID-19. Awake proning led to improved oxygenation in two recent small observational studies involving 24 and 15 patients. In patients with severe respiratory distress, prone positioning and prone ventilation for >12 hours per day is strongly recommended.

If conditions do not improve or even get worse within a short time (1–2 hours), tracheal intubation and invasive mechanical ventilation should be used in a timely manner.


  Conclusion Top


Oxygen therapy is based on our understanding of the pathophysiologic mechanisms of hypoxia. Multiple guidelines exist. Standard protocol, newer delivery systems and rigid monitoring are mandatory to achieve the desired result.

Acknowledgement

I have received inputs from Dr. Indranil Halder and Dr. Raja Dhar in preparing the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E et al. ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307:2526-331.  Back to cited text no. 12
    
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Beasley R, Chien J, Douglas J. Thoracic Society of Australia and New Zealand oxygen guidelines for acute oxygen use in adults. Respirology 2015;20:1182-91  Back to cited text no. 16
    
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