COVID-19-associated hypoxemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rija Gul, M.B.B.S.

Synonyms and keywords:

Overview

COVID-19 emerged as a pandemic, after its outbreak in Wuhan, China in December 2019. It is caused by a new type of Coronavirus (novel Coronavirus), based on its genomic study. The virus binds to ACE-2 receptors on Type 2 pneumocytes in the lower respiratory tract. Its clinical presentation varies from asymptomatic disease to severe acute respiratory distress syndrome (ARDS). Hypoxemia is present with an increased A-a gradient. Hypoxemia is diagnosed by Pa02<60mmHg in a sample of Arterial Blood Gas. Mechanisms involved in hypoxemia are widely reported to be due to ventilation perfusion mismatch and intrapulmonary shunting. Diffusion impairment can cause hypoxemia during recovery period due to fibrosis in the lung. Older age, male sex, hypertension and dyspnea have been identified as risk factors for development of hypoxemia in COVID-19. Complications of hypoxemia include acute respiratory failure and multi-organ failure. Treatment is based on oxygen supplementation to keep target Spo2> 90%.

Historical Perspective

• In December 2019, novel coronavirus outbreak occurred in Wuhan, China

• On 11th March 2020, it was declared as Pandemic by WHO.

Classification

• There is no established system for the classification of COVID-19 associated hypoxemia.

Pathophysiology

• COVID-19 is caused by the novel Coronavirus. It binds to ACE-2 receptors in the lower respiratory tract which causes pulmonary manifestations.
• The virus causes alveolar injury which stimulates an inflammatory response in the host tissue.
• Mononuclear inflammatory cells are recruited at the site of injury which release cytokines e.g Interleukin-6 and activate procoagulants
• As a result of this insult, the alveolar epithelium and capillary endothelium are damaged.
• Alveoli collapse occurs due to fluid accumulation and loss of surfactant
• Simultaneously, the activation of Coagulation cascade by cytokines leads to widespread thrombosis in multiple organs of the body, including lungs.
• It has also been suggested that there is down-regulation of the Hemostatic Oxygen Sensing system of the body (e.g Carotid bodies) through alteration of expression of mitochondrial proteins by the Coronavirus, occurring at a cellular level.
• The above mechanism supports the lack of dyspnea in proportion to the severity of hypoxemia, on clinical presentation, a phenomenon known as "happy hypoxemia".

Mechanisms of Hypoxemia in COVID-19

• Hypoxemia in COVID-19 is marked by an increased A-a gradient.

Ventilation Perfusion Mismatch

• V/Q mismatch is typically seen due to ARDS.
• Initially the lungs have good compliance but there is marked hypoxemia.
• This can be explained by abnormal vasoregulation which disrupts the physiological, hypoxic pulmonary vasoconstriction response to hypoxemia.
• If hypoxemia is not addressed early, the patient increases inspiratory efforts which exerts more pressure on the tissues, causing a rise in the transpulmonary pressure.
• These changes in lung dynamics promote capillary leakage which further increases alveolar exudates and the lungs become poorly compliant.
• The ventilation-perfusion mismatch, therefore, progresses from a high Va/Q ratio to a low Va/Q ratio.
• Pulmonary vascular thrombi also contribute to Va/Q mismatch.
• Both acute pulmonary embolism and small vessel thrombosis are seen on autopsy.
• This increases the alveolar dead space causing Va/Q mismatch.

Intrapulmonary Shunt

• Blood is shunted from the poorly ventilated alveoli to well-aerated lung regions.
• Intra-cardiac shunts can be detected in 20% of the patients being treated for ARDS. Patent foramen ovale opens due to positive pressure ventilation.
• Shunt can be differentiated from Va/Q mismatch due to the lack of response to supplemental oxygen.

Diffusion Impairment

• Persistent hypoxemia has been seen in recovered patients, due to postviral fibrosis.

• A study was conducted in China to measure DLCO of discharged patients. The researchers concluded that the decrease in DLCO correlated with the severity of pneumonia on admission.

Causes

• Hypoxemia in COVID-19 patients is associated with the development of the following:
  • Acute Respiratory Distress Syndrome
  • Microvascular Thrombi
  • COVID-19 Pneumonia (see Covid-19-associated pneumonia)

Differentiating COVID-19-associated hypoxemia from other Diseases

Dyspnea is not a prominent feature of hypoxemia due to COVID-19 in contrast to other diseases causing hypoxemia

Epidemiology and Demographics

• COVID-19 is seen more commonly in men.
• 80% of patients with Coronavirus disease develop a respiratory infection.
• According to a study conducted in Hubei, China, 5%-25% of patients admitted in hospital for COVID-19 needed ICU admission. Of the patients admitted in ICU, 60%-70% developed ARDS.
• There is no geographical association of hypoxemia in COVID-19.

Risk Factors

• According to a study conducted in Wuhan, China, the following risk factors were identified in patients presenting with hypoxemia(Spo2< 90%):
  • Older age (median - 60 years)
  • Male sex
  • Hypertension
  • Dyspnea on clinical presentation

Natural History, Complications, and Prognosis

• COVID-19 has a wide range of clinical presentation, varying from asymptomatic to severe disease, requiring ICU admission.
• Acute Respiratory Distress Syndrome (ARDS) (see COVID-19-associated acute respiratory distress syndrome) and pneumonia, which are a common cause of hypoxemia, can develop in 15% of patients.
• Common complications of hypoxemia include acute respiratory failure, (see COVID-19-associated respiratory failure) and multiorgan failure( Acute Kidney injury, Liver dysfunction, Cardiac injury).
• Prognosis is generally poor for patients presenting with hypoxemia. It has been identified as an independent risk factor for mortality due to COVID-19.
• Patients who require mechanical ventilation have a mortality rate of 50%-60%.

Diagnosis

Diagnostic Study of Choice

• The diagnosis of COVID-19 associated hypoxemia can be established by the following investigations:
  • Reverse Transcriptase- Polymerase Chain Reaction from nasal or throat swab sample positive for COVID-19
  • Chest Tomography images showing peripheral and bilateral ground-glass opacities
  • Arterial Blood gas showing Pa02 (Partial Pressure of oxygen) below 60mmHg
  • Oxygen Saturation below 90% on Pulse oximeter

History and Symptoms

• Dry cough (most common symptom)
• Fever
• Tachypnea
• Nausea
• Vomiting
• Diarrhea
• Loss of sense of smell and taste

Laboratory Findings

• Lymphopenia (80% of patients)
• Thrombocytopenia
• Elevated C- Reactive Protein
• Elevated LDH (40% of patients)
• ELevated D-Dimer
• Elevated level of IL-1, IL-6

Imaging Studies

• Chest x-ray demonstrates multi-lobar infiltrates
• Computed Tomography shows consolidation and bilateral ground glass opacities located peripherally.

Treatment

Treatment of Hypoxemia due to COVID-19

Overview

• Hypoxia due to COVID-19 warrants hospital admission
• Oxygen target should be Spo2>90%
• Some centres have suggested to restrict oxygen supplementation by High Flow Nasal Cannula(HFNC) and Non Invasive Ventilation( Bipap, CPAP) as they generate aerosol and pose a threat to the healthcare workers
• Invasive mechanical Ventilation by early intubation is recommended for hypoxemia not responding to Non Invasive Ventilation

Venturi Mask

• SpO2< 93%-94%
• Respiratory rate > 28-30 breaths per minute
• Deliver oxygen via 40% Venturi mask
• If response is seen in 5-10 minutes, continue treatment for the next 6 hours
• NIV is recommended if there is no improvement

High Flow Nasal Oxygenation(HFNO)

• Use is recommended in negative pressure environment due to aerosol generation
• Apply if SpO2< 92%
• No response to Oxygen delivery is observed via nasal cannula, face mask or Venturi mask
• Use Oxygen flow of 30-50L/min
• Keep FiO2 between 50%-70%

Non Invasive Ventilation

• Used when dyspnea/ hypoxemia does not improve within 1 hour of HFNO used at 50L/min and FiO2>70%
• Recommended to use pressure setting of 8-10cm Hg and FiO2of 60%
• Monitor with hourly Arterial Blood Gas sampling
• Use for 4-6 hours, allowing 1 hour break for feeding

Invasive Mechanical ventilation

• Performed in patients with severe hypoxemia ( Pa02/FiO2 <200) and failure of NIV
• Rapid Sequence intubation is preferred to avoid aerosolisation by Bag mask ventilation
• Lung protective Ventilation is used in patients with severe ARDS
• Tidal Volume at 4-6ml/kg of body weight
• Plateau Pressure(Pplat) < 30cm H2O
• High Positive End Expiratory Pressure (PEEP) is recommended to keep driving pressure(Pplat-PEEP)<14cm H2O

Prone Position

• Recommended in severe ARDS(PaO2/FiO2<150) along with Invasive Mechanical ventilation
• Recommended for total duration of 12-16 hours daily
• Not recommended for infants less than 6 months of age
• It decreases Va/Q mismatch by eliminating gravitational forces exerted on lung portion by mediastinal structures, allowing maximum lung recruitment when positive pressure mechanical ventilation is applied
• Meta analysis have shown that Prone positioning can decrease mortality when used for long duration within intial 48hours in severe ARDS.
• In a pilot study performed in New York emergency, awake proning was associated with improved oxygen saturations in non intubated patients.
• Position should be changed every 2 hours to prevent pressure ulcer formation

Extra Corporeal Membrane Oxygenation

• Used in refractory hypoxemic respiratory failure
• PaO2/Fio2 < 50mmHg for more than 1 hour
• PaO2/FiO2 < 80mmHg for more than 2 hours
• Arterial Blood Gas indicating pH<7.2 persisting for more than 1 hour, due to uncompensated respiratory acidosis
• It is has shown improved clinical outcome in severe COVID-19

Prevention

Primary Prevention

• Infection with COVID-19 can be prevented by practicing the following:
  • Social distancing
  • Frequent hand washing
  • Personal Hygiene
  • Wearing mask

References

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