Introduction

Definition of Acute Respiratory Failure (ARF)

Respiratory failure is a disorder in which one or both of the gas exchange functions of the respiratory system (i.e, the supply of oxygen and/or the removal of carbon dioxide from mixed venous blood) do not work.¹  Type 1 respiratory failure happens when the respiratory system fails to supply enough oxygen to the body, resulting in hypoxaemia. It can be triggered by alveolar hypoventilation, low atmospheric pressure/fraction of inspired oxygen, diffusion problem, ventilation/perfusion mismatch, and right-to-left shunt. Type 2 respiratory failure happens when the respiratory system can't effectively eliminate carbon dioxide from the body, resulting in hypercapnia, and can be triggered by respiratory pump malfunction and heightened carbon dioxide generation.²

Generally, lung failure caused by a variety of lung diseases such as pneumonia, interstitial lung disease, and emphysema can cause hypoxemia with normocapnia or hypocapnia (hypoxaemic or type I respiratory failure). Drug overdosing may result in pump failure causing hypercapnia or alveolar hypoventilation (hypercapnic or type II respiratory failure).¹

Overview of corticosteroids

Corticosteroids are a type of steroid hormone released by the adrenal cortex, including glucocorticoids and mineralocorticoids. The name “corticosteroids” reflects their effect on carbohydrate metabolism. Glucocorticoids regulate diverse cellular functions including development, homeostasis, metabolism, cognition and inflammation.

Corticosteroids are important therapeutic agents used to treat allergic and inflammatory disorders and to remove unwanted or inappropriate immune system actions.³

Types

There are two types of corticosteroids - glucocorticoids and mineralocorticoids.

Glucocorticoids are a class of drugs that are structurally and pharmacologically similar to the endogenous hormone cortisol and have multiple functions, including anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive functions.⁴

Mineralocorticoids are steroid hormones that regulate salt and water balance. Aldosterone is the primary mineralocorticoid. Mineralocorticoids promote the transport of sodium and potassium, which normally accompanies changes in fluid balance, a function necessary for life.⁵

Pathophysiology of acute respiratory failure

Causes of acute respiratory failure

Acute respiratory failure (ARF) can be caused by various aetiologies, which may include primary pulmonary or extrapulmonary pathologies. The causes are often multifactorial. ARF can result from the following abnormalities:⁶

• Central Nervous System (CNS):  Drugs, metabolic encephalopathy, CNS infection, elevated intracranial pressure (ICP), obstructive sleep apnoea (OSA), central alveolar hypoventilation
• Spinal cord: Trauma, transverse myelitis
• Neuromuscular system: Polio, tetanus, multiple sclerosis (MS), myasthenia gravis, Guillain-Barre syndrome, intensive care or steroid-induced myopathy
• Chest wall: Kyphoscoliosis, obesity
• Upper airway: Obstruction caused by tissue enlargement, infection, mass, vocal cord paralysis, tracheomalacia
• Lower respiratory tract: Bronchospasm, congestive heart failure (CHF), infection
• Lung parenchyma: Infection, interstitial lung disease
• Cardiovascular system

Inflammatory response in ARF

Systemic pulmonary inflammatory damage locally or at extrapulmonary sites affects the bronchial epithelium, alveolar macrophages, and vascular endothelium, leading to the accumulation of protein-rich oedema fluid in the alveoli and subsequent hypoxaemia due to impaired gas exchange. Alveolar macrophages play a key role in orchestrating inflammation and resolution of ARF.⁷ 

When the alveolar macrophages are stimulated, they recruit neutrophils and circulate macrophages in the lungs for damage. These cells participate in the development of a variety of bioactive mediators, including protease, reactive oxygen species, eicosanoids, phospholipids and cytokines that capture the inflammatory reaction. An in-depth effect of these mediators is to damage or induce distal cell death, specifically alveolar type 2 epithelial cells. These cells serve vital functions by synthesising and secreting lung surface-active agents, which is an indispensable material that lines the inner lung surface to lower alveolar surface tension. Type 2 cells are also actively involved in ion transport to control lung fluid. 

Together, these inflammatory events lead to the histological changes typical of the acute exudative phase, resulting in significant impairment of lung mechanics and gas exchange.⁸ During the initial inflammatory and/or resolution phases of acute respiratory distress syndrome (ARDS), alveolar macrophages also coordinate other cells in a paracrine manner, including epithelial cells, lymphocytes, and mesenchymal stem cells, which may result in increased inflammatory response or increased tissue damage. A prolonged M1 (classically activated macrophage) or M2 (alternatively activated macrophage) phenotype appears to be associated with incurable chronic ARDS.⁹

Mechanism of action of corticosteroids

Anti-inflammatory effects

Corticosteroids suppress multiple inflammatory genes activated in chronic inflammatory diseases such as asthma. They reverse histone acetylation of active inflammatory genes by binding to ligand-bound glucocorticoid receptors (GR).. This process is mediated through the recruitment of histone deacetylase 2 (HDAC2) to the activated transcription complex. At higher concentrations, the GR homodimer interacts with DNA at specific recognition sites, promoting the transcription of anti-inflammatory genes and inhibiting the transcription of genes related to pro-inflammatory effects.¹⁰

Effects on airway inflammation and oedema

Corticosteroids help reduce inflammation and swelling in the airways through the following mechanisms:

Reducing inflammation

Corticosteroids may reduce inflammation by inhibiting the production of inflammatory genes, stimulating the production of anti-inflammatory proteins, and decreasing the presence of inflammatory cells in the airways.¹¹

Reducing mucus production

Corticosteroids can reduce mucus production by blocking the release of secretagogues from macrophages.¹²

Decreased airway sensitivity

Corticosteroids can manage asthma symptoms by decreasing airway hyperresponsiveness.¹³

Treating upper airway obstruction

Corticosteroids help treat upper airway obstruction caused by swelling due to infection, allergies, or injury.¹⁴

While effective, corticosteroids can lead to complications, including:

• Osteoporosis, fractures, and osteonecrosis
• Electrolyte imbalances
• Increased risk of peptic ulcer disease

Clinical use of corticosteroids in ARF

Corticosteroids is occasionally utilised in the treatment of acute respiratory failure, like ARDS and severe pneumonia. Corticosteroids are potent anti-inflammatory agents that can decrease pulmonary inflammation and avoid respiratory failure.¹⁵

Key benefits of corticosteroids in ARF

• Enhanced cardiac and pulmonary function: Corticosteroids can enhance cardiac and pulmonary function in 3 to 7 days¹⁶
• Decreased death rate: Some research studies have demonstrated that corticosteroids can decrease the rate of mortality¹⁵
• Corticosteroids can decrease the harm caused by oxygen-free radicals¹⁷
• Enhanced blood flow in small blood vessels: Corticosteroids have the ability to improve microcirculation¹⁷

The effectiveness of corticosteroids varies depending on the individual patient, disease severity, and timing and duration of treatment. One study discovered that beginning methylprednisolone treatment over two weeks after ARDS onset resulted in a notably higher mortality rate.

Indications of corticosteroid therapy in ARF

Corticosteroid therapy is used to treat a variety of conditions due to its anti-inflammatory and immunosuppressive effects. Here are some common indications for corticosteroid therapy:

• Asthma exacerbation
• COPD exacerbation
• Pneumonitis
• Interstitial lung disease
• Allergic rhinitis
• Inflammatory conditions
• Organ transplantation¹⁸

Dosage and administration

The dosage and administration of corticosteroids for acute respiratory failure varies depending on the specific condition being treated:¹⁹

Asthma

Severe asthma exacerbation:

• Intravenous (IV): Methylprednisolone 40-125 mg IV every 6-8 hours for 24-48 hours, followed by oral therapy as needed
• Oral: Prednisone 40-60 mg daily for 5-7 days, often divided into 1-2 doses

Chronic obstructive pulmonary disease (COPD)

Acute exacerbation:

• Oral: Prednisone 40-60 mg daily for 5-7 days. Dosage may vary based on severity and patient response
• Intravenous (IV): In severe cases or if patient cannot take oral medications, initially methylprednisolone 40-125 mg IV every 6-8 hours, then gradually reduce oral therapy as needed

Acute respiratory distress syndrome (ARDS)

• High-dose therapy: Methylprednisolone 1-2 mg/kg body weight daily in divided doses. This high-dose regimen is often used in severe cases and for short periods of time
• Moderate-dose therapy: Some protocols recommend a moderate dose of methylprednisolone, such as 0.5 to 1 mg/kg body weight per day

Pneumonia

Acute chemical or drug-induced pneumonitis:

• Oral: Prednisone 0.5 to 1 mg/kg body weight per day, usually for 1 to 2 weeks, followed by a gradual taper
• Intravenous (IV): In severe cases, methylprednisolone 40 to 125 mg IV every 6 to 8 hours for a short period of time, then transition to oral therapy

Tapering and monitoring

• Tapering: For conditions requiring prolonged treatment, a gradual tapering is necessary to avoid withdrawal symptoms and adrenal insufficiency
• Monitoring: Regular monitoring for side effects such as hyperglycemia, hypertension and gastrointestinal problems is essential, particularly with high doses or prolonged use

Benefits and risks

Potential benefits

Corticosteroids can offer several potential benefits in the management of ARF, particularly in conditions such as ARDS, COVID-19-related respiratory failure, and exacerbations of COPD. Here are the key potential benefits:²⁰

• Anti-inflammatory effects
• Reduction in pulmonary oedema
• Prevention of fibrosis
• Mortality reduction in specific conditions
• Improved gas exchange
• Reducing COPD exacerbations
• Immunomodulation 

Risks and side effects

These agents can cause several negative effects, like high levels of sugar in the blood, retention of fluids, changes in electrolytes, inflammation of the pancreas, higher risk of infection, weakness in the muscles and nervous system, bleeding in the gastrointestinal tract, and more, which could be a significant drawback of this treatment.²¹

Strategies to mitigate risks

To reduce the risks associated with the use of corticosteroids in ARF, it is important to use targeted strategies that balance benefits with minimisation of side effects. Here are the main strategies:⁴

Optimisation of dose and duration

Use of the lowest dose of glucocorticoids for the shortest period needed to achieve the treatment goals.

Prophylaxis for infections

Immunosuppression by corticosteroids increases the risk of infection. Prophylactic measures include:

• Antibiotic prophylaxis in high-risk patients (e.g., those with immunosuppression)
• Antifungal or antiviral medications as needed, especially in patients at risk of opportunistic infections
• Monitor for infections: Monitor regularly for signs of infection (e.g. fever, respiratory changes) to detect infections early

Monitor blood sugar levels

Corticosteroids can cause hyperglycemia (high blood sugar), in people with or without diabetes. Frequent monitoring of blood glucose levels and appropriate adjustments of insulin therapy or other hypoglycemic agents may help control this risk.

Bone health monitoring

Long-term use of corticosteroids can lead to osteoporosis and bone loss. Preventive strategies include Calcium and vitamin D supplements to maintain bone health.

Electrolyte and fluid monitoring

Corticosteroids may lead to fluid retention and electrolyte imbalances, specifically by causing sodium retention and potassium loss. Frequent electrolyte level monitoring (especially sodium and potassium) can assist in mitigating this risk.

Muscle strength and mobility

Muscle weakness known as steroid myopathy can develop from taking corticosteroids. Promoting physical therapy and initiating early mobilisation in critically ill patients can prevent muscle weakening and lessen the chances of developing severe muscle loss.

Gastroprotection                                                                          

Corticosteroids raise the likelihood of experiencing gastrointestinal bleeding and ulcers, especially when combined with nonsteroidal anti-inflammatory drugs (NSAIDs). Patients at a high risk of gastrointestinal issues can use proton pump inhibitors (PPIs) or H2 blockers for prevention.

Summary

Corticosteroids are frequently prescribed anti-inflammatory drugs in the management of acute respiratory failure, especially when inflammation is a significant factor in the root cause. During instances such as acute respiratory distress syndrome (ARDS), exacerbations of chronic obstructive pulmonary disease (COPD), and severe pneumonia, corticosteroids aid in diminishing lung inflammation, reducing immune response, and enhancing oxygen levels. By inhibiting inflammation pathways, they can lessen fluid buildup in the lungs and enhance gas exchange, aiding in the treatment of respiratory failure. Nevertheless, cautious management is required when using them as they can lead to potential side effects like heightened infection vulnerability and fluctuations in blood sugar levels. The use of corticosteroids in treating acute respiratory failure is dependent on the patient's condition, ensuring that the benefits outweigh the risks.