Respiratory Failure in Adults

Etiology

Respiratory failure can occur if there is an abnormality with any component of the respiratory system. Components of the respiratory system include the upper and lower respiratory tracts, the central and peripheral nervous systems, in addition to the chest wall and muscles of respiration.[1] The pathophysiology section of this article will review specific etiologies of respiratory failure.

Epidemiology

Respiratory failure (RF) is a syndrome caused by a multitude of pathological states; therefore, the epidemiology of this disease process is difficult to ascertain. In 2017, in the United States of America, however, the incidence of respiratory failure was found to be 1,275 cases per 100,000 adults. The case definition used in this study included all diagnosis codes that included respiratory failure as a component.[2] The epidemiology of respiratory failure is dependent mainly on the cause leading to the failure. Below, we list some common causes of respiratory failure and the relevant trends: 

• Acute myocardial infarction-related (AMI-RF): Between the years 2000 and 2014, 439,436 admissions due to AMI-RF were noted in 57% and required mechanical ventilation in 43% of total cases.[3]
• Acute respiratory failure due to acute respiratory distress syndrome (ARDS) ranges in incidence from 10-80/100,000/y based on where it is recorded worldwide. This is partly due to different practices and thresholds for intubation in these cases and the use of different definitions of ARDs. According to one report, it is estimated that 10% of all patients admitted to ICU and 23% of mechanically ventilated patients meet ARDS criteria.[4]
• Acute respiratory failure related to Coronavirus (COVID-19): It is estimated early in the COVID-19 pandemic that up to 79% of hospitalized patients developed respiratory failure requiring invasive mechanical ventilation.[5] 
• Acute exacerbation of COPD (AECOPD) is the third most common etiology in patients hospitalized because of acute respiratory failure.[6]

Pathophysiology

Type 1 respiratory failure:

The distinguishing characteristic of Type 1 respiratory failure is a partial pressure of oxygen (PaO2) < 60 mmHg with a normal or decreased partial pressure of carbon dioxide (PaCO2). Depending on the cause of hypoxemia, the alveolar-arterial (A-a) gradient may be normal or increased. Formulas of the A-a gradient and alveolar gas equation are provided below, as these concepts are helpful in understanding the pathophysiology of respiratory failure.

     A-a gradient:

• A-a gradient = PAO2 - PaO2, where
  • PAO2 = Alveolar partial pressure of oxygen
  • PaO2 = Arterial partial pressure of oxygen

     Alveolar gas equation:[7]

• PAO2 = FiO2 (PB - Pwater) - PaCO2/0.8, or PIo2= (PB - 47) × FIo2,
  • PAO2 = Alveolar partial pressure of oxygen
  • FiO2 = Fraction of inspired oxygen
  • PB = Barometric (Atmospheric) pressure
  • Pwater = Vapor pressure of water at body temperature (37°C)=47 mmHg
  • PaCO2 = Partial pressure of arterial carbon dioxide

 Etiologies of Type 1 respiratory failure with normal A-a gradients include:

• Alveolar hypoventilation: Alveolar hypoventilation increases the arterial partial pressure of carbon dioxide (PaCO2). The alveolar gas equation demonstrates that an increase in PaCO2 causes a decrease in the alveolar partial pressure of oxygen (PAO2). In this situation, the A-a gradient is normal, as the PAO2 and PaO2 decrease in equal magnitudes. When severe, alveolar hypoventilation may progress to Type 2 respiratory failure.[8] (as discussed later in this section under Type 2 respiratory failure). 

• Low atmospheric pressure/fraction of inspired oxygen: The alveolar gas equation demonstrates that the alveolar partial pressure of oxygen (PAO2) decreases with low atmospheric pressures (Patm) and with low levels of inspired oxygen (FiO2). In either situation, the A-a gradient remains normal, and the PaCO2 is decreased, given the response to hypoxia is hyperventilation. Clinically, this cause of respiratory failure occurs at high altitudes.[9]

 Etiologies of Type 1 respiratory failure with increased A-a gradients include:

• Diffusion defect: Gas exchange between the environment and the body occurs at the alveolar-capillary interface. Structural changes to the alveolar component of the alveolar-capillary interface, such as decreased surface area or increased thickness, may result in diffusion defects across the membrane. Additionally, reducing pulmonary capillary transit time through the alveolar-capillary interface may result in diffusion defects across the membrane. In either situation, hypercapnia does not occur, as carbon dioxide diffuses more readily across the alveolar-capillary membrane than oxygen.[10] Etiologies of diffusion defects include:
  • Emphysema
  • Interstitial lung disease

• Ventilation/perfusion (V/Q) mismatch: The alveolar gas composition depends on the balance of alveolar ventilation and pulmonary capillary blood flow that occurs at the alveolar-capillary interface. When perfectly matched, the V/Q ratio is equal to one. When ventilation is excessive to perfusion, the V/Q ratio is greater than one; Dead space ventilation occurs when the V/Q ratio reaches infinity. When perfusion is excessive to ventilation, the V/Q ratio is less than one; Shunt occurs when the V/Q ratio reaches zero. In healthy subjects, however, the V/Q ratio is approximately 0.8, as the balance between ventilation and perfusion differs from the apex to the base of the lungs. V/Q mismatch is the most common cause of Type 1 respiratory failure.[11] Etiologies of V/Q mismatch include:
  • Acute respiratory distress syndrome
  • Chronic obstructive pulmonary disease
  • Congestive heart failure
  • Pulmonary embolism

• Right-to-left shunt: As discussed above, shunt occurs when the V/Q ratio reaches zero. The absence of gas exchange at the alveolar-capillary interface represents a true shunt and is analogous to intracardiac right-to-left shunting seen in atrial septal defect and patent foramen ovale. Unlike V/Q mismatch, true shunt does not improve with supplemental oxygen therapy.[12] Etiologies of pulmonary right-to-left shunts include:

  • Arteriovenous malformation
  • Complete atelectasis
  • Severe pneumonia
  • Severe pulmonary edema

Type 2 Respiratory Failure

Hypercapnic respiratory failure is defined as an increase in arterial carbon dioxide (CO2) (PaCO)> 45 mmHg with a pH < 7.35 due to respiratory pump failure and/or increased CO₂ production. In general, according to the modified alveolar ventilation equation, the PaCO2 level is proportionally related to the rate of CO2 production (VCO2) and inversely associated with the rate of CO2 elimination (i.e., alveolar ventilation) (PaCO2 =VCO2 /VA). The relationship between minute ventilation and CO2 production in response to exercise can be affected by age and pregnancy.[13] 

Alveolar ventilation (VA) is the product of minute ventilation (VE) and the ratio of dead space (VD) to tidal volume (Vt) (VA = VE x [1 - VD/Vt]). While decreased VA is the most common reason for the respiratory failure of hypercapnia, increased CO2 production is a very rare reason. Depending on the cause of respiratory failure, the partial pressure of oxygen (PaO2) may be normal or decreased. The two main paradigms responsible for hypercapnia respiratory failure are either manifested by "won't breathe" due to a central drive issue or "can't breathe" as a result of a peripheral neuromuscular defect, resistive loading (narrow airway) or restrictive defect that lead to hypoventilation and hypercapnia. 

Respiratory pump failure: The respiratory pump is comprised of the chest wall, the pulmonary parenchyma, the muscles of respiration, as well as the central and peripheral nervous systems. The inability to ventilate can occur if any of the components mentioned above of the respiratory pump fails.

• Decreased central dive: Sedatives (i.e., alcohol, benzodiazepines, and opiates) and diseases of the central nervous system (i.e., encephalitis, stroke, tumor, and SCI) may impair the respiratory drive, resulting in hypoventilation.[14]
• Altered neural and neuromuscular transmission: Amyotrophic lateral sclerosis, botulism, Guillain-Barre syndrome, myasthenia graves, organophosphate poisoning, poliomyelitis, spinal cord injury (SCI), tetanus, and transverse myelitis may impair the function of the respiratory pump, resulting in hypoventilation.[14]
• Chest wall and pleural disorders: Flail chest, kyphoscoliosis, hyperinflation, large pleural effusions, obesity, and thoracoplasty may impair the function of the respiratory pump, resulting in hypoventilation.
• Dead space ventilation: Conditions that increase the V/Q ratio, such as acute respiratory distress syndrome, bronchitis, bronchiectasis, emphysema, and pulmonary embolism, can result in hypoventilation. Hypoventilation typically occurs once dead space ventilation exceeds 50% of total ventilation.
• Muscle abnormalities: Diaphragmatic paralysis, diffuse atrophy, muscular dystrophy, and ruptured diaphragm may impair the function of the respiratory pump, resulting in hypoventilation. 

Increased dead space: Dead space (VD) refers to areas of the lung that are not anatomically or physiologically able to exchange gas. Tachypnea can contribute to high CO2 by increasing the dead space to tidal volume ratio (VD/Vt). High alveolar VA and the associated ventilation-perfusion mismatch are considered one of the main mechanisms for developing hypercapnia in individuals with COPD.[15]

Increased CO production: CO2 is a by-product of oxidative metabolism, and high CO2 production may occur due to fever, exercise, hyperalimentation, sepsis, and thyrotoxicosis. High CO₂ production becomes pathologic if the compensatory increase in minute ventilation mechanism fails.[16] 

Alveolar hypoventilation: Alveolar hypoventilation may progress to Type 2 respiratory failure.[8] (as discussed later in this section under Type 2 respiratory failure). 

History and Physical

Respiratory failure is a syndrome with a myriad of etiologies; therefore, a thorough history and physical examination are required to narrow the differential diagnosis.

History

Patients typically present with respiratory symptoms (i.e., dyspnea, cough, hemoptysis, sputum production, and wheezing); however, symptoms from other organ systems (ie, chest pain, decreased appetite, heartburn, fever, and significant weight loss) are important. Loss of smell and/or exposure to sick people or unprotect contact with individuals with coronavirus infection (COVID-19) is essential in suspecting COVID-19 illness and associated respiratory failure, particularly in high-risk patients (older patients, men, and morbidly obese).[17] For a specific population, the presence of immunocompromised conditions or taking immunosuppressants is also essential in risk-stratifying patients at risk for respiratory failure early on.

For patients already diagnosed with airway disease, it is important to assess inhaler compliance and technique, recent steroid use, as well as exposure to environmental triggers. For patients with hypertension and chronic cough, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be investigated.

Social history is also crucial when considering respiratory failure. Alcohol use and sexually transmitted diseases may lead to an immunocompromised state, making patients more susceptible to certain infections, while a sedentary lifestyle may increase the risk of pulmonary embolism. Habits such as having birds and hobbies such as diving and flying may have implications when considering etiologies of respiratory failure. Most importantly, a patient's tobacco smoking history should be investigated, including exposure to second-hand smoke, marijuana smoking, smoking e-cigarettes, and vaping.[18]

Finally, an occupational history may be helpful when considering work-related lung disease (i.e., hypersensitivity pneumonitis and pneumoconiosis), while a family history may be beneficial when considering atopic, genetic (ie, alpha-1-antitrypsin deficiency and cystic fibrosis), and infectious diseases (i.e., tuberculosis).[19]

Physical Examination

Signs of respiratory failure may be present throughout the body. Physical examination findings by region appear below:

• General inspection: Accessory muscle use, altered mental status, cachectic, conversational dyspnea, diaphoresis, fever, respiratory distress (i.e., at rest or with exertion), obesity, and purse-lipped breathing
• Head: Cushingoid appearance, central cyanosis, Horner's syndrome, and pale conjunctiva
• Neck: Jugular venous distention, lymphadenopathy, and tracheal deviation
• Chest/thorax: Asymmetrical chest expansion, bradypnea, bronchial breath sounds, Cheyne-Stoke breathing, crackles, decreased breath sounds, dullness to percussion, hyper-resonance to percussion, Kussmaul breathing, kyphoscoliosis, loud P2, paradoxical breathing, pectus carinatum, pectus excavatum, pleural rub, reduced chest expansion, rhonchi, stridor, tachypnea, tactile vocal fremitus, vesicular breath sounds, vocal resonance, wheezes, and whispering pectoriloquy
• Abdomen: Hepatomegaly
• Upper extremities: Asterixis, digital clubbing, peripheral cyanosis, tobacco staining, and tremor
• Lower extremities: Edema, peripheral cyanosis, and unilateral swelling.[20]

Evaluation

As discussed above, respiratory failure is a syndrome caused by a multitude of pathological states. As such, a single algorithm for evaluating respiratory failure does not exist. Appropriate diagnostic studies may include laboratory assays (i.e., complete blood count with the differential, comprehensive metabolic panel with magnesium/phosphorous, procalcitonin, troponin, and thyroid-stimulating hormone), infectious workup (i.e., blood cultures, sputum cultures, respiratory pathogen panel test, and urinary antigen test), and 12-lead electrocardiography. Evaluation of respiratory failure with arterial blood gas, capnometry, radiography, pulse oximetry, and ultrasonography are discussed below.

Arterial Blood Gas

Arterial blood gas (ABG) is the gold standard for diagnosing respiratory failure. At a minimum, the information obtained from an ABG includes pH, partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2), and serum bicarbonate (HCO3). It should be noted that the HCO3 obtained from an ABG is a calculated value and may, therefore, be inaccurate. Analysis of an ABG should instead be performed using a measured HCO3 obtained from a basic metabolic panel.

Oxygenation is assessed through the interpretation of the PaO2. Hypoxemia is defined as a PaO2 less than 60 mmHg. Ventilation is assessed through the interpretation of the PaCO2. Hypercapnia is defined as a PaCO2 greater than 45 mmHg.

Information from the ABG can also be used to differentiate acute from chronic respiratory failure by evaluating the renal response to PaCO2. In respiratory acidosis, the kidneys respond by increasing the absorption of HCO3 in the proximal convoluted tube. As this is a slow process, the magnitude of HCO3 absorption in acute respiratory acidosis is less than the magnitude of HCO3 absorption in chronic respiratory acidosis. This difference allows for the distinction between the chronicity in acute and chronic respiratory failure.[21]

Capnometry

Capnometry, the measurement of carbon dioxide in exhaled gas, may be qualitative or quantitative. Colorimetric capnometry is a qualitative measure of carbon dioxide in exhaled gas that relies on the color change of a pH-sensitive indicator. Infrared capnometry is a quantitative measure of carbon dioxide in exhaled gas that relies on measuring the partial pressure of carbon dioxide (pCO2). Quantitative capnometry provides more information than qualitative capnometry.[22]

In the non-pathological state, the partial pressure of carbon dioxide at the end of expiration, or end-tidal pCO2 (PETCO2), approximates the partial pressure of carbon dioxide in the arterial blood (PaCO2). The PaCO2 is typically 2 to 3 mmHg greater than the PETCO2. In the pathological state, where gas exchange is impaired, the difference between the PaCO2 and PETCO2 becomes greater than 3 mmHg due to increased dead space ventilation.[23]

Values obtained from quantitative capnometry can be plotted graphically and displayed as waveform capnography. Analysis of these waveforms allows for detecting pathological states (i.e., apnea, bronchospasm, hyperventilation, and hypoventilation).[24] 

Radiography

Various imaging modalities are available for the evaluation of respiratory failure. Such options include plain films, computed tomography, magnetic resonance, nuclear medicine, angiography, and ultrasonography.[25] 

Pulse Oximetry

Pulse oximetry relies on spectrophotometry, the process of identifying the composition of a substance via measurement of the absorption of specific wavelengths of light transmitted through the substance in question. The composition and structural configuration of hemoglobin are dependent upon molecular oxygen. In the tense state, oxygenated hemoglobin has a lower affinity for oxygen. In the relaxed state, deoxygenated hemoglobin has a higher affinity for oxygen. Pulse oximetry takes advantage of the conformational states of the hemoglobin molecule as deoxygenated hemoglobin absorbs light at wavelengths of 660 nm, and oxygenated hemoglobin absorbs light at wavelengths of 940 nm. Measurement of arterial oxygenation is ensured through the analysis of pulsatile blood. Proprietary algorithms allow for the conversion of light absorption to the fraction of hemoglobin saturated with oxygen, known as oxygen saturation (SpO2). This non-invasive modality is greatly useful in diagnosing and managing respiratory failure.[26]

Ultrasonography

The bedside lung ultrasound in emergency (BLUE)-protocol is the bedside gold standard for the immediate diagnosis of acute respiratory failure. The protocol allows for reproducible analysis and relies on standardized thoracic locations (BLUE points) and ten ultrasonographic signs or profiles. The BLUE protocol is performed by analyzing the ultrasonographic profiles obtained at each of the three BLUE points on each side of the body. The standardized BLUE points are known as the Upper BLUE point, the Lower BLUE point, and the postero-lateral alveolar and/or pleural syndrome (PLAPS)-point. In total, there are six BLUE points. The theory behind and the application of the BLUE protocol are beyond the scope of this article; however, the ten ultrasonographic profiles are grouped with their corresponding clinical states below:

• Normal lung surface: Bat sign, lung sliding, and A-lines
• Interstitial syndrome: Lung rockets
• Lung consolidations: Fractal and tissue-like signs
• Pleural effusions: Quad and sinusoid sign
• Pneumothorax: Stratosphere sign and the lung point. [27]

Bronchoscopy, echocardiography, nocturnal polysomnography, and pulmonary function tests may also be included in evaluating respiratory failure. Pulmonary consultation is warranted if the aforementioned diagnostic studies are required.

Treatment / Management

Treatment of respiratory failure should be directed towards the underlying cause while providing support with oxygenation and ventilation, if necessary. The treatment includes supportive measures and treatment of the underlying cause. However, the initial steps in managing patients with acute respiratory failure should start by assessing the airway, breathing, and circulation (ABC). Supportive measures depend on patent airways to maintain adequate oxygenation, ventilation, and correction of blood gas abnormalities.

Correction of Hypoxemia

The goal is to maintain adequate tissue oxygenation, generally achieved with an arterial oxygen tension (PaO2) of 60 mm Hg or arterial oxygen saturation (SaO2), about 90%.

Uncontrolled oxygen supplementation can result in oxygen toxicity and CO2 (carbon dioxide) narcosis. The inspired oxygen concentration should be adjusted at the lowest level (90-94%), which is sufficient for tissue oxygenation.

Oxygen can be delivered by several routes depending on the clinical situations in which we may use a nasal cannula, simple face mask, nonrebreathing mask, or high-flow nasal cannula.

Extracorporeal membrane oxygenation may be needed in refractory cases.[28]

Correction of Hypercapnia and Respiratory Acidosis 

This may be achieved by treating the underlying cause or providing ventilatory support.[29](B3)

Ventilatory Support

Patients with severe acute respiratory failure are usually intubated. The goals of ventilatory support in respiratory failure are to:

• Correct hypoxemia
• Correct acute respiratory acidosis
• Resting of ventilatory muscles

Common Indications for Mechanical Ventilation Include the Following

• Apnea with respiratory arrest
• Tachypnea with respiratory rate >30 breaths per minute
• Disturbed conscious level or coma
• Respiratory muscle fatigue
• Hemodynamic instability
• Failure of supplemental oxygen to increase PaO2 to 55 to 60 mmHg
• Hypercapnia with arterial pH less than 7.25[30]

The choice of invasive or noninvasive ventilatory support depends on the clinical situation, whether the condition is acute or chronic, and how severe it is.[31] It also depends on the underlying cause. Noninvasive ventilation (NIV) is preferred, particularly in cases of chronic obstructive pulmonary disease (COPD) exacerbation, cardiogenic pulmonary edema, and obesity hypoventilation syndrome.[32][33][34][33][35][36](A1)

Differential Diagnosis

The differential diagnosis for respiratory failure is broad and includes, but is not limited to, the following:

• Acute respiratory distress syndrome
• Aspiration pneumonia
• Aspiration pneumonitis
• Asthma
• Atelectasis
• Bacterial pneumonia
• Bronchitis
• Cardiogenic pulmonary edema
• Cardiogenic shock
• Central sleep apnea
• Cervical cord injury
• Cor pulmonale
• Diaphragmatic paralysis
• Distributive shock
• Drug overdose
• Emphysema
• Fat embolism
• Granulomatous lung disease
• Idiopathic pulmonary arterial hypertension
• Kyphoscoliosis
• Myxedema
• Myocardial infarction
• Neurogenic pulmonary edema
• Obesity hypoventilation syndrome
• Obstructive shock
• Obstructive sleep apnea
• Pleural effusion
• Pneumothorax
• Pulmonary fibrosis
• Restrictive lung disease
• Pneumoconiosis
• Primary muscle disorders
• Pulmonary arterial hypertension
• Pulmonary embolism
• Viral pneumonia

Prognosis

 Respiratory failure is a syndrome caused by a multitude of pathological states; therefore, the prognosis of this disease process is difficult to ascertain. In 2017, in the United States of America, however, the in-hospital respiratory failure mortality rate was 12%. The case definition used in this study included all diagnosis codes, which included respiratory failure.[2] In-hospital mortality rates for patients requiring intubation with mechanical ventilation for asthma exacerbation, acute exacerbation of chronic obstructive pulmonary disease, and pneumonia were found to be 9.8%, 38.3%, and 48.4%, respectively.[37][38][39] Lastly, the in-hospital mortality rate for acute respiratory distress syndrome was found to be 44.3%.[40]

Complications

Respiratory failure is associated with both pulmonary and extrapulmonary complications, especially in the acute setting. Pulmonary complications include bronchopleural fistula, nosocomial pneumonia, pneumothorax, pulmonary embolism, and pulmonary fibrosis, while extrapulmonary complications include acid-base disturbances, decreased cardiac output, gastrointestinal hemorrhage, hepatic failure, ileus, infection, increased intracranial pressure, malnutrition, pneumoperitoneum, renal failure, and thrombocytopenia. Clinicians should be aware of the conditions mentioned earlier and be prepared to offer prophylactic therapy or proper treatment for such complications when applicable.[41][42]