Pathophysiology of Respiratory Insufficiency

Abstract

This chapter will discuss the pathophysiology of the two types of respiratory failure type 1 and type 2, also known as hypoxic type and hypercapnic type respectively, which will help in understanding how respiratory diseases emerge. The next few pages will go through anatomy, physiology, and mechanisms of developing hypoxia and hypercapnia. This will be the fundamental of respiratory diseases. Diseases that can cause any type of respiratory failure will be mentioned without going into detail as it has a separate chapter. Hypoxia can be caused by V/Q mismatch, right-to-left shunt, and diffusion restriction. Hypoventilation can result in both hypoxic and/or hypercapnic types.

1. Introduction

This chapter will shed light on the pathophysiology of respiratory failure or the new term respiratory insufficiency to understand how respiratory diseases emerge, their complications, and management. This chapter will include the anatomy and physiology of the lungs, the pathophysiology of respiratory insufficiency, and the interpretation of ABG.

2. Anatomy of the respiratory system

2.1 General

The respiratory tract can be categorized into upper and lower or conduction and gas exchange parts (Figure 1).

1. Upper vs. Lower

   The upper respiratory tract includes the nasal cavity, paranasal sinuses, pharynx, and larynx above the vocal cord.

   The lower respiratory tract includes the larynx below vocal cords, trachea, bronchi, and lungs (bronchioles and alveoli) [1].

2. Conduction vs. Ventilation (Gas exchange)

   Conduction includes all parts from the nose to the terminal bronchioles.

   Gas exchange includes respiratory bronchioles and alveoli.

Figure 1.

This figure illustrates the difference between a; Normal lung function, B: Obstructive lung diseases, C: Restrictive lung diseases. Note the change of width of different lung function parameters.

2.2 Blood supply

Lungs receive arterial blood supply from both bronchial arteries branches of the thoracic aorta (oxygenated blood) and pulmonary artery originating from the right ventricle of the heart (deoxygenated blood for gas exchange). Venous drainage via bronchial veins (deoxygenated blood) which drain into the azygos vein (right) and left superior costal vein or hemiazygos vein (left) and pulmonary veins (oxygenated blood) which drain into the left atrium [1].

2.3 Nerve supply

Respiratory system is supplied primarily by sympathetic and parasympathetic fibers originated from pulmonary plexuses which lie anterior and posterior to the lungs roots, it provide supply to the smooth muscles of the bronchial tree, the vessels and the mucus membranes [1].

2.4 Lymphatic drainage

Bronchopulmonary lymph nodes at the bifurcation of the large bronchi drain lungs and visceral pleural lymphatic that then passes to hilar tracheobronchial nodes, which drain into the broncho mediastinal trunk on each side [1].

3. Physiology of the respiratory system

Gas exchange between the alveolus and the blood capillary depends on the passive diffusion of PO₂ in the alveolus (around 100 mmHg), and the blood entering the capillary (around 40 mm). This difference results in the diffusion of O₂ from the alveolus to the capillaries. The barrier to this process includes a cytoplasmic extension of type 1 cells, the basement membrane, and the capillary endothelial layer. CO₂ diffuses more readily than O₂ because of its high plasma solubility [2].

Another important part of lung physiology is compliance which simply means the opposite of stiffness. During inspiration, contraction of the diaphragm creates negative pressure around the lungs allowing the lungs to expand in addition to the positive pressure exerted on the lungs from the airways. Thus, the difference between the positive pressure (from airways) exerted on alveoli, and negative pressure in the pleural space is called transpulmonary pressure. So, the compliance relationship (pressure-volume relationship) between transpulmonary pressure and the volume inside the lungs can be represented by a curve that flattens at high distending pressure when the lungs reach their upper limit of expansion. That means the elastic tissue of the lungs at this point cannot be stretched further, and no additional volume of air can be added [2].

So, diseases affecting the alveoli may disrupt compliance making the lung either stiffer (more resistant to expansion) or less stiff (easily expandable). For stiff lungs (less compliance), the curve is shifted to the right, so lower volume is achieved for any transpulmonary pressure. So, patients with more compliant lungs shift the curve to the left, and higher volume can be achieved with low pressure [2]. as shown in Figure 1, changes in lung volumes in obstructive vs. restrictive vs. normal lung [2].

Airway resistance is inversely proportional to lung volumes which means during inspiration, airway resistance decreases, especially in small bronchioles, to enhance expansion. Conversely, airway resistance increases during forceful expiration due to flow-limiting segments [2].

Given the compliance, the lung can have different volumes and capacities as shown in Table 1 and Figure 1.

Volume/capacity	Definition	Normal values
Tidal volume (TV)	amount of air passing into and out of the lungs during breathing.	300–500 ml; (6–8 ml/kg)
Inspiratory reserve volume (IRV)	the extra volume of air that can be inhaled into the lungs during maximal inspiration, i.e., over and above normal TV	1900–3300 ml
Expiratory reserve volume (ERV)	the volume of air that can be expelled from the lungs during maximal expiration	700–1200 ml
Residual volume (RV)	the volume of air remaining in the lungs after forced expiration.	approximately 1200 ml (20–25 ml/kg)
Inspiratory capacity (IC)	amount of air that can be inspired with maximum effort; IC = TV + IRV	2200–3800 ml
Vital capacity (VC)	the maximum amount of air a person can expel from the lungs after a maximum inhalation.; VC = IC + ERV	approximately 4800 ml
Functional Residual Capacity (FRC)	Amount of the air remaining in the lung after normal expiration; FRC = RV + ERV	1800–2200 ml
Total lung capacity (TLC)	The maximum amount of air the lungs can accommodate; TLC = VC + RV	4–6 L

Table 1.

Definition of lung volumes and normal ranges.

In normal adults, only 70% of tidal volume (350 ml) is available to exchange as 30% remains in what is called anatomical dead space (150 ml) (which extends from nose to terminal bronchioles).

4. Pathophysiology of hypoxemia and hypercapnia

4.1 Pathophysiology of hypoxemia

Hypoxemia can be defined as PaO₂ < 10.6 kPa. Also known as lung failure.

Alveolar – Arterial Oxygen Gradient:

It’s the difference between alveolar oxygen level (A) and arterial oxygen level (a).

A-a: PAO₂ – PaO₂, it is simply reflecting the integrity of the alveolocapillary membrane and the effectiveness of gas exchange:

Hypoxemia with a normal A-a gradient indicates hypoventilation, whereas a High A-a gradient indicates V/Q mismatch, diffusion restriction, and shunt. See Table 2, how to calculate alveolar oxygen pressure.

PAO2 = FiO2× (Pb − PH2O) − (PACO2/R); PAO2 = mean alveolar oxygen pressure.; FiO2 = fractional concentration of inspired Oxygen. Which is 021 in room air.; Pb = barometric pressure (760 mmHg at sea level).; PH2O = water vapor pressure (47 mmHg at 37 C).; PACO2 = alveolar Pressure of CO2, which is almost equal to PaCO2.; R = respiratory quotient and is approximately 0.8 at steady state on the standard diet.; From this, normal PAO2 = 0.21× (760–47) − (40/0.8) = 100 mmHg.

Table 2.

PAO₂ is not measured unlike PaO₂, but it is calculated using the following equation.

A-a difference is <10 mmHg in young people, but it increases with age due to an increase in V/Q mismatch. It is estimated that after 70 years of age, PaO₂ drops by 0.43 mmHg every year. A high gradient indicates high FiO₂, which increases both alveolar and arterial oxygenation, but arterial O₂ pressure does not increase in the same proportion to the alveolar O₂ pressure due to mixing with deoxygenated blood from Bronchial veins and mediastinal veins.

Also referred to as Type 1 respiratory failure, it can be divided into four categories

1. V/Q mismatch.

   It is the commonest mechanism for hypoxemia, normal V/Q level is 0.8. it varies across the lung where apexes are well-ventilated and poorly perfused, which means a higher V/Q ratio. And bases are well perfused than ventilated, giving low V/Q. This explains why the apical region has higher O_2, and low CO₂ and bases have low O₂ and high CO₂ content [3].

   Parts of the lungs where there is a low Ventilation-perfusion ratio return more deoxygenated blood to the systemic circulation. i.e., fluid-filled alveoli or airway disease impairs the ventilation of alveoli. e.g., pneumonia, or the broad term ARDS (acute respiratory distress syndrome), where there is an increase in permeability of pulmonary capillaries leading to increase extravasation of fluids to the surrounding tissue and alveoli [4].

   The normal physiological response of pulmonary vasculature to poorly-ventilated regions is constriction and diversion of blood to well-ventilated areas (this creates shunting), but that can fail to compensate in extreme situations and lead to hypoxia. This physiological response is called Hypoxic pulmonary vasoconstriction (HPV).

   HPV is a protective mechanism to maintain a normal ventilation/perfusion ratio. But it has a negative consequence in chronic cases as it can lead to chronic pulmonary hypertension. As shown in Table 3, the mechanism of development of HPV.

   Characteristics of high V/Q mismatch [4]:

   • Hypoxemia is easily treated by increasing FiO₂. Hence supplemental oxygen therapy.

   • Widened A-a Gradient can indicate a high V/Q mismatch.

   • Examples of common diseases that can result in hypoxemia due to V/Q mismatch are asthma, COPD, bronchiectasis, cystic fibrosis, interstitial lung disease (ILD), pneumonia, and pulmonary hypertension. Note most of these diseases can progress to type 2 respiratory failure.

2. Right-to-left shunt [4].

   Right-to-left shunt means blood from the right side of the heart (deoxygenated) mixes with blood in the left side circulations (oxygenated). Normally there is a 2% fraction due to anastomosis between bronchial veins carrying deoxygenated blood and pulmonary veins carrying oxygenated blood.

   Shunt is considered an extreme form of V/Q mismatch where there is no ventilation. It has a poor response to oxygen therapy, so the failure to increase PaO₂ is due to the failure of delivering O₂ (PAO₂) to unventilated parts of the lung. It can progress to hypercapnia when the shunt fraction is>50%. Lack of hypercapnia is due to stimulation of the respiratory center by chemoreceptors as a result of an increase in PaCO₂.

   Characteristics of pulmonary shunt:

   • P (A-a) O₂ is elevated

   • Poor response to oxygen therapy

   • PCO₂ is normal until the late stages

   • Examples of common diseases associated with a shunt are pneumonia, ARDS, alveolar collapse, and pulmonary arteriovenous communications.

3. Diffusion restriction

   It means diffusion of O₂ across the alveolocapillary membrane is reduced due to a decrease in alveolar surface area as a result of inflammation, fibrosis, low alveolar oxygen, and short capillary transit time.

   As both O₂ and CO₂ diffuse through the membrane during gas exchange, low permeability should result in both hypoxemia and hypercapnia, but that is not the case since CO₂ is 20 times more soluble than O₂, hence less likely affected by diffusion restriction [3].

   Normal gas exchange time is 0.25 sec, whereas capillary transit time is 0.75 sec. So, diffusion restriction can result in the development or worsening of hypoxemia during exercise. This can be explained as a shortening of capillary transit time during exercise due to the rise of CO. Additionally, venous O₂ level drops due to increased oxygen consumption by tissues. In a normal person, that usually does not happen as compensatory mechanisms come into action, such as recruitment of the capillaries, distention of capillaries, and increase in PAO₂. Thus, patients with pulmonary fibrosis are unable to recruit more capillaries which results in exercise-induced hypoxemia [3].

   Characteristics of diffusion restriction:

   • Good response to oxygen therapy

   • A-a gradient is elevated

   • PaCO₂ is normal

   • Examples of common causes of hypoxemia due to diffusion limitations are emphysema and ILD.

4. Hypoventilation [4]

The inhibition of the oxygen-sensitive potassium channel initiates the process of HPV. Hypoxia inhibits the voltage-gated K+ channels present in the pulmonary artery leading to the accumulation of intracellular K+ and depolarization of the cells. Depolarization opens the voltage-gated L-Type Ca2+ channels resulting in Ca2+ influx and subsequently results in vasoconstriction.

Table 3.

Mechanism of HPV.

Ventilation contributes to oxygenation and CO₂ washout; thus, the hallmark of hypoventilation is a rise in PaCO₂ and the development of hypercapnia, i.e., type 2 respiratory failure. But initially, hypoventilation results in low PAO₂ and eventually hypoxemia (low PaO₂), i.e., type 1 respiratory failure. As mentioned earlier, hypoventilation is associated with normal A-a gradient but not exclusively, as prolonged hypoventilation can cause atelectasis which leads to the widening of the A-a gradient [4].

Normal pulse oximetry indicates adequate ventilation (normal PaCO₂) in the patient’s breathing room air, but it is difficult to interpret in a patient on supplemental oxygen, as hypoventilation may persist. In other words, hypoventilation-induced hypoxemia is responsive to supplemental oxygen but does not mean correction of PaCO₂ as well.

COPD, asthma, and ILD patients initially develop type 1 respiratory insufficiency, but after a period, it can progress to type 2 respiratory failure due to the retention of PaCO₂.

Alveolar gas equation [4]:

$$\mathit{\text{PaCO}}2=K\frac{V^{\prime }\mathit{CO}2}{\mathit{VT}X\mathit{RR}\left(1-\frac{\mathit{VD}}{\mathit{VT}}\right)}$$E1

PaCO₂ = arterial partial pressure of CO₂.

V′CO₂ = CO₂ production in the body.

K = Factor (0.863) is constant.

V_T = tidal volume.

RR = respiratory rate.

VD = Dead space Ventilation.

Note:

• VT X RR = minute ventilation (V’E).

• Alveolar Ventilation (V’A) = V’E − V’D.

Thus, the reasons for the increase in PaCO₂ could be due to the increased production of CO₂ by the body (V′CO₂). Without a compensatory rise in alveolar ventilation (V’A), rise in dead space ventilation VD, and drop in RR and/or VT.

A-a oxygen gradient can help differentiate whether the high PaCO₂ is due to the reduction in VT or an increase in VD. The gradient will be normal on VT reduction and high in increased VD. If compensatory functions are normal, increased body production of CO₂ will not increase PaCO₂.

Conditions that may raise body production of CO₂ are burns, sepsis, exercise, hyperthermia, intake of carbohydrate-rich diet, tetanus, seizures, and tremor.

Conditions that may give rise to VD/VT ratio are PE, COPD, ARDS, and Bronchiectasis.

Mechanism of Hypoventilation:

Hypoventilation arises from respiratory dysfunction at various levels; hence it can be divided into central and peripheral causes:

1. Central: - impaired central drive

   1. Brain stem: hemorrhage or infarction

   2. Drugs overdose: opioids, benzodiazepines, alcohol

   3. Primary alveolar hypoventilation

   4. Spinal cord level: amyotrophic lateral sclerosis, cervical spinal cord injury.

2. Peripheral:

   1. Nerve supplying respiratory muscles: Guillain–Barre syndrome

   2. Neuromuscular junction: Myasthenia gravis, Lambert–Eaton syndrome

   3. Respiratory muscles: Myopathy

   4. Defects in chest wall: Kyphoscoliosis, thoracoplasty, fibrothorax.

Characteristics of hypoventilation:

• Hypoxemia has a good response to supplemental oxygen.

• A-a gradient is usually normal

• PaCO₂ will eventually rise if hypoventilation persists.

4.1.1 Essential measurements for hypoxemia

Arterial oxygen partial pressure: PaO₂ indicates dissolved oxygen, not hemoglobin-bound oxygen. It is measured by an arterial gas analyzer.

In mixed venous blood, PaO₂ is 40 mmHg, 75% saturation. On the other hand, in arterial blood, it is 97% saturation. It never gets to 100% saturation as the presence of anatomical dead space.

Arterial oxygen content (CaO₂) is the summation of hemoglobin-bound oxygen and the dissolved oxygen in the arterial blood. The following equation calculates it

$${\mathrm{CaO}}_2=\left(\mathrm{Hgb}\times 1.34\times {\mathrm{SaO}}_2\right)+\left(0.0031\times {\mathrm{PaO}}_2\right).$$E2

From the above equation, it can be noted that dissolved PaO₂ has minimal contribution to the arterial oxygen content, which explains normal PaO₂ in anemia.

Arterial oxygen saturation (SaO₂): means the percentage of hemoglobin saturated with oxygen. It can be measured by both pulse oximetry and gas analyzer.

PaO₂/FiO₂ ratio: it is the ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen. The normal ratio is between 300 and 500 mmHg. It plays a major role in prognostication in ARDS patients. ARDS is categorized into mild (PaO₂/FiO₂ ratio 200–300 mmHg, moderate 100–200 mmHg, and severe PaO₂/FiO₂ < 100 mmHg). As mentioned earlier, it can be used to estimate shunt fraction. A PaO₂/FiO₂ ratio of <200 indicates a shunt fraction is more than 20%.

4.2 Pathophysiology of hypercapnia

On the other hand, hypercapnia, defined as an increase in PaCO₂ > 6 kPa, also can be referred to as pump failure. And the mechanism of development of hypercapnia can be divided into four categories:

1. Decreased minute ventilation (i.e., hypoventilation) which can be due to central or peripheral causes (see above).

2. Increased dead space

3. Increase CO₂ production

4. Multifactorial.

Decreased minute ventilation: It has been discussed earlier in the pathophysiology of hypoxemia [3].

4.2.1 Increased dead space

Dead space is defined as the area of the lung that is unable to provide gas exchange, whether anatomically or physiologically incapable.

There are two types of dead space anatomical (from nose to bronchi), and physiologic dead space which is equal to the summation of anatomical dead space and alveolar dead space (volume of air in the alveolar that does not participate in gas exchange).

Anatomical dead space represents 30% of tidal volume which is roughly equal to 150 ml.

Tachypnea which could contribute to washing out CO₂ from blood can also participate in hypercapnia by increasing dead space to tidal volume ratio VD/Vt. High alveolar ventilation (VA) and associated with V/Q mismatch are considered the main reasons for hypercapnia in COPD patients [3].

4.2.2 Increased CO₂ production

As we know, CO₂ is a by-product of oxidative metabolism. Thus, any increase in metabolic status can lead to an increase in CO₂, such as fever/sepsis, exercise, total parenteral nutrition, and thyrotoxicosis. In the normal respiratory system, this rise in CO₂ production is well compensated by the rise in minute ventilation, but that may become pathological if there is a failure of the compensatory mechanism.

Normal young adult production of CO₂ (V′CO₂) is around 200 mL.min⁻¹ or 110 ml in males and 96 ml in females. It increases by 14% for each degree Celsius rise in temperature [5].

5. Physiological response to hypoxia

5.1 Physiological response to hypoxia

The body’s response to low levels of oxygen in the blood can be divided into two [5]:

1. Systemic response:

   • Several chemosensory systems act in sync during reduced availability of O₂ by modulating ventilation, perfusion, and blood circulation to optimize oxygen supply mainly to vital organs.

2. Vascular smooth muscles response:

   • The instant response of vascular smooth muscle to low oxygen is the dilation of peripheral vessels and constriction of pulmonary vessels to shunt blood away from poorly oxygenated lung tissue.

3. Carotid and neuroepithelial bodies:

   • Airway neuroepithelial bodies sense changes in inspired oxygen. However, carotid bodies work by monitoring arterial oxygen levels. Both send feedback signals to the brain to modulate ventilation and various mechanism to maintain oxygen supply.

   • Carotid bodies are highly vascularized and found at the bifurcation of the common carotid arteries on both sides.

   • Neuroepithelial bodies are situated at the airway bifurcation.

5.2 Regulation of cellular metabolism

Cell thrives by maintaining a high level of ATP, which plays a crucial role in different parts of metabolic pathways. Cell death occurs when ATP production fails to meet the energy maintenance demands of ionic and osmotic equilibrium. ATP production depends on oxygen supply. Thus, hypoxia induces cell death [5].

Mitochondria represent the main target of hypoxia, as it is responsible for generating ATP, response to hypoxia is by reallocation of cellular energy between essential and non-essential AT demands process.

Regulation of Gene Expression:

Response to hypoxia is by:

1. Increase ventilation

2. Increase cardiac output

3. Switch from an aerobic to an anaerobic mechanism

4. Improve vascularization

5. Increase oxygen carrying capacity of the blood

These responses take place early in hypoxia and are regulated by modifying gene expression.

1. Pathological response of hypoxia [5]:

2. Cerebral ischemia: The brain has high oxygen consumption, around 20% of the whole-body consumption. Under normal physiological conditions, this demand is met by an increase in cerebral blood flow. Ischemia develops when this process can no longer maintain an adequate oxygen supply to the brain. The longer the hypoxia, the more brain areas are affected.

   It is found that the most vulnerable areas are the brainstem, hippocampus, and cerebral cortex.

3. Myocardial ischemia: A brief period of ischemia (<20 minutes) is reversible if reperfusion is obtained.

4. Tumor angiogenesis: Most tumors during the growth period develop in the area of low oxygen supply that may trigger the formation of new vessels to maintain the growth, which explains how some anti-cancer treatments work.

Symptoms and signs of hypoxemia:

1. Headache

2. Dyspnea

3. Tachycardia

4. Bluish discoloration of the peripheries.

5. Cough

6. Wheeze

7. Confusion

Symptoms and signs of hypercapnia:

1. Shallow breath

2. Altered consciousness

3. Headache (cerebral vasodilation)

4. Pounding pulse and Tachycardia

5. Flushed skin

6. Profuse sweating

7. Irritability

8. Fever

9. Fatigue or sleepiness

10. Tremor and seizures

6. Pulse oximetry

It is a non-invasive method to detect the oxygen content of the blood by placing a probe on the finger or earlobe [6].

Uses:

1. detection of/screening for hypoxemia

2. targeting oxygen therapy

3. routine monitoring during anesthesia

4. diagnostic (e.g., sleep apnea)

Limitation:

1. Presence of carboxyhemoglobin, methemoglobin, fetal hemoglobin, and sickling red cells

2. Surgical and imaging dyes: methylene blue, indocyanine green, and indigo carmine may cause falsely low saturation levels.

3. Nail polish/varnis

4. High ambient lights level (fluorescents, xenon lamp)

5. Motion artifact

6. Reduced pulse volume: hypotension, low cardiac output, vasoconstrictions, and hypothermia.

Pulse oximetry is not affected by the following:

1. Anemia

2. Jaundice

3. Skin pigmentation.

7. Conclusion

In conclusion, Respiratory insufficiency can be divided into two main categories: hypoxic type and hypercapnic type, both have different pathophysiological mechanisms to develop. Note most of type 1 respiratory failure (hypoxic) diseases can progress to type 2 respiratory (hypercapnic) if not treated urgently.

Hypoxia could be a result of V/Q mismatch, right-to-left shunt, or diffusion restriction. However, decreased minute ventilation increased dead space, and increased CO₂ production lead to the development of hypercapnia.

Pulse oximetry is a noninvasive way to monitor the oxygen content of blood, but it has certain limitations that need to be considered before completely relying on it.