Pathophysiology of Respiratory Insufficiency

*Mohammed Mohammednoor*

#### **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.

**Keywords:** respiratory failure, respiratory insufficiency, pathophysiology, hypoxemia, hypercapnia

#### **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.

### **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



**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.*

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 (pressurevolume 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**.


#### **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:


```
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).

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.**

PACO2 = alveolar Pressure of CO2, which is almost equal to PaCO2.

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

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.

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 O2, 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 poorlyventilated 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]:


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


**Table 3.** *Mechanism of HPV.*

> 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:


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:


#### 4.Hypoventilation [4]

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]:

$$P aCO2 = K \frac{V'CO2}{VT \, X \, RR \, \left(1 - \frac{VD}{VT}\right)} \tag{1}$$

PaCO2 = arterial partial pressure of CO2. V0 CO2 = CO2 production in the body. K = Factor (0.863) is constant. VT = tidal volume. RR = respiratory rate. VD = Dead space Ventilation. Note:


Thus, the reasons for the increase in PaCO2 could be due to the increased production of CO2 by the body (V<sup>0</sup> 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

	- i. Nerve supplying respiratory muscles: Guillain–Barre syndrome
	- ii. Neuromuscular junction: Myasthenia gravis, Lambert–Eaton syndrome
	- iii. Respiratory muscles: Myopathy
	- iv. Defects in chest wall: Kyphoscoliosis, thoracoplasty, fibrothorax.

Characteristics of hypoventilation:


#### *4.1.1 Essential measurements for hypoxemia*

Arterial oxygen partial pressure: PaO2 indicates dissolved oxygen, not hemoglobinbound 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

$$\mathbf{^1CaO\_2} = (\mathbf{^1Hgb} \times \mathbf{1.34} \times \mathbf{SaO\_2}) + (\mathbf{0.0031} \times \mathbf{PaO\_2}).\tag{2}$$

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:


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<sup>0</sup> CO2) is around 200 mL.min�<sup>1</sup> 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:

	- 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:


#### **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


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


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


Symptoms and signs of hypoxemia:


Symptoms and signs of hypercapnia:


### **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:


Limitation:


Pulse oximetry is not affected by the following:


#### **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.

### **Author details**

Mohammed Mohammednoor Internal Medicine Trainee, University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom

\*Address all correspondence to: mohammed.mohammednoor@nhs.net

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

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[3] Roussos C, Koutsoukou A. Respiratory failure. European Respiratory Journal. 2003;**22** (Supplement 47):1-4

[4] Sarkar M, Niranjan N, Banyal PK. Mechanisms of hypoxemia. Lung India. 2017;**34**(1):47-60. DOI: 10.4103/ 0970-2113.197116, Erratum in: Lung India. 2017;34(2):220

[5] Michiels C. Physiological and pathological responses to hypoxia. The American Journal of Pathology. 2004; **164**(6):1875-1882

[6] UK RC. Advanced Life Support. S.l.: Resuscitation Council UK; 2021

## Section 2
