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The Mechanism of Gas Exchange and Respiratory Insufficiency

The Mechanism of Gas Exchange and Respiratory Insufficiency

When we breathe, air first circulates to the bronchi, followed by the bronchioles and terminal bronchioles, which opens up at the end to create an alveolar duct from which air sacs derive.  Each lung has over 300 million alveoli1, which gives a total surface area of 70 meters squared. This is a very expansive surface area for the facilitation of gas exchanges, namely O2 and CO2. Oxygenation occurs by simple diffusion of the alveoli to the blood. In turn, CO2 is more concentrated in the blood than the alveoli, which is why it diffuses from the capillaries and into the alveolar space.

Alveoli are covered by a very thin monolayer of epithelial cells that possess an excellent supply of blood, which allows O2 and CO2 to diffuse freely between the alveoli walls and capillaries. The red blood cells from the capillaries will be in charge of transporting oxygen to the cells by using an oxygen-binding protein molecule inside the cell called hemoglobin, which changes to oxyhemoglobin when bonded with oxygen. On the other hand, there are 3 ways humans use and expel CO2. 2

  1. Dissolved and transported in plasma water (between 5-8 %)
  2. Attached to hemoglobin, which turns it into carbaminohemoglobin (approximately 10%)
  3. Carried as bicarbonate ions, which form part of the bicarbonate buffer system.

Respiration makes use of several gas laws

  • Boyle’s law: establishes that the pressure of a gas on a closed system is inversely proportional to the volume of the recipient if temperature remains constant. A simple way to put it would be: * if gas pressure increases by X, volume decreases by X * if pressure decreases by X, volume increases by X.  3
  • Fick’s law of diffusion: states that the velocity of diffusion across a bilayer membrane is directly proportional to the concentration gradient of the substance on both sides of the same and inversely proportional to the membrane thickness. 4
  • Henry’s law: the quantity of dissolved gas in a liquid with constant temperature is proportional to the partial pressure of gas in equilibrium with liquid.5
  • Dalton’s law of partial pressures: the total pressure of a mixture of gases is the same as the sum of the pressures of each individual gas. 6
  • General gas law: affirms a relationship between volume, pressure, and temperature of a constant amount of gas. The formula consists of the product of its pressure times the volume it occupies divided by temperature.7

It should also be noted that respiration involves a series of known mechanisms, such as perfusion, diffusion, ventilation, and transportation of gases.

Definition of Respiratory Failure (RF)

Acute respiratory failure is the inability of the respiratory system to maintain its basic function, which is the exchange of O2 and CO2 between the blood and the environment.  It’s diagnosed via gasometry, which also provides CO2 levels, degree of severity, and any notable imbalance in pH.

The classification of RF refers to the quantitative level of gas

  • Type I (hypoxemic*):  ↑ (QS/QT), (PaO2) < 60mmHg8

  • Type II (hypercapnic):  ↑PaCO2 >50mmHg, PaCO2 >50
  • Type III (peri-operative RF): ↓Functional Residual Capacity (FRC)
  • Type IV (shock). 9

*‘’Although the terms hypoxia and hypoxemia are often used interchangeably, they are not synonymous. Hypoxemia is defined as a condition where arterial oxygen tension (Pao2) is below normal. Hypoxia is defined as the failure of oxygenation at the tissue level’’, according to Jacob Samuel and Cory Franklin, authors of Hypoxemia and Hypoxia10. In healthy people, the normal PaO2 reading is between 80 – 100 mmHg. 11 

To add context to what this means in terms of oxygen saturation, consider that a 90-92% oxygen saturation is equivalent to a PaO2 of 60-65 mmHg.12 It’s important to mention that a situation where hypoxemia occurs without the respiratory tract being deficient can arise. This can happen when we breathe air with a low partial pressure of oxygen, such as is the case in high altitudes. There is a direct relationship between Fi02 (the concentration of oxygen in the air of the environment) and PaO2. Typically, the air we breathe is made up of 21% oxygen, 78% nitrogen, and 1% of trace elements13. However, in high altitudes, atmospheric pressure is less than at sea level surfaces, which results in a partial pressure of oxygen that is lower than physiologically optimal. And, as a consequence, so will the PAO2 (note the capital ‘A’, which refers to ALVEOLAR partial pressure, instead of arterial partial pressure which would be lowercase ‘a’).

According to a national survey conducted by Mihaela S. Stefan MD, et al., to determine the epidemiology and prognosis of acute respiratory failure in the United States, it showed that, “over the period of 2001 to 2009, there was a steady increase in the number of hospitalizations with a discharge diagnosis of acute respiratory failure, with a decrease in inpatient mortality”. 14

Figure 1 - Shows that the incidence of acute respiratory failure between male and female has increased
Figure 1 – Causes of Acute Respiratory Failure per 100,000 Population in the United States, 2001 to 2009. Shows that the incidence of acute respiratory failure between male and female has increased from 491 (Male) (standard error [SE] = 10) cases per 100,000 in 2001 to 782(Male) (SE = 20) cases per 100,000 in 2009; from 512(Female) (standard error [SE] = 10) cases per 100,000 in 2001 to 786 (Female) (SE = 19) cases per 100,000 in 2009.[15]

Pathophysiological Mechanisms of Hypoxemia

  • Hypoventilation
  • Diffusion Alterations
  • Pulmonary shunt
  • V/Q mismatch

Hypoventilation

Hypoxemia is present in all types of respiratory insufficiency, but in this case, it’s accompanied by retention of carbon dioxide16. The production of CO2 occurs as a consequence of metabolic processes, and is measured as VCO2, or volume of carbon dioxide expelled. As we’ve mentioned, the only way to get rid of CO2 is via respiration.

Hypoventilation refers to a physiological disorder of respiration in which several pathological situations lead to alveolar hypoventilation, which is confirmed by pulse oximetry or capnography. The result is an increase of PaCO2 and decrease of PaO2. Hypoventilation manifests with superficial or slow-like breathing that results in an insufficient amount of alveolar airflow, and thus, an inadequate partial pressure of oxygen in arterial blood takes place. This is accompanied by an increase of the partial pressure of CO2. If this persists, a drop in the acidity (pH) of the blood will occur, and is called respiratory acidosis.

With ventilation, air is passed along the alveolar-capillary membrane for gas exchange. This alveolar ventilation (VA) depends on the respiratory minute volume (VE) and dead space ventilation (VD), expressed by the equation VA = VE – VD. The majority of situations in which VA lowers are due to the decrease in respiratory minute volume. A reduction of dead space ventilation is very infrequent.17

On the other hand, PCO2 depends on the VA: PCO2 = (VCO2 / VA) x K

Where:

PCO2 = partial pressure of CO2

VCO2 = production of CO2 in mL/min

VA = alveolar ventilation

K = a correction factor expressed as a constant of 0.86318

Therefore, the existence of hypoventilation leads to an elevation of PCO2, which is inversely proportional to a decrease in alveolar ventilation. 19 Further, considering the alveolar ventilation equation and a respiratory quotient of 1 (a ratio between the volumes of CO2 produced by an organism and the volume of oxygen that it consumes), for every rise in 1 mmHg of CO2, a descension of 1 mmHg PAO2 mmHg will occur.

Causes that lead to hypoventilation seldom originate in the pulmonary parenchyma. They’re more frequent from extra pulmonary tissue.  

Diffusion Alterations

Once oxygen reaches the alveoli, it must be exchanged with blood gases for distribution via passive diffusion, which is regulated by the physical laws of the diffusion of gases. However, diffusion plays a lesser role in respiratory insufficiency when compared to imbalances of V/Q (ventilation/perfusion) and pulmonary shunts, both of which play a crucial role in PO2. Diffusion is a more important factor during exercise, since the capillary transit time decreases with physical activity.

When at rest, diffusion does not have a functional repercussion, since the transit time of blood through the capillary allows the lung to reach an equilibrium between PAO2 and the PO2 in the capillary. Under normal conditions, this balance is achieved when the blood has travelled a third of the length of the capillary. With respect to the elimination of CO2, slight hypocapnia is normal, since CO2 has a rate of diffusion 20 times higher than O2.[20]

Pulmonary Shunt

A shunt is an increase of the A-a gradient of O2 during respiration. Normally, partial pressure of oxygen in the alveolus should be approximately equal to arterial partial pressure. Let’s say there is 100 mmHg of PAO2; in healthy individuals, this would translate to a PaO2 of 100 mmHg. Shunting is used to describe a situation where PAO2 is 100 mmHg, but PaO2 is abnormally less, for example, 70 mmHg. This example represents an A-a gradient of 30 mmHg.  The A-a gradient calculation is simple subtraction: PAO2 – PaO2 = A-a gradient. Under normal circumstances, healthy people present physiological shunting with an A-a gradient range of 5-15 mmHg.21 What all of this means is that deoxygenated blood mixes with oxygenated blood. The perfusion of blood may be just fine, but for various reasons, ventilation is zero, resulting in an extreme imbalance of V/Q. Intrapulmonary shunting can be the result of abnormal communications between arteries and veins, such as arteriovenous fistulas or cardiac septal defects.22

With this said, the most frequent causes of shunt development are cardiogenic edemas, atelectasis, pneumonia, acute respiratory distress syndrome, and alveolar collapse; perfusion is maintained, but there is no oxygenation for the blood that passes through. Intrapulmonary shunting is the main cause of hypoxemia, and is normally accompanied by hypocapnia. 

V/Q Mismatch

A ventilation/perfusion mismatch is the most important pathophysiological mechanism of respiratory insufficiency, as it is the most frequent mechanism of hypoxemia in the majority of obstructive, vascular, and interstitial pulmonary diseases. The lungs are made up of millions of alveoli, each one with a predetermined ventilation and perfusion capacity. In ideal conditions, the ratio of each is 1, but this relationship can in theory vary from 0 to infinity. The existence of V/Q inequalities means that ventilation and blood flow do not concur in different regions of the lung, resulting in an inefficient exchange of gases.23 One way to evaluate the severity of V/Q imbalance is measuring the A-a gradient. The higher the gradient, the more severe the imbalance of V/Q. In this mechanism, we can find alveoli with low V/Q in which diminished ventilation with adequate perfusion exists. However, compensatory mechanisms tend to resolve the situation by lowering the perfusion between alveoli and capillaries via hypoxic vasoconstriction, and rerouting them to other areas of good ventilation.

There are also situations when V/Q is elevated, where ventilation is good but perfusion inadequate. Here, bronchoconstriction can take place, where ventilation can be rerouted to areas with good perfusion.

At first, hypoxemia gets corrected by hypoxic stimulus to ventilation, which is why hypercapnia is rare in the initial phases, but afterwards when V/Q imbalances are severe, hypercapnia appears. The resulting hypoxemia can be corrected by taking supplemental oxygen. It should be noted that quite often, the mechanisms involved in hypoxemia tend to be numerous, where it’s difficult to attribute hypoxemia to just one. Mechanisms that lead to hypercapnia are hypoventilation and alterations in the V/Q relationship.

Pathophysiological Mechanisms of Hypercapnia:

  • Increased CO2 production[24]
  • Hypoventilation
  • Rebreathing
  • Decreased alveolar ventilation
  • Increased dead space

Diagnosis of Acute Respiratory Failure

Respiratory failure can be inferred by the presence of symptoms and signs of hypoxemia and/or hypercapnia, especially in patients who have been diagnosed with acute or chronic pulmonary, or non-pulmonary diseases. Symptoms include acute thoracic pain, hemoptysis, confusion, rapid breathing, cyanotic skin, fatigue, and sleepiness. [25]

Arterial saturation (SaO2) readings can be obtained with the use of pulse oximeters, which are non-invasive devices that allow the monitoring of SaO2[26]. However, saturation can be affected by an underlying condition, such as anemia.

Normally, an SaO2 of 90% corresponds to 60 mmHg of PaO2, but we need to keep in mind that the oxygen dissociation curve varies according to the degree of the existing affinity between Hb and O2, which is influenced by temperature, intraerythrocytic concentration of 2,3-bisphosphoglyceric acid, CO2 tension, and acidity of the environment.[27] 

Acidosis, hypercapnia, and hyperthermia produce a deviation in the oxygen-hemoglobin dissociation curve towards the right, which reflects decrease in affinity of the Hb-O2 bond affinity. This facilitates the liberation of oxygen to tissue. [28] A radiography of the thorax can help with differential diagnosis. Other complementary tests are a gammagraphy and CT scan if a thromboembolism is suspected.

Treatment

Treatment for respiratory failure begins with targeting the culprit of an underlying causal disease, such as pneumonia, with antimicrobial therapy.[29]

As for the RF itself, it’s usually handled with the following considerations[30]:

  • Securement of airways by removing foreign bodies, secretions, etc.
  • Orotracheal intubation, if necessary.
  • Monitoring of SaO2 and vitals.
  • Venous catheterization
  • Treating or preventing oxygen consumption increase due to fever or general activity.
  • Nutrition and hydration.
  • Treatment for anemia and hypotension (if any exists) to improve oxygen saturation and distribution.
  • Prophylaxis against thromboembolic processes.

Oxygen Therapy

By maintaining proper tissue oxygenation, the patient can balance O2 levels and improve the quality of oxygen in the blood. However, oxygen therapy should be based on the results of a gasometry (when permissible). Once determined oxygen therapy is appropriate, O2 should be administered through a Venturi mask, with which we can know the fraction of inspired oxygen (FiO2) provided to the patient. A target SaO2 above 90% (or PO2 above 60 mmHg) should be maintained for chronic cases that become acute, or if the patient presents a hypercapnic tendency. In the same token, cardiac output and the transportation of O2 needs to be stabilized.

Non-invasive ventilation (NIV) has demonstrated its efficacy in patients with episodes of acute COPD31, acidosis, and hypercapnia. Additionally, the need for intubation and mechanical ventilation is reduced with NIV, as is mortality rate and length of hospital stay. 32

Figure 2 - Shows the Increase in NIV utilization from year 2011 to 2015
Figure 2 – Shows the Increase in NIV utilization from year 2011 to 2015. An analysis made by Nikolina Maric, et al., showed steady increments in NIV utilization from 2011 (7%) to 2015 (15.7%). According to this study, “three Italian cohort studies with historical or matched control groups have suggested that long-term outcome of patients treated with NIV is better than that of patients treated with medical therapy and/or endotracheal intubation”. [33]

 

An analysis made by Nikolina Maric, et al., showed steady increments in NIV utilization from 2011 (7%) to 2015 (15.7%).  According to this study, “three Italian cohort studies with historical or matched control groups have suggested that long-term outcome of patients treated with NIV is better than that of patients treated with medical therapy and/or endotracheal intubation”.33

 

References:

  1. Matthias Ochs, et al. The Number of Alveoli in the Human Lung (American Journal of Respiratory and Critical Care Medicine, 2004) https://doi.org/10.1164/rccm.200308-1107OC
  2. Steven E. Weinberger MD, MACP, FRCP, et al.1 – Pulmonary Anatomy and Physiology: The Basics ( Principles of Pulmonary Medicine, 2019) https://www.sciencedirect.com/topics/medicine-and-dentistry/carbon-dioxide
  3. John B. West. The original presentation of Boyle’s law (Journal of Applied Physiology, 1999) https://doi.org/10.1152/jappl.1999.87.4.1543
  4. Pittman RN. Regulation of Tissue Oxygenation (Morgan & Claypool Life Sciences, 2011) https://www.ncbi.nlm.nih.gov/books/NBK54103/
  5. Todd Helmenstine, Henry’s Law Example Problem [Online] (Thoughtco, November 2018) https://www.thoughtco.com/henrys-law-example-problem-609500
  6. [Online] CoursesLumenLearning.com , Gas Exchange – Module 6, The Respiratory System https://courses.lumenlearning.com/suny-ap2/chapter/gas-exchange/
  7. Kevin M. Tenny, Jeffrey S. Cooper. Ideal Gas Behavior (StatPearls Publishing, 2018) https://www.ncbi.nlm.nih.gov/books/NBK441936/
  8. Puneet Katyal, et al., Pathophysiology of Respiratory Failure and Use of Mechanical Ventilation (Mayo Clinic, https://www.thoracic.org/professionals/clinical-resources/critical-care/clinical-education/mechanical-ventilation/respiratory-failure-mechanical-ventilation.pdf
  9. Eman Shebl, Bracken Burns. Respiratory Failure (StatPearls Publishing, 2018) https://www.ncbi.nlm.nih.gov/books/NBK526127/
  10. Jacob Samuel, Cory Franklin. Hypoxemia and Hypoxia (Common Surgical Diseases, 2008) https://doi.org/10.1007/978-0-387-75246-4_97
  11. Malay Sarkar, et al. Mechanisms of hypoxemia (Lung India. 2017) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234199/
  12. O’Driscoll BR, Overdose on Oxygen? AHRQ WebM&M [online journal]. March 2008 http://www.webmm.ahrq.gov/case.aspx?caseID=172
  13. Katerina Stamati, et al. Evolution of oxygen utilization in multicellular organisms and implications for cell signalling in tissue engineering (J Tissue Eng. 2011) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258841/
  14. Mihaela S. Stefan, MD, et al. Epidemiology and outcomes of acute respiratory failure in the United States, 2001 to 2009: A national survey (Journal of Hospital Medicine, 2013) https://www.journalofhospitalmedicine.com/jhospmed/article/127448/acute-respiratory-failure-epidemiology
  15. Mihaela S. Stefan, MD, et al. Epidemiology and outcomes of acute respiratory failure in the United States, 2001 to 2009: A national survey (Journal of Hospital Medicine, 2013) https://www.journalofhospitalmedicine.com/jhospmed/article/127448/acute-respiratory-failure-epidemiology
  16. Christopher Cielo DO, Carole L. Marcus MBBCh. Central Hypoventilation Syndromes (Sleep Med Clin. 2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963184/
  17. Sal Intagliata, Alessandra Rizzo – Physiology, Lung Dead Space (StatPearls Publishing, October 2018) https://www.ncbi.nlm.nih.gov/books/NBK482501/
  18. [Online] Physiology Cases and Problems http://www.course.sdu.edu.cn/G2S/eWebEditor/uploadfile/20130329171230177.pdf
  19. Henry M. Thomas III, M.D. Ventilation and Pco2: Make the Distinction (CHEST Journal, 1981) https://doi.org/10.1378/chest.79.6.617
  20. Alexander Kolettas, Influence of Apnoeic Oxygenation  in Respiratory and Circulatory Systems Under General Anesthesia (Journal of Thoracic Disease, March 2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966167/
  21. [Online] Amboss.com, Airways and Lungs (January 2019) https://www.amboss.com/us/knowledge/Airways_and_lungs
  22. James R Gossage MD – Pulmonary Arteriovenous Malformations, (American Journal of Respiratory and Critical Care Medicine, 1998) https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.158.2.9711041
  23. Glenny RW. Gas exchange and ventilation-perfusion relationships in the lung (Eur Respir J. 2014) https://www.ncbi.nlm.nih.gov/pubmed/25063240
  24. Shivani Patel, Sapan H. Majmundar. Physiology, Carbon Dioxide Retention (StatPearls Publishing, 2018)https://www.ncbi.nlm.nih.gov/books/NBK482456/
  25. Respiratory Failure (National Heart, Lung, and Blood Institute) https://www.nhlbi.nih.gov/health-topics/respiratory-failure
  26. Bhakti K. Patel, MD. Respiratory Failure / Lung Failure (MERCK MANUAL, 2018) https://www.merckmanuals.com/home/lung-and-airway-disorders/respiratory-failure-and-acute-respiratory-distress-syndrome/respiratory-failure#v38285685
  27. Aakash K. Patel, Jeffrey S. Cooper, Physiology, Bohr Effect (StatPearls [internet] October 2018) https://www.ncbi.nlm.nih.gov/books/NBK526028/
  28. Alex Yartsev, Factors Which Influence the Affinity of Oxygen for Hemoglobin (DerangedPhysiology, June 2015) https://derangedphysiology.com/main/core-topics-intensive-care/arterial-blood-gas-interpretation/Chapter%204.0.5/factors-which-influence-affinity-haemoglobin-oxygen
  29. Kyung-Yil Lee, Pneumonia, Acute Respiratory Distress Syndrome, and Early Immune-Modulator Therapy (International Journal of Molecular Sciences, February 2017) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343923/
  30. Arnedillo Munoz, et al., Acute Respiratory Insufficiency [Online] https://www.neumosur.net/files/EB03-18%20IRA.pdf
  31. Hess DR. Noninvasive ventilation for acute respiratory failure (Respir Care. 2013) https://www.ncbi.nlm.nih.gov/pubmed/23709194
  32. Brochard, J. Mancebo, M.W. Elliot, Non-Invasive Ventilation for Acute Respiratory Failure (European Respiratory Journal, 2002) https://erj.ersjournals.com/content/19/4/712
  33. Nikolina Maric, et al. Noninvasive ventilation in treatment of acute respiratory failure in ICU (Journal of Intensive Care and Emergency Medicine, 2016) http://www.signavitae.com/2016/06/noninvasive-ventilation-in-treatment-of-acute-respiratory-failure-in-icu/

 

Robert Velasquez
28 July, 2019

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Hello everyone, my name is Robert Velazquez. I am a content marketer currently focused on the medical supply industry. I studied Medicine for 5 years. I have interacted with many patients and learned a lot...read more:

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