Saturday, 13 June 2015

Question 3: Multiple questions on a patient with chronic lung disease and shortness of breath

*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.

Question 3: Davy Smith is a 65-year-old male with a 50-year history of smoking 2 packets of cigarettes a day. Over the past 5 years, he has become increasingly short of breath. At first, he noticed this only when exercising, but now he is even short of breath at rest. Over the past two years, he has had several bouts of lower respiratory tract infection treated successfully with antibiotics. His shortness of breath hasn't subsided, and his breathing is assisted by use of his accessory muscles of respiration. Pulmonary function testing revealed the graph below:

a.      Based on the graph, fill in the following data:
The tidal volume: ____________
The inspiratory reserve volume: ______________
The expiratory reserve volume: _______________
The forced vital capacity: ______________
b.      Describe the microscopic changes that are occurring in Davy's lungs. What effect do these microscopic changes have on Davy’s ability to transfer oxygen and carbon dioxide in the lungs?
c.       Blood testing showed Davy’s hematocrit to be 59% (normal = 42-50%). Why was his hematocrit so high?
d.      Why is Davy susceptible to lower respiratory tract infections?


Part a:

Each box on the graph is roughly 125 cc of volume.
The tidal volume is the amount of air breathed in during a relax breath. On the graph this is roughly 4 boxes in height.  4x125 = 500 cc.
Therefore, the tidal volume is 500 cc in volume.
The inspiratory reserve volume is the extra air that can be inhaled after a relaxed inhalation. Thus it is the difference between the height of the forced inhalation and that of the normal inhalation on the graph. This is approximately 14 boxes in height. 14x125 = 1750 cc.
Therefore, the inspiratory reserve volume is 1750 cc in volume.
The expiratory reserve volume is the extra air that can be exhaled after a relaxed exhalation. So it is the difference between the height of the forced exhalation and that of the normal exhalation on the graph. This is approximately 3.5 boxes in height. 3.5x125= 437.5 cc.
Therefore, the expiratory reserve volume is 437.5 cc in volume.
The forced vital capacity is the total volume of air which can be exhaled after a full inhalation. This is can calculated as either the difference between the highest and lowest points of the graph, or by adding up the tidal volume, inspiratory reserve volume and expiratory reserve volume. This is roughly 21.5 boxes in height. 21.5x125 = 2687.5 cc
Therefore, the forced vital capacity is 2687.5 cc in volume.
(Bass, 1974 p.7).
The work of Bass showed how to calculate volumes from a lung function graph, however much of its other work may be outdated so it was only used for this initial piece of work.

Part b:

It is likely that Mr. Smith is suffering from chronic obstructive pulmonary disease. This is a chronic lung disease that is usually caused by cigarette smoking. Given that Mr. Smith has a history of 100 pack-years of cigarette smoking (packets of cigarettes per day multiplied by years of duration, i.e. 2 packets daily x 50 years = 100 pack-years) this particular pulmonary condition is highly likely. It encompasses other respiratory diseases such as chronic bronchitis, emphysema and possibly also chronic obstructive airways disease. The repeated lower respiratory tract infections also point to this diagnosis so Mr. Smith is certainly at risk of the disease and he has the decreased lung function test to match. With regard to the microscopic changes occurring in Davy’s lungs, there is probably dilation and enlargement of the bronchioles, which is only partially reversible, i.e. much of the damage at this stage of illness is likely to be permanent (Mescher, 2013 p. 361). Alveoli are also enlarged in this condition as shown in Figure 3.1. This is due to the walls separating each alveolus gradually being destroyed over the years. Alveolar enlargement can occur because cigarette smoking provokes an inflammatory immune response which causes the release of various proteases (enzymes that break-down proteins, in this case these enzymes are mostly elastase and trypsin, and the immune cells they are most associated with are neutrophils, however macrophages are also involved in alveolar destruction), in the lungs from immune cells (Davies and Moore, 2003 pp. 26-28). This can break down the elastic protein in alveoli (called elastin) and render them inflexible (Seeley, VanPutte, Regan, and Russo, 2011, pp. 830-862).  In healthy persons the use of these enzymes is inhibited by a chemical called alpha-1-antitrypsin. This stops the immune cell-induced damage from continuing. However, in smokers and persons with a genetic fault causing an alpha-1-antitrypsin deficiency, the damage goes largely unchecked and pulmonary destruction ensues. In smokers the lack of alpha-1-antitrypsin activity is attributed to its reaction with free radicals in cigarette smoke, rendering it ineffective. What can then result from this is that instead of having very many alveoli, the alveoli can break down their walls to the extent that they form one larger air sac (Mayo Foundation for Medical Education and Research, 2015a). This results in a much lowered surface area for the diffusion of gases both into and out of the lungs which causes many of the reduced volumes seen on the lung function test (Mayo Foundation for Medical Education and Research, 2015b). Chronic bronchitis obstructs the larger airways of the respiratory tract while emphysema causes the same effect in small airways, as well as air-trapping in the alveoli (The McGraw-Hill Companies, 2000). The differences between healthy alveoli and those affected by emphysema are shown in Figure 3.2. Initially, the damage will reduce the amount of oxygen diffusing into the bloodstream, leading to an increase in ventilation. This hyperventilation lowers the concentration of carbon dioxide in the blood, while attempting to compensate for lowered oxygen. Usually, there is still some decrease in blood oxygen levels despite the hyperventilation. As the damage progresses however, there comes a point when the respiratory tract is so compromised that eventually carbon dioxide will accumulate in the bloodstream because it cannot diffuse out of the lungs at this stage and oxygen in the blood becomes significantly more decreased as well. The conditions of elevated carbon dioxide and decreased oxygen in the blood are termed hypercapnia and hypoxemia respectively (University of Maryland Medical Center, 2013).  The inability to adequately remove air from the lungs explains the elevated residual volume in Mr. Smith’s lungs. The use of accessory muscles of respiration helps to create more pressure in the lungs to expel air during expiration.
One beneficial effect of the elevated level of carbon dioxide in the blood is that oxygen is unloaded more readily from haemoglobin. This is known as the Bohr Effect and may occur due to the conversion of carbon dioxide to carbonic acid with simultaneous release of a hydrogen ion which reduces the blood pH. This effect is very useful during exercise because the increased carbon dioxide concentrations in the blood cause subsequent reduction in pH (which also occurs via other metabolic by-products, e.g. lactic acid) will cause preferential off-loading of oxygen to cells that are respiring more vigorously. This allows cells that are under the heaviest workload to receive adequate amounts of oxygen from haemoglobin (Razani, B., 2014). This means that in the case of Mr. Smith, his body actually requires less oxygen to reach his erythrocytes, (i.e. not as high an oxygen saturation in the blood is required) because it is off-loaded to other cells and tissue within his body more readily. A similar effect also occurs as the concentration of a substance called 2, 3-Diphosphoglycerate (2,3-DPG) increases. This is a compound that is formed as a result of anaerobic glycolysis, therefore its production increases under hypoxic / hypoxemic conditions. It is important to note that hypoxia and hypoxemia are not equivalents. Rather, hypoxemia is the state of reduced oxygen content in the blood stream of arteries (or a pathologically low arterial oxygen tension), whereas hypoxia is a condition in which too little oxygen is delivered to tissues. It can therefore be possible, though unlikely, that hypoxemia may exist in a patient, but compensatory mechanisms may be sufficient to encourage oxygen dissociation from haemoglobin in order to oxygenate tissues adequately. The aforementioned 2, 3-DPG however, increases under hypoxic conditions (given its production occurs under anaerobic conditions), and consequently, increases tissue oxygenation in a similar way to the Bohr Effect (Jardins, 2008, p.236).
Figure 3.3 shows the oxygen-haemoglobin dissociation curve. Note that when exercising, erythrocytes will off-load oxygen more readily to respiring tissue (possibly due to any number of reasons, for example, increased CO2 or 2, 3-DPG production as well as increase in temperature) which explains the point labelled deoxygenated blood on the graph. At rest, tissues respire more slowly, and produce less CO2, 2, 3-DPG, heat and other metabolic by-products that encourage the dissociation of oxygen from haemoglobin. The dashed curve to the right of the continuously drawn curve shows what would happen if any or all of the following components were increased: CO2, 2, 3-DPG, acidity, and temperature, though more possibilities exist. This produces an effect known as a “right-shift”, which means that a higher pressure of oxygen is required to produce the same oxygen saturation percentage compared to normal conditions. This means that under right-shift conditions, haemoglobin loses oxygen more readily, and consequently, respiring tissue receives oxygen in greater amounts.
Figure 3.4 shows the diffusion of carbon dioxide and oxygen into and out of an alveolus. This forms a diagrammatic representation for the equation of Fick’s Law of diffusion, which is also shown in this figure. Relating this to the case at hand, the reduced ability to both remove carbon dioxide from and deliver oxygen to the alveoli in Mr. Smith’s lungs results in a higher partial pressure of carbon dioxide and lower partial pressure of oxygen in these air sacs. A consequence of this is that less carbon dioxide will diffuse out of the bloodstream and into each alveolus, while less oxygen will diffuse from the atmosphere into the same region. This is because the difference in partial pressure between the blood stream and alveoli, relating to carbon dioxide, is smaller for Mr. Smith than a regular person. Similarly, the partial pressure difference of oxygen between the atmosphere and the diseased alveoli will be smaller as well. Thus, less carbon dioxide is encouraged to diffuse into the alveoli and be removed from the lungs in expiration, and less oxygen will diffuse into the lungs during inspiration (Jardins, 2008, p. 139). This explains why Mr. Smith is forced to use his accessory muscles of respiration.
The use of accessory muscles of respiration can improve the delivery of gases both from the atmosphere to the lungs and vice versa. Firstly, the accessory muscles of inspiration must be considered. The largest muscles of this category are the scalenus, sternocleidomastoid, pectoralis major, trapezius, and external intercostal muscles. Without getting into excessive detail, the overall function of these muscles is to help decrease the pressure within the lungs to such a level below atmospheric pressure that gases flow more readily into the alveoli, diffusing via a pressure and concentration gradient. As the concentration of any gas increases in a given area, so also does its tension. Therefore, the fact that Mr. Smith is having difficulty ventilating his lungs, means that the concentration of oxygen normally extracted from the alveoli into the blood stream has decreased (therefore, both alveolar partial pressure and concentration of oxygen have decreased) and Mr. Smith’s blood carbon dioxide levels have increased (regarding both partial pressure and concentration of arterial carbon dioxide). Thus, for inspiration, the lower the pressure inside the lungs, relative to the surrounding atmosphere, the greater the diffusion gradient for gases moving from the atmosphere into the lungs (and consequently alveoli). Therefore, the result of using the accessory muscles of inspiration is to increase oxygen supply to the blood stream. A person who is using their accessory muscles of inspiration while breathing will be quite noticeable, with much of their upper chest expanding and elevating during each inhale and some shrugging occurring also (Jardins, 2008, pp. 54-58). Conversely, the accessory muscles of expiration will increase the pressure within the lungs, relative to that of the surrounding atmosphere. This helps compensate for airway resistance, such as that seen in COPD. The primary accessory muscles of expiration are the rectus and transversus abdominis muscles, the external and internal abdominis obliquus muscles and the internal intercostal muscles. The basic movement of these muscles during expiration is of compression. The abdomen becomes compressed, and the diaphragm is pushed into the thoracic cage, increasing the pressure in the lungs well above atmospheric pressure and causing a diffusion of gases out of the alveoli into the surrounding environment (Jardins, 2008, pp. 59-61).
Part c:
Haematocrit is the proportionate measure of red blood cells compared to the overall blood volume (Seeley, VanPutte, Regan, and Russo, 2011, p 668).Thus, if Davy’s haematocrit was 59% then this is the percentage of his blood which was composed of red blood cells.
Red blood cells are used strongly in the transfer of various gases both to and from the lungs, and from and to cells. Therefore, an elevated level of red blood cells would occur in an individual who had trouble dealing with both the build-up of gases, and the inadequate diffusion of gases into the blood. In the case of Davy, he is suffering from both hypoxemia and hypercapnia. Therefore, he will need additional red blood cells to carry oxygen from his lungs. This sets up a steeper concentration gradient between the alveoli of the lungs and the bloodstream, thus allowing more oxygen to diffuse into the blood and be carried to various cells. Approximately 98.5% of the oxygen in our blood is bonded to haemoglobin to form oxyhaemoglobin, the remainder is dissolved in plasma (Seeley, VanPutte, Regan, and Russo, 2011, p 652) and tends to be ignored in calculations of arterial oxygen content.

There are numerous equations for approximating oxygen delivery and content within the body. Shown below is an equation for oxygen content in arteries (Gutierrez, and Theodorou, 2009).
CaO2, shorthand for the content or amount of oxygen in the arterial blood, is calculated by the following equation:
CaO2 ~ [Hb](SO2)x1.34
Where ~ means roughly equal to (because here we are neglecting the amount of dissolved oxygen within plasma [roughly 1.5 to 2%], and instead focusing entirely on oxygen bonded to haemoglobin), [Hb] is the concentration of haemoglobin in the blood, and SO2 is the fractional oxygen saturation of haemoglobin.
Thus, we can see that the oxygen content of arterial blood is proportional to the concentration of haemoglobin, and also to the fractional oxygen saturation of haemoglobin. This means that if either haemoglobin concentration or oxygen saturation increases while the other remains the same, then oxygen content of arterial blood will also increase. Also, if CaO2 remains the same value, then [Hb] and SO2 are inversely proportional to each other. This means that as one quantity increases, the other will decrease in order to achieve the same result for CaO2. Therefore, if we assume CaO2 to be an unchanging quantity, then we can clearly see that if oxygen saturation of haemoglobin decreases, then the concentration of haemoglobin must increase.
In the case of Davy Smith, his ability to extract oxygen from alveoli has greatly decreased. Even with a normal tidal volume of 500 cc, his blood is still not receiving an adequate supply of oxygen. This means that in our equation SO2 has decreased. Mr Smith’s body will still need to utilise roughly the same amount of oxygen, provided that compensatory mechanisms are not in place to reduce overall metabolic rate. Thus, the concentration of haemoglobin (also known as the haematocrit) will have to increase in order to supply to the same demand for oxygen content. This particular form of increased erythrocyte production (i.e. from hypoxic lung disease) is called either secondary erythrocytosis or secondary polycthemia (Seeley, VanPutte, Regan, and Russo, 2011, p. 669). This means that if Davy Smith was to somehow have his lung condition cured, then his haematocrit would drop to normal levels. However, while his condition remains, his kidneys will secrete more erythropoietin in response to decreased oxygen delivery.
Carbon dioxide is also a highly important consideration in this situation. As Davy Smith’s lung function deteriorates, his carbon dioxide levels will continue to increase. This accumulation of carbon dioxide must be dealt with. The body will naturally convert much of its extracellular carbon dioxide into bicarbonate ions (roughly 66% takes this form). Of the remaining 34%, 7% will be dissolved in plasma and the remaining 27% will bind to haemoglobin. The formed complex is called the carbaminohemoglobin molecule (Mescher, 2013, p. 236). Thus, elevated carbon dioxide levels will cause increased erythrocyte concentrations in order to bond the plasma carbon dioxide and transport it away from cells.
A more serious gas in the body that requires an elevated haematocrit level is carbon monoxide. Carbon monoxide is a poisonous gas found in cigarette smoke among other sources, especially those involving combustion of carbon-containing compounds in a region of inadequate oxygen (incomplete combustion) which has a very high affinity for haemoglobin and bonds to form carboxyhaemoglobin. Once carboxyhaemoglobin has formed, it is unlikely that the carbon monoxide will dissociate again in the lifespan of the red blood cell, usually it stays bonded until the red blood cell is broken down by the body. During this time the haemoglobin is unable to bind to oxygen or carbon dioxide molecules, or anything else for that matter. Thus, carbon monoxide essentially disables the effect of haemoglobin towards other molecules and requires increased red blood cell concentrations. It has been found that the blood of chronic smokers contains between 5 and 15% carboxyhaemoglobin. This alone provides a strong reason for the elevated red blood cell concentration found in Davy Smith (Seeley, VanPutte, Regan, and Russo, 2011, pp 653-655).
Part d:
Davy is susceptible to lower respiratory tract infections. This could be due to the act of smoking tobacco which has been reported to damage cilia in the lungs (Mueller, 1997). Cilia are microscopic projections that protrude from cells and sweep away various substances and microbes that can damage the body. When these are damaged, various toxins and microbes can enter the lower respiratory tract in greater numbers, requiring a stronger immune system to combat it.
Further to this, differences in bacterial populations within regions of the respiratory tract between smokers and non-smokers have been found. The exact location of these bacterial colonies is unlikely to be of concern, considering that as long as they are present somewhere in the respiratory tract, they may allow pathological microbes to travel past them into lower regions, whereas bacterial populations in healthy non-smokers would have some sort of inhibitory effect. Brook, and Gober (2005) found that the nasopharyngeal flora of smokers contained more potential pathogens than non0smokers, as well as fewer beneficial bacteria which might inhibit their growth and harm. Fujimori, et al. (1995) also found that healthy smokers had higher levels of Streptococcus Aureus (S. Aureus) and lower levels of alpha-streptococci (the forms which inhibit S. Aureus), as compared to healthy non-smokers. Forms of alpha-streptococci that inhibit another potential pathogen called S. pyogenes were similar in both healthy smokers and non-smokers. This indicates that smokers are more susceptible to infections via Streptococcus Aureus.
A review of many studies by Arcavi, and Benowitz (2004) revealed some interesting data about smokers. Several studies that were examined showed decreases of 10-20% in serum Immunoglobulins IgA, IgG and IgM. These are all vital antibodies that play a major role in the response against infection. These same authors also found that specific antibody responses to influenza (both as an unaltered virus and as vaccine) and Aspergillus fumigatus were decreased in smokers.
Additionally, the act of smoking can cause excessive mucus production and due to the impaired function of the damaged cilia in the respiratory tract, this mucus can build up without being removed. Mr. Smith likely has a “smoker’s cough”, a heavy cough which attempts to dislodge and remove this built-up mucus. Unfortunately, this accumulating mucus in the bronchial tree provides vital nutrients for pathological microbes that take up residence in the lungs. Thus, Mr. Smith is more susceptible to lower respiratory tract infections. Antibiotics are likely only to act as a short-term aid, with recurrent infections being a part of his life in the long-term (The McGraw-Hill Companies, 2000).

Question 3 References:
Arcavi, L., and Benowitz, N.L., 2004. Cigarette Smoking and Infection. [online] Available at: <> [Accessed 6 April 2015].
Bass, B.H., 1974. Lung Function Tests An introduction. 4th ed. London: H.K. Lewis & Co. Ltd.
Brook, I., and Gober, A.E., 2005. Recovery of potential pathogens and interfering bacteria in the nasopharynx of smokers and nonsmokers. [online] Available at: <> [Accessed 6 April 2015].
Davies, A., and Moore, C., 2003 The Respiratory System. Spain: Churchill Livingstone.
Fujimori I., Goto R., Kikushima K., Ogino J., Hisamatsu K., Murakami Y., and Yamada T. 1995.
Isolation of alpha-streptococci with inhibitory activity against pathogens, in the oral cavity and the effect of tobacco and gargling on oral flora. [online] Available at: <> [Accessed 6 April 2015].
Gutierrez, J.A., and Theodorou, A.A, 2009. Oxygen Delivery and Oxygen Consumption in Pediatric Critical Care, [online] Available at: <> [Accessed 6 April 2015].
Jardins, T.D., 2008. Cardiopulmonary Anatomy & Physiology Essentials of Respiratory Care, 5th ed. Delmar, USA: Nelson Education, Ltd.

Mayo Foundation for Medical Education and Research, 2015a. Diseases and Conditions Emphysema. [online] Available at: <> [Accessed 6 April 2015].

Mayo Foundation for Medical Education and Research, 2015b. Diseases and Conditions Emphysema. [online] Available at: <> [Accessed 6 April 2015].

Mescher, A.L., 2013. Junqueira’s Basic Histology Text & Atlas, 13th ed. China: The McGraw-Hill Companies.

Mueller, D.M., 1997. Smoking Any Substance Raises Risk of Lung Infections, [online] Available at: <> [Accessed 6 April 2015].
Razani, B., 2014. Bohr Effect. [online] Available at: <> [Accessed 6 April 2015].
Seeley, R.R, VanPutte, C.L., Regan, J. and Russo, A.F., 2011. Seeley’s Anatomy & Physiology, 9th ed. New York, USA: McGraw-Hill.

The McGraw-Hill Companies, 2000. Case History 13: Restrictive and Obstructive Lung Disease, [online] Available at: <> [Accessed 7 April 2015].   
University of Maryland Medical Center, 2013. Chronic obstructive pulmonary disease. [online] Available at: <> [Accessed 6 April 2015].

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