This assignment will answer five set questions in response to a scenario of medical student (PF) and his expedition to base camp at Mount Everest. The answers cover topics ranging from anatomy, cardio-respiratory physiology and pharmacology.
Effects of high altitude on ventilation and its control
Ventilation includes both the replenishment of gases in the lungs and the oxygenation of blood through the pulmonary capillary bed1. In healthy individuals such as PF the main variable affecting ventilation is the environment.
Barometric pressure (the pressure the earth's atmosphere exerts on objects) varies with altitude; at 5300 metres (base camp) the barometric pressure is 52 kPa. However the theoretical value for the partial pressure of inspired oxygen (PIO2) is 9.6 kPa which takes into account the dilution factor of water vapour 6.3 kPa and the portion or air that constitutes oxygen (21 %).2
Under normal circumstances the partial pressure of arterial carbon dioxide (PaCO2) is detected by central chemoreceptors of the medulla oblongata. Central chemoreceptors have the lead role in the control of respiration. The role of peripheral chemoreceptors (located in the carotid and aortic bodies) are negligible in comparison. However, in hypoxic conditions peripheral chemoreceptors principally regulate ventilation. Peripheral chemoreceptors detect hypoxic, hypercapnic, and acidic conditions. (Refer to graph in appendix a showing when hypoxic drive is stimulated). Research has shown that it is the glomus cells in peripheral chemoreceptors which react to these changes 3,4.
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Under normal conditions, glomus type 1 cells regulate their oxygen sensitive sodium potassium pumps maintaining a resting membrane potential. In hypoxic conditions the Na+-K+-pump is inhibited thus causing depolarisation of a nearby branch of the glossopharyngeal nerve and the carotid sinus nerve. Action potentials travel to the respiratory centre (RC) of the medulla. The RC houses both inspiratory (I) and expiratory (E) neurones in different compartments of which the ventral and dorsal respiratory groups are of high importance. The solitary tract nucleus is located in the dorsal respiratory group which consists of mostly I neurones, which projects into the phrenic and intercostal nerves, innervating the diaphragm and intercostal muscles respectively. Furthermore the ventral respiratory group consists of a collection of nuclei known as the Botzinger complex containing both E and I neurones. The E neurones extend into the intercostal motor neurones and assist in expiration. The combined stimulatory effect of these neurones alters the respiratory pattern and leads to a hyperventilatory response 4. Whilst peripheral chemoreceptors do play a major role in hypoxic conditions, there are several different receptors and reflexes that also contribute to regulating and altering the rhythm of breathing.
When PF reached base camp blood tests were taken showing blood oxygen, carbon dioxide and pH. These tests were repeated the following day.
Discussion of the blood gases obtained and the differences between them
The initial blood tests are suggestive of a typical response to high altitude. As stated previously when the PO2 falls below 8 kPa, as in the case of PF, this leads to the stimulation of hypoxic drive in order to increase oxygen concentration. The next day's set of blood tests showed a reduction in arterial PO2 and PCO2 of 1.8 kPa and 0.6 kPa respectively. There was also an increase in blood pH by 0.4.
The pH and the PCO2 can be explained by the effects of hyperventilation. Carbon dioxide is a respiratory acid; hyperventilation removes carbon dioxide reducing the acidity of the blood. The increase in arterial pH is known as respiratory alkalosis.
However the reduction in PO2 is unexpected. Exposure to high altitude does initially lead to hyperventilation whereas; in the short term there is a reduction in both PO2, and PCO2. After 1 day there is a degree of acclimatisation. Typically there would be an increase in minute ventilation resulting in an increase in alveolar and arterial PO2. (Refer to appendix B for a graphical representation) 5(pp 254- 257).
The continued reduction in PaO2 can be explained by understanding the formation of oxyhaemoglobin. This is formed in a reaction between oxygen and deoxyhaemoglobin at equilibrium. Based on Le Chatellier's principle on equilibrium dynamics, the reduction in atmospheric oxygen favours the reverse reaction and thus a decrease in oxyhaemoglobin. As a compensatory mechanism the individual would induce polycythemia to maintain adequate levels of oxygen in the blood. Based on the results it would appear that PF has not acclimatised 6.
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The alveolar gas equation can be used as a measure of the relationship between the levels of alveolar (PAO2) and arterial oxygen. In healthy subjects the PaO2 and the PAO2 are identical. When applying the alveolar gas equation to the first set of blood tests PAO2 matches the PaO2. However the second round of blood test show a difference between the PaO2 and PAO2 of 2.5 kPa (refer to calculation in appendix c).
Based on this information and the calculations it is suggestive that PF is suffering from Type 1 Respiratory failure. Type 1 respiratory failure can be defined as having hypoxia combined with normal or low levels of carbon dioxide. This is mainly due to a ventilation perfusion mismatch or a shunt; the consequence of which is to reduce the oxygen carrying capacity of the blood7(pp 50-53). The details of this shall be explained later. In order to be able to understand the mechanics involved in respiratory failure, one has to appreciate the anatomical network of blood vessels that supply the lungs.
Anatomy of blood supply to the lungs
The lungs are the recipient of two distinct circulatory systems. The bronchial circulation is very much a high pressure vascular network which has a predominant role in providing nourishment, except to the alveoli. On the other hand the pulmonary circulation is a low pressure low resistance network, primarily focused on gas exchange8.
On the medial surface of each lung is a collection of tubular vessels known as the hilum. The hilum is located in the middle mediastinum. Furthermore the hilum also contains the main blood vessels, bronchus, nervous and lymphatic tissue 9.
The right lung is supplied by the right pulmonary artery, which is found superior to the two pulmonary veins that leave at the hilum. The bronchus is more posterior in relation to the blood vessels. The left lung mirrors the right lung, except for the, left pulmonary artery which is located inferiorly to the bronchus. (Refer a diagram in appendix D). Extending from the right ventricle, the pulmonary trunk bifurcates at the region of the sternal angle (T4/5) forming the left and right pulmonary arteries. The pulmonary arteries further divide in to arterioles, which supply small segments of lung tissue know as the bronchopulmonary segments. There are ten of these bronchopulmonary segments (as illustrated in appendix e). Branches of the pulmonary vein form anastomoses with the branches of the pulmonary artery. They then gradually merge to form the superior and inferior pulmonary veins at the hilum, which subsequently empty in to the left atrium 9, 10 (pp139-150).
The bronchial arteries arise variably either directly from the thoracic aorta or from the intercostal arteries. They are involved in the nourishment of the tracheobronchial tree (the collective term used to describe the divisions of the bronchi). In addition the bronchial arteries are involved in supplying mediastinal lymph nodes, pulmonary nerves, visceral pleura and a portion of the oesophagus. Venous blood from the first two to three generation of the tracheobronchial tree is drained in to the intercostal, azygous and hemizygous veins. The remaining bronchial venous blood drains into the pulmonary circulation. Vasoconstriction of the pulmonary capillaries and arterioles lead to HAPE, producing symptoms such as coughing up of pink frothy fluid10.
The likely mechanism of HAPE
PF has been diagnosed with high altitude pulmonary oedema (HAPE). HAPE is a form of noncardiogenic pulmonary oedema that results from high altitude. HAPE is induced by number of reactions in response to hypoxic conditions. The primary factor is lack of oxygen which inhibits the oxygen sensitive potassium channels in the vascular smooth muscle of the pulmonary arterioles. Inhibition of the potassium channels leads to the opening of calcium channels. Calcium moves in down the concentration gradient activating the myosin light chain kinase protein, resulting in contraction of smooth muscle. Subsequently, there is an increase in pulmonary arterial pressure (by approximately 50 mmHg) and an increase in capillary pressure resulting in the extrusion of fluid and localised oedema. This process is known as hypoxic vasoconstriction (HPV) 11 (pp 80-83). Additionally, there is evidence to show that hypoxia also inhibits the endothelial cells' ability to release nitric oxide hence reducing the magnitude of vasodilatation thus contributing to HAPE. Furthermore studies also suggest the balance of fluid in the alveoli is affected by hypoxia. Alveolar epithelium is involved in the reabsorption of alveolar fluid by a process of co-transportation of sodium through sodium channels. This process generates an osmotic gradient required for the transportation of water into the cells. In hypoxic conditions there is a down regulation of both the specific sodium channels (ENac) and the sodium potassium pump that drives this process. Consequently alveolar fluid accumulates and patients can present with HAPE 12, 13. Regardless of the extensive research into HAPE there remains no consensus on the actual cause.
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The symptoms of HAPE correspond with type 1 respiratory failure resulting in a ventilation perfusion (V/Q) mismatch and a shunt. V/Q mismatch is when the blood flow in the capillaries (perfusion) is not adequately oxgygenated through ventilation, due to the barrier posed by the alveolar fluid. The congestion caused by the accumulation of fluid leads to a diffusion block, whereby the diffusion distance for the movement of gases is increased. A 'shunt' refers to the bypassing of blood from regions in the lungs which are not adequately oxygenated to areas that are better oxygenated. This process becomes pathological in HAPE. The V/Q mismatch, diffusion block and shunt are responsible for the symptoms of HAPE, such as nausea breathlessness and tachypnoea etc 5.
Compare and contrast the actions of Nifedipine and Sildenafil
Nifedipine is a calcium ion antagonist. It is a common drug used to treat HAPE, belonging to the dihydropyridine class. It is taken orally as a tablet, and once digested it undergoes extensive first-phase metabolism. Nifedipine is primary metabolised by the cytochrome P450 in the liver whilst, utilising the isoenzymes CY3PA4, CYP1A2 and CYP2A6. It primarily blocks voltage dependant L-type calcium channels found on alpha-1 receptors located on cardiac and vascular smooth muscle. It works by preventing the transmembrane influx of calcium ion thus inhibiting the contraction of smooth muscle, and inducing vasodilatation. With regards to its specific purpose in the treatment HAPE, the vasodilatory effect reduces the HPV, reversing the symptoms of HAPE. Nifedipine is metabolised very quickly and has a half life of two hours 14. This can also be used in the treatment of angina hypertension etc. Nifedipine has negative ionotropic effects on myocardial tissue and can depress sinoatrial node and atrio-ventricular node conduction in myocardium. However Nifedipine will preferentially bind on to receptors on the vascular smooth muscle. 15,16.
Sildenafil is a drug whose effects are related to nifedipine. Sidenafil is more commonly known as Viagra. Sildenafil is a phosphodiesterase V (PED5) inhibitor; it is taken orally and converted into an active metabolite via the liver, using the same family of cytochrome P450 enzymes. Once activated its effects are exerted mainly on vascular smooth muscle as opposed, to Nifedipine which affects cardiac and vascular smooth muscle. Sildenafil works by inhibiting the PED5, reducing the levels of cyclic-GMP (cGMP) thus maintaing a state of vasodilatation. Its actions primarily focus on the smooth muscle of corpora cavernosa, inducing erection in males. There has been some research indicating that it can reduce HPV, thereby reversing the symptoms of HAPE17.18. Sildenafil has a half life of 4-5 hours. Research has shown that Sildenafil can be used as a prophylaxis to prevent HAPE as it has been shown to reduce pulmonary arterial pressure. However research is still on-going and Sildenafil remains a front-line drug in the treatment of HAPE. Side-effects of Nifedipine include; hypotension, flushing headaches, and disruption of cardiac rhythm. The unwanted effects of Slidenafil are; headaches, flushing and retinal damage 19.
In conclusion this assignment has explained the mechanics of ventilation at high altitude. The roles of peripheral and central chemoreceptors have been explained with regards to, their different methods of sensory detection and their interactions with different brain centres.
Interpreting blood gas data is extremely important in diagnosis. Being able to incorporate relevant data into the alveolar gas equation, and identifying differences is alveolar and arterial gradient enables a better appreciation of the extent of PF's health.
The basis of understanding how HAPE causes symptoms, is interlinked to the anatomy of the blood supply to the lungs. By recognising the anatomical differences in the bronchial and pulmonary circulation, and their roles, correlations can be made between symptoms and the site of the injury.
HAPE is a complex disorder mainly characterised by hypoxic vasoconstriction, however its underlining pathology remains idiopathic. The main treatment is a calcium channel blocker. Nifedipine is primarily a vasodilator used as a from-line drug in the treatment of HAPE. Sildenafil is also a vasodilator; however has a lesser effect on pulmonary capillary pressure 19.