Tissue Oxygenation and CFS
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Oxygen Delivery Overview
Carbon Dioxide, pH and Breathing Technique
CO2, HCO3- and pH
The Bohr Effect
Hypocapnia - Too Low Blood CO2 Levels
Hypercapnia - Too High Blood CO2 Levels
Inefficient Oxygen Perfusion
Porphyrins and Heme Production
Cardiac Insufficiency and ASBAs
Reduction in Oxygen-Permeability of Capillaries
Methemoglobinemia - Oxidised Hemoglobin, Free Radicals & Peroxynitrite
Hydrogen Sulphide (H2S)
Dr Paul Cheney's Theory on Oxygen Toxicity and PFOs
Dr Paul Cheney's Theory on Low CO2 Levels
Markers of Low Oxygenation
O2 Concentrators - General
O2 Concentrators - Maintenance Schedule
Bitmos Oxy 6000 Review
Oxygen Delivery Overview:
Before we look at some of the potential problems associated with oxygenation in CFS patients, let us first briefly remind ourselves how Oxygen (O2) is delivered to the tissues and how Carbon Dioxide (CO2) is removed from the tissues.
The purpose of breathing is to absorb oxygen into the blood and expel carbon dioxide and other gaseous waste products from the blood, in accordance with requirements.
Under normal circumstances, the air we breathe in contains 0.04% CO2 and the air we breathe out contains 4% CO2. Normally, in each breath only 10% of the alveolar gas is replaced in each breath (including both O2 and CO2). The percentage of O2 exhaled from each breath depends on your oxygen consumption (VO2) and metabolic rate.
Oxygen is required by all the cells of the body in the process of respiration, where carbon-containing sugar chains and other storage compounds are 'burnt' using O2, involving a complex cycle of mitochondrial co-factors, resulting in the production of water and CO2.
Oxygen is absorbed in the lungs, where it is transported around the body in the arterial blood, until it arrives at the capillaries, the very thin and permeable blood vessels which form a 'web' or 'matrix' around the tissues they supply. The capillaries at the tissues and the alveoli in the lungs both provide a enormous surface area where diffusion and absorption can occur.
The capillaries supply nutrients and oxygen to the target cells, nutrients coming from the blood plasma and the oxygen coming from the Red Blood Cells. The capillary blood removes/absorbing waste products and Carbon Dioxide (from respiration). The CO2 is then transported in the venous bloodstream to the lungs where it diffuses and is expelled from the body. Breathing of course does not occur only when blood has completed a complete circuit around the body (!) but happens continously, with this exchange occuring continuously.
RBCs have one main purpose which is gaseous exchange. RBCs also perform secondary functions including:
RBCs are anucleate when mature, meaning that they do not have a cell nucleus unlike other bodiliy cells. RBCs have an average life span of 100-120 days, after which time they are 'eaten' by Macrophages, a type of White Blood Cell. The blood stream is able to absorb and transport large quantities of gases by having a high concentration of Red Blood Cells. The concentration of RBCs may vary depending on the partial pressure of oxygen one is habitually used to breathing (e.g. altitude).
The Hemoglobin protein molecule in a RBC is comprised of 4 Heme molecules bound together. Each Heme molecule is able to accommodate one O2 or CO2 molecule. Heme is a type of metalloprotein containing a Ferrous Iron (Fe2+) in the centre of a carbon ring. Of course not all Hemoglobin molecules in the RBCs in the blood are fully saturated with gases. The extent of saturation and diffusion is dependent on the partial pressures of the gases at the exchange point and also the relative affinity of the gas-Hemoglobin bond inside the RBC. A number of factors may affect the strength of the Hemoglobin bond with the O2, including pH and 2,3-BPG concentration. The general trend across all the RBCs in the blood is described by the Oxygen-Hemoglobin Dissociation Curve.
The Oxygen-Hemoglobin Dissociation Curve is described by % O2 Saturation on the y-axis (SaO2 %) and Partial Pressure of O2 in mmHg on the x-axis (PaO2). It is not a linear relationship, of course, and forms a S-curve or Sigmoid-curve pattern. Each person will have a slightly different curve, which can be conceptualised by either a shift to the left or a shift to the right of the 'Satndard' curve.
The midpoint of the curve, the point of 50% O2 saturation, is used for reference purposes, and is the partial pressure of O2 necessary to produce that degree of O2 saturation in the RBCs. 50% saturation is of course not something to aim for but is just a useful point on the graph to use to compare Oxygen-Hemoglobin DIssociation Curves.
When describing the degree of saturation of Hemoglobin, the following terms are generally used.
Hemoglobin bound to CO2 loses its affinity to O2, described by the Bohr effect, shifting the O2-Hemoglobin-Dissociation Curve to the right. The Hemoglobin bond to CO2 is reversible.
Most of the O2 in the blood is carried in the Hemoglobin of the Red Blood Cells (RBCs or Erythrocytes), with a small amount dissolved in the blood plasma. Conversely, most of the CO2 is dissolved in the blood plasma in the form of bicarbonate (HCO3-), with only a small amount of CO2 molecules actually dissolved in the blood plasma or bound to the Hemoglobin of the RBCs. Most of the Hemoglobin in the venous blood is therefore deoxygenated and is not bound to any gases, but instead bound to H+ ions from the blood (once the O2 has been squeezed out at the capillary sites). These H+ ions are released into the blood plasma once the RBCs arrive at the lungs, when they are substituted at the hemoglobin bindings sites with O2. H+ ions bind most readiliy to DeoxyHemoglobin (containing no O2).
H+ ions bind with great affinity to Hemoglobin, especially DeoxyHemoglobin (in the venous blood). DeoxyHemoglobin bound to H+ has a slightly reduced affinity for O2, in the same way that Carbaminoglobin (CO2-bound Hemoglobin) has a reduced affinity for O2 also. With greater H+ ion concentrations, or lower blood pHs, Hemoglobin binds more readily to H+ and subsequently has slightly reduced affinity to O2. This similarly shifts the O2-Hb-Dissoc. Curve to the right. Higher CO2 blood levels result in a lower pH or increased H+ ion concentration too.
There are a number of factors that control how much oxygen is absorbed by the cells and tissues of the body. Some of these are examined in subsequent sections of this page.
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Carbon Dioxide, pH and Breathing Technique:
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CO2, HCO3- and pH:
As mentioned above, CO2 can be carried in the blood in three different ways, the exact percentages varying whether it is in the arterial or venous blood.
CO2 is converted into Bicarbonate ions by the action of the metalloenzyme Carbonic Anhydrase inside the RBCs. CO2 is very slow to combine with H20 (water) to form Carbonic Acid (H2CO3) and to further ionise, but this enzymatic process greatly speeds this up.
The amount of CO2 therefore exists in an equilibrium with H2CO3 and HCO3- in the blood, with most of it being in the aqueous and ionised form rather than the actual dissolved gaseous state. When we talk about CO2 in the blood, what we really mean is the total of all the forms of CO2, most of which is in the form of HCO3- ions.
The H+ ion is strongly acidic in nature and HCO3- ion is weakly alkaline in nature. Together they form what is effectively a weak acid.
The H2CO3/HCO3- dissolved in solution (including a very tiny proportion of CO3(--) or Carbonate at this pH) act as a kind of buffer to blood pH. When acidic or alkaline compounds are produced or ingested and enter the bloodstream, the Bicarbonate pH buffer keeps the blood pH from fluctuating too much, by shifting the equilibrium between the different states of CO2 (up to a certain point). pH stability is required for organisms to function properly. However, the optimal buffering range for CO2/HCO3 is between 5.1 and 7.1, which is somewhat lower than the blood pH of 7.365, so the buffering capacity of the blood is less than optimal.
The body can remove CO2 from the body in two ways.
Of course, all the while, the blood at the capillaries is absorbing more CO2 from the respiring tissues, converting most of it to HCO3-.
A high pulse rate, for example, during exercise, will hinder CO2 removal from the lungs. Blood passes through the capillaries rapidly and CO2 does not have such a chance to dissolve into the blood and react with the enzymes in the RBCs to be converted to HCO3-. The blood passes through the lungs rapidly also does not tend to lose as much CO2 as it absorbs O2 (which is used up rapidly by the tissues at the capillary sites).
As some of the CO2 is lost from the blood in the lungs from its dissolved form and from its Hemoglobin form, more HCO3- will turn into CO2 to restore the equilibrium.
When we talk about the amount of CO2 in the blood, one unit of measurement is the equivalent partial pressure of CO2 (a.k.a. PaCO2), in mmHg. Of course, this amount of the gas CO2 is literally not present in the blood, as most of it has ionised in the form of bicarbonate ions. However, if we add up all the CO2 in all its forms in the blood and express it as a gas pressure, then this is the value that we would come up with. Another measurement of CO2 levels in the blood is a direct measurement of the ionised HCO3- concentration. This is expressed as mg of HCO3- per decilitre/decilitre (mg/dl). This is likely to also include the actual dissolved gaseous CO2 concentration in the blood also, expressed as HCO3-, as when you react HCO3- ions with an alkali, you use up more of the
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The Bohr Effect:
Whilst CO2 is indeed a toxic gas in high enough concentrations, and a waste product from respiration, it is also required to assist in the regulation of the blood's pH and to control blood vessel dilation/constriction. Blood pH is critical for cellular health, enymatic reactions and indeed O2 diffusion from the RBCs themselves. Proteins and enzymes will become denatured at the wrong pH. The presence of Bicarbonate ions (the ionised form of Carbonic acid) in the blood is therefore crucial for regulating the blood's pH.
The Bohr Effect was defined by Danish physiologist Christian Bohr in 1904. It is the observation that in a lower pH (more acidic) environment, Hemoglobin will bind to oxygen with less affinity. Blood pH is governed to a large degree on the balance between CO2 and O2 partial pressures, Carbon Dioxide being acidic in nature and the blood naturally alkaline. In addition, Hemoglobin bound to CO2 loses its affinity to O2, described by the Bohr effect, shifting the O2-Hb-Dissociation Curve to the right.
The same effect is noted with H+ ion concentration. H+ ions bind with great affinity to Hemoglobin, especially DeoxyHemoglobin (in the venous blood). DeoxyHemoglobin bound to H+ has a slightly reduced affinity for O2. With greater H+ ion concentrations, or lower blood pHs, Hemoglobin binds more readily to H+ and subsequently has slightly reduced affinity to O2. This similarly shifts the O2-Hb-Dissoc. Curve to the right. Higher CO2 blood levels result in a lower pH or increased H+ ion concentration too. The reverse is also true.
It is clear that blood pH and HCO3-/CO2 levels in the blood are carefully balanced by a number of factors:
We shall now examine the effects of too low or too high CO2 levels.
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Hypocapnia - Too Low Blood CO2 Levels:
Too low Carbon Dioxide (CO2) partial pressure and Bicarbonate Ion (HCO3-) concentration in the blood is known as Hypocapnia. Hypo means 'too little' and capnia refering to CO2.
Hypocapnia is usually caused by Hyperventilation (Hyper-ventilation, i.e. over breathing) and can result in the elevation of blood pH and respiratory alkalosis. Acidosis and Alkalosis in general, mainly from a nutritional pespective are discussed on the Acidosis page.
Hyperventilation, or overbreathing, is a type of breathing wherein the person breathes faster and/or deeper than necessary for requirements (i.e. faster than normal but at the rate depth of breath; or deeper than normal but at the same number of breaths per minute; or faster AND deeper than normal).
In general, hyperventilation increases O2 levels in the blood but decreases CO2 levels. Deep or rapid breaths increase the rate/percentage of exchange of the alveolar gases with the ambient air and have the net effect of expelling more CO2 from the body than normal, there being less CO2 in the air than O2. O2 levels are marginally increased. The decrease in HCO3- (effectively the partial pressure of CO2) in the blood plasma effectively raises the pH of the blood (reducing its acidity and making it more alkaline). Hyperventilation can be a response to respiratory acidosis or underbreathing, or indeed metabolic acidosis, but usually it is a stress response or instigated voluntary.
The nervous system assumes that when CO2 levels are low, O2 levels are high. When a raised blood pH is detected (i.e. alkalosis), caused by too little plasma HCO3-), the cerebral blood vessels constrict accordingly, probably as the respiration rate is deemed to be reduced and less O2 is deemed to be required. Alkalosis of the bood (hypocapnea) therefore initiates the constriction of the blood vessels that supply the brain and prevents the transport of O2 and other nutrients and molecules necessary for the proper functioning of the nervous system. Some of the associated symptoms include lightheadedness, dizziness, anxiety, visual disturbances and possible fainting.
In addition, alkalosis results in a reduction in the Calcium ion concentration in the blood (Hypocalcemia), which instigates vasoconstriction around the muscles and nerves. This can result cause tingling and pins and needles on the skin, muscle cramps and even tetany (involuntary constraction of muscles, usually at the extremities).
Hypocapnea is sometimes induced by hyperventiation as a deadly schoolyard fainting game and also by freedivers who wish to extend their underwater time (by suppressing the instinct to breathe, which is driven by CO2 levels in the blood), but of course this does not increase their O2 levels significantly, so they may be at a much greater risk of blacking out underwater when they run out of O2, but the nervous system has not given them such strong signals to breathe on account of the CO2 levels not having had the chance to build up properly to the levels where the freediver would abort the dive and return to the surface.
Hyperventilation should not be confused with Hyperpnea. Hyperpnea, a.k.a. Hyperpnoea, is an increased depth of breathing when required to meet oxygen demand in the body, for instance at high altitudes or as a result of anaemia.
Tachypnea, a.k.a. Tachypnoea, is a form of rapid, shallow breathing. It is performed to meet oxygen requirements, and is usually performed immediately after strenuous exercise. Hyperventilation is not performed to meet O2 requirements and usually involves deeper, rapid breaths. Tachypnea can also occur in the instance of Carbon Monoxide poisoning where O2 delivery to the tissues and organs is blocked causing hypoxia (discussed below).
Hyperventilation should also not be confused with deep breathing exercises for relaxation or meditation. Although these involve using more of the lung capacity in each breath, they do some at a very much reduced rate, providing probably the same amount of gas exchange as normal breathing, but which helps in relaxation and in producing Alpha waves in the brain. Deep breathing exercises, if performed incorrectly, can be a form of overbreathing or hyperventilation. In general, for shallow chest breathers, deep, slow breathing can be very beneficial. The in breath tends to lower CO2 levels and increase O2 levels, but a slow outbreath tends to lower the heart rate and increase CO2 levels. This is why a deep inhalation followed by exhalation is used by people who are shallow breathing and are stressed.
As stated above, reduced CO2/HCO3- levels in the blood will tend to raise the pH and lower H+ ion concentration. This tends to shift the O2-Hb-Dissociation Curve to the left and increase the affinity of O2 to Hemoglobin. O2 is harder to release from the RBCs but is binds much more readily to the RBCs in the lungs. Thus it is easier to achieve a high blood O2 saturation level, but lower tissue O2 levels. A very high Hemoglobin % O2 Saturation reading on a Pulse Oximeter may perhaps be indicative of too low blood CO2 levels. Of course it will not tell you anything about the tissue levels of these gases.
Because of metabolic acidosis or an over ingestion of acidic or acid-producing foods, an individual may be overbreathing in order to remove more CO2 from the blood in order to balance the pH. Whilst the pH of the blood may be normal, the level of HCO3- in the blood may be somewhat low for the nervous system. It could equally work the other way around with too alkaline a diet meaning the person underbreathes in order to compensate. When considering O2 and CO2 levels and breathing techique, one should also consider diet and metabolic factors to give a true picture of what is going on and to ensure there are no compensatory mechanisms in place.
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Hypercapnia - Too High Blood CO2 Levels:
Too high Carbon Dioxide (CO2) partial pressure and Bicarbonate Ion (HCO3-) concentration in the blood is known as Hypercapnia. 'Hyper' means 'too much' and 'capnia' refering to CO2.
Hypercapnea can result in respiratory acidosis and carbon dioxide toxicity. A blood CO2 gas toxicity level over 45mmHg is considered as Hypercapnea. As we know, this partial pressure of CO2 is not present in the blood, as most of this CO2 is in the form of dissolved HCO3- ions (i.e. bicarbonate, in other words, ionised carbonic acid.) The PaCO2 value in mmHg is a convenient comparative measurement. It is more realistically expressed in terms of the actual elevated blood serum bicarbonate (HCO3-) concentration, which is defined as Hypercapnea at anything over 28mg/dl of HCO3-.
Hypercapnea is in general caused by inadequate gas exchange for the body's requirements, e.g. insufficient or inadequate breathing (Hypoventilation - examined below), lung disease or diminished consciousness. In these states the body continues to produce CO2 as a result of respiration but the body does not ventilate itself effectively enough, so that CO2 levels in the blood rise. Inadequate gas exchange in the lungs also results in low O2 levels also. It is most like the failure of the reflex to ventilate properly (controlled by the Central Respiratory Centre), in acute respiratory acidosis, that affects those some CFS sufferers, in certain body positions (e.g. in the supine position). Another cause of elevated CO2 levels may be rebreathing momentarily (e.g. breathing into a plastic or paper bag over several breaths), or remaining in a small enclosed environment (e.g. a car with no fan or a/c on, and no windows open. Of course rebreathing will eventually lower O2 levels if more O2 is not introduced into the breathing loop, but the initial effect is a rapid rise in blood CO2 levels. One should consider if only shallow breaths are taken, then one is increasing the amount of gas that is not exchanged and thus being rebreathed, CO2 building up more in the bottom of the lungs where there is less gaseous exchange. Hypercapnea also affects some scuba divers who breathe too shallow or skip breathe on very deep technical dives (often because of increased breathing resistance), and of course can affect anyone in an unventilated environment, especially with a large number of people; individuals exposed to volcanic emissions can also suffer.
Clearly the definition of what constitutes Hypoventilation or underbreathing (discussed below) depends on the individuals' actual respiration rate and the body's requirement for O2 to enable this level of respiration. If an individual has a depressed respiration rate and metabolic rate, for example, in some CFS patients, then there is a reduced requirement for O2 and hence the breathing rate will slow down or breaths will be shallower. This should be considered in conjunction with the efficiency of gas diffusion and transport which may of course be reduced, so the body may be slightly deficient in O2, but not excessively so, in most bodily positions. In other words, with very shallow breathing, the body may more or less meeting its O2 requirements, so the breathing technique is not considered to be either overbreathing or underbraething. However, if respiration rates are lower, then CO2 production will also be lower. This may possibly result in smaller amounts of CO2 being put into the blood. Blood volume will stay more or less the same regardless of a person's respiration rate, so if there is less CO2/HCO3- going into it, then the result may well be a decrease in acidity, i.e. potential alkalosis. Equally, when gas exchange is poor, it is likely that less CO2 may be being removed from the lungs, which might allow CO2 levels to build up to normal. However this brings up back to the respiration rate again. So the net effect could in fact be neither respiratory alkalosis or acidosis. It is clearly dependent on many factors being balanced as to what the exact outcome really is.
The nervous system, using CO2 receptors, work on the basis that if CO2 levels are high, then O2 levels must be low (i.e. there is an airway obstruction or otherwise problem with breathing) and this triggers vasodilation to increase blood availability to the tissues and also the urge to breathe more (above the normal autonomic nervous system controlling of breathing in the background if you do not override this consciously). Under normal circumstances, CO2 in the blood in a relaxant and the associated vasodilation helps to relax a patient. Excessive CO2 levels in the blood may interfere with sleep patterns (e.g. arousal or head turning during sleep) as the nervous system tries to trigger the body to breathe more and if necessary brings one out of one's sleep cycle phase as it is deemed an 'emergency'. This may be especially noticeable in patients where the CO2 and O2 diffusion in the supine position is rather poor. This may be helped by the use of supplemental oxygen, described below.
Hypercapnea, as well as the vasodilation and breathing reflex, can cause an flushed skin, a full pulse, extrasystoles (Premature Ventricular Contraction) or PVC/VPC/VPB - presented as palpitations or skipped heart beats), muscle tremors, hand flaps, reduced neural activity and elevation in blood pressure. It can also result in a shortness of breath, increased heart rate, sweating, drowsiness, mild narcosis, confusion, headaches and even unconsciousness.
Extrasystole can have many other causes, including imbalances in the Mg, Ca and K ratios in the body, but can also be triggered by caffeine consumption or stress. Please see the Cardiac Insufficiency page for strategies for dealing with palpitations.
As stated above, elevated CO2/HCO3- levels in the blood will tend to lower the pH and increase H+ ion concentration. This tends to shift the O2-Hb-Dissociation Curve to the right and reduce the affinity of O2 to Hemoglobin. O2 is released more easily from the RBCs but is harder to move into the RBCs in the lungs and achieve an equivalent level of blood O2 saturation to normal. A relatively low Hemoglobin % O2 Saturation reading on a Pulse Oximeter may perhaps be indicative of too high blood CO2 levels. Of course it will not tell you anything about the tissue levels of these gases.
Dr Peter Julu has found that elevated CO2 levels in the blood can result in abnormal functioning of the brainstem, including Abnormal Spontaneous Brainstem Activation, which is one cause of Cardiac Arrhythmia, as discussed on the Cardiac Insufficiency page.
One additional contributary factor to acidosis could also be metabolic acidosis, which when combined with elevated CO2 levels (respiratory acidosis), produces a significant level of Acidosis of the blood.
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Inefficient Oxygen Perfusion:
Below we shall examine some of the various ways in which CFS patients can develop low levels of tissue oxygenation.
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Porphyrins and Heme Production:
Porphyrins are the conjugate acids of ligands that bind with +2 or +3 metal ions to form complexes. Porphyrins are intermediary compounds in the production of Heme (used in Hemoglobin and also protective antioxidant Cytochrome enzymes), and the respective enzymes involved with converting one form of Porphyrin to another are particularly sensitive to the presence of heavy metals or certain organic chemical toxins. Presence of these foreign toxins can inhibit the enzymes involved in these intemediary steps, thereby resulting in elevated levels of these intermediary products in the urine; and consequently too little Heme being produced.
Clearly if heavy metal toxicity has impacted the Porphyrin conversion and Heme metabolism pathway, then there could be a serious impact on Hemoglobin levels in the red blood cells in the blood stream and Oxygen transport in the body.
In addition, if low levels of Iron, L-Histidine and various methylating cofactors are present in a given individual, then Heme production may be further impaired, further affecting an individual's ability to absorb and transport O2.
For more information on Porphyrins and Heme Production Impairment, please see the Effects of Toxicity page.
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A number of factors are important in the production of Red Blood Cells (RBCs). RBC production takes place in the bone marrow are requires sufficient dietary iron, as well as the B-vitamins Folic Acid (B9) and Methylcobalamin (B12), and various amino acids including L-Histidine. The B-vitamins are vital for the process of methylation, the addition of a carbon group to a protein or amino acid. Methylation is vital for a large number of bodily processes, but in this instance, it concerns RBC production. Deficiencies in either of these B vitamins, on account of insufficient intake and/or poor absorption from the GI tract, may well result in a bottle neck in RBC production.
For more information about the role of Iron, L-Histidine, B9 and B12 in RBC production, please see the Iron section on the Nutritional Deficiencies page. For more information about methylation, please see the Methylation section on the same page.
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Cardiac Insufficiency and ASBAs:
Cardiac Insufficiency is largely a result of decreased mitochondrial function, as discussed on the Cardiac Insufficiency page. However, there are other factors to consider besides a decreased output of the heart muscle. The autonomic nervous system is responsible for maintaining cardiac function in response to a variety of changing bodily requirements, which is performed unconsciously. Tests on CFS patients have shown that a degree of dysautonomia is also often present in CFS patients, with a degree of instability in the maintenance of blood pressure and heart rate, in response to changing postural and other requirements. Certain postures may result in abnormally low oxygen diffusion rates into the tissues or sluggish increases in oxygen diffusion in response to increased requirements, e.g. beginning exercise. In addition, the brainstem may be irritated and produce Abnormal Spontaneous Brainstem Activations (ASBAs), which result in erratic variations in the blood pressure and heart rate, with no external cause identifiable. All these failures in normal regulation of the blood pressure and heart rate result in inefficient supply of oxygen and nutrients to the cells of the body, and of course accompanying fatigue. Specific examples may be considered below. For more information, please see the QIFT section on the Tests page.
A sustained drop in DBP by 10mmHg or more within 3 minutes of having assumed an erect posture in comparison with the level in a horizontal posture, is an indication of orthostatic hypotension (a.k.a. postural hypotension - a sudden drop of blood pressure when a person stands up, a 'head rush'). When a healthy person stands up, the blood pressure increases hugely momentarily, but then drops down again 'like a stone' to a normal level. This reflex is designed to preserve blood flow into the brain and to maintain consciousness. An example of very poor control of BP when standing up, would follow the usual pattern of a big increase in BP followed by a sharp drop in BP, but then a period of oscillation of BP, fluctuating, until it eventually settles down.
O2 levels are intended to be greater when one is sitting up or standing up, as opposed to reclining in the supine position - to reflect levels of cellular activity, energy expenditure, relative alertness and also the blood pressure requirements of the respective postures. An excessive drop in what is effectively tissue O2 levels, particularly evident in dysautonomia cases, when lying down, is evidence of poor oxygen diffusion and perhaps also poor BP and HR regulation. This may perhaps be exacerbated by abnormal brainstem activity and also elevated Nitric Oxide levels.
During deep breathing exercises we expect to see a significant rise in O2 levels and a significant drop in CO2 levels, as well as a drop in heart rate instigated by the nervous system. A late and slight change in these gas levels in the deep breathing exercise is seen as a sign of poor gas diffusion in the tissues.
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2,3-BiPhosphoGlycerate (2,3-BPG or BPG for short), a.k.a. 2,3-DiPhosphoGlycerate (2,3-DPG), is the chemical compound that encourages the release of partially deoxygenated hemoglobin (deoxyhemoglobin), to ensure as much oxygen is released from the red blood cells (RBCs) as possible. 2,3-BPG shifts the equilibrium of haemoglobin to the deoxy-state. 2,3-BPG binds with high affinity to haemoglobin, displacing and releasing some of the remaining oxygen from the semi-deoxygenated RBCs, which then passes out of the capillaries and into the surrounding cells. 2,3-BPG selectively binds to the deoxyhemoglobin, making it harder for oxygen to bind with the hemoglobin and more likely to be released to the surrounding tissues.
The tissues, e.g. organs or muscles, of course require oxygen and when under increased work loads, the presence of hygrogen ions (i.e. acidic ions) allows oxygen to separate from the hemoglobin. Acidic conditions inside the RBCs help in this regard. The capillaries are also very narrow and actually act to squeeze the RBCs to help release their oxygen.
'[2,3-BPG]...binds with greater affinity to deoxygenated hemoglobin (e.g. when the red cell is near respiring tissue) than it does to oxygenated hemoglobin (e.g. in the lungs). In bonding to partially deoxygenated hemoglobin it allosterically upregulates the release of the remaining oxygen molecules bound to the hemoglobin, thus enhancing the ability of RBCs to release oxygen near tissues that need it most...2,3-BPG is part of a feedback loop that can help prevent tissue hypoxia in conditions where it is most likely to occur. Conditions of low tissue oxygen concentration...will tend to cause RBCs to generate more 2,3-BPG in their effort to generate energy by allowing more oxygen to be released in tissues deprived of oxygen. Ultimately, this mechanism increases oxygen release from RBCs under circumstances where it is needed most.'
2,3-BPG is generated from inside Red Blood Cells. Bisphosphoglycerate mutase (BPGM) is an enzyme responsible for the catalytic synthesis of 2,3-BPG from 1,3-BPG. BPGM has also both mutase and a phosphatase function which are less pronounced that its effect as a catalyst in 2-3-BPG synthesis. BPGM is unique to erythrocytes (Red Blood Cells or RBCs) and placental cells,i.e. those cells that contain haemoglobin. 1,3-BPG is an intermediate formed in Glycolysis (the metabolic process of converting glucose in pyruvate (examined on the Food Intolerance page with respect to Fructose metabolism and Fructose intolerance).
2,3-BPG levels are not altered dynamically as the blood circulates around the body (from the lungs to the tissues), but tend to be fairly constant in a given individual, depending on physiological adaptation. High levels of 2,3-DPG create a decreased affinity for O2 in the hemoglobin, and shift the Oxygen-Hemoglobin Dissociation Curve to the right so that a higher partial pressure of O2 is required to achieve the same level of O2 saturation in the Hemoglobin. However, higher 2,3-BPG levels also ensure that hemoglobin loses more of the O2 that it is carrying at the capillaries (i.e. when hemoglobin is in the deoxy-state). Conversely, lower 2,3-BPG levels result in an increased affinity for O2 in the hemoglobin, i.e. a leftward shift in the Oxygen-Hemoglobin Dissociation Curve, and lower partial pressure of O2 required to achieve the same level of O2 saturation in the Hemoglobin, but that there is less tissue perfusion and delivery of O2 to the tissues as less of the RBC's Oxygen i delivered in the capillaries (i.e. more is retained).
Low 2,3-BPG levels are usually observed in patients with Septic Shock and Hypophosphatemia, the latter which can be caused by respiratory alkalosis (in the RBCs). However, Dr Peter Julu theorises that low 2,3-BPG levels in some CFS patients may also result in similar patterns of low oxygen perfusion into the tissues, and may mean that the enzyme BPG mutase may not be functioning inefficiently (i.e. not producing enough 2,3-BPG) or there is not enough 1,3-BPG available (from Glycolysis), despite sufficient oxygen levels in the red blood cells. This can set the body up for an oxygen-deficient state (i.e. anoxia). Some parallels could be drawn between Hypophosphatemia and CFS in that in both conditions, a lack of ATP (a source of phosphate) could be a contributary factor.
As stated above, 1,3-BPG, the precursor to 2,3-BPG, is formed as a byproduct of aerobic respiration (glycolysis), and so if cellular oxygen availability is very low, then clearly the ability to respire aerobically (i.e. using oxidisation) to produce 1,3-BPG and thus 2,3-BPG to help increase that oxygen transport is going to be impaired, regardless of the BPG mutase enzyme count, perhaps resulting in the vicious circle of reduced energy production seen in CFS patients. CFS patients, who may be more anaerobic in their metabolism, are also not producing energy as efficiently. Please see the Mitochondrial page for more information.
Elevated 2,3-BPG levels may indicate that tissue anoxia has been present for a significant period of time and that the body is trying to compensate (with higher levels of BPG mutase). This would presumably signify an improvement in oxygen diffusion but a decrease in overall oxygen saturation (higher partial pressures of O2 being required). Oxygen may not of course be the only problem in given individuals, and a variety of other mitochondrial bottlenecks may well exist. Elevated 2,3-BPG levels tend to occur in smokers and those acclimatised to high altitude environments, on account of less oxygen being absorbed into the lungs, and also in the case of smokers, high levels of carbon monoxide which scavenges oxygen from the hemoglobin to form carbon monoxide. Sufferers of chronic anemia also have increased 2,3-BPG levels, as there is less hemoglobin in the RBCs, so the oxygen that is being carried must be removed and utilised even more efficiently than before. There are other adaptation mechanisms at work in individuals living at high altitudes, including a higher RBC count.
The BPG mutase and 2,3-BPG blood test measures the levels of both compounds and is a useful indicator of anoxia and associated mitochondrial and respiration issues (which should probably be rather obvious in any case).
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Reduction in Oxygen-Permeability of Capillaries
When the body has problems with oxygen perfusion from the RBCs passing (being squeezed) through the capillaries and connective tissue to the target tissues, one of the responses of the target cells that are requiring sufficient oxygen is to release a signalling chemical known as Vascular Endothelial Growth Factor (VEGF), which instigates the growth of new local capillaries. This is known as capillary 'budding'. VEGF and the VEGF blood test is discussed in more detail on the Tests page.
Elevated VEGF levels are one indicator of an anoxic or low oxygen environment and might potentially indicate an issue with the actual capillaries themselves (or perhaps not). Dr Peter Julu believes that in some CFS patients, this might be due to the clogging up of the basement membrane on the outside of the capillaries with immunoglobulins, which are generated from excessive allergic responses. The basement membrane is secreted by the thin cells of the capillaries, the capillary wall being one cell thick. The basement membrane is sticky and helps keep the capillary cells together. If the immunoglobulin build up is indeed occurring then the tissue cells release VEGF in order to stimulate the creation of new capillaries which can then hopefully provide them with sufficient oxygen. The endothelial linings of these newly created 'budded' capillaries produce extra nitric oxide (NO).
However, if immunoglobulins (antibodies) are to blame, then they will proceed to clog up these newly created capillaries also. Dr Julu likens Immunoglobulin release to chemical warfare. They are not targetted locally but are produced by the liver and travel all around the body wherever the blood carries them. There is no decontamination after the 'attack' or their release per se. Whilst the kidneys do indeed filter out what is in the bloodstream, there is no decontamination of the basement membrane afterwards.
The only way to treat this condition according to Dr Julu is to address the root cause of the immunoglobulin production, i.e. the continual allergic response by the body using low dose immunotherapy or elimination diets, nutritional and/or other means. Dr Julu believes that heavy metals toxicity is not a contributary factor to this possible condition, as they tend instead to produce free radicals, inflammation and big molecule immunoglobulins are produced in response to them (unlike the smaller sized immunoglobulins that may clog up the basement membrane.
The basement membrane is not continually regenerated by capillary wall cells and only disappears along with the cell when the cell dies, so the only chance for a new basement membrane free of immunoglobulins would be when the replacement cell creates its own new section of basement membrane coating. Once the levels of immunoglobulins are down, these new sections of basement membrane and capillary walls would become fully permeable to Oxygen again. Dr Julu estimates that it takes approximately 6 months to a year for these cells to regenerate themselves (for the capillaries by the muscle cells).
It is hard to prove this model, and there may be other factors operating that might prevent O2 leaving the RBCs in the capillaries efficiently or competely, such as low 2,3-BPG levels; or perhaps issues with a low Hemoglobin count to start with (which the tissue cells that are excreting the VEGF are 'not aware of'! One could also speculate whether this clogging up of the basement membrane in the capillaries might also render the capillaries less permeable to other gases or nutrients besides oxygen, for example, minerals, amino acids, vitamins and so forth. There may well be other mechanisms for the failure of effecive delivery of nutrients, starting from the digestive tract and finishing at the target cells in the body.
Dr T Michael Culp argues that this phenomenon may not be as common in CFS patients as Dr Julu believes, as excessive immunoglobulin production would be evident as mild kidney disease - the kidney being the organ that filters the blood and removes excess immunoglobulins from the blood. This could be presumably tested by a urine test or perhaps other allergy testing methods. Either way, if you know you have food allergies or intolerances, then it would be shrewd to do something about it either way.
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Methemoglobinemia - Oxidised Hemoglobin, Free Radicals and Nitric Oxide:
Methemoglobinemia is a disorder characterised by the presence of elevated levels of oxidised hemoglobin in the blood, a.k.a. methemoglobin (metHb). This results from the Ferrous (Fe2+) Iron ion inside the Hemoglobin molecule being oxidised by free radicals to Ferric (Fe3+) Iron. Methemoglobin is a non-oxygen binding form of Hemoglobin. On average, a person will have 1% or less of his total Hemoglobin count as Methemoglobin, the remaining 99% present as Hemoglobin. Elevated levels of Methemoglobin can result in tissue hypoxia. Spontaneous formation (oxidation) of metHb by free radicals is normally mitigated by protective antioxidants in the RBCs.
Hereditary Methemoglobinemia can be both congenital or acquired. In the former case it is a result of a recessive gene. In the latter case, oxidising or other predisposing compounds include oxidising drugs, nitrates, antibiotics, local anaesthetics, aniline dyes, metoclopramide, chlorates, bromates etc. Related forms of non-O2-binding hemoglobin include Carboxyhemoglobin (COHb - Carbon monoxide-bound Hemoglobin - discussed below) and Sulfhemoglobin (resulting from medicines such as Phenacetin or Sulfonamides reacting with Hemoglobin). These forms of Hemoglobin are often grouped together with metHb as causes of 'Methemoglobinemia'.
Blood high in metHb is a characteristic brown colour (i.e. rust present!) compared with the bright red colour of healthy blood. Treatments for Methemoglobinemia include supplemental O2 and administration of diluted methylene blue solution which reduces the Ferric Iron back to Ferrous Iron. Other treatments may include other antioxidant (reducing agents) for example Vitamin C (Ascorbic Acid).
Nitric Oxide is a natural messenger molecule, vasodilator in blood vessels and also antimicrobial molecule used in the body. In excess however, its free radical properties can result in oxidative damage, particularly Hemoglobin. Excessive NO and Peroxynitrite formation, for example during a severe infection and in the presence of excessive levels of heavy metals that create an environment of free radicals and suppressed protective Glutathione levels, may be one possible contributary factor towards low tissue oxygenation, on account of its role in the oxidation of Hemoglobin and Myoglobin. Peroxynitrite formation is discussed on the Nitric Oxide and Peroxynitrite page. Dr Paul Cheney has also commented (see below) on the deformity of Hemoglobin exposed to excessive Peroxynitrite, affecting its ability to bind with O2. Methemoglobinemia is probably what he is referring to. Peroxynitrite has other detrimental effects on the vascular system also.
'Nitric oxide forms complexes with transition metal ions, including those regularly found in metalloproteins. The main trap for NO is oxyhemoglobin, which binds NO faster by five to six orders of magnitude than oxygen. The reaction with haemoglobin produces nitrate and methaemoglobin (met-Hb).'
According go Susanna Herold and Kalinga Shivashankar's article 'Metmyoglobin and Methemoglobin Catalyze the Isomerization of Peroxynitrite to Nitrate' Biochemistry, 2003, 42 (47), pp 14036-14046:
'Hemoproteins, in particular, myoglobin and hemoglobin, are among the major targets of peroxynitrite in vivo. The oxygenated forms of these proteins are oxidized by peroxynitrite to their corresponding iron(iii) forms (metMb and metHb).'
Of course, excessive free radical damage also affects the mitochondrial membranes and indeed cell membranes systematically in the body, which will have a knock on effect on cardiac function and red blood cell function. Low ATP availability affects virtually all the processes of the body, and cardiac is especially important, as discussed above, in supplying the body with sufficient oxygen.
With regards to CFS patients, it is likely to be slight but significant contributary factor, but a small part of a bigger picture. A study by R. Richards, L. Wang and H. Jelinek, 'Erythrocyte Oxidative Damage in Chronic Fatigue Syndrome', Archives of Medical Research, Volume 38, Issue 1, pp 94-98, examined 31 CFS patients and 41 healthy control subjects and evidence of oxidative damage was present in the CFS patients with statistically significant increases in 2,3-BPG (an indicator of long term low oxygenation - described above), metHb and MDA (Malondialdehyde - an indicator of oxidative damage of the mitochondrial membranes).
metHb cannot be detected by using a Pulse Oximeter, the usual pocket device for monitoring blood oxygen saturation levels, which only works with Hemoglobin. One can view the colour of one's blood.
FAQS.Org's article on Pulse Oximetry in Methemoglobinemia
There is a dedicated blood test however to detect the metHb levels as well as the levels of related non-O2-binding forms of Hemoglobin, e.g. carboxyhemoglobin (Carbon monoxide-bound Hemoglobin) and Sulfhemoglobin (resulting from medicines such as Phenacetin or Sulfonamides reacting with Hemoglobin).
Long term use of psychotropic (psychoactive) drugs may result in the accumulation of Lipofuscin or lipopigment waste in cellular membranes, which tends to accelerate the ageing process and decrease neurotransmitter release from neuronal cells.
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Lipofuscin is a type of lipopigment, a fine granular waste that is an indirect result of both glycation (uncontrolled addition of sugar molecules to lipids and proteins without the involvement of enzymes) and free radical attack of lipids and proteins. The waste from the above products is broken down by the cell's lysosomes and the resultant waste is Lipofuscin. There are no natural methods of Lipofuscin removal, besides cell division (mitosis) and death, and it tends to accumulate in the longer lived cells of the body, particularly in the nervous system, heart, lungs and skin. It tends to concentrate in the cellular membranes and affects the cellular membrane fluidity and permeaability. This affects the ability of minerals to be transported in and out of the cells as well as water and oxygen transport into the cells. This results in anoxia and dehydration and tends to accelerate the ageing process in these long lived cells. With respect to the lungs, it is possible that its accumulation in cells in the lungs may reduce the efficiency of lung function, thereby reducing the amount of oxygen that reaches the blood, although this is more my own speculation. Anoxia also causes increased free radical production, which in turn results in more free radical attack on cellular lipids, which in turn results in more Lipofuscin accumulation. Lipofuscin is in many respects both a marker and a cause of low cellular oxygenation.
Lipofuscin can be removed by the use of Nootropic drugs such as Centrophenoxine. Centrophenoxine (and also the complimentary drug Piracetam) can also help to oxygenate the brain directly.
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Carbon Monoxide (CO) binds 240 times more readily with Hemoglobin that Oxygen (O2) does. The presence of CO on one of the 4 Heme sites of the Hemoglobin molecule causes the other 3 Heme sites to bind with greater affinity to O2, which makes it more difficult for the Hemoglobin to release this O2 to the tissues in the capillaries. This has the effect of shifting the oxygen-hemoglobin diffusion curve to the left. With increased levels of CO, a person can suffer from severe hypoxemia whilst still maintining a seemingly normal pO2, i.e. the O2 saturation levels are normal but much of that O2 cannot leave the RBCs and simply recirculates around the body whilst the tissues are O2 starved. Hemoglobin that has bound to CO is known as Carboxyhemoglobin (COHb). It is referenced above in relation to Methemoglobin, another rogue type of Hemoglobin.
CO is not a normal byproduct of metabolism and comes frome external sources, chiefly from burnt petroleum sources in the external environment, particularly when driving or in cities, and also from indoor sources, such as malfunctioning fossil fuel burning devices, such as boilers, heaters, generators, fireplaces etc. (where it can rise to lethal levels and kills 170 people a year in the USA). CO is also found in cigarette smoke. Assuming you are not exposed to cigarette smoke regularly, and have your gas appliances checked and inspected annually, then the most likely source of any CO poisoning you may have is from traffic fumes in urban environments. This may contribute to the worsening of your condition to some degree, and if you move out to the countryside you are likely to feel slightly better ('fresh air'). Of course, it is difficult to get away completely from traffic or busy roads, even in the countryside in many densely populated countries, but every little helps.
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Hydrogen Sulphide is examined in detail on the Effects of Toxicity page. A brief summary shall be provided here.
An example of exotoxins produced by bad bacteria, parasites and fungi includes Hydrogen Sulphide (Sulfide in the USA), or H2S. As stated in the Sources of Exogenous Toxins section, on the Bacterial Overgrowth page and Mitochondrial Dysfunction page, Hydrogen Sulphide (H2S) is an exotoxin produced in the body by the action of bad bacteria and fungi (such as Candida Albicans) fermenting sugar in the gastrointestinal tract. H2S is also natural by product of various bodily processes (e.g. produced by brain, pancreas and GI tract) and it plays a part in regulating the blood pressure, body temperature, vascular smooth muscle,cardiac function, cerebral ischemia, and in modulating the hypothalamus/pituitary/adrenal axis.
Since hydrogen sulfide occurs naturally in the environment and the gut, oxidative enzymes exist in the body capable of detoxifying it by oxidation to (harmless) sulfate. Hence low levels of sulfide may be tolerated indefinitely. Humans can smell the odour of hydrogen sulfide at 0.02 ppm. The toxicity of H2S is comparable with that of Hydrogen Cyanide. H2S is characterised by the 'rotten eggs' smell at low gaseous concentrations. Levels of H2S are normally regulated by the body's oxidative enzymes.
Elevated levels of H2S in the blood and tissues, that the body's oxidative enzymes cannot effectively deal with (or being overwise engaged with oxiding drugs and other chemical toxins from the blood in addition to the additional H2S), can result in mitochondrial dysfunction by their action on the Cytochrome C Oxidase enzyme which is involved in ATP production. It forms a complex bond with iron in the mitochondrial cytochrome enzymes, thereby blocking oxygen from binding and stopping cellular respiration.
With regards to dealing with cases of low (non-toxic) levels of Hydrogen Sulphide poisoning in the body's mitochondria, for example that which arises as exotoxins produced by bad bacteria, fungi and parasites in the digestive tract over long periods of time, then treatment options may include boosting the body's natural oxidative enzyme count and assisting liver functioning; cutting out toxins and drugs that require removal by the Cytochrome P450 enzymes (i.e. alleviating the burden on these enzymes to allw them to focus on removing the H2S movlecules); removing the source of the additional exotoxins (i.e. eliminating the bad bacterial/fungal/parasitic overgrowth that is producing the extra H2S); and proper breathing (i.e. diaphragm breathing rather that the shallow breathing that is typified by use of the rig cage only). Oxygen therapy and even hyperbaric therapy may well be useful too.
Elevated bodily Hydrogen Sulphide levels are said to result in elevated levels of Hydrogen Sulphide in the urine, according to Kenny De Meileir, which forms the basis of a new 2009 home test by Protea Biopharma.
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Dr Paul Cheney's Theory on Oxygen Toxicity and PFOs:
In Dr Paul Cheney's seminar from 9 September 2006, University of North Texas, Health Science Center, Fort Worth, Texas, discussed on the Cardiac Insufficiency page, he states that from his clinic's findings, CFS patients have been observed to consume only 67% of the oxygen compared with a 'normal' control group, and breathe in a more shallow manner. This is most likely explained by inefficient mitochondrial function, which acts to reduce cardiac output and perhaps also to reduce actual requirements for oxygen in the tissues. It is assumed these were resting measurements and not measured during exercise. Normally one associates decreased oxygen demand that with a higher level of cardiovascular fitness with lower oxygen consumption and a lower heart rate. However, one would assume the non-CFS sufferers would be of a lower level of cardiovascular fitness than the control group, but potentially with a higher heart rate and lower cardiac output.
Cheney has also observed that CFS patients also demonstrate little desaturation of oxygen in their hemoglobin compared with a 'normal' control group. That is to say, the hemoglobin in the red blood cells that scavenge oxygen from the lungs and transport it to the tissues do not actually readily release that oxygen, but the oxygen remains bound to the red blood cells to a much greater extent than in non-CFS affected individuals. Thus, more oxygen simply circulates around the blood stream within the hemoglobin and is not so readily absorbed by the tissues.
The reduced pattern of desaturation of the hemoglobin is known as a left-shift in the Oxygen-Hemoglobin Dissociation Curve, meaning greater oxygen affinity and increased difficulty transferring oxygen.
We have examined some of the reasons for the Left Shift on this page, including low 2,3-BPG levels, clogged up capillaries, less Hemoglobin in the blood, elevated levels of rogue hemoglobin molecules that do not bind with O2 (e.g. Methemoglobin), etc. A left shift in the Oxygen-Hemoglobin Dissociation curve normally means that oxygen binds very well to the Hemoglobin, but that it is not easily released to the tissues.
The matter of whether the RBCs are able to absorb less O2 from the lungs (less demand for oxygen or less ability to absorb oxygen), for whatever reason, is a different issue to how readily they are to oxygenate the tissues. They may be describing the same problem of course, but then again they may not be.
A left-shift in the Oxygen-Hemoglobin Dissociation Curve should mean that increasing the partial pressure of O2 makes little difference to the degree of additional oxygenation of the blood and thus little benefit for the target tissues. Cheney's findings do not quite back up this idea, in fact, arguably contradict it. Low oxygen doses (i.e. slightly enriched oxygen mixtures) has shown to improve most of the CFS patients with a PFO at Cheney's clinic (who seem to comprise the vast majority of his CFS patients, in contrast to the general trend of CFS patients elsewhere). I myself have benefitted from breathing O2 at various points in my condition.
One can speculate as to whether these patients had less hemoglobin or less functioning hemoglobin, which under normal breathing patterns in those patients, was fairly well oxygenated, but that did not respond so well to increases in the partial pressure of O2. However, one would expect the blood of such patients to be fairly well deoxygenated, assuming no other problems were present in oxygen delivery, which there may well have been. Without further test data to go on, Cheney's findings can only go so far.
Cheney states in his 2006 seminar that elevated Peroxynitrite levels in CFS patients may be a factor explaining the inability of hemoglobin in CFS patients to bind well with O2 (a right shift in the Oxygen-Hemoglobin Dissociation Curve). He describes Peroxynitrite's affinity to hemoglobin, deforming the hemoglobin molecules and preventing them from absorbing oxygen. Is he actually talking about the oxidation of Hemoglobin to the non-O2 binding form, Methyemoglobin, described above? Are multiple mechanisms at work here? Cheney does appear to be contradicting himself somewhat otherwise. Oxidative damage of Hemoglobin and reduced ability to absorb O2 is not the same as high levels of oxygen saturation, but rather a lack of oxygen saturation. One must be clear about what one means by Oxygen Saturation and how it is being measured, i.e. what is actually being measured - functioning Hemoglobin? In normal measurements of O2 saturation, only Hemoglobin is measured, not Methemoglobin.
Cheney's theory regarding Oxygen Toxicity (in PFO patients) states that oxygen consumption and diffusion is limited purposely in order to prevent oxygen toxicity from occurring. This is the reverse logic of most commentators, who state that there is an oxygen deficiency in the tissues and that they require more oxygen. Cheney argues that they are getting the correct amount of oxygen, respiration being the limiting factor. A measure of VEGF levels in his test patients would verify whether this was indeed correct or not, as elevated VEGF levels would indicate whether the tissues were signalling for more oxygen or not (stimulating the growth of new capillaries).
The main crux of Cheney's hypothesis of Oxygen Toxicity is based on respiration being limited by the antioxidant availability to protect against the free radicals produced by respiration, and that additional oxygen is not required as it would overburden the body with free radicals. However, if there are other explanations for the high oxygen saturation of venous blood, then this argument may well be fallacious.
Cheney describes the cellular 'cooling system', a figure of speech for the protective internal antioxidants that the cells produce in order to protect themselves from oxidative damage caused by respiration in the mitochondria (the 'heating' or energy production system). The 'cooling system' therefore has a role to mop up the downstream products of respiration (i.e. mitochondrial function). These antioxidants and antioxidant enzymes include, in order of decreasing potency, Superoxide Dismutase (SOD), Glutathione (GSH) and Catalase (CAT). These are described in more detail in the Antioxidants section on the Nutritional page and also on the Liver Function page. Essentially one's mitochondrial rate has to adjust to or be capped by the maximum ceiling abilitiy of the 'cooling system' of protective antioxidants or severe free radical damage/oxidative damage can occur to the inside of the cell. The mitochondrial rate is also capped by the lack of availability of ATP. The effect of Superoxide is hugely magnified in the presence of heavy metals. Too much respiration and the oxidative damage that can occur includes DNA and RNA damage, Protein and Lipid Damage, etc.; affecting individual cells in many systems of the body.
Oxygen intake results in the formation of dangerous free radicals, superoxide by oxidase enzymes, as well as NO (Nitric Oxide) and H2O2 (Hydrogen Peroxide), all powerful oxidising agents. The presence of superoxide and these other compounds stimulates the body's enzymes. However, over a certain threshold concentration/level of production of superoxide and other oxidising agents/free radicals, the body is unable to compensate, i.e. not enough SOD etc., and the result is simply a huge increase in the number of free radicals. Thus too much oxygen is regarded by Cheney as being toxic or being 'oxygen toxicity'; what he is really talking about is a level of oxygenation or metabolism that results in more free radicals than the body can handle, which would result in excessive free radical damage to the mitochondria and cell membranes of the body's cells. This is the crux of Cheney's theory that reduced mitochondrial and cardiac output are mechanisms to keep oxygen levels in line with what the body actually requires.
Dr Paul Cheney, as stated in some of his seminars, believes that Peroxynitrite is primarily formed by Superoxide (a byproduct of ADP to ATP conversion, i.e. energy production, inside each cell) leaking out of the mitochondria and reacting with Nitric Oxide (NO - a byproduct of NOS enzyme activity). This is not strictly speaking correct. Some ONOO- is indeed formed inside the mitochondrial membranes, but normally only a very small amount. The Superoxide Dismutase (SOD) present in the mitochondria inhibits ONOO- production by reacting with the O2- before it can react with NO to form ONOO-. The mitochondria also contain some levels of Glutathione (hopefully sufficient) to protect the mitochondrial membranes against ONOO-. As discussed above, Superoxide is produced outside of the mitochondria as well inside them, so the Superoxide that reacts with NO to form ONOO- in the cytoplasm of cells and also outside of the cells themselves is far more likely to be responsible for cystoplasmic and extracellular ONOO- than Superoxide 'leaking' out of the mitochondria.
The Superoxide produced as part of respiration and ADP to ATP conversion stays inside the inner mitochondrial membrane. It can only escape and 'leak out' if the mitochondrial membrane is damaged. This can and does of course occur, especially in some CFS patients with excessive free radical damage, but not to the extent that would be necessary to account for such Peroxynitrite build up in the body. Indeed, this degree of mitochondrial membrane damage would likely result in death, as demonstrated by laboratory mice that had no mitochondrial SOD and had their mitochondrial membranes attacked and ravaged by O2-, which did not live very long. In the majority of CFS cases, this route is unlikely to be the dominant one for ONOO- production in the body. The mechanisms cited by Martin Pall above seems to make more sense, including the production of SOD by cytoplasmic NOS enzymes (outside the mitochondria) in the absence of sufficient L-Arginine or BH4 to make their usual NO.
Cheney stresses the importance of Glutathione and Selenium (an antioxidant metal and constituent of Glutathione) as a defence against ONOO- and in this he is correct, as Glutathione is the body's main intracellular and extracellular antioxidant enzyme, particularly with regards to controlling free radical damage. However, whilst both Glutathione and SOD help to prevent oxidative damage to the mitochondrial membranes, SOD is directly responsible for containing Superoxide, which is arguably of most primarly importance, Glutathione being a secondary line of defence.
So what happens to oxygen that is not used in respiration to produce superoxide? Presumably there is a limit to how much oxygen can be converted to superoxide by oxidase enzymes? According to Cheney any remaining that is not converted to superoxide is extruded through the skin.
Cheney states that anti-ageing theory has it that the less calories one consumes, the less 'ageing' that will occur. This can be directly translated to calories burnt and thus oxygen consumption. We need oxygen to survive, but the more we consume, the more potential for oxidative damage we incur (if we exceed the cellular limits of defence).
His argument is that increasing oxygen levels in the tissue will by default increase respiration in the tissues which is not what you want, but this cannot occur without an increase in blood supply. Cheney's findings show that increasing oxygen supply through supplemental oxygen ends to improve mitochondrial function slightly, but not enough in most patients to pose any problems for the heart. Introducing more O2 into the bloodstream and target tissues by correcting some of the problems in the oxygen delivery system, as discussed on the Tissue Oxygenation page, can only increase respiration rates and metabolism by so much, because the Krebs Cycle and blood sugar availability would still be impaired. In my opinion, there is no 'protective mechanism' per se, it just appears that way. Of course, I am no expert in mitochondrial function and would welcome any clarifications or commentary to the contrary.
Cheney emphasises the sequential sacrifice of the organs and systems of the body on account of reduced mitochondrial function, mainly a result of excessive Peroxynitrite formation. He cites various 'protective mechanisms' of the body to prevent normal levels of respiration and oxygenation. However, whilst he may be correct in his observations of the effect of O2 on PFO patients, these two conclusions do not seem to be correct to me. For example, excessive Peroxynitrite formation can surely not be both a cause and a solution at the same time? Peroxynitrite along with NO oxidise Hemolglobin into its non-O2 binding form, Methemoglobin. Surely the body cannot be purposely wanting to have free radical damage occur generally within it and in particular to damage the oxygen tranport capability of the body (along with everything else)? A reduction in Hemoglobin or RBC production, not limited by bottlenecks in Heme production or Methylation would be a more logical route. Of course, one cannot say that Hemoglobin levels are lower than in a healthy subject 'on purpose' if it would not be possible to produce more even if the body wanted to, on account of biochemical bottlenecks and inefficiency. It strikes me that Cheney has included a number of contradictory themes in his overall theory which he cites as being congruent and proof of a wider scheme of things regarding O2 and respiration management.
Cheney's most recent findings on oxygen toxicity (oxygen response deficit with exercise) as a major factor in causing CFS are shown at the link below. His research outlines some very interesting findings, but his hypothesis is perhaps not fully developed at present in this area. The results are far from conclusive.
http://cfsfm.org - 'Oxygen Toxicity as a Locus of Control for Chronis Fatigue Syndrome' by Dr Paul Cheney, 27 May 2008'
'The missing piece to this puzzle may be that we see a super-select group of CFS patients at our clinic.'
Cheney cites evidence of his theory in PFO patients who react badly to increased levels of oxygen. Supply of oxygen enriched mixtures or oxygen under pressure as in hyperbaric oxygen therapy has shown mixed results amongt his patients. Whilst low oxygen doses (i.e. slightly enriched oxygen mixtures) has shown to improve most of his CFS patients with a PFO at Cheney's clinic, high oxygen doses (i.e. pure oxygen or oxygen mixtures under pressure) has resulted in a larger percentage of patients getting worse with slightly fewer showing improvement again. Cheney states that the cardiac muscle has an oxygen threshold, and below this the PFO stays shut (if one is present), but above certain partial pressures of oxygen, the PFO opens and stays open. He therefore concludes that too much oxygen is not a good thing and can simply worsen the diastolic dysfunction of a person with a PFO. Cheney theorises that there is an increased pressure in the heart resulting from lower oxygen levels and that it is more likely to result in a re-opened Foramen Ovale.
Cheney therefore concludes that too much oxygen is not a good thing in general for CFS patients and can simply worsen the diastolic dysfunction of a person with a PFO. Of course, it is one thing breathing 90% O2 at atmospheric pressure, but it is quite another breathing O2 enriched air or pure O2 under pressure, and Oxygen becomes toxic and inflames the lungs at 1.6 and can cause CNS toxicity, and may also displace Nitrogen and CO2 in the blood, so it is not surprising that some problems can be observed with O2 under pressure in CFS patients.
A number of questions arise however from Cheney's test data (which he does not present in the aforementioned seminar. To what extent were PFOs represented in those patients that got worse? And to what extent were PFOs not represented in those patients that continued to improve with increasingly higher levels of oxygen? Perhaps the oxgyen 'toxicity' issue is really just a PFO associated issue that does not affect those (to such a large extent or at all) that do not have one? Indeed the concept of this oxygen threshold in CFS patients is not widely or at all accepted in many circles because of the lack of reserach or evidence. It would be preferably to see further research from Cheney in this area with specific references to hard data, amongst PFO and non-PFO CFS patients.
In non-PFO patients, it is likely that there is a certain optimal amount of additional O2 that can be breathed with maximal benefits, with increased amounts not really giving much extra benefit. It is even possible that the body may adapt to O2 usage by producing less RBCs, if the patients uses O2 for many hours each day. Supplemental O2 however should only really be used when it is required. Please see the Supplemental Oxygen section for more information.
It appears on the surface that his theory is specific to PFO patients, who do not appear to make up the majority of CFS paitents outside of his clinic, and that with non-PFO patients it does not apply. Indeed, the fact that most of his PFO patients improved with some additional oxygen actually implies that perhaps their bodies are not delivering quite enough oxygen, but slightly too little - and that a slight improvement in oxygen delivery would help them - but within certain limits of course as not to induce the negative response observed. Cheney appears to have tacked this observation of CFS patients with PFOs onto his observations of cardiac insufficiency in CFS and his concept of sacrificial prioritisation, which seems to fit more CFS patients more of the time.
Patent Foramen Ovale (PFO) is discussed in detail on the Cardiac page.
Sufficient oxygenation and indeed hyperbaric oxygen therapy (i.e. increased pressure of oxygen, as above) is one method used to treat CFS cases where there are high levels of hydrogen sulphide present in the mitochondria (which prevent their proper function). Supplying sufficient oxygen to assist mitochondrial function in my opinion is also likely to help in many CFS cases. I myself tried breathing pure oxygen from my decompression diving scuba tanks when I first came down with CFS and found it made me feel MUCH better. When breathing O2 in a normal fashion, the extra partial pressure of O2 helps to eliminate more CO2 from the body, increasing O2 levels and decreasing CO2 levels. If one breathes deeply and very slowly, then one could argue that the CO2 should be raised rather than lowered on account of the slow rate of breathing, but then perhaps the higher partial pressure of O2 forces more out.
In addition, at various points in my CFS, I felt HUGE improvements by deep breathing exercises and nutritional supplements (e.g. mitochondrial co-factors like Magnesium and also methylation supporting B-vitamins) - at different times individually and done both together.
In short, whilst Cheney may be making valid obserations on the effects of Oxygen on CFS patients with PFOs, I do not believe that this constitutes a general trend for CFS patients as a whole, and quite to the contrary, finds it missing the point, in light of a variety of other measurements of Oxygen Transport problems that he does not consider. Many of Cheney's cited mechanisms are contradictory in nature.
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Dr Paul Cheney's Theory on Low CO2 Levels:
Dr Paul Cheney, in his seminar from 9 September 2006, University of North Texas, Health Science Center, Fort Worth, Texas, discussed on the Cardiac Insufficiency page, argues that Peroxynitrite build up in the body may explain many of the Cardiac and Oxygenation issues we observe in CFS patients. This is probably true in many cases, taking many other factors and mechanisms into account of course. Methods of reducing elevated Peroxynitrite levels are discussed on the Nitric Oxide page.
Cheney argues that one way to reduce Peroxynitrite levels is to increase the body's CO2 levels, CO2 being a Peroxynitrite scavenger. This is based on the idea Hyperponea (or deep breathing to meet O2 requirements) at altitude results in a decrease in CO2 levels which makes CFS patients feel worse, and conversely by rebreathing or going below sea level, CFS patients tend to feel better as they raise their CO2 levels. Whilst Cheney has argued that too much oxygen may be detrimental to many CFS patients, but that a little extra O2 is beneficial for most but not all, it seems perhaps strange that one of his recommendations for reducing peroxynitrite levels is to live in an area with a higher air pressure, which may actually result in a higher oxygen concentration in the blood! Is this 'dangerous'? He reports those that CFS patients that move to areas of higher air pressures feel better. Clearly not everyone breathes in the same way when responding to changes in air pressure.
Whilst CO2 may well be a Peroxynitrite scavenger, if one needs to raise one's CO2 levels, one should be doing so because they are too low and not solely to scavenge elevated Peroxynitrite levels (if present), as otherwise respiratory acidosis can arise - as CO2 is a toxic gas in high enough concentrations. Before embarking on any such regimes, a CFS patient should have their tissue O2 and CO2 levels measured. Many CO2 patients may well have normal CO2 levels and some may even suffer from respiratory acidosis and require less CO2 in their blood! So I believe that Cheney is grossly generalising about CFS patients, or that his patients do not reflect the trends of other CFS patients as a whole.
It should be noted that deep breathing, in the context of slow deep breathing, as opposed to hyperventilation, will also probably stimulate GABA and Dopamine production, to downregulate various systems including Nitric Oxide production. So increasing CO2 levels is not the only breathing-related strategy to reducing Peroxynitrite levels. In addition, at various points in my CFS, I felt HUGE improvements by deep breathing exercises and nutritional supplements (e.g. mitochondrial co-factors like Magnesium and also methylation supporting B-vitamins) - at different times individually and done both together.
Cheney further refines this concept in the 2006 seminar and states the various factors discussed above contribute to intracellular acidosis and extracellular alkalosis. Whilst there may be some truth in this for certain patients, it does not seem completely intuitive to me. If the relevant alkaline metals are not getting into the cells and mitochondria, e.g. Magnesium, Calcium and Potassium, then perhaps the pH is slightly elevated inside individual cells. But this is not to say that the blood pH is high, i.e. too alkaline, as often alkaline metals are simply not being absorbed effectively from the GI tract into the blood and are merely passing out of the body in the faeces. Clearly some proportion is absorbed into the blood, and this will depend on the invdividual, and supplementation will increase the amount that the blood absorbs, but the majority is probably wasted, remaining in the GI tract - on account of digestive inefficiency. However, if one considers the average CFS patient who has not altered his diet (ie. typical acidic food and drink intake) or lifestyle, and has perhaps build up a significant amount of some form of harmful bacteria or microbes in the GI tract, and likely elsewhere, then the blood is likely to be more acidic than it should be, not less. There is also the issue of low stomach acid levels, perhaps lowering the pH. So the net effect is far from clear and must surely depend on the individual.
Cheney's theory regarding Oxygen Toxicity, Reduced Oxygen Demand and PFOs is discussed above. If the body is trying to 'protect itself' from more O2 than it can use by downregulating the heart function and related areas, and the breathing rate and level of O2 transport is reduced, then presumably the level of respiration must also be reduced to match this, or otherwise CO2 levels would build up in the body and acidosis would occur (the opposite pattern that Cheney predicts).
To what extent has a poor breathing pattern contributed to the onset of CFS in the first place (i.e. high CO2 levels, low O2 levels, acidosis etc.)? Is shall breathing in many CFS patients an adaptive response to their condition or a contributary factor to their condition? CFS sufferers are also frequently out of breath after light exercise or mental activity, or during a 'flare', i.e. when their hormones are playing catch up and when their ATP is depleted, usually after over exertion physically, mentally or a poor stress adaptation. Ths would suggest to me that one of the main bottle necks in mitochondrial function is insufficient oxygen rather than too much oxygen at certain points in time, regardless of the severity of the CFS condition, rather than oxygen-related toxicity as Cheney has proposed. However, if one always remains within one's limits of oxygen 'toxicity' or does not exceed them, it is clearly very hard to say either way. The body seeks to increase the breathing rate in order to provide oxygen to provide presumably oxygen starved tissues with sufficient O2 after their largely anaerobic bursts of energy, lactic acid build up, and temporary ATP depletion.
CFS sufferers are also frequently out of breath after light exercise or mental activity, or during a 'flare', i.e. when their hormones are playing catch up and when their ATP is depleted, usually after over exertion physically, mentally or a poor stress adaptation. Ths would suggest to me that one of the main bottle necks in mitochondrial function is insufficient oxygen rather than too much oxygen at certain points in time, regardless of the severity of the CFS condition, rather than oxygen-related toxicity as Cheney has proposed. However, if one always remains within one's limits of oxygen 'toxicity' or does not exceed them, it is clearly very hard to say either way. The body seeks to increase the breathing rate in order to provide oxygen to provide presumably oxygen starved tissues with sufficient O2 after their largely anaerobic bursts of energy, lactic acid build up, and temporary ATP depletion.
Whilst Cheney has argued in his seminars that too much oxygen may be detrimental to CFS patients, one of his recommendations for reducing peroxynitrite levels is to live in an area with a higher air pressure, which may actually result in a higher oxygen concentration in the blood! Is this 'dangerous'? He reports those that CFS patients that move to areas of higher air pressures feel better. Clearly not everyone breathes in the same way when responding to changes in air pressure.
Cheney blames shallow breathing for what he perceives to be reduced CO2 levels in CFS patients as a whole. Test results of patients outside of Cheney's clinic however do not hold this to be true. For example, Dr Peter Julu has tested a number of CFS, ME and Fibromyalgia patients and many do not exhibit this pattern. In order to have reduced CO2 levels, a patient would have to be hyperventilating. Given that many CFS sufferers have a reduced demand for O2 on account of a lowered metabolic and respiration rate (mitochondrial and hormonal factors), then one would expect that it might be easy to accidentally exceed one's breathing requirements by a breathing style that is above what they require to inhale enough O2 but noticeably less depth (but same speed) of breathing compared with the average healthy subject. I am not convinced that the majority of CFS sufferers hyperventilate most of the time. In general, most people tailor their breathing rate according to respiration rates, and those who over- or underbreathe are usually in a minority not a majority. It may be the case in some CFS patients that they may breathe with less vigour than a normal, healthy subject as to breath more deeply would require more energy expenditure which the CFS patient wants to avoid as energy levels are limited.The issue of reduced metabolic rate and shallow breathing is discussed in the Hypercapnia section above. Cheney's hypothesis does not take into account the variations in gas diffusion in different body positions, some of the markers of insufficient oxygenation etc. As breathing is only one factor in oxygenation, then it is wise to consider all the other factors involved, on a case by case basis, rather than devise fanciful, generalising theories.
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Markers of Low Oxygenation:
Markers or diagnostic measurements of low oxygenation are listed below. Some of these are discussed on the Tests page in the Neurophysiological Tests section.
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If your tissue oxygen levels become low during certain prolonged bodily positions, and even though your blood (haemoglobin) oxygen levels may be normal, taking supplemental oxygen may help to slightly increase your tissue oxygen levels and rate of oxygen diffusion into the tissues. This may potentially assist you if you are experiencing postural oxygen perfusion problems, e.g. having palpitations or perhaps muscle ache on the body parts you are sleeping on. Your neurologist or cardiologist should be able to advise you on this. A series of neurophysiological tests are described on the Tests page.
Discussion on the use of 'oxygenating' supplements (i.e. oxidising agents) can be found on the Viral page, the Bacterial page and also on the Alternative Treatments section of the links page.
If you are shifted to the right of the Oxygen-Hemoglobin-Diffusion Curve, then increasing the partial pressure of oxygen into the lungs will help increase oxygenation of the RBCs as well as the delivery to the tissues. One way of achieving this is to breathe O2-enriched air. Some patients may respond very well during a deep breathing exercise to increasing O2 levels and decreasing CO2 levels, and in such a case, deep breathing exercises may be recommended for the purposes of increased oxygenation. However in other patients, deep breathing makes little difference to their O2 and CO2 levels, but may of course still be useful for mind quietening and relaxation if performed long and slowly enough in conjunction with meditation exercises. In such cases where O2 levels do not significantly increase with deep breathing, then one may wish to consider increasing the partial pressure of O2 yet further, and O2-enriched air may be helpful to a limited extent, but perhaps more in certain body positions than others (e.g. in a reclined, supine position.) For more information on such tests, please see the QIFT section on the Tests page.
The use of supplemental O2 is only really recommended for those who actually need it and when they need it. Excessive use of supplemental O2 may simply make the body too used to high levels of O2, which it may adapt to accordingly with less Hemoglobin or fewer RBCs in the blood. The key is to use supplemental O2 when it is really needed, for example, in those body positions when O2 levels drop significantly. For some CFS patients, this is in the supine position. A full Autonomic Profile (QIFT) and Transcutaneous Gases test would reveal the full picture. When a person's O2 levels drop, then supplemental O2 increases the partial pressure of the O2 in the lungs and encourages the O2 levels in the blood to return to normal, effectively alleviating the effect of the various problems in the body that are causing the low O2 levels in the first place. One should of course be working in parallel to fix these problems over the medium term.
Sometimes a sensation of urgent need for supplemental O2 may be misleading and what may actually be required by the body is supplementation of the prohormone Pregnenolone. I have myself felt like I have overdone it in the past or become stressed by something and adverse adrenal type symptoms, including extreme breathlessness - supplementation with 10mg of Pregnenolone have made these disappear - something that did not happen by simply breahting O2. Please see the Neurotransmitter and Hormone Deficiencies page for more information.
There are various methods of supplying oxygen-enriched air or pure oxygen to a patient, besides deep breathing techniques. Breathing O2 from a tank of compressed O2 is the most expensive method of delivery, on account of the costs of regularly supplying heavy cylinders to patients and the costs of running an oxygen compressor. Scuba divers who take part in technical (decompression) diving may be familiar with the safety issues and indeed medical issues with oxygen use; and may well have dedicated Oxygen tanks and oxygen-clean regulators already, getting their O2 tanks filled at a scuba shop. Typically O2 tanks vary in size from 3L to 7L and O2 fills are usually supplied at 150 bar, and up to a maximum of 200 bar, depending on availability.
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Oxygen Concentrators - General:
It is much more cost effective to use a medical device known as an Oxygen Concentrator. This essentially separates the Nitrogen from the air using an electrically charged Zeolite membrane, which is expelled, sending the Oxygen at pressure to the user via an oxygen tube. Oxygen concentrator typically produce 90-95% oxygen, the remaining proportion being mainly Nitrogen with a small amount of Carbon Dioxide. Oxygen Concentrators should be kept externally clean and used in a reasonably well ventilated and dust-free area, at least 40cm from any nearby wall.
The cheapest and most commonly used type of Oxygen Concentrator is a continuous flow unit, with a user controllable flow rate up to a maximum of 4 or 5 litres per minute. This is the type of Medical Oxygen Concentrator we shall examine here.
Another type of Oxygen Concentrator is a portable type, that uses a pulse delivery system, i.e. O2 is not emitted continuously but in user definable pulses, through to the Cannula. This saves on battery power. Such portable O2 concentrators tend to be considerably lighter or smaller than the more Medical O2 Concentrators described above, but can still be plugged into the mains if being used at home. They are designed for use on the move, in the car or whilst sat on a park bench etc. An example is the Inogen One. If one is to use an O2 concentrator purely at home, then there is no benefit in purchasing such an O2 concentrator but many disadvantages, namely price and method of O2 delivery.
Other types of Oxygen Concentrator include Positive Airway Pressures (PAP) devices, such as Continuous Positive Airway Pressure (CPAP), Bi-level pressure devices (BiPAP), Automatic Positive Airway Pressure (APAP) devices. They are used in conjunction with face masks that seal around the face and encourage breathing in with a positive airway pressure, and allow expiration and a certain breathing pressure. They are often used in hospital settings with sleep apnea patients and also those with respiratory failure. Such devices are perhaps not relevant for home usage. A face mask can also be rather uncomfortable to wear.
Let us now consider how to use a Medical O2 Concentrator (Continuous Flow).
Delivery for such devices is usually by nasal cannula (without the mouth tube). The oxygen tube splits into two and the two thinner tubing sections form a loop which has two prongs at the end. The prongs are inserted up one's nose and simply expel oxygen continuously. When you breathe in through your nose, you draw in this oxygen. When you breathe out through your nose, you simply blow out this expelled oxygen. A typical flow rate could be anywhere between 1 and 3 litres per minute, depending on the cannula prong design and patient requirements. Prong designs include straight, curved or flared. Nasal cannulae are consumable items.
Oxygen Concentrators emit dry gas and if breathed from directly will soon dry out the lungs and nasal passages, resulting in a sore nose and very sore lungs. This is clearly not desirable. For this reason, they are generally used in conjunction with a bubble humidifier.
The bubble humidifier is a simple and inexpensive consumable item. Essentially the O2 concentrator is connected to the O2 concentrator outlet valve. This can be performed either directly with a steel angle connector - if one is to use the device close to one's person (known as 'internal humidification'); or by connecting the two devices together with some clear, PVC oxygen tubing - if one is to breathe in the O2 some distance away from the O2 concentrator (known as 'external humidification'). The internal/external is a reference to the proximity of the bubble humidifer to the O2 concentrator, being connected directly to the device being deemed 'internal' to the unit in some sense. Of course if you are using 'external' humidification, then the length of PVC oxygen tubing can be any length you want within reason, but clearly the longer the tubing between you and the O2 concentrator, the higher the flow rate you will need to set to get the same actual flow rate at the cannula (i.e. you will need a slightly higher pressure). The oxygen tubing connects to the top of the humidifier using a small plastic angle connector. The humidifier is filled within the maximum and minimum marks with distillled water preferably (not tap water). The water passes down a tube with small holes in the bottom, into the water and bubbles up through the water and the gas is then goes out of the humidifer by an outlet on the top of the lid. There is an overpressure valve on the top of the humidifier to prevent accidental overpressurisation. In general, however, the noise of the oxygen concentrator may drive you nuts and the electrical field from the O2 concentrator is more than that of a Television, even when the unit is plugged in but not switched (i.e. not emitting gas), so you really don't want to be sat right next to it or even 2m from it (which is the most common length of nasal cannula on the market. The nasal cannula which is connected to the outlet of the humidifier should ideally be less than 5m in length. The longer it is, the more risk there is of the condensation build up in the cannula, which is of course not desirable as water drops may go up your nose and bacteria may build up in the unit. Humidifiers, when used for external humidification, need to be securely held in place as otherwise they may be pulled or knocked over. This will result in water in tubing at both ends. Most O2 concentrators are supplied with a bubble humidifier and also a humidifier clamp or holder (like a portable cup holder) which is supposed to be screwed into the wall but could be held in place otherwise with some weights or similar to keep it from moving around if the cannula tubing is pulled slightly.
I experimented with various types of cannulae and found that one piece cannulae were preferable to two piece (joined together with a connector). Straight prongs tend to 'whistle' when in the noise, either all the time, or at the beginning and end of each breath, depending on flow rate, and a flow rate higher than 1.4-1.5l/min could not be used as a result as it was too noisy! However a curved prong nasal cannula was not only more comfortable (the ends of the prongs did not dig into the side of one's noise) but also quietier and it was possible to use them on higher flow rates without any whistling noises (e.g. 6l/min).
I got used to sleeping with prongs up his nose after a couple of nights. The first few nights of use were fantastic as I almost felt 'high' and such a boost, but this sensation went away after that. Sleeping with a nasal cannula when lying on one's side in bed can mean that the thin tubing is caught between your ear and your head and when lying on that ear, can become quite painful after a while. I found that having a little more slack in the cannula and pulling the tubing up over the ear but still next to the head meant that the thin tubing was only between his head and the bed, but this is a more precarious set up, even with the draw cord synched (either at the back of the head or under one's chin) as the prongs would be more likely to fall out of the nose during the night. Curved prongs stayed in the nose considerably better than the straight pronged cannulae. Curved prongs are worn facing down so they go with the curvature of the nose, and do not blast gas at the lining of the nasal cavity, which would happen if worn with the prongs facing up.
Wearing the nasal cannula in the above manner whilst sleeping on one's side was tolerable for about 5-6 months, afterwhich time I noticed that it became increasingly painful, particularly behind the ear. This would be a dull pain that would last all night on and off. After 5-8 months of wearing a cannula in bed, I noticed that a lump had developed in the area of his right occipital lymph node on the back of his skull. I am sure that this was due to the nasal cannula, possibly to circulation restriction in certain parts of the surface of the tissue surrounding the skull from sleeping on the nasal cannula. After this time, it became so uncomfortable that I started wearing the nasal cannula completely off the head whilst sleeping on his side, meaning that it was threaded around my left ear, but on the right side that I slept on, it would be in front of the face and go round the side of the top of the head. If tightened up at the back with the toggle, it would not put any significant pressure on the skull at any point, and was hugely more comfortable. It was not as comfortable in the nose, as the cannula prongs were not quite level. If necessary, this could be remedied with some surgical tape to hold them level.
I have found that I get a large amount of bloody 'snot' or dried mucus in his nasal passages when using the O2 concentrator every day. When on higher flow rates, I found that there was a general slight increase in nasal congestion, but that one nostril would tend to get heavily blocked with mucus so in effect he was only really breathing in the O2 through the 'good' nostril (i.e. the O2 being emitted by the other prong largely not being inhaled).
Ear cushions (e.g. Salter E-Z Wrap) which are thin tubes of foam that go around the thin tubes of the nasal cannula, by the ear, can be used to provide some cushioning between your head/ear and cannula tubing, although they can only really be used when sitting upright on when lying on one's back (and not when sleeping on one's side as they dig into your head/ear even more than without one! They are also prone to falling off. You can't wear glasses either whilst wearing them - if you want O2 when you are not in bed. An alternative to E-Z Wrap is the Salter Labs product Comfort Care Head Cannula, which is a cannula with a head band, that takes the pressure off the ears completely.
One thing to consider when buying or using an O2 concentrator is that because a humidifier is necessary, then the room in which you use it will of course become more humid than other rooms in your house or apartment. Whilst in most cases, daily ventilation and using the heating removes the humidity from most rooms, the use of an O2 concentrator means that your designated room will inevitably be more humid than the others. In essence it is the room in which the cannula is used (i.e. where the moist O2-rich air is being pumped out) that will become humid and not necessarily the room in which you use the O2 concentrator (if in a different room to the actual O2 usage - if running a long cannula into your bedroom, for instance). Most people tend to keep all their clothes in their bedrooms, traditionally, and as such I have found that everything apart from his sliding door, walk in wardrobe, becomes very humid. This includes cupboards and chests of drawers. This can be partially offset by the use of portable dehumidifiers (which are reusable and are plugged into a power socket to dry them out when they become full of moisture and put back in situ for reuse). I found that basically you would need a portable dehumidifier in every drawer where there are clothes, in a chest of drawers, and to dry the dehumidifiers out every 1-2 weeks. Under bed storage drawers (only really suitable for spare/guest bedrooms anyway) are particularly prone to damp build up. The dehumidifer in his walk-in wardrobe only needed drying out every 4 weeks (this could be partly because the boiler is on the other side of the wall and keeps it slightly warm). So in essence, you may have significant mildew problems in your bedroom over time. Even with such portable dehumidifiers, drawers and so on will still be damper than elsewhere in the house.
You can of course buy a plug in, electric dehumidifier, to really remove the humidity from the room. The rate at which it extracts moisture from the air is much higher than portable dehumidifiers. But these are noisy and will use even more electricity than you are using with the O2 Concentrator. And when you are using the O2 concentrator, you don't want a noisy dehumidifier running all the time in your bedroom (probably), and the additional EM smog might not do you any favours either! So if you are going to use an O2 concentrator, don't bother buying any bedroom furniture in the short term - unless you don't mind all the extra maintenance.
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O2 Concentrator Maintenance Schedule:
Using an O2 concentrator requires a small amount of daily maintenance and slightly more weekly, biweekly and monthly maintenance work. Whilst opinions vary and manufacturer recommendations vary, those recommended by Bitmos are described below, with some minor modifications by myself.
Maintenance may seem excessive, but once you are used to it, it does not take much time, and the daily benefits outweigh the inconvenience.
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Bitmos Oxy 6000 Review:
Examples of Continuous Flow Medical Oxygen Concentrators are the DeVilbiss 525-ADS (manufactured in the USA) and Bitmos Oxy 6000 (manufactured in Germany). Both can be purchased directly from the manufacturer or official resellers in the country of origin and imported if necessary; or purchased at greater expense from a reseller in your own country. Your National Health Service may also be prepared to provide you with one for free. Renting such units is prohibitively expensive and you may as well buy one if you intend to use one.
The DeVilbiss (not Devil-biss) is the more widely recognised and arguably more robust unit, but the Bitmos is very highly specified for its price. The Bitmos Oxy 6000 is reputedly the quiet of the two at 35db, which is allegedly whisper quiet, but the volume or power requirements do not appear to change (at all) between maximum output of 5L/min compared with a flow rate of 1L/min. The DeVilbiss by contrast is a slightly smaller, lighter unit that is said to reduce in volume and power consumption with lower flow rates, although it quotes an overall higher volume figure. The DeVilbiss also uses less power on its maximum setting. However, do not let the figures deceive you, whilst I have not tried any other units, the Bitmos is still very loud, and too loud for me to have in the same room whilst resting. Some Continuous Flow O2 Concentrators have a battery pack included, which allows them to run for a few hours on battery alone, but these tend to deplete very quickly, like on many laptop and notebook computers, and when being used at home shouild really be plugged into the mains.
Overall the Oxy 6000 is fairly smart looking, although somewhat heavy at around 20kg. It has wheels and a carrying handle so can be wheeled around or picked up and moved if necessary. The device appears to emit a fairly constant noise level, as stated above, which is just about bearable for me if watching television with the volume turned up, but otherwise is too much. I use my unit whilst lying down in bed, and came to the conclusion that both the bubble humidifier and the O2 concentrator were too loud when in use to have in the same room whilst trying to sleep. Therefore, I elected to place the O2 concentrator in another room, the living room, and thread the oxygen tubing along the floor and under the door so that the living room door could be closed (leaving a window open). As it is more critical to keep the cannula length shorter than the oxygen tubing length, I elected to use external humidification, using a 7m long Oxygen Tubing and a 5m long Cannula. 5m nasal cannulae are hard to come by, but Bitmos were able to supply 5m nasal cannulae by Hum. The prongs were not quite wide enough apart but worked out at low flow rates. I also tried a 7m cannula which worked fine, a 25' Cannula with curved prongs, perfect width apart, by Medline, part number HCS4515A (individual or packs of 25). I found a seller on fleabay called 'sellingnelly' who was able to offer good export rates from the US. I had the humidifer set up outside the bedroom room, and around a corner, and threaded the cannula under the bedroom door. It was too noisy to have the O2 concentrator in the very next room, even with all the doors closed as the noise went through his thin English wall. Whilst some may tolerate a bubble humidifier in the same room, ideally one wants to put a certain distance between oneself and the O2 concentrator because of the electrical field it produces. The gas inhaled from the unit stank of plastic or some other chemical for a couple of days before the smell levelled off. How much of this was due to the new plastic humidifier I am not sure. New PVC nasal cannulae also tend to impart a slight odour to the gas, although this is most noticeable on the first day of use.