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Core
The pH of plasma is important because having a high or low pH can affect the ability of certain proteins to function. For example, the pH changes how tightly haemoglobin holds on to oxygen (the Bohr effect). A lower pH makes haemoglobin release oxygen more easily. A higher pH makes it hold on to oxygen more tightly. The body therefore keeps the pH of plasma between 7.35 and 7.45, so that proteins keep working and oxygen delivery stays steady.
In clinical practice, plasma pH is measured on an arterial blood gas (ABG), a test on a blood sample taken from an artery. The interpretation of this test is explained at the end of the article (it is important to understand the physiology behind the control of plasma pH to be able to interpret an ABG).
Hypercapnia occurs when there is a rise in the partial pressure of carbon dioxide (pCO2) above 6 kPa. Hypocapnia occurs when there is a reduction in the pCO2 below 4.7 kPa.
Hypoxaemia means abnormally low oxygen in arterial blood. Hypoxia means inadequate tissue oxygenation; it can occur even without hypoxaemia. The normal reference range for the partial pressure of oxygen (pO2) on an arterial blood gas is about 11-13 kPa in a healthy adult breathing air. It is lower in older people, and local laboratory ranges vary.
When there is an increased ventilation rate, the pO2 will increase and the pCO2 will fall as more oxygen is inhaled and more carbon dioxide is expired. The opposite can be seen when the ventilation rate decreases.
In times of hypoxia, the ventilation rate will increase (hyperventilation) as an attempt to increase the pO2, but this leads to a decrease in the pCO2.
Based on the oxygen-haemoglobin dissociation curve, the oxygen saturation of haemoglobin falls much more steeply below 8 kPa. Above 8 kPa the curve is flatter, but saturation still rises slowly as the pO2 rises. For example, a healthy young adult breathing air has a saturation of about 94 to 98%, rather than 100%. The steep part of the curve is explained by co-operative binding. When one oxygen molecule binds to haemoglobin, the shape of the haemoglobin changes. This makes it easier for more oxygen molecules to bind. This is why there is a steep drop in percentage saturation of haemoglobin below 8 kPa.
Diagram - Graph of the oxygen-haemoglobin dissociation curve. Saturation falls steeply below approximately 8 kPa. Above that the curve is flatter, but saturation still rises slowly as pO2 rises.
Note: this sketch marks 50% saturation at 3.0 kPa. In normal adult blood, the pO2 at which haemoglobin is 50% saturated (the P50) is approximately 26 mmHg, which is about 3.5 kPa.
SimpleMed original by Dr. Peter Parkinson
Once the pCO2 begins to increase, the pH of the plasma will begin to fall, causing acidosis (a plasma pH below the normal range). When the pCO2 begins to decrease, the pH of the plasma will increase, resulting in alkalosis (a plasma pH above the normal range).
Structures and mechanisms within the body can be affected by changes to pH of the plasma. Enzymes can lose normal function and may denature (lose their normal three-dimensional shape) at extremes of pH, which can affect processes that rely on enzymes such as aerobic respiration and gluconeogenesis.
When the pH of the plasma rises, as in alkalosis from hyperventilation, the distribution of free calcium ions changes. Less ionised calcium (calcium that is not bound to protein) is available, because more of it is bound to proteins. This increases neuronal excitability, making neurones more likely to depolarise and can cause tetany (involuntary muscle contraction).
Hypoventilation (breathing too slowly or too shallowly) can cause a build up of carbon dioxide in the blood. Carbon dioxide reacts with water to form carbonic acid, which dissociates into hydrogen ions (H+) and hydrogen carbonate ions (HCO3-, also called bicarbonate), lowering blood pH. This is known as respiratory acidosis. Type 2 respiratory failure (failure to clear carbon dioxide from the blood) can lead to respiratory acidosis. Causes include severe chronic obstructive pulmonary disease (COPD, long-term lung damage that narrows the airways), drug overdose and neuromuscular disease (disease of the nerves and muscles that control breathing).
Hyperventilation (breathing faster or deeper than the body needs) removes carbon dioxide faster than it is produced, lowering blood pCO2. The balance between carbonic acid and hydrogen carbonate then shifts towards carbon dioxide and water. This reduces free H+ and raises pH. The result is respiratory alkalosis. Panic attacks are one example of a cause.
Breathing helps regulate the partial pressures (tensions) of oxygen and carbon dioxide in arterial blood. Peripheral chemoreceptors (sensors that detect chemical changes in the blood) in the carotid and aortic bodies (small groups of sensory cells at the division of the common carotid artery and at the aortic arch) respond to reduced arterial pO2, increased pCO2 and reduced pH. Their ventilatory response to falling oxygen becomes stronger below approximately 8 kPa.
Peripheral chemoreceptors contribute to the graded ventilatory response to changes in arterial carbon dioxide and pH.
Central chemoreceptors in the brainstem respond to changes in the pH of surrounding extracellular fluid and CSF. Carbon dioxide crosses the blood-brain barrier readily and forms hydrogen ions locally. Hydrogen ions and hydrogen carbonate ions in the blood cross the barrier much more slowly. They can cross, but only in small amounts. Acute changes in arterial carbon dioxide therefore strongly influence the central chemoreceptors.
The blood-brain barrier is formed by specialised brain capillary endothelial cells (the cells that line the small blood vessels of the brain). The choroid plexus (a network of small blood vessels and cells in the brain ventricles) produces and helps regulate the composition of CSF, including hydrogen carbonate transport. Tight junctions (seals between neighbouring cells) link its epithelial cells and form the distinct blood-CSF barrier.
The pH of CSF depends on the balance between hydrogen carbonate and dissolved carbon dioxide. Carbon dioxide equilibrates readily, while regulation of CSF hydrogen carbonate occurs more slowly. CSF pH therefore still depends partly on plasma hydrogen carbonate, particularly during sustained acid-base disturbances.
If arterial pCO2 rises, there will be a short delay before the CSF pCO2 increases. This change will be detected by central chemoreceptors and will lead to an increase in ventilation to attempt to remove the excess carbon dioxide. This is a form of negative feedback.
Diagram - Central chemoreceptors respond to local extracellular fluid and CSF pH changes after carbon dioxide crosses the endothelial blood-brain barrier. Rapid hydrogen and hydrogen carbonate movement is limited. Choroid plexus epithelium forms the separate blood-CSF barrier.
SimpleMed original by Dr. Peter Parkinson
Diagram - The homeostatic control of plasma pH and the responses made to changes to pH
Creative commons source by OpenStax College [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
In people with healthy lungs, this system works well, as changes in pCO2 are detected centrally and the ventilation rate changed accordingly.
However, in people with chronic lung conditions, like COPD, increased levels of CO2 become normal as their lungs are not very good at getting rid of CO2. If the system worked in these patients as it does in a healthy patient, they would be persistently hyperventilating, which would be very uncomfortable.
In reality, with cases of chronic hypercapnia, extra HCO3- ions are moved into the CSF, mainly by the choroid plexus and also across other brain barriers, which helps to return the CSF pH to normal. This brings the ratio of carbon dioxide to hydrogen carbonate into normal range (even though both of these results are high), and this means that the pH is normal. This returns the breathing rate of this patient to normal, and ‘resets’ the system around a higher tolerated pCO2.
This ‘resetting’ of the central chemoreceptors to accept much higher pCO2 as ‘normal’ means that these patients may rely more on their oxygen sensitive peripheral chemoreceptors to modify their ventilation rate. For example, in a patient with COPD, their central chemoreceptors may have ‘reset’, but their peripheral chemoreceptors still detect a low pO2, so the ventilation rate is increased. This is known as the ‘hypoxic drive’. Raising the pO2 reduces peripheral chemoreceptor stimulation, which can contribute to reduced ventilation. This is one reason why high levels of oxygen can be dangerous in some COPD patients. It is not the only reason. Other factors may contribute, including worse matching of airflow to blood flow in the lungs (ventilation-perfusion or V/Q mismatch) and the Haldane effect (oxygenated haemoglobin carries less carbon dioxide). The mechanism is complex and not fully understood. These patients still need oxygen if they are hypoxic. Current British Thoracic Society guidance suggests aiming for an oxygen saturation of 88 to 92% in patients with COPD, or other risk factors for type 2 respiratory failure, until an arterial blood gas result is available.
Metabolic Acidosis and Alkalosis
The body produces acids in various processes. One is lactic acid, made during anaerobic respiration (energy release without oxygen). Another is acidic ketones (ketoacids), made by ketogenesis, the breakdown of fatty acids and ketogenic amino acids (amino acids that can be turned into ketones).
Hydrogen carbonate ions react with the H+ ions produced by the body. When there is an excess of H+ ions, this can lead to the depletion of HCO3- ions. As the concentration of H+ ions increases, the ratio of HCO3- to pCO2 decreases, resulting in a decrease in plasma pH. This is called metabolic acidosis. The body tries to counteract the decrease in plasma pH by increasing ventilation to decrease pCO2 and bring the plasma pH into the normal range.
Persistent vomiting causes loss of gastric hydrogen and chloride ions and can produce metabolic alkalosis. Compensatory hypoventilation raises carbon dioxide, but is limited by the need to maintain oxygenation (enough oxygen in the blood). Normally the kidneys can excrete excess hydrogen carbonate. However, volume depletion (a low circulating fluid volume), chloride depletion and hypokalaemia (a low serum potassium) favour renal hydrogen carbonate retention and can maintain the alkalosis, rather than allowing effective renal correction.
Renal Production and Control of Hydrogen Carbonate Ions
The pH of the plasma depends on the ratio of the concentration of HCO3- ions to the pCO2 of the blood. The kidneys are responsible for controlling the concentration of HCO3- ions by altering the excretion of the ion.
Hydrogen carbonate ions are filtered at the glomerulus of the kidneys and enter the filtrate (the fluid that has been filtered out of the blood), but the majority of these ions are recovered at the proximal convoluted tubule (PCT, the first coiled part of the kidney tubule). PCT cells excrete H+ ions into the lumen as they transport sodium ions into the cell. The H+ ions react with HCO3- ions present in the filtrate, resulting in carbon dioxide and water being formed. The carbon dioxide diffuses into the PCT cells and the reverse reaction occurs, producing H+ and HCO3- ions inside the PCT cell. The HCO3- ions can then be secreted into the extracellular fluid (ECF) before moving into the plasma.
Diagram - The movement of hydrogen ions out of proximal convoluted tubule (PCT) cells and movement of hydrogen carbonate ions into the extracellular fluid from PCT cells
SimpleMed original by Dr. Peter Parkinson
Kidneys also produce HCO3- ions from amino acids, in the proximal tubule cells of the kidney, but this process is slow. Glutamine (an amino acid) is broken down to ammonium (which further breaks down into H+ ions and ammonia) and α-ketoglutarate (another breakdown product). The ammonia molecules diffuse into the filtrate. There they bind with H+ ions present in the lumen to form ammonium. Ammonium cannot diffuse back across the cell membrane, so it is trapped in the filtrate. This is a form of buffering in the urine. It lets the kidneys excrete acid as ammonium, which makes up about half to two-thirds of the net acid they excrete. Urine pH normally ranges from about 4.5 to 7. The α-ketoglutarate is converted to HCO3- ions inside the cells of the PCT. These ions can be secreted into the ECF before being transported into the blood.
Diagram - The generation of ammonium and hydrogen carbonate ions from glutamine
SimpleMed original by Dr. Peter Parkinson
In the distal convoluted tubule and collecting ducts, H+ ions are also actively secreted into the lumen via α-intercalated cells (specialised cells that secrete acid). These H+ ions bind with ammonia and phosphate ions; these molecules are then excreted in urine. Phosphate ions act in the same way as ammonia, by buffering H+ ions.
Inside the α-intercalated cells, carbon dioxide and water react to form H+ ions and HCO3- ions. This forward reaction is favoured because H+ ions are excreted into the lumen. Hydrogen carbonate ions are secreted into the ECF by α-intercalated cells as chloride ions are moved into the α-intercalated cells.
Diagram - Secretion of hydrogen ions by α-intercalated cells in the distal convoluted tubule, and their buffering by phosphate ions in the lumen
SimpleMed original by Dr. Peter Parkinson
When there is an increase in the pCO2 (for example secondary to hypoventilation), the pH of the blood will decrease. The kidneys respond by secreting more H+ ions into the urine, and they will begin to excrete less HCO3- ions, so there are more HCO3- ions present in the blood. This will help the pH to go back to normal, and is a form of compensation (see later).
If the pCO2 begins to decrease (for example secondary to hyperventilation), the pH of the plasma will begin to increase. The kidneys will then excrete more HCO3- ions to try to bring the pH of the plasma back within normal range. However, this change is slow. Full renal compensation typically takes several days, so a compensatory change in HCO3- of this kind is seen in a chronic disorder rather than an acute one.
Potassium Ions and Acid Base Disturbances
There is a relationship between potassium ions and the plasma pH.
To regulate the amount of H+ in the plasma, the body can move it into or out of cells. K+ ions tend to move in the opposite direction. This means that any changes in plasma pH can cause changes in K+ levels. This swap is known as the reciprocal cation shift (a cation is a positively charged ion).
Acidosis can increase serum potassium through movement of potassium out of cells, particularly in mineral metabolic acidosis (acidosis caused by a mineral acid such as hydrochloric acid). The effect is smaller in organic acidoses (caused by organic acids such as lactic acid or ketoacids). It is not a universal one-for-one hydrogen/potassium exchange. Serum potassium also depends on insulin, renal function, urinary losses and volume status, so acidosis does not always cause hyperkalaemia (a high serum potassium).
Alkalosis can favour movement of potassium into cells. In persistent vomiting, gastric acid and chloride loss can cause metabolic alkalosis, while volume depletion (a low circulating fluid volume) stimulates aldosterone (a hormone that makes the kidneys retain sodium and lose potassium), which increases renal potassium loss. These mechanisms can contribute to hypokalaemia (a low serum potassium), but renal potassium excretion also depends on volume status, renal function and other factors; alkalosis alone does not invariably cause increased potassium loss.
The relationship can also work the other way round, with a potassium abnormality coming before the pH change:
- Hyperkalaemia can contribute to metabolic acidosis by reducing renal ammonia excretion and therefore net acid excretion (the total amount of acid the kidneys remove). In type 4 renal tubular acidosis (a kidney tubule disorder in which acid is not excreted properly), impaired aldosterone production or action also reduces potassium and hydrogen ion excretion. This association depends on the underlying renal and hormonal disturbance. Hyperkalaemia does not always cause acidosis through urinary hydrogen carbonate loss.
- Hypokalaemia can promote and maintain metabolic alkalosis, including through increased renal hydrogen carbonate reabsorption and hydrogen ion excretion. The acid-base outcome depends on the underlying illness, volume status and renal function; a low potassium concentration alone does not establish metabolic alkalosis.
Diabetic ketoacidosis (DKA) is a key condition when considering the relationship between pH and potassium disturbance. It causes metabolic acidosis. It also causes a total body depletion of potassium ions, even though the serum potassium measured at presentation is often normal or high. In DKA, ketones are produced as a source of fuel. Ketones are acidic, so the blood pH falls. The lack of insulin, which normally drives potassium into cells, also contributes. Together, these cause K+ ions to move out of the cells and into the blood. The high concentration of glucose in the lumen of the nephrons (the working units of the kidney) increases the osmolality (the concentration of dissolved particles) of the filtrate. This causes an osmotic diuresis, which is a large urine volume driven by the dissolved glucose. K+ ions are lost in this urine as well, which leads to a depletion of potassium in the whole body. After insulin treatment is started, the serum potassium almost always falls, so potassium needs frequent monitoring and replacement.
Compensation and The Anion Gap
As previously discussed, the plasma pH depends on the ratio between concentration of hydrogen carbonate ions and the partial pressure of carbon dioxide.
If there are changes in the pCO2, the kidney can compensate by altering the excretion of HCO3- ions. In respiratory acidosis, the kidneys will compensate by excreting less HCO3- ions and in respiratory alkalosis, the kidneys will compensate by excreting more HCO3- ions. However, it can take the kidneys several days to compensate, so this is not an immediate management strategy.
In a patient with compensated respiratory acidosis, the arterial blood gas will show: high pCO2, raised [HCO3-] (square brackets mean concentration) with a relatively normal plasma pH.
In a patient with compensated respiratory alkalosis, the arterial blood gas will show: low pCO2, low [HCO3-] with a relatively normal plasma pH.
The anion gap is the difference between the concentrations of cations and anions in the blood. It includes the concentrations of sodium and potassium ions as the cations, and the concentrations of chloride and hydrogen carbonate ions as the anions.
The normal anion gap is usually around 8 to 12 mmol/L when potassium is excluded from the calculation (local reference ranges may vary). This reflects the presence of unmeasured anions in normal plasma.
The anion gap can help to work out the cause of an acid-base abnormality. Two points to remember:
- Changes in potassium concentration have little direct effect on the anion gap, as potassium contributes minimally to the calculation.
- In compensated respiratory acidosis, renal compensation leads to a raised HCO3- concentration, and the anion gap is typically unchanged.
Image - The anion gap equation
SimpleMed original by Dr. Peter Parkinson
It is important to remember that the anion gap is calculated using a limited number of measured ions, but it does reflect the build-up of unmeasured anions such as lactate or ketoacids, which increase the gap.
The anion gap is increased if HCO3- ions are replaced by another anion; this is seen when there is metabolic production of an acid such as diabetic ketoacidosis and lactic acidosis.
Some renal causes of metabolic acidosis, such as renal tubular acidosis (RTA, a failure of the kidney tubules to reabsorb hydrogen carbonate or excrete acid), give a normal anion gap. When HCO3- ions are lost, the fall in HCO3- is matched by a rise in chloride ions in a 1:1 ratio, so the anion gap is unaffected. In chronic kidney disease the anion gap can be raised, because anions such as sulphate are retained.
In metabolic alkalosis, the kidneys can try to compensate by reducing H+ ion excretion and HCO3- recovery (reabsorption). However, metabolic alkalosis is often accompanied by systemic volume depletion, for example after vomiting. This leads to the kidneys increasing the recovery of sodium ions and HCO3- ions whilst excreting H+ ions, which maintains the alkalosis. The anion gap is not a reliable guide here, because it can sometimes be raised in metabolic alkalosis.
Arterial Blood Gas Interpretation
As mentioned at the start of this article, all of this information is provided on an arterial blood gas (ABG). It is important to remember that pCO2 and HCO3- results can be outside the normal range for two reasons. Either there is pathology affecting their formation or removal, or they have compensated for a change in the other variable to move the pH closer to the normal range.
This is one method that can be used to interpret the results of an ABG:
First look at the pH - is it low (below 7.35) indicating acidosis, or high (over 7.45) indicating alkalosis?
If Acidotic:
- Look at the pCO2 - is it high (respiratory cause of the acidosis) or low (compensating for a metabolic cause)
- Look at the HCO3- - is it low (metabolic cause of the acidosis) or high (compensating for a respiratory cause)
If alkalotic:
- Look at the pCO2 - is it low (respiratory cause of the alkalosis) or high (compensating for a metabolic cause)
- Look at the HCO3- - is it high (metabolic cause of the alkalosis) or low (compensating for a respiratory cause)
Things to remember with ABGs:
- Remember that changes in HCO3- reflect renal handling and metabolic processes. Renal compensation takes time, but a low bicarbonate does not by itself indicate whether a disorder is acute or chronic.
- Remember that compensation is done to get the pH back into the normal range. This means that there are two levels of compensation:
- Partial compensation occurs when both variables are outside the normal range, and the pH has not been pushed back into the normal range.
- Full compensation occurs when both variables are outside the normal range, but the pH is within normal range.
- It is always important to interpret the ABG in the clinical context of the patient - this may help determine whether the cause is chronic or acute.
Edited by: Dr. Maddie Swannack
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
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