hydrogen ion homeostasis (acid base balance)
TRANSCRIPT
A BIRD’S-‐EYE VIEW OF
HYDROGEN ION HOMEOSTASIS
(ACID BASE BALANCE)
DR. C. S. REX SARGUNAM, M.D. (Ped), D.C.H.
Retired Director and Superintendent
Institute of Child Health and Hospital for Children, Egmore, Chennai, INDIA
Pediatric Consultant, Department of Pediatrics, St. Isabel’s Hospital, Chennai, INDIA and
Voluntary Health Service Hospital, Adyar, Chennai, INDIA
President, Tamilnadu Health Development Association, Chennai
Under normal circumstances as a result of cellular respiration utilizing oxygen 𝑂! (aerobic metabolism) carbon dioxide is generated (𝐶𝑂!). 𝐶𝑂! combines with water to form carbonic acid catalyzed by an enzyme, carbonic anhydrase (CA) present in the red blood corpuscles and renal tubular cells. This is a
reversible reaction: 𝐶𝑂! + 𝐻!𝑂!" 𝐻!𝐶𝑂!. Most of the 𝐶𝑂! is excreted in the lungs. The carbonic acid
may disintegrate into free hydrogen ion (𝐻!) and bicarbonate ion (𝐻𝐶𝑂!!). This is one of the normal main sources of hydrogen ions (𝐻!). Other than this, hydrogen ions are released directly during the metabolism of amino acids or carbon containing compounds. A net amount of 50 to 100 mM (1mM/kg) of hydrogen ions per day is released from the cells into the ECF and because of the homeostatic mechanisms, the ECF hydrogen ion (𝐻!) concentration is kept constant, 40 + 5 nM/L (pH 7.4).
What is pH
pH is a measure of 𝑯! ion concentration.
Normal pH 7.4 (range 7.35 to 7.45).
The greater the 𝐻! ion concentration the lower is the pH.
e.g., pH 6 acidemia.
The lower the 𝐻! ion concentration the greater is the pH.
e.g., pH 8 alkalemia.
Under pathological conditions as in circulatory shock and collapse, anaerobic metabolism occurs; that is, cellular metabolism takes place in the absence of oxygen, producing lactic acid. Lactic acid yields free hydrogen ions enormously. Similarly, in severe diabetes mellitus, as glucose is not metabolized acetone, acetoacetic acid and beta-hydroxybutyric acid are formed from fat yielding free hydrogen ions, lowering the pH.
pH is the measure of free hydrogen ion concentration of a solution. pH and hydrogen ion concentration are inversely related. That is, the higher the pH the lower will be the hydrogen ion concentration and vice versa.
Severe acidosis depresses myocardial contractility, sensitizes the heart to arrhythmias, produces arteriolar dilatation, hypotension and predisposes to pulmonary oedema. Severe alkalosis produces tetany and convulsions.
Henderson Hasselbalch Equation and Derivation of pH
The law of mass action states that the rate of a chemical reaction is directly proportional to the
product of 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑟𝑒𝑎𝑐𝑡𝑖𝑛𝑔𝑠𝑏𝑠𝑡𝑎𝑛𝑐𝑒𝑠, 𝑎𝑡 𝑎 𝑔𝑖𝑣𝑒𝑛 𝑡𝑒𝑚𝑝𝑒𝑟𝑎𝑡𝑢𝑟𝑒.
Then, to remove the minus sign, invert the last term
𝑝𝐻 = 𝑝𝐾 + log [𝐻𝐶𝑂3−]
[𝐻2𝐶𝑂3]
𝐶𝑂! is inserted in the place of 𝐻!𝐶𝑂!
𝑝𝐻 = 𝑝𝐾 + log [𝐻𝐶𝑂3−]
[𝐶𝑂2]
pK is 6.1.This is constant for 𝐻!𝐶𝑂!:𝐻𝐶𝑂!! buffer state
𝐶𝑂! concentration is derived by multiplying 𝑃𝐶𝑂! by the solubility constant for 𝐶𝑂! (If 𝑃𝐶𝑂! is expressed in mm Hg the solubility constant of the gas is 0.03 and if the 𝑃𝐶𝑂! is expressed in kilopascal the solubility constant is 0.23.
(𝑅! and 𝑅! are rates of one forward and backward reaction respectively. 𝐾! and 𝐾! are the rate constants of the forward and backward reactions respectively.
([𝐻!𝐶𝑂!] and [𝐻!] and [𝐻𝐶𝑂!!] denote concentrations of 𝐻!𝐶𝑂!, 𝐻! 𝐻𝐶𝑂!! respectively).
Homeostatic Mechanism to Maintain normal pH
To prevent acidosis or alkalosis, three important control systems are available.
1. All the body fluids are supplied with acid-base buffer system which acts within a fraction of a second to combine with excess acids or bases to prevent excessive changes in hydrogen ion concentration.
2. If the hydrogen ion concentration is increased considerably, the respiratory centre is stimulated to alter the rate of breathing, and the removal of carbon dioxide from the body fluids is automatically ensured causing the hydrogen ion concentration to return to normal. This readjustment takes place in one to fifteen minutes.
3. When there is a change in hydrogen ion concentration, the kidneys excrete either an acidic or alkaline urine, restoring the pH to normal or near normal: being the most powerful of the acid-base regulating mechanisms, this requires several hours to several days to readjust the hydrogen ion concentration.
The Buffer Mechanisms
Here, certain terminology has to be defined. An acid is a substance which can dissociate to produce hydrogen ions (Protons 𝐻!).
A base is one which can accept hydrogen ions. An alkali is a substance which dissociates to produce hydroxyl ions (𝑂𝐻!).
A strong acid is one which gives rise to greater ionization (formation) of hydrogen ions due to the greater ionization of the acid.
haemoglobin is normally six times as important as the plasma protein in the total buffering capacity of blood.
Respiratory Regulation of Acid-Base Balance
Blood carries oxygen from the lungs into the tissues and it carries carbon dioxide (𝐶𝑂!) from the tissue to lungs, where 𝐶𝑂! is eliminated. Most of the carbon dioxide combines with water in the presence of carbonic anhydrase enzyme in the RBC to form carbonic acid (𝐻!𝐶𝑂!). They immediately dissociate into hydrogen (𝐻!) and bicarbonate (𝐻𝐶𝑂!!) ions. Most hydrogen ions combine with the haemoglobin in the RBC, because haemoglobin is a powerful acid-baae buffer. Many of the bicarbonate ions diffuse into the plasma while chloride ions diffuse into the RBC.Thus the chloride shift occurs. As much as 70 percent of 𝐶𝑂! in the body is transported like this. In the lungs, the opposite reaction takes place. Chloride ions leave the RBC and bicarbonate ions enter the RBC. Carbonic acid (𝐻𝐶𝑂!) is formed and 𝐶𝑂! is eliminated in the lungs.
Thus in acidosis there is an increased rate of respiration to eliminate 𝐶𝑂!; and in alkalosis,respiration becomes slower so as to retain 𝐶𝑂!.
Renal Regulation
This is an important and sustained control system in maintaining acid-base balance.
Bicarbonate Reclamation
The 𝐻𝐶𝑂!! filtered in the glomeruli is completely titrated by the 𝐻! ion secreted into the tubules. 𝑁𝑎!ion which is reabsorbed in exchange for 𝐻! ion which is derived from the dissociation of carbonic acid formed by the combination of 𝐶𝑂! and 𝐻!𝑂 in the presence of carbonic anhydrase. This 𝐶𝑂! is from the tubular lumen after the dissociation of carbonic acid in the presence of carbonic anhydrase. This is a self perpetuation cycle where there is no loss of 𝐻! ion but 𝐻𝐶𝑂!! ion is reclaimed. There is no net gain of 𝐻𝐶𝑂!!. This mechanism can not correct acidosis, but can maintain a steady buffer state.
The carbonic anhydrase enzyme is present in the RBC and proximal tubules of kidney. The reaction of 𝐶𝑂! and 𝐻!𝑂 to form carbonic acid occurs very slowly in the distal tubule and in the presence of carbonic anhydrase the reaction is accelerated 5000 times as in the proximal tubule.
The bicarbonate ion is mainly reclaimed in the proximal tubules.
Bicarbonate Generation
As there is a slight excess secretion of 𝐻! ion over the 𝐻𝐶𝑂!! ions filtered, the excess 𝐻! ions are secreted in two buffer forms as 𝑁𝑎!𝐻!𝑃𝑂!! and 𝑁𝐻!!𝐶𝑙!.
The new generation of 𝐻𝐶𝑂!! occurs in more distal segments of the nephrons. (The mechanisms for both reclamation and generation of bicarbonates are highly developed, energy-‐
Its pH to 7.4 of the glomerular filtrate. The titratable acidity obviously measures only a fraction of the acid secreted since it does not measure the 𝐻! that combines with 𝐻𝐶𝑂!! or that is buffered as 𝑁𝐻!𝐶𝑙. Disodium monohydrogen phosphates (𝑁𝑎!𝐻𝑃𝑂!) filtered in the glomeruli is excreted as monosodium dihydrogen phosphate (𝑁𝑎𝐻!𝑃𝑂!) with the absorption of sodium (𝑁𝑎!) along with bicarbonate 𝐻𝐶𝑂!!) which is generated and 𝐻! ion which is secreted.
Ammonia Buffer System
Most of the sodium chloride filtered in the renal glomeruli, is absorbed as such, Proximal tubule cells metabolise glutamine to 𝑁𝐻!! and alpha-‐ketaglutarate. The alpha-‐ketalutarate is metabolized in the proximal tubule cell by a process that generates 𝐻𝐶𝑂!!. Thus each 𝑁𝐻!! that appears in the urine completes an overall process that generates one 𝐻𝐶𝑂!!. If each 𝑁𝐻!! molecule formed from glutamine is not excreted in the urine but is returned to the liver, the 𝑁𝐻!! is metabolized to one 𝐻! and part of urea. This 𝐻! thus balances the 𝐻𝐶𝑂!! produced by the kidney and no change in acid-‐base balance occurs. Therefore the renal execration of 𝑁𝐻!! is essential to the process of net 𝐻𝐶𝑂!! generation.
𝑯! ion secretion in the collecting Tubule
Aldosterone Dependent
Non-‐Adosterone Dependent
1. 𝑃𝑂! buffer system 2. 𝑁𝐻! buffer system
Serum electrolytes
Blood pH (Arterial Blood Gas Analysis)
Venous blood-‐Obtained without using a tourniquet from non-‐excercising extremities provides pH and 𝐻𝐶𝑂!! values for assessing and following a patient with acid-‐base disorders, provided oxygenation is not unquestionably compromised.
Metabolic Acidosis
The causative factor must be corrected simultaneously with the management of metabolic acidosis. In diabetic ketosis, the core treatment consists of insulin, intravenous fluids with dextrose, sodium bicarbonate for acidosis and other supportive measures. In diarhoea with severe dehydration, child is hydrated along with the correction of acidosis and in shock with metabolic acidosis, shock is treated, perfusion improved and acidosis corrected.
In metabolic acidosis, certain organic anions like lactate, and acetate
are present. These are called potential bicarbonates, because the metabolism is reverted to normal by correction, for example: in treating conditions with poor tissue perfusion with intravenous fluids, blood and other antishock measures, these potential bicarbonates are converted into actual bicarbonates. If this is not considered and more than required sodium bicarbonates are administered mechanically, one is likely to over-‐correct resulting in alkalosis.
Metabolic acidosis is combated specifically by administrating sodium bicarbonate. It will be rational to correct empirically
Rather than to follow the formula for sodium (Na) correction, given as follows, Na to be replaced = (Na 125 mEq/l-‐serum Na) x total body water (in L/kg).
This formula cannot be applied for bicarbonate, because bicarbonates can be created or destroyed unlike sodium which is inert and can neither be created nor destroyed. Bicarbonates are created when 𝐻! ions are secreted and the urine is acidified or formed from certain lactate, and acetate ions and from certain buffer reactions. Bicarbonates are lost in conditions when an alkaline urine is passed when intestinal juice is lost.
The initial amount of sodium bicarbonate given to correct metabolic acidosis is 2 to 4 mEq/kg depending upon the severity, over a period of 6 to 8 hours. Bicarbonate should not be given by bolus infusion because it may precipitate cardiac arrhythmias, paradoxical intracellular acidosis, overexpansion of ECF and hyperosmolality. After this period a fresh clinical assessment should be made with acid-‐base data, whether to give next dose or not. If it is to be given, the dosage is decided and given. This process is continued till patient is declared free of acidosis.
Treat the Cause
Acidosis
𝑵𝒂𝑯𝑪𝑶𝟑 2 mEq/kg eighth hourly by IV infusion. Never by bolus. (In acute respiratory acidosis, moderate amount of 𝑵𝒂𝑯𝑪𝑶𝟑 may be given to mitigate acidosis to prevent the serious cardiovascular effects of severe acidosis).
Alkalosis
It occurs due to the administration of excessive alkalies, improperly composed oral rehydration solution, hypokalemia, loss of chloride ions as in upper intestinal obstruction, excessive diuretic therapy, etc.
Metabolic alkalosis will correct itself if sufficient amount of cations sodium and potassium with chloride ions are administrated. As 𝑁𝑎! is retained for exchange of 𝐾! and 𝐻! ions, 𝑁𝑎! ion has to be adequately supplied as NaCl to be absorbed. Otherwise in an attempt to retain 𝑁𝑎! ion, there will be increased regeneration of 𝐻𝐶𝑂!! and increased secretion of 𝐻! ion. If 𝐾! ion is deficient, kidney will excrete 𝐻! in exchange for 𝑁𝑎! retention and for each ion of 𝐻! secreted one ion of 𝐻𝐶𝑂!! is formed.
Potassium deficiency has to be rectified by giving potassium chloride, as chloride is the main anion with sodium reabsorbed in the tubules. If chloride id deficient, the sodium which would have been reabsorbed with chloride is instead reabsorbed in exchange for potassium and hydrogen thus alkalosis is perpetuated, along with hypokalemia.
The above mentioned measures take some time to correct metabolic alkalosis. At present, attempts are made to treat metabolic alkalosis specifically when immediate partial correction is required like prior to subjecting a patient to general anaesthesis to avoid cardiac arrhythmia. Preparations attempted are parenteral ammonium chloride up to 6mM/kg/day and intravenous arginine hydrochloride 2-‐4 mEq/kg for a six hour period. These measures are only in an experimental stage and not to be attempted clinically.
Respiratory alkalosis occurs as a result of overbreathing due to hysterical conditions, hyperpyrexia, high altitudes, etc. This is best treated by rebreathing the expired 𝐶𝑂!.
The ideal fluid for the management in alkalosis is normal saline, as sodium chloride supplied will be absorbed as NaCl avoiding further formation of sodium bicarbonate.
The management of infantile hypertropic pyloric stenosis with hypochloraemic alkalosis in treating hypovolemia with normal saline and allowing the kidneys (if the renal function is normal) to correct the alkalosis. Potassium should be supplemented by oral or intravenous fluids containing potassium not exceeding 40mEq/L if there is evidence of hypokalemia.
Acid-‐Base Disturbances Under Special Circumstances Due to Change in ECF Volume
Under normal circumstances, bicarbonate concentration is 24 mM/litre and carbondioxide concentration is 1.2 mM/litre. The following diagrams on dilution acidosis and concentration alkalosis are self explanatory.
Potassium
The normal serum potassium is 3.5 mEq/L to 5.5 mEq/l. Hypokalemia is present when 𝐾! is less than 3.5mEq/l and hyperkalemia is present when 𝐾! is more than 5.5mEq/l. The normal adult ingets 1 to 2 mEq potassium per kilogram of body weight. In healthy persons, about 90 percent of the ingested potassium is absorbed from the gastrointestinal tract
into the ECF. The rest 10 percent appears in the stools. 98 percent of the body potassium enters the ICF. The plasma potassium level is low and constant as it is mainly excreted in the urine by the kidneys. The potassium filtered at the glomerulus is reabsorbed by the proximal tubule and is secreted into the distal tubule and collecting duct along with hydrogen ion, in exchange for sodium ion, thus playing an important role in acid-‐base homeostasis in the body. The potassium and hydrogen ions compete for sodium reabsorption. In hyperkalemia, excess potassium is secreted in preference to hydrogen ion thus resulting in acidosis. The potassium secretion also mainly depends on the amount of sodium filtered at the glomerulus and presented to the distal segments for reabsorption. In Addison’s disease, the potassium excretion is impaired. Sodium filtration is impaired in acute glomerular failure eg.: in acute glomerulonephritis, 𝑁𝑎!/𝐾! exchange cannot take place. In both these conditions, plasma 𝐾! is increased resulting in hyperkalemia.
Factors Producing Hypokalemia
1. Alkalosis
Here potassium is secreted in preference to hydrogen for sodium reabsorption in the distal tubule and collecting duct producing hypokalemia.
At the cellular level, more of potassium enters the cells instead of hydrogen perpetuating hypokalemia.
2. Reduction in the total body potassium (TBK)
For example: in diarrhea. But reduction in TBK can be associated with normokalemia, eg.: in acidosis.
If the KCl concentration is more than 40 mEq/L, a central vein may be secured to avoid irritation to peripheral veins.
Severe hyperkalemia and hypokalemia are acute medical emergencies. ECG monitoring is a must. Intensive care management is essential.
Hyperkalemia
Factors Producing Hyperkalemia
1. In acidosis, where excess hydrogen ions are secreted instead of potassium in exchange for sodium reabsorption in the distal tubules and collecting ducts and at cellular level more of hydrogen ions enter competing for potassium.
2. Acute renal failure and end stage renal failure. 3. Circulatory collapse and shock with poor perfusion. 4. Tissue necrosis. 5. Ardrenal cortical failure.
Hyperkalemia can produce cardic arrhythmias and death.
Treatment
Calcium gluconate 0.5 ml/kg of 10% solution is given intravenously over 10 to 15 minutes with caution. The heart rate must be closely monitored with ECG during the infusion; a fall in a rate of 20 beats/minute require stopping the infusion until the pulse returns to the preinfusion state. The onset of action is within minutes and lasts for about half an hour. Calcium gluconate does not
5. Peritonial dialysis. 6. Hemodialysis
The last two measures are used in severely hyperkalemic patients as life saving measures.
𝛽-‐Andrenergic agonists, are the new additions to the armamentarium for the treatment of acute hyperkalemia. 5 microgram/kg of Salbutamol, given IV over 15 miunutes, or by nebuilizer at 2.5-‐5 mg. is very effective in lowering serum 𝐾! level for up to 2 to 4 hours.
Choride
The intake and absorption of chloride occurs as those of NaCl andKCl absorption is through the intestinal route. Most of the chloride is reabsorbed as NaCl and little is excreted in the urine and negligible amount in faces and sweat. The distribution of chloride is well illustrated by the following diagram.
Chloride is the main anion accompanying the cation sodium. In the kidneys it is filtered as sodium chloride and 99% of it is reabsorbed in the tubules. In the proximal tubule about 65 percent of the sodium is actively absorbed along with the passive diffusion of chloride. In the diluting segment consisting of the ascending limb of the loop of Henle and about half of the proximal convoluted portion of the distal tubule, chloride is actively absorbed followed by passive absorption of sodium. In the late distal tubule and collective duct sodium is actively reabsorbed in exchange for potassium and hydrogen ions which are secreted into the urine in the presence of aldosterone.
Hypochloraemic Alkalosis
This condition may be caused by infantile hypertrophic pyloric stenosis or after excessive gastric suction. Here both 𝐻! and 𝐶𝑙! ions are lost. This is accompanied by generation of 𝐻𝐶𝑂!! ions which are not lost. In the proximal tubule sodium is released along with passive reabsorption of chloride that is available. A reduction in the available chloride limits this isotonic reabsorption of 𝑁𝑎𝐶𝑙 and more of 𝐻𝐶𝑂!! formation. This results in alkalosis and hyperkalemia which is corrected by administrating appropriate amounts of normal saline.
In potassium deficiency also, this should be corrected by giving potassium chloride than with any other potassium salt because the sodium which would have been reabsorbed with chloride is instead reabsorbed in exchange with potassium and hydrogen ions to preserve electroneutrality, producing hypochloraemic alkalosis.
Calcium
The normal plasma concentration is 9 to 11 mg/dl. Total calcium exists in three forms:
1. Ionized or free calcium (45 to 50 percent). 2. Protein bound calcium (40 percent). 3. Complexes, eg.: with 𝑃𝑂!! in bones, 𝐻𝐶𝑂!! and citrate (10 to 15 percent).