Professional Documents
Culture Documents
G M Kellerman
Hunter Area Pathology Service
GENERAL CONSIDERATIONS - 1
Enzymes, membrane carriers and other components of the cell are proteins and their amino acid side chains have a mixture of + and charges. Each protein has its optimal activity with an appropriate constellation of these charges, which is pH dependent. Accordingly, there is a narrow optimum pH for the entire body, as the numerous proteins all have their own personal optimum and overlap of all of them is limited. Outside this optimum pH range, viability declines in both the direction of acidosis (limit in plasma pH about 6.7 in young patients, 6.8-6.9 in elderly patients with many comorbidities) and alkalosis (limit about pH 7.7-7.8). We can assess the acid-base status by measuring any pair of buffer components, and the CO2/bicarbonate pair is the most convenient.
GENERAL CONSIDERATIONS - 2
Metabolic sources of acid: quantitatively the greatest is CO2, of which we produce some 15000 mmols per day or even more with exercise or hard work. This is all removed by respiration and a disturbance in this process leads to a respiratory acidosis (less effective removal = hypoventilation) or a respiratory alkalosis (more effective removal = hyperventilation) Far less quantitatively are other non-volatile acids, but they must be buffered in the body until the kidney can excrete them. Normally these are sulphuric (from aminoacids cystine/methionine) and phosphoric (from phospholipids), and a variety of organic acids such as lactic, ketone bodies and a number of abnormal toxic substances (methanol, ethylene glycol) which are metabolised to acids. Lactic and ketone acids are normally metabolised almost completely and their accumulation signifies metabolic derangement. Several rare genetic errors can lead to metabolic acidosis.
GENERAL CONSIDERATIONS - 3
Disturbances in the handling of these metabolic acid products lead to metabolic acidosis (accumulation of too much acid) or metabolic alkalosis (excretion of too much acid) On relatively uncommon occasions, patients consume too much base (sodium bicarbonate for indigestion, rarer with PPI drugs) or have an almost exclusively vegetarian diet and metabolise components of the diet to excess bicarbonate. Acid can be lost by stomach (vomiting), while bicarbonate can be lost by colon. The major adjustment is made by the kidney, so disturbances of acid base metabolism frequently follow disordered renal function, either from metabolic changes in otherwise normal cells (low K alkalosis, renal tubular acidosis) or from loss of nephrons in renal failure.
RESPIRATORY ACIDOSIS - 1
Remember the Henderson-Hasselbalch equation pH = pK + log [Base]/[Acid], in this case [bicarbonate]/[CO2] Consider the consequences of an acute rise in pCO2 When the pCO2 increases, without a corresponding increase in BIC, this ratio decreases, and its log, and the pH will decrease or in other terms, the H+ ion concentration will increase In consequence, some of this increased H+ will bind to proteins especially haemoglobin, with consequent increase in BIC The amount of increase in BIC in normal blood is about 1 mmol/L for each 10 mmHg increase in pCO2 above its normal 40 mmHg. The blood gas machine compensates for this chemical adjustment in calculating the Base Excess.
RESPIRATORY ACIDOSIS - 2
Because CO2 diffuses rapidly through cell membranes and fluids, there is essentially a complete equilibrium between its concentration in the blood capillary and alveolar air. So inequalities of perfusion in different parts of the lung average out and the plasma pCO2 depends only on the volume of air respired each minute and the rate of production. Thus a respiratory acidosis, with increase in pCO2, results from hypoventilation. (Compare the different behaviour of oxygen) Frequent causes of hypoventilation include: Respiratory centre depression from brain stem pathology or depressant drugs such as opiates, barbiturates, anaesthetics etc Respiratory muscle weakness or fatigue, or painful respiration Obstruction anywhere in tracheobronchial tree from a multitude of conditions, or loss of lung volume from pneumothorax or effusion Stiffness or deformity in chest wall or costovertebral joints
RESPIRATORY ACIDOSIS - 3
When the respiratory acidosis has been present for some time, the kidney begins to compensate. This is believed to result from the increased pCO2 enabling a greater production of carbonic acid in the tubules, which ionises to BIC- + H+. The BIC is transported back to the plasma, and the H+ is excreted into the urine, bound to urinary buffers such as phosphate or ammonia. The resulting ammonium cation needs a chloride anion to maintain electrical neutrality, so there is a net loss of Cl- which is replaced 1:1 by BIC in the blood. A normal kidney completes this compensation in 2-3 days, and the increase in plasma BIC is about 3.5 mmol/L for each 10 mmHg increase in pCO2. Damaged kidneys are slower and less effective. This increase in BIC restores the BIC/CO2 ratio towards normal, and the pH rises towards normal, but stays at least a little lower. The blood gas machine does not compensate for this BIC increase, it records it as a positive Base Excess
RESPIRATORY ALKALOSIS - 1
A decrease in pCO2 from any cause, without a corresponding decrease in BIC, will increase the ratio of BIC/CO2 and its log, so the pH will rise, that is the H+ concentration will fall. A decrease in CO2 can result only from an increase in respiratory volume without an increase in CO2 production = hyperventilation. Common causes of hyperventilation Voluntary but usually self limited Anxiety states acute or chronic Many types of lung disease, via receptors in lung and transmitted via the vagus nerve Severe hypoxia from any cause, severe anaemia Respiratory stimulant drugs Normal pregnancy
RESPIRATORY ALKALOSIS - 2
When the pCO2 falls and the H+ concentration falls, haemoglobin acts as an acid (instead of acting as a base in acidosis) and the H+ that it releases reacts with BIC in plasma to form CO2 which is expired. The fall in plasma BIC averages about 2 mmol/L for each 10 mmHg fall in pCO2 in an acute episode. The kidney compensates over 2-3 days by not making as much H+ as normal, because it has less CO2 to make carbonic acid, so that BIC is lost in the urine due to incomplete reabsorption of filtered BIC. Cl- is retained in its place if it is available in the diet. This compensation restores the BIC/CO2 ratio towards normal and the pH falls towards normal, but usually stays a little higher. The usual compensation is about 4 mmol/L decrease in BIC per 10 mmHg drop in pCO2 The blood gas machine compensates for the acute change but shows the renal compensation for the chronic condition as a negative Base Excess
METABOLIC ACIDOSIS - 1
Addition of any acid other than CO2 results in combination of its H+ with BIC to form CO2 (expired) and the anion from the acid remains in the plasma replacing the BIC whose concentration decreases. Thus the ratio of BIC/CO2 decreases, as does its log, and the pH falls This change rapidly penetrates into and stimulates the respiratory centre so that the respiratory excursion is increased and the pCO2 is consequently lowered. In contrast to the renal compensation for respiratory disturbances, which takes 2-3 days to be complete, the respiratory compensation for metabolic acidosis (or alkalosis) is very rapid. Very approximately a decrease in BIC of 1mmol/L results in a decrease in pH of 0.01-0.015 and a decrease in pCO2 of approximately 1-1.5 mmHg if all else is normal, but when the BIC falls much below 10 mmol/L the changes are greater. These numbers depend on a normal respiratory function.
METABOLIC ACIDOSIS - 2
Common causes of metabolic acidosis are: Failure of the kidney to excrete H+ appropriately either a specific tubular defect in H+ generation or transport with normal GFR, or a low GFR due to a variety of damaging conditions. Loss of BIC from bowel Abnormally high amount of formation of acids in the body or abnormally low rate of removal, including: Lactic acid is made normally and in increased amount in exercise or tissue anoxia, removed by gluconeogenesis in liver and a little in kidney. Excess production, or slow removal (liver pathology, metformin) cause accumulation Ketone bodies (betahydroxybutyric acid and acetoacetic acid) from fatty acid oxidation accumulate in starvation and diabetic ketosis, in amounts greater than heart, brain and muscle can use.
METABOLIC ACIDOSIS - 3
Many foreign substances either act as acids, or are converted into acids by metabolism. Common substances are: Methanol which forms formic acid Ethylene glycol (antifreeze) glycolic, glyoxylic and oxalic acids Acidic antibiotics such as some synthetic penicillin analogues can accumulate Paracetamol and several other drugs detoxicated by glutathione can cause pyroglutamic acidosis Many inborn errors (genetic lack of catabolic enzymes) cause acidosis due to accumulation of the products they cannot remove Severe tissue breakdown as in rhabdomyolysis can cause acidosis
METABOLIC ACIDOSIS 4
INVESTIGATIONS
The blood gas machine will show the BIC, pCO2 and pH, and will record an appropriate negative base excess On the usual laboratory electrolyte picture we can calculate the anion gap which is a representation of the amount of unmeasured anions in the normal grouping of Na, K, Cl and BIC. These unmeasured anions are predominantly on proteins, especially albumin, + small quantities of some organic acids such as citrate, lactate etc, none at more than about 1-2 mmol/L. This anion gap (Na + K) (Cl + BIC) is normally about 12 (7-17 range). When the acidosis results from failure of the kidney selectively to secrete enough H+ as in proximal or distal renal tubular acidosis the decrease in BIC is balanced by an excess of Cl- because nearly all the other functions of the kidney are preserved. In such a case the anion gap is normal.
METABOLIC ACIDOSIS 5
INVESTIGATIONS
When there is the accumulation of any normally present anion other than chloride, or any abnormal anion, then the anion gap will be increased because this other anion is not represented in the calculation. In principle, and approximately, the excess of the anion gap above 12 should be equal to the amount of the unmeasured extra anion, but all the measurements are plus/minus and exact correspondence is not to be expected to better than about 5 mmol/L. These extra anions can be sulphate + phosphate in renal failure when GFR is not enough to clear normal production, or any of the other anions mentioned or others in the textbooks. Remember that as albumin is the major contributor to the anion gap with its many negative charges, the gap depends on the plasma albumin level and in hypoalbuminaemia (common in sick patients) the normal anion gap is proportionately lower.
METABOLIC ALKALOSIS - 1
Increase in BIC without corresponding increase in CO2 increases the BIC/CO2 ratio and the pH The respiratory centre compensates rapidly by decreasing the respiratory volume, so that pCO2 rises and the pH comes back towards normal, usually not quite there. Even large intakes of alkali such as Na bicarbonate have little effect on plasma BIC, as the kidney has a great capacity to excrete both of the ions when they are in excess (normal filtrate has 4500 mmol/day BIC, and even 100g NaBIC is only 1200 mmol BIC). A high Ca intake, as with milk, can impair this excretion. Most patients with metabolic alkalosis have a degree of effective circulating volume depletion with deficits of Na, K and/or Cl, and therapy aims to replete the missing ion(s)
METABOLIC ALKALOSIS - 2
Common causes include: Gastrointestinal losses vomiting, suction, antacids, high Cldiarrhoea (genetic error in carrier, villous adenoma) Renal losses especially diuretics, excess mineralocorticoids Ion exchange across cell membranes hypokalaemia Excess BIC or citrate administration Most of these result in the contraction alkalosis where there is insufficient Cl- available due to selective losses (gut, sweat, kidney) and the only way to get rid of the excess BIC- would require loss of Na+ to balance its charge. The resultant loss of extracellular and intravascular volume would make the patient worse. Blood gas machine shows a positive Base Excess
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