has been excreted (Singer et al,
1956). This effect may be prolonged if CO2
excretion is impaired (Ostrea and
Odell, 1972).Clinical problems of pH are all related to pH of the plasma of whole blood. pH in extracellular fluid is always close to that of blood. pH inside cells differs from that of blood but it is not recognised as being an important clinical problem apart from blood pH changes.
In the clinical situation if the actual pH of the blood is lowered, one can usually assume that the primary disturbance has been the addition to the blood of acid or the removal of base and vice versa.
Blood pH may be changed if acids or bases are added to or removed from the blood. Secretion of an acid (e.g. gastric juice) implies that the acid involved (HCl in this case) is removed from the blood.
The acids which can cause changes in blood pH are:
|
or non-respiratory acids |
|
|
Hypoxia |
|
|
|
Diabetes |
|||
|
|
|
|
||
|
|
||||
|
|
||||
|
acids |
|
|
|
|
A rise in concentration of any of these acids in the blood causes a fall in the pH of the blood. Loss of acid from the blood (e.g. into gastric juice) causes a rise in the pH. Only HCl and H2CO3 can be lost from the blood in appreciable quantities.
The bases which can cause changes in blood pH are:
Administration of base by mouth or parenterally may cause blood pH to rise if rate of excretion does not match rate of administration. Loss of alkaline fluid from bowel (diarrhoea, intestinal obstruction or intestinal fistulae), or urine (after acetoazolamide) will cause blood pH to fall.
Clinical states of pH disturbence (acid-base inbalance) can conveniently be divided into two groups, i.e. (a)respiratory and (b)metabolic or non-respiratory. The reasons for this division into respiratory and non-respiratory are that:
i) the compensatory mechanisms (Section 3.5.1) and treatments (Section 7) of the two types are different.;ii) the recognition of non-respiratory disturbances is masked by compensatory alterations in PCO2 and the recognition of changes in pH caused by PCO2 changes are masked by renal compensation.
6.3.1 RESPIRATORY ACIDOSIS. This is synonymous with CO2 retention and is usually a sign of hypoventilation. Compensation is renal. There is renal loss HCl in the form of buffer or as NH4Cl. During recvovery chloride has to be supplied and retained.
6.3.1.1 Causes of hypoventilation:
6.3.1.2 Inhalational of CO2 This is another cause of respiratory acidosis, but it is only likely to occur under situations of re-breathing, e.g. under anaesthesia or during resuscitation with a Water's cannister circuit without the cannister, i.e. ward resuscitators or Type C anaesthetic systems. (Mapleson, 1954).
6.3.1.3 Increased production of CO2. This very rarely causes a high PaCO2. In thyrotoxicosis and fever CO2 production is raised but the rise is well within the capacity of a normal respiratory system. In malignant hyperpyrexia high PaCO2s have been recorded due undoubtedly to increased production.
NaHCO2 therapy in non-respiratory acidosis
causes a rise in PaCO2 until the
CO2 generated by the neutralization of
HCO3
has been excreted (Singer et al,
1956). This effect may be prolonged if CO2
excretion is impaired (Ostrea and
Odell, 1972).
Acute respiratory acidosis is diagnosed by high
PaCO2 and low actual pH associated with near
normal non-respiratory pH, (standard
HCO3
and base excess). (See Appendix
4.2).
Chronic respiratory acidosis is compensated by loss of H
Cl
by the kidney and generation (not reabsorption) of (Na)
HCO3.
(See Appendix 3.4). Compensation
causes slightly lowered actual pH with a high non-respiratory pH
(positive base excess and high standard
HCO3.).
Steroids and diuretics (except acetazolamide (Diamox) ) may produce a
non-respiratory alkalosis which may cause a respiratory acidosis to
appear to be "over compensated". There will then be a high (actual)
pH.
In chronic respiratory failure ventilation is maintained by hypoxic drive and also by the acid pH of the blood. If the pH stimulus is removed by the actual pH being raised, some of the respiratory drive will be removed causing a diminution of respiratory effort and further CO2 retention.
When a chronic respiratory acidosis (with compensation, i.e. high
non-respiratory pH, Base excess, and Standard
HCO3.)
is improved by increasing alveolar ventilation the actual pH may rise
above 7.4. The resulting chemical picture of high pH, high
non-respiratory pH (positive base excess), and high
PaCO2 is indistinguishable chemically from a
primary metabolic alkalosis with compensatory
CO2 retention. Clinical information is
required to distinguish them. (Plot this and other examples on a
standard Siggaard-Andersen nomogram as an exercise). ( See Footnote
to table 4.2.2.)
N.B. The compensatory renal or respiratory changes which partially correct pH disturbances are chemically true pH changes in the opposite direction to the original disturbances. It is a semantic problem whether the compensatory renal change induced for example by primary chronic CO2 retention is called a metabolic alkalosis or not. This semantic muddle can be avoided if the term alkalosis is used only in a non-precise term.
6.3.2. RESPIRATORY ALKALOSIS. This is associated with hyperventilation. Usually these are acute so there is no time for renal compensation, but if prolonged, such as in acclimatization to high altitudes, there would probably be renal compensation.
6.3.2.1. Deliberate induced hyperventilation during anaesthesia.
6.3.2.2. Some causes of hypoxia associated with hyperventilation. This would include "air hunger" of hypovolaemia, severe ventilation-perfusion abnormalities and acclimatization to high altitudes. Critically ill patients without arterial hypoxaemia can have severe hypocapnia (Mazzara et al,1974). This may be explained by low cardiac output.
In asthma attacks, unless severe, the PaCO2 is usually lowered, i.e. the alveolar ventilation is increased (McFadden and Lyons, 1968). This is at least sometimes associated with hypoxaemia due to mismatching of ventilation and perfusion.
6.3.2.3. Fever. This may cause hypocapnia due presumably to central stimulation of the respiratory control mechanisms (Chapot et al, 1974).
6.3.2.4. Some types of C.N.S. damage.
6.3.2.5. Hysterical hyperventilation.
This (non-respiratory acidosis) is due to increase in acids (i.e.
H
donating substances) other than
H2CO2 or decrease in
base (i.e. H
acceptors) in the blood. Compensation is by hyperventilation. This
lowers the PaCO2 thus deducing the any pH
change. The causes of non-respiratory acidosis are:
6.3.3.1 Increased alimentary or parenteral intake of acid or alimentary loss of base.
6.3.3.1.1. Adding acid. The acid content of blood may be
raised by ingestion or injection of ammonium chloride or dilute
hydrochloric acid. The hydrochloric acid directly increases
[H].
The ammonium chloride produces hydrochloric acid by the NH3 being
split off and converted to urea. Adding ammonium chloride directly to
blood would not change the pH greatly until the NH4+ has been
metabolised.
6.3.3.1.2 Alimentary loss if Base. Loss of intestinal
contents by diarrhoea, low small bowel obstruction or intestinal
fistulae causes loss of fluid of high pH, i.e. containing an excess
of base (NaHCO3
or KHCO3).
This results in the fluid left in the body having a lower base
content than normal. The removal of base causes the blood pH to fall
(Leading Article, 1966). A
similar disturbance has been reported from loss of lymph. (Siegler
et al, 1978).
6.3.3.1.3 Intravenous infusions. These can cause an acidosis.
6.3.3.1.3.1 Stored blood for transfusion. This has la ow pH. The anticoagulant contains citric acid. When mixed with the blood the pH drops. PCO2 rises because of the action of acid on bicarbonate ions. Most of the pH drop is due to this CO2 which does not escape from the stored blood. The non-respiratory pH of the stored blood is not as low as the actual pH. The pH of stored blood does not fall progressively if stored for up to three weeks at 4°C (Gaudry, Joseph and Duffy, 1974).
The acidic salt of sodium citrate and "dilutional" acidosis are the main contributers to the non-respiratory pH of stored blood. There is a variable amount of lactic acid acid in stored blood This usually contributes less to the non-respiratory pH change. If stored concentrated red cells are washed there will be a considerable and even an increased non-respiratory acidosis in the product. If 27meq NaHCO2 is added to each litre of washing fluid this would not occur, but would introduce other problems.
Stored blood transfusion rarely causes a non-respiratory acidosis if the circulation and temperature are maintained normal. It is possible that if the circulation and temperature are not maintained, that metabolic acidosis could occur with massive transfusion. In a situation where a massive transfusion is given it will not usually be possible to distinguish the low pH due to blood, from that due to the condition for which the blood is being given. From personal observations the low base excess observed during liver transplantation appears to be mainly a combination of lactic acidosis from the transfused blood and released or generated in the new liver and dilutional acidosis. The sodium citrate in the anti-coagulant solution can cause a metabolic alkalosis after the citrate has been metabolised and replaced by bicarbonate ion.
Howlands et al (1965) have advocated routine use of sodium bicarbonate during massive blood transfusion to counteract the acidosis of the infused blood. This is usually unnecessary (Bookallil and Joseph, 1968), and will probably only aggravate post transfusion alkalosis (Miller et al, 1971).
If the temperature and circulation are not maintained as is common in when more than say 5 litres in 2 hours are transfused in trauma the composition of the circulating blood approaches that of the transfused blood. In liver transplantation 3 times the blood volume may be replaced in an hour and up to 30 times the blood volume during the operation. This can result in pH<6.9 and base excess <-20meq/litre. The cause is lactic and dilutional acidosis. There appars to be little circulatory effects and spontaneous recovery occurs without alkali therapy (Personal observation).
6.3.3.1.3.2 "Dilution Acidosis" (Shires et al, 1948; Garella et al, 1973) is an acidosis due to the intravenous infusion of a neutral non-buffer solution.
Intravenous solutions which contain only non-acids or non-bases, e.g. sodium chloride, glucose and other carbohydrates usually have a pH slightly less than 7. This is usually due to pharmaceutical details in the preparation. In these non-buffer solutions this low pH represents a very small amount of acid. One would only have to add a fraction of a miliequivalent of strong base to a litre to make the solution alkaline.
If such a non-buffer solution (e.g. Saline or 5% glucose) is equilibrated with a gas mixture containing 40mmHg CO2 it has a pH of 4.9 (Gaudry et al, 1972). 24meq Na0H (or NaHC03) would have to be added to it to give a pH of 7.4, therefore a neutral solution plus 24meq NaHC03 will on infusion cause no change in pH in the blood. The original solution of saline or glucose will act in a similar fashion to an injection of 24meq HCl for each litre infused. This will only be importasnt if large volumes of intravenous fluid are given in a short time,e.g. in burns or cholera (see Diuretic Alkalosis, 6.3.4.2).
6.3.3.1.3.3 Metabolic acidosis associated with intravenous alimentation. Intravenous feeding with amino acid solution in the form of hydrochlorides can cause a metabolic acidosis associated with a high serum Cl level (Chan, Ghadimi, Kaminski and Heird et al, 1973). Lactic acidosis may be associated with intravenous feeding regimes which contain fructose, xylotol or sorbitol (Alberti and Nattrass, 1977).
In some cases hypertonic glucose also has been associated with lactic acidosis (Ames et al, 1975).
6.3.3.4 Ingestion or injection of oganic acids. This would not ordinarily produce change in pH because the liver would metabolise them. In liver disease and during liver transplantation organic acids introduced to the body gain access to the systemic circulation.
6.3.3.5 Accumulation of Acid. Excess acid may accumulate in the blood from processes of metabolism and cause a fall in the pH. There are two main mechanisms for this:
6.3.3.5.1 Hypoxia. Hypoxia from any cause prevents the products of anaerobic glycolysis being further metabolised. Excess lactic acid appears in the blood and lowers the pH.
The causes of hypoxia are:
In cardiac arrest there have been several studies which document low blood pH (Ledingham et al, 1962; Chazan et al, 1968 and Fillmore et al, 1970). All cardiac arrests do not have non-respiratory acidosis. Respiratory acidosis (high PaCO2) is a feature of some. High PaCO2 for practical purposes means inadequate alveolar ventilation, which of course, might be present. Fillmore et al. imply that aspiration may be a cause of high PaCO2. This is only the case if it associated with hypoventilation. If ventilation is inadequate not only will the PaCO2 be high but what is more important the oxygenation will be inadequate unless oxygen is given. High levels of alveolar oxygen will not be present if mouth-to-mouth ventilation is being used. A transient rise in PaCO2 will occur for a few minutes after NaHC03 administration, due to increased CO2 release (Bishop et al, 1976).
Circulatory occlusion of any large area causes accumulation of organic acids in the area supplied. On restoration of the circulation these acids are distributed systemically. This is a possible cause of acidosis, but in practice if the general circulation and temperature are maintained in a satisfactory state only transient acidosis results as the acids are quickly metabolised (Bookallil and Joseph, 1968).
Non-hypoxic lactic acidosis is a syndrome being more commonly discussed. It is a serious syndrome of unknown aetiology (Oliva: Leading Article, 1970; Leading Article, 1973; Harken, 1976: Alberti et al, 1977). It probably includes syndromes of varying aetiology, e.g. phenformin associated acidosis in diabetes (Gale et al, 1976), and the acidosis associated with parenteral nutrition with some carbohydrates (See 6.3.3.1.3.3 and Appendix 6.3.3.2.1).
6.3.3.5.2 Diabetes and Starvation. In both these states excess acetone and keto-acids are produced. There will be some attempt at renal excretion (ketonuria) but if this is inadequate the quantity of acid in the blood will rise and the pH wil fall (Peters and Van Slyke, 1931). All acidoses in diabetes are not due to keto-acid. In some instances lactic acid is the cause. Patients clinically diagnosed as diabetic keto-acidosis sometimes have alkalosis (Lim and Walsh, 1976).
6.3.3.5.3 Others. There are some other disturbances of intermediary metabolism which may cause blood pH to fall from accumulation of organic acids. One of these which is mentioned in 6.3.3.1.3.3 and 6.3.3.2.1 occurs from intravenous administration of some sugars.Another is iso-valeric acidaemia - a rare inborn error of metabolism due to an enzyme deficiency (Cohn et al, 1978).
6.3.3.3 Failure of excretion of acid. This may lead to
acidosis. Normally during metabolism some inorganic acids are
produced, i.e. sulphuric and phosphoric acids. The anions have to be
excreted by the kidney covered either by Na
, K
, H
(small amount) or NH4
(produced in the kidney). Normally the quantity of acid involved is
not great (40-60meq/day), but over a long period, if there is failure
of excretion, accumulation will occur with a fall in pH. This is
renal acidosis (Relman, 1968).
Renal acidosis may also be due to loss of base induced by
acetazolamide (Diamox). Renal acidosis is usually a manifestation of
generalised renal failure but there is also a syndrome of renal
tubular acidosis where metabolic acidosis of renal origin is an
isolated disorder.
6.3.4 METABOLIC ALKALOSIS (non-respiratory alkalosis). This is due to loss of HCl from the ECF or addition of alkali. Metabolic alkalosis is compensated by respiratory depression which causes CO2 retention (Tuller and Mehdi, 1971; Shear et al, 1973; Aquino et al, 1973) but may also cause hypoxia. The pH is usually raised but may be high normal if there is much CO2 retention. Metabolic alkalosis is due to:
6.3.4.1. Loss of gastric juice
containing HCl. Patients with pyloric obstruction lose some
K
and Na
as well as HCl. The loss of K
is mainly through the kidney (Kassirer
et al, 1966). At first the urine is alkaline but after stable
conditions are established the urine becomes acidic as the normal
inorganic acid load from protein breakdown still has to be excreted
(Schwartz et al, 1978). If
it were not, it would correct the alkalosis. The acid urine used to
be thought to be paradoxical (Van
Slyke and Evans, 1947), and was attributed to K
deficiency.
The situation of a chronic metabolic alkalosis with acid urine is probably the best clinical example where balance or status as destinct from input, output or turnover (section 2.1) should be distinguished. The blood pH status is stable and alkaline. For the non-respiratory pH to remain high the normal acid output must continue, i.e. acid excretion in the urine will be normal and the urine pH will be low.
6.3.4.2 Diuretic alkalosis.
Thiazide diuretics, frusemide and ethacrynic acid can produce a
metabolic alkalosis. HCl, its equivalent NH4Cl
or HCl having acted on phosphate buffer is lost in the urine. The
central role of Cl
in the production of diuretic alkalosis has been established
(Kassirer et al, 1965).
6.3.4.3 Ingestion or injection of excess base, e.g.
NaHCO3
or NaOH.
Post transfusional or post-cardiac surgery metabolic alkalosis is
usually due to the administration and metabolism of sodium citrate
(Kappogoda et al, 1973;
Barcenas et al, 1976). If
NaHCO2 is given to "correct" an acidosis it
may result in a high serum Na and osmolality and later an
alkalosis.
6.3.4.4 Steroid alkalosis (Kassirer et al, 1970; Schambelan et al, 1971).
Any of the clinical conditions mentioned can be associated with pH
or acid-base status disturbances and one can usually suspect pH
changes by the clinical picture, e.g. hypoventilating, acute on
chronic obstructive airway disease, probably has
CO2 accumulation; intestinal obstruction or
severe diarrhoea probably has acidosis due to loss of base
Na
and/or K
+ HCO3
); a diabetic who is drowsy and hyperventilating with urinary glucose
and ketones probably has keto-acidosis; "shock" with poor tissue
perfusion may have lactic acidosis.
The signs of acid-base disturbances are not diagnostic but in association with the clinical picture, a suspicion of variable certainty can be entertained. Definite daignosis is only possible by measurements on blood which should usually be arterial but can be capillary, venous or mixed venous. See tables 4.2.1 and 4.2.2.
It is often stated that blood pH below some arbitrary level, usually 6.8, is incompatible with survival (Andreoli 1988). This is not so. Low pHs' have been recorded in association with CO2 retention (Schultz, 1960, pH 6.71, PaCO2 234mmHg. Prys-Roberts et al, 1967, pH 6.86, PaCO2 248mmHg) and severe exercise (Osnes and Hermansen, 1972, Hermansen and Osnes, 1972) with little physiological disturbance attributed to the low pH, and with complete recovery.
Two cases of strychnine poisoning who recovered after low pHs' were recorded, have been reported, (Goldstein, 1975, pH 6.57 PaCO2 18mmHg; Loughhead et al, 1978, pH 6.59 PaCO2 59.5mmHg).
If the blood pH is abnormal, the cause of the disturbance is usually severe, and compensatory or correcting mechanisms have not occurred or have been insufficient. It is in practice impossible to distinguish the physiololgical effects of the cause from those of the pH change itself.
There are many effects of pH changes which are reversible when the cause and/or the pH change are removed. As far as the whole organism is concerned the cardiovascular effects of pH change are the most important. A low pH is said to aggravate cardiovascular depression. This then further lowers pH due to lowered perfusion, thus setting up a vicious circle.
There is evidence that correcting a low non-respiratory pH in circulatory insufficiency improves the prognosis (Manger, 1962, Ledingham et al, 1962). Low non-respiratory pH can worsen arrhythmias (Anderson, 1968). Artificially induced pH changes due to infusion of acid in normal animals does not reduce cardiovascular activity with moderate falls in pH (Anderson, 1967, 1968, Caress et al, 1968). Maybe a low pH has a much greater effect in an already impaired circulatory system than in the normal. There is controversy (Stackpool,1986, Narins & Cohen 1987) about use of alkali in states of of low pH.
The cardiovascular effects of pH changes are probably different in the various chemical causes, e.g. hypoxic lactic acidosis produces more disturbance than a similar pH change due to CO2 (Schultz, 1960, Prys-Roberts et al, 1967).
Alteration of enzyme action when the pH is abnormal is usually given as the mechanism of the deleterious effects of pH changes. This, of course, is the basic mechanism in all disturbances but it does not indicate in which system the effect is critical. It is cardiovascular effects of pH changes which set the limit.
High pH levels also produce physiological disturbances. These are less well documented and of less clinical importance. The main clinically important effects are CNS effects (tetany and impaired consciousness) hypoventilation (if the high pH is not due to hyperventilation and a low PCO2) and possible cardiovascular effects (Streisand et al, 1971; Lawson et al, 1973; Galmarini et al, 1973; Lock et al, 1975).
The serum potassium concentration falls when the PaCO2 is acutely lowered. Return of the potassium concentration may be slower than the return of the pH when the PCO2 recovers (Edwards et al, 1977; Sanchez et al, 1978; Finsterer et al, 1978).
A review article "Lactic Acidosis" by Alberti and Nattrass (1977) gives a rational and useful classification of lactic acidosis drawing on the book by Cohen and Woods, "Clinical and Biochemical Aspects of Lactic Acidosis" (1976).
This classification is:
Type A Shock syndrome and hypoxia.Type B1 Common disease states, e.g. diabetes, liver disease, infection.
Type B2 Drugs, e.g. phenoformin, sorbitol, fructose.
Type B3 Hereditary metabolic disorders.
They state that as these categories are better defined, the reporting of so-called iodiopathic lactic acidosis decreases.
It is sensible to treat the cause if this is known. This may be all that is required in Type A. Restored circulation and oxygenation will permit the lactic acid to be metabolised. In Type B more active measures are suggested to correct the pH abnormality as a low pH may cause the liver to produce further lactic acid. Large doses of NaHCO2 (up to 2,500mmol) have been given. This quantity would usually produce problems of its own which would necessitate dialysis. Such situations are very rare or else are unrecognised.
In the preface of Cohen and Woods' Monograph which contains an exhaustive literature review, it is stated, "We strongly suspect that the comparatively small number of cases (of the syndrome of severe lactic acidosis without shock) recorded in the literature reflect merely the tip of the iceberg". One might as logically say that "I strongly suspect that there is no iceberg"!!!!