anions and the anesthetist

140 q 2002 Blackwell Science Ltd

REVIEW ARTICLE

Anions and the anaesthetist

D. G. Maloney,1 I. R. Appadurai2 and R. S. Vaughan2

1 Specialist Registrar and 2 Consultant Anaesthetist, Department of Anaesthetics, University Hospital of Wales, Heath

Park, Cardiff CF14 4XW, UK

Summary

Anions are the negative components of most chemical structures and play many important

physiological and pharmacological roles that are of interest to the anaesthetist. Their relevance is

reviewed with a particular emphasis on the inorganic anions (halides, bicarbonate, phosphate and

sulphate) and the significance and limitations of the anion gap. Organic anions (albumin, lactate) are

also discussed, albeit briefly. The suitability of anions for their role in neurotransmission and

acid2base balance is outlined.

Keywords Anions: chloride; fluoride; bromide; phosphates; sulphates; albumin; lactate. Acid2base

equilibrium: anion gap.

.................................................................................................

Correspondence to: Dr D. G. Maloney

E-mail: [email protected]

Accepted: 9 June 2001

Anions have many important physiological and pharma-

cological functions and have, to a large extent, been

ignored in anaesthetic textbooks. They are invariably

linked to cations but can have pronounced effects in their

own right. Although their concentrations are measured in

the extracellular fluid compartment in clinical practice, the

ion shifts that occur across the cell membrane are not only

involved in acid2base and electrolyte balance, but may also

form the basis of the molecular mechanisms of anaesthesia.

Inorganic anions

Halogens

Halogenation of hydrocarbons and ethers decreases

flammability and increases anaesthetic potency. It also

increases cardiac sensitisation to catecholamines in the

order: F2 . C12 . Br2 . I2. Fluorination increases

the stability of adjacent halogen2carbon bonds but may

also increase convulsant properties, especially if the

compound has four or more carbon atoms or contains

other halogens.

Chloride

Chloride is the main anionic constituent of extracellular

fluid (ECF) contributing < 100 mosm.l21 to its tonicity,

and is normally present in the body, unlike the other

halogens. Because it is exchangeable with bicarbonate, it

has a role in maintaining a normal acid2base state,

normal renal tubular function and in the formation of

gastric acid. It has been the subject of review in the

context of critical care medicine [1] and has important

implications for the anaesthetist in the areas of fluid

resuscitation and acid2base balance.

Chloride intake

The daily requirement of 1±3 mmol.kg21 is absorbed

from the upper part of the small intestine by the Na1/

K1/C12 co-transport mechanism. The active absorption

of sodium and potassium creates an electronegative

gradient in the chyme along which chloride ions move.

However, in the ileum and large bowel, the enterocytes

have an anti-transport mechanism that exchanges chloride

ions for bicarbonate. The physiological significance of the

latter is uncertain but impairment of this transport

mechanism leads to congenital chloride diarrhoea, an

autosomal recessive disorder.

Chloride output

The greatest loss is from the stomach in gastric juices

(<1.5 mmol.kg21.day21). There is a further loss from the

Anaesthesia, 2002, 57, pages 140±154................................................................................................................................................................................................................................................

gastrointestinal tract (<1 mmol.kg21.day21) in the form

of bile, pancreatic and intestinal secretions. Chloride is

secreted into the intestinal lumen via channels regulated

by protein kinases. One of these is activated by protein

kinase A and therefore by cyclic adenosine monopho-

sphate (cAMP). Some bacteria, notably Vibrio cholerae,

produce a toxin that binds to the Gs protein, producing a

marked increase in cAMP, leading to profuse secretory

diarrhoea. Normally about 15 mmol.day21 are lost in

sweat.

In the renal tubule, chloride excretion varies with the

need for bicarbonate. Chloride is excreted with ammo-

nium ions to eliminate hydrogen ions in exchange for

sodium. This occurs mainly in the proximal tubule and

can result in the production of acid urine even in the

presence of a metabolic alkalosis, as seen in pyloric

stenosis. In the ascending limb of the loop of Henle,

chloride is reabsorbed with sodium. Regulation of

chloride is passively related to sodium and inversely

related to plasma bicarbonate. Therefore, aldosterone

indirectly influences chloride concentrations.

Chloride shifts

As erythrocytes move through the peripheral tissues,

carbon dioxide is converted by the action of carbonic

anhydrase to bicarbonate. About 70% of the bicarbonate

produced will diffuse into the plasma and chloride shifts

into the cell to maintain electrochemical neutrality. The

reverse occurs when the blood reaches the lungs. These

exchanges are known as chloride shifts. In respiratory

disturbances, up to 30% of an acid load can be buffered by

similar chloride2bicarbonate ionic shifts between the

intracellular fluid (ICF) and extracellular fluid [2]. In

chronic respiratory acidosis, a compensatory metabolic

alkalosis occurs with a subsequent chloride shift from

the erythrocyte to the plasma in exchange for bicarbo-

nate. In respiratory alkalosis, hydrogen moves from the

intracellular space to maintain electroneutrality, whereas

excess bicarbonate moves into the erythrocyte in

exchange for chloride. The causes of chloride flux are

given in Table 1.

Implications for fluid resuscitation and acid2base management.

The choice of fluids containing chloride ranges from

hypertonic, e.g. 1.8% NaCl, to hypotonic, e.g. 0.18%

NaCl, in dextrose saline. These are normally chosen for

their sodium content and osmolarity and therefore their

effect on expanding the ECF. They are usually unbuffered

and can have a profound effect on acid2base balance.

It is important to be aware that over-reliance on normal

saline as a resuscitation or maintenance fluid will result in

a hyperchloraemic acidosis [3±5]. This can have sig-

nificant effects in the postoperative period [6] that may be

ascribed erroneously to other pathology [7]. It can be

corrected by the judicious use of sodium bicarbonate and

is preferable to allowing hyponatraemia to develop peri-

operatively, as may occur with transurethral resection of

the prostate (TURP syndrome). There may be an added

benefit to using hypertonic saline as a `preload' before

regional anaesthesia in such cases [8].

Just as an excess of chloride can cause a metabolic

acidosis, it is notable that metabolic alkalosis and

hypokalaemia are the hallmarks of chloride depletion.

The classic example is that of gastric outflow obstruction,

in particular pyloric stenosis [9]. Metabolic alkalosis can

be divided, for therapeutic purposes, into saline-resistant

and saline-responsive types. Urinary chloride concentra-

tion can be helpful in determining the aetiology of the

alkalosis provided no diuretic has been administered [1]. A

urinary chloride of , 10 mmol.l21 implies that the

Table 1 Causes of chloride flux.

Hypochloraemia (, 95 mmol.l21) Hyperchloraemia (. 106 mmol.l21);

Gastrointestinal loss Vomiting, e.g. pyloric stenosisNasogastric suction

Increased intake Intravenous fluid infusions

Increased renal excretion Diuretics Decreased renal excretion Uretero-ileostomy;Renal tubular acidosis

Endocrine HyperaldosteronismSyndrome of inappropiateantidiuretic hormone secretion(SIADH)Cystic fibrosis

EndocrineIonic shiftConcentration effectArtefactual

Diabetes insipidusRespiratory alkalosisSevere dehydrationSampling errorLaboratory error

Ionic shift Chronic respiratory acidosis

Dilutional Congestive cardiac failureInfusion of hypotonic solutions

Artefactual Sampling errorLaboratory error

Anaesthesia, 2002, 57, pages 140±154 D. G. Maloney et al. � Anions and the anaesthetist................................................................................................................................................................................................................................................

q 2002 Blackwell Science Ltd 141

patient should respond to saline, whereas a urinary

chloride of . 20 mmol.l21 suggests that a saline-resistant

metabolic alkalosis is present. The latter is caused mainly

by hyperadrenocorticism in which renal bicarbonate

excretion is stimulated and these patients remain alkalotic

despite chloride administration.

Fluoride

Fluorine has been known to decrease the boiling point,

increase the stability and generally decrease the toxicity of

anaesthetic vapours since 1932 [10]. Although it forms

stable bonds, it was not until after World War II that

advances in chemistry enabled the fluorination of organic

compounds to become a reality.

The problem with fluorination became apparent soon

after the introduction of methoxyflurane with the first

report of nephrotoxicity [11], followed shortly thereafter

by the conclusive dose2response study by Cousins &

Mazze [12]. An apparent renal threshold for nephrotoxi-

city was established at . 50 mmol.l21 and went unchal-

lenged for . 20 years. It was even extrapolated to other

fluorinated volatile anaesthetics, a view that can no longer

be supported [13, 14]. It was found to be more common

in cases in which cytochrome P450 2EI induction had

occurred [15, 16] or in which there was pre-existing renal

disease [17]. The former was noted with chronic isoniazid

therapy, obesity [18, 19], untreated diabetes mellitus and

alcohol abuse [16]. It has not proven to be a problem with

children taking antiepileptic drugs [20].

As explanations were sought, the original concept of

MAC-hours gave way to that of the area under the

fluoride concentration curve (AUC) [21]. Methoxyflur-

ane has a much larger AUC than expected, given that the

half-life of fluoride in blood is 90 min. It also has a much

larger AUC than any other volatile agent, including

sevoflurane. The difference was at first thought to be

related to both the greater lipid solubility and the degree

of metabolism of methoxyflurane. Sevoflurane undergoes

considerable metabolism to fluoride ions (3±5%) but its

lipid solubility is low and therefore its uptake by tissues

much less. However, studies have shown that even after

sevoflurane anaesthesia that produced fluoride ion con-

centrations . 50 mmol.l21 for prolonged periods,

nephrotoxicity did not occur [22±25]. Similarly, pro-

longed anaesthesia [26] or sedation on the intensive care

unit (ICU) [27±30] with isoflurane did not produce

clinically significant kidney damage. Enflurane, however,

has been observed to cause decreased urine concentrating

capacity at a fluoride concentration . 33.6 mmol.l21

[31]. It was subsequently proposed that there may be

additional or confounding factors in the aetiology of

nephrotoxicity that include intrarenal formation of

fluoride ions [32], formation of other toxic compounds,

e.g. hexafluoroisopropanol (HFIP) [33], or changes in

renal plasma flow. More recently, it has been observed that

maximum fluoride concentrations do not exceed

20 mmol.l21 in children undergoing sevoflurane anaes-

thesia and they are therefore unlikely to be at risk from

renal toxicity [34, 35]. Despite some early misgivings [33],

sevoflurane is now well established as the agent of choice

for inhalational induction in both adults and children.

It has been noted that at a urinary pH . 7.0 [36, 37],

mannitol, but not furosemide, increases fluoride excretion

[38], although this has not been put to specific therapeutic

use. Fluoride also stimulates periosteal and endosteal bone

formation, but as it replaces the hydroxyl ion in the

hydroxyapatite lattice, there may be a consequent loss of

strength and the potential for fracture. However, there

have not been any reports of fluorosis after long-term

exposure in operating theatre personnel outside the

setting of drug abuse [39].

Bromide

Locock introduced bromide in 1857 as a sedative

anticonvulsant. Its inclusion lends stability to molecular

structures, as exemplified by the non-depolarising neu-

romuscular blocking drug vecuronium bromide and the

inhalational anaesthetic halothane. The metabolism of

halothane leads to debromination and the bromide may

reach psychoactive concentrations (480 mg.ml2l) after

anaesthesia [40]. This has been observed in both adults

[41±43] and children [44]. The extent of this debromina-

tion is not possible to predict [45]. The half-life of

bromide is 12±14 days and its cumulative effects are an

important consideration with repeat anaesthesia, e.g. for

neuro-oncology treatments [44, 46]. Elevated concentra-

tions have also been noted in anaesthetic [47] and

operating theatre personnel [48] when measured using

X-ray fluorescence spectrometry. However, psychoactive

side-effects have not been demonstrated in these groups.

Debromination has not been shown to be a problem

with neuromuscular blocking drugs, as the amounts used

are much smaller. Halides in high concentrations have

been shown to displace some basic drugs from albumin,

but this has not been demonstrated with bromide up to

concentrations of 4 mmol.l21 [49].

Bicarbonate

Bicarbonate has two main physiological functions. It

forms the main buffer and facilitates the carriage of

carbon dioxide in the blood (80% as bicarbonate). These

two functions are inextricably linked to the body's main

system for the regulation of pH. This relationship is

expressed in the Henderson2Hasselbach equation. The

modified Henderson equation does not contain negative

D. G. Maloney et al. � Anions and the anaesthetist Anaesthesia, 2002, 57, pages 140±154................................................................................................................................................................................................................................................


logarithms and is consequently easier to understand and is

recommended to the reader.

Henderson2Hasselbach equation:

pH � pK 1 log �HCO23 �/�H2CO3�:

Modified Henderson equation:

�H1�:�HCO23 � � k�Pco2�:�H2O�:

The ratio of bicarbonate to carbonic acid is 20:1. Its pK

value is 6.1 and at first glance one would expect the

chemical buffering capacity at pH 7.4 to be poor.

However, it is the quantity of bicarbonate in plasma

(24±28 mmol.l21) that is significant. Furthermore, as

blood becomes more acidotic, its pK value is approached

and the efficiency of the buffer system increases. One of

the most important features of the system is its

responsiveness. In the short-term, changes in pH can be

compensated for by adjustments of Paco2 achieved via the

lungs, and in the longer term by adjustments in plasma

bicarbonate achieved via the kidneys. It is important to

mimic this system and to increase the minute ventilation

appropriately when managing patients with a metabolic

acidosis. The ventilatory management of patients with

metabolic alkalosis is more difficult, as a normal minute

volume may reduce the patient's own compensatory

hypercapnia and initially worsen the alkalosis. Ideally,

ventilation should be avoided until the alkalosis has been

reversed. If this is not possible, ventilatory strategies that

allow Paco2 to increase, i.e. permissive hypercapnia,

should be considered. The main causes of changes in

plasma bicarbonate concentration are listed in Table 2.

Therapeutic uses of bicarbonate

Correction of metabolic acidosis

The first solutions of sodium bicarbonate (2.74%) were

formulated at the Westminster Hospital. It was first used

in an anaesthetic context in 1962 to treat the metabolic

acidosis that was thought at the time to cause `neostig-

mine resistant curarisation' [50]. Hunter had earlier

described this syndrome that caused high mortality in

patients with long-standing intestinal obstruction. The

therapy was a resounding success and marked a milestone

in the evolution of the therapeutic uses of bicarbonate.

The amount of bicarbonate, in mmols, necessary to

correct an acidosis can be calculated by the product of the

treatable volume (0.3 � body weight in kg) and the base

deficit. This equates to the amount, in ml, of an 8.4%

bicarbonate solution (1 mmol.ml21). However, over treat-

ment with bicarbonate can have many deleterious effects. It

may not only cause an initial increase in Paco2, worsening

intracellular acidosis, but it may also result in a rebound

metabolic alkalosis after correction of the metabolic acidosis.

Hypokalaemia may result from an intracellular shift of

potassium. The sodium load may cause severe hypernatrae-

mia and increased osmolarity [51], which can result in fluid

overload in patients with heart failure, or intracranial

haemorrhage in neonates [52] and premature infants [53].

Bicarbonate can have adverse vasodilatory effects, especially

under anaesthesia [54], and it has been recommended that

invasive monitoring be used to guide administration [55].

Bicarbonate is best avoided in diabetic ketoacidosis, as it can

precipitate impaired oxygen delivery to the tissues by

unmasking the unopposed action of 2,3-diphosphoglycerate

(2,3-DPG) [56]. Bicarbonate administration causes a

decrease in ionised calcium as a result of increased binding

to albumin, and this may lead to tetany.

To avoid some of these complications, in particular the

increase in Paco2, other buffers have been investigated, e.g.

trihydroxymethylaminomethane (THAM), Carbicarb and

Tribonat. All these agents are anions. Guidelines for the

administration of THAM have been reviewed [57]. The

main advantages are regeneration of bicarbonate with a

lowering of Paco2, slow penetration of the intracellular space,

maintenance of buffering power in hypothermia and

effectiveness in a closed or semiclosed system. However, it

has been associated with severe thrombophlebitis and tissue

necrosis, alkalosis with hypoventilation and arterial vasodila-

tation, with a consequent decrease in coronary perfusion

pressure. Tribonat is a mixture of THAM, sodium

Table 2 Causes of bicarbonate flux.

Bicarbonate deficit Bicarbonate excess

Gastrointestinal losses Small bowel, pancreatic, biliary fistulaeDiarrhoeaCholestyramine

Metabolic compensationBicarbonate administration

Type II respiratory failureSelf-administration, e.g. treatment of dyspepsiaIatrogenic, e.g. overcorrecting an acidosis

Renal losses Renal tubular acidosisCarbonic anhydrase inhibitors

Chronic vomiting with acid lossChronic diuretic use

Gastric outlet obstructionMetabolic alkalosis from potassium loss



bicarbonate, phosphate and acetate and has been proposed as

an effective buffer without the side-effects of its parent

compounds [58].

Emergency treatment of hyperkalaemia

Bicarbonate administration results in the intracellular

redistribution of potassium ions. This may restore ECG

morphology and occasionally lead to the return of the

cardiac output after cardiac arrest [59].

Decreasing latency of local anaesthetic blocks

There are numerous studies that show that the onset [60±

64] and duration of action [65, 66] of local anaesthetic

blocks can be increased by alkalinisation of local anaes-

thetics. The proposed mechanism is that the alkaline pH

promotes the local anaesthetic to remain in the unionised

state, in which form it crosses the neural membrane.

Others have suggested that the effect is limited to solutions

containing epinephrine [67], albeit in vitro.

Forced alkaline diuresis for removal of acidic drugs or toxins

Myoglobinuria is a feature of rhabdomyolysis and cast

formation may cause acute renal failure. Myoglobin

remains soluble if the urinary pH is kept . 6.5. Ron

et al. first described a protocol for alkalinizing the urine

with bicarbonate and maintaining a diuresis [68]. Forced

alkaline diuresis has also been used as an adjunct in the

treatment of overdosage with tricyclic antidepressants but

is no longer recommended.

Phosphate

Phosphorus comprises < 1% of total body weight in the

form of phosphate ion. It is the most abundant anion in

the intracellular compartment. The majority (85%) is

stored in bone as hydroxyapatite crystals, with the rest

being stored in the soft tissues (14%) and blood (1%).

Approximately 1 g of phosphorus is ingested daily. This

is well in excess of the dietary needs as only < 70%

(700 mg) is absorbed, mainly through the small intestine.

Phosphorus absorption from the intestine is remarkably

efficient and hypophosphataemia secondary to deficient

absorption is rare in the absence of antacids. There are

both passive and active mechanisms, the latter being more

active when dietary intake is low, with absorption

approaching 90%. The kidneys normally excrete

700 mg.day21 by filtering 6 g and reabsorbing 5.3 g,

thus maintaining a balance between intake and output.

Phosphorus absorption occurs under the influence of

vitamin D, whereas phosphate excretion is primarily

influenced by parathyroid hormone.

Phosphate exists in the body in both organic and inorganic

forms. Most intracellular phosphate is organic, taking the

form of adenosine triphosphate (ATP), nucleic acids,

phospholipids and phosphoproteins. Extracellular phosphate

exists mainly in the inorganic form. This is the freely diffusible

form and is the fraction that is measured in plasma. In contrast

to calcium, only 12% of phosphate is bound to albumin and is

thus not affected by changes in serum albumin.

The functions of phosphate in the body have been

outlined in a recent review [69]. The main function is to

store and release energy via compounds such as ATP that

contain high-energy phosphate bonds. Phosphate is an

integral part of the structure of proteins, lipids and bone.

It is an intracellular and renal tubular buffer with a pKa of

6.8. Phosphate achieves maximum buffering power when

it is concentrated in the renal tubules where the pH is

closer to its pKa, although the ammonium buffer system

has a greater buffering capacity. It is the most important

intracellular buffer and is essential for the intermediary

metabolism of carbohydrate [70]. The activity of

phosphofructokinase, the rate-limiting enzyme in glyco-

lysis, is increased by alkalosis. This causes increased

cellular uptake and hypophosphataemia. Therefore, over

ventilation of patients' lungs during surgery may not only

remove the stimulus to breathe (co2) but may also

potentially impair the ability to breathe.

Phosphate is a component of 2,3-DPG, which is

crucial to tissue oxygen delivery [71], and of the

intracellular messengers, cAMP and cyclic guanosine

monophosphate (cGMP). It is necessary for the optimal

functioning of both the immune system and the

coagulation cascade. The process of opsonisation and

phagocytosis by leukocytes, and many of the steps in the

coagulation cascade require ATP.

Regulation of phosphate in the ECF

The normal concentration of phosphate in the ECF is

maintained between 0.8 and 1.0 mmol.l21 by two

mechanisms.

Overflow mechanism. Phosphate filtered through the

glomerulus is normally reabsorbed through the proximal

tubules. Renal tubules have a transport maximum of

0.1 mmol.min21 and when more phosphate is presented,

the excess is excreted and is normally < 10±15% of the

filtered load. This reabsorption from the proximal tubule

is dependent on parallel sodium absorption and therefore

diuretics that act on this part of the nephron will cause

phosphaturia.

Role of the parathyroid glands. The parathyroid glands,

which have a major role in the regulation of calcium ions,

can decrease phosphate ion concentration in two different

ways. Parathyroid hormone decreases the transport

maximum for phosphate in the renal tubules, thereby

increasing the proportion of phosphate that is lost in the



urine. It also promotes bone reabsorption with a loss of

phosphate from the ECF.

Causes of hypophosphataemia [69, 72]

1 Decreased intake and/or absorption: malnutrition,

aluminium antacids.

2 Increased urinary excretion: carbonic anhydrase

inhibitors, diuretics, the osmotic effect of glycosuria,

glucocorticoids.

3 Internal redistribution: alkalosis (metabolic and

respiratory), total parenteral nutrition and catecholamine

release which cause hyperglycaemia, resulting in an

intracellular shift of phosphate.

4 Haemodilution: hypophosphataemia has long been

recognised as a consequence of intravenous fluid therapy

during surgery. However, as the 2,3-DPG concentration

[71] and postoperative muscle function [73] are unaf-

fected, it is of limited significance in fit patients with

normal cellular stores and does not require treatment.

However, established hypophosphataemia has been shown

to cause respiratory muscle weakness in the general

inpatient population [74]. It may even result in respiratory

failure on its own [75, 76] or in combination with other

causes [77, 78], such as pneumonia. There is a need to

recognise those subgroups of patients who are at risk from

chronic phosphate deficiency [79], as it is likely to

contribute to postoperative hypoventilation. Patients with

chronic obstructive airways disease may have phosphate

depletion from a combination of malnutrition, steroid and

diuretic use [80]. The severe alcoholic also suffers from

malnutrition. In uncontrolled diabetes, phosphate excre-

tion and redistribution are increased [76] and hypopho-

sphataemia may be made worse by insulin administration.

The cardiovascular effects of hypophosphataemia

include ventricular arrhythmias and, in chronic states, a

reversible congestive cardiomyopathy. Erythrocyte and

leukocyte dysfunction may ensue due to ATP depletion.

Haemolytic anaemia may occur because of increased red

cell fragility and 2,3-DPG depletion may result in impaired

oxygen delivery. Neurological features may be pro-

nounced, usually developing over 7±10 days after hyper-

alimentation or refeeding has commenced, and consist of

agitation, confusion and hyperventilation that can progress

to seizures, coma and death. Skeletal demineralisation

occurs after chronic deficiency, especially where there is

increased bone turnover and this may mimic osteomalacia.

Metabolic acidosis occurs infrequently considering phos-

phate's renal buffering capacity and deficiency also impairs

ammonium production. Carbonate ions are also released

during demineralisation and buffer the hydrogen ions.

Conditions in which hydroxyapatite cannot be mobilised,

e.g. vitamin D deficiency and severe magnesium defi-

ciency, may result in metabolic acidosis. Rhabdomyolysis is

thought to occur only in patients with pre-existing

myopathies such as that which occurs in chronic alcoholics.

Treatment of hypophosphataemia

The mainstay of treatment is supplementation or replace-

ment. Hypophosphataemia has been shown to be a poor

prognostic factor in patients requiring intensive care [81].

Although an increase in single indices such as the P50 for

oxygen dissociation have been demonstrated [82], good

studies showing an improved clinical outcome with

phosphate therapy are, as yet, lacking. Various treatment

protocols have been described. Vannatta et al. [83]

concluded that it is safe to infuse 0.32 mmol.kg21 of

phosphate over a 12-h period. If that failed to increase the

serum phosphate by . 0.2 mmol.l21 then a larger dose of

0.5 mmol.kg21 was given over the following 12 h.

Another regimen described by Rosen et al. [84] used

much larger doses without complications. It involved

giving sodium phosphate 15 mmol (potassium phosphate

if the plasma potassium was , 3.5 mmol.l21) in 100 ml

over 2 h. If the serum phosphate concentration remains

, 0.65 mmol.l21, a repeat dose was recommended.

Causes of hyperphosphataemia

1 Decreased renal excretion, increased intestinal reab-

sorption.

2 Exogenous sources: parenteral administration, poi-

soning [85].

3 Release after cell damage. This has been shown to

occur commonly after tumour lysis [86] but not after

abdominal aneurysm repair [87].

4 Internal redistribution: acidosis, reduced insulin

concentration.

5 Spurious: thrombocytosis, hyperlipidaemia.

No direct symptoms can be ascribed to hyperpho-

sphataemia. It may cause arrhythmias, hypotension and

hypocalcaemia with associated tetany, renal failure, and

ectopic calcification if high concentrations are maintained

for long periods.

Treatment of hyperphosphataemia

Hyperphosphataemia in concentrations of up to three

times the normal are well tolerated in the short-term.

Therapy should be directed at the cause wherever

possible. This will involve the discontinuation of any

exogenous sources of phosphate. Phosphate binding

antacids given orally, e.g. aluminium hydroxide, may be

used to decrease the amount absorbed from the gastro-

intestinal tract. An intracellular shift of phosphate can be

achieved by the administration of hypertonic dextrose

solutions while maintaining a normal pH. Ensuring

adequate hydration will promote excretion by the

kidneys. When cell death or tumour lysis is the cause of



hyperphosphataemia, further measures to increase renal

excretion, such as the use of diuretics, may be considered.

Haemodialysis and haemofiltration are both extremely

effective at phosphate removal and would be indicated in

renal insufficiency or where other treatment measures

have failed.

Sulphate

The dietary requirements for sulphur are met by the

breakdown of the amino acids methionine and cysteine.

Sulphur is excreted as the inorganic anion, sulphate. The

disulphide bond is crucial to the three-dimensional

structure and hence the function of proteins. Sulphate

readily forms conjugates with drugs and protein structures.

It is a major biotransformation pathway for phenolic drugs

in humans, particularly in neonates [88]. Propofol, for

example, has both glucuronidated and sulphated conju-

gates, e.g. 4-quinol sulphate. This pathway is a saturatable

system and it is thought that the depletion of inorganic

sulphate by exogenous substances can affect the metabolism

of neurotransmitters [88]. It can combine with haemoglo-

bin to form sulph-haemoglobin, and cyanosis will occur if

the concentration exceeds 0.5 g.dl21 [89]. The latter is

more likely with the breakdown of phenacetin and

sulphonamides that have numerous sulphur atoms in their

structure. Sulphates may also form conjugates with

polysaccharides and proteoglycans on cell surfaces. These

have been postulated to form the trigger for anaphylaxis

[90]. Sulphates may accumulate up to 10-fold during renal

failure and may cause a metabolic acidosis with an increased

anion gap that responds readily to haemodialysis [91]. It has

also been suggested that sulphates may play a role in the

osteodystrophy of renal failure [92].

Anion gap

The principle of electroneutrality requires that the total

positive electrical charge in body fluids equals the total

negative electrical charge [93]. However, clinical labora-

tories only measure the most common electrolyte profiles,

i.e. sodium, potassium, chloride and bicarbonate. This

results in an apparent imbalance on the anion side of the

equation that is known as the anion gap.

Anion gap � �Na1 1 K1�2 �Cl2 1 HCO23 �

The normal mean (SD) anion gap is 12 (4) mmol.l21,

although newer methods of assaying chloride have in

some series led to a lower range, and it is best to be guided

by the local laboratory. The factors that may increase or

decrease the anion gap are summarised in Table 3.

Albumin is strongly polyanionic at physiological pH

and is largely responsible for the magnitude of the anion

gap. Therefore, changes in its concentration and dissocia-

tion will lead to a corresponding change in the anion gap.

Gabow et al. [94] proposed that the anion gap is decreased

by a factor of 2.5 mmol.l21 for every 1 g.dl21 decrease in

albumin, and this has been validated scientifically [95].

However, it has not yet been shown that hypoalbumi-

naemia can mask a significant anion gap acidosis [96]. As

sodium is the largest portion of the measured cations,

changes in its concentration can have a profound effect on

the anion gap. Cations that are not included in the

equation, such as magnesium and calcium, normally do

not have an effect on the anion gap unless the disturbance

in their concentration is severe. Halide salts can cause

interference with most chloride assays, giving falsely high

values.

Significance of the anion gap

An increased anion gap in a patient is a poor prognostic

indicator [97] and should prompt consideration of

intensive care or high-dependency care. The anion gap

may also help diagnose the cause of a metabolic acidosis.

To counter an effective decrease in bicarbonate, there

must be a corresponding increase in another anion or a

decrease in cation concentration. If the anion gap and the

cation concentrations remain normal, the balancing anion

must be chloride, as this is the only other anion that is

Table 3 Changes in the anion gap.

Increases in the anion gap Decreases in the anion gap

Increased unmeasured anions Lactate, ketone bodies, drugs,e.g. salicylates, albumin ororganic poisonsPhosphates or sulphates

Decreased unmeasured anionsDecreased measured cationsIncreased unmeasured cations

AlbuminHyponatraemia

Increased measured cations Hypernatraemia Metabolic acidosisLaboratory error

Decreased unmeasured cationsAlkalaemiaLaboratory error Underfilled blood sample bottles



measured, and the cause of the acidosis is likely to be

hyperchloraemia [3, 98].

However, if the anion gap is increased, then the

balancing anion must be one that is unmeasured. If urea,

glucose and electrolyte measurements are normal,

increased anions from renal failure, e.g. phosphate or

sulphate, or diabetes (3-hydroxybutyrate) are unlikely.

Other osmotically active substances must be present and it

is worth noting from the outset that if the anion gap is

. 25 mmol.l21, an organic cause is likely [94]. A lactate

level can be easily measured in most hospitals and a

toxicology screen normally excludes the more common

poisons such as alcohol and salicylates. If there is a high

index of suspicion for abuse of substances such as

methanol or ethylene glycol, then it is worth calculating

the osmolal gap (calculated 2 measured osmolalities).

Early treatment on this basis before poison levels were

available has been shown to be highly effective [99, 100].

The anion gap can also be useful in distinguishing the

primary imbalance in mixed acid2base disorders. The

simplest example is that of diabetic ketoacidosis with

alkalaemia [101]. In this condition, the metabolic acidosis

caused by the ketone bodies is countered by the metabolic

alkalosis caused by persistent vomiting. Arterial blood

gases may not be helpful if both conditions are of equal

severity. An increased anion gap demonstrates the under-

lying aetiology.

Limitations of the anion gap

It is important to be aware of the limitations [102] and

pitfalls in interpretation [96] of the anion gap.

1 Insensitivity: it has been found that the anion gap is

relatively poor at identifying small changes in ion

concentrations, especially lactate [103], even when they

would be considered clinically significant.

2 Competing factors: if two clinical conditions known

to cause opposing effects on the anion gap were to

coexist, the diagnostic usefulness of the anion gap may be

diminished.

3 Slow onset metabolic acidosis: when a metabolic

acidosis is of sufficiently slow onset and renal function

remains normal, the patient may be able to excrete

enough anions so that the anion gap remains normal. This

may explain why some cases of diabetic ketoacidosis may

present with a normal anion gap [104].

4 Mixed acidosis: occasionally, a metabolic acidosis can

be caused by a combination of conditions that have

opposing effects on the anion gap, potentially masking

one another. It is possible to resolve this diagnostic

conundrum through the calculation of the change in the

anion gap divided by the change in the bicarbonate

concentration (DGap/DHCO32) [105]. However, it

assumes that each mmol of acid will decrease the serum

bicarbonate by a similar amount, but this will only hold

true when the proton and its conjugate base have the same

volume of distribution. This is certainly not the case in

lactic acidosis (lactate has a smaller volume of distribution

than the protons) or severe acidosis [96, 106].

5 Unidentifiable anions: it has been found in some

series that the offending anion contributing to the anion

gap cannot be identified despite special effort [94].

6 Laboratory error: an error in the measurement of

any of the cations or anions in the equation will be

translated into an error in the anion gap.

Strong ion difference

The limitations of the anion gap have led some researchers

to adopt a physicochemical approach using the strong ion

difference or gap (SID) [107]. This approach takes into

account not only the principle of electroneutrality but also

the law of conservation of mass. In order to understand the

body's defence of pH, it is necessary to understand the

regulation of three independent variables: SID, Pco2 and

ATOT (total weak acid concentration) [108]. The advantage

of this approach is that it takes account of the smaller cation

concentrations, plasma albumin and phosphate concentra-

tions. It helps explain `dilutional acidosis' and how

hyperlactataemia can exist without acidaemia. It is also

more helpful than the anion gap in establishing the

presence of unidentified anions in the critically ill and in

mixed acid2base disorders [109]. It has been explored in

both adult and paediatric intensive care settings [110, 111].

However, it has not been introduced without controversy

and as yet has not received wide acceptance [112, 113]. It

does provide a different perspective on acid2base balance

and merits further study and debate.

Organic anions

The commonest organic anions in the body are albumin

and lactate and their physiological importance is discussed

here for completeness.

Albumin

Albumin is a medium-sized plasma protein with a

molecular mass of 69 000 Da. It is a polyvalent anion

and can readily accept further negative charge. Its effect

on the anion gap has already been discussed. The normal

half-life of albumin in plasma is between 18 and 20 days,

but this is not the case with exogenously administered

albumin, which has a shorter half-life. Although it is a

medium-sized molecule, it has a transcapillary escape rate

(TER) of 5%.h21. Ninety per cent of the extravascular

albumin returns to the circulation and the other 10%

undergoes catabolism.



Albumin has a fundamental role in the transport of

hormones and ions, and forms a reservoir or buffer

preventing wide variations in serum concentrations.

Competition between drugs does occur and is increased

during hypoalbuminaemia. The effects are more marked

for drugs that are highly protein bound, such as propofol,

than for midazolam or thiopental.

Albumin is thought to be responsible for 75±80% of

the colloid osmotic pressure of human plasma. It was

considered that measures to maintain colloid osmotic

pressure in the critically ill could make a difference in

outcome. However, a systematic review [114] reported an

increase in mortality in critically ill patients who had

received albumin. This sparked a vigorous debate with the

methodology in the study being severely criticised [115±

117]. Two recent reviews by Boldt [118] and Nicholson

[119] dealt with this vexed issue and are strongly

recommended to the reader.

Albumin is a scavenger of free radicals. It also exhibits

anticoagulant effects in its own right by inhibiting platelet

aggregation and enhancing the inhibition of factor Xa by

antithrombin III. Despite its multiple functions, it is not

crucial for life, as cases of analbuminaemia occur rarely.

These patients display only moderate oedema and are able

to handle drugs. It is thought that other plasma proteins

increase and take on the role of albumin [120].

Lactate

Lactic acidosis is one of the commonest causes of metabolic

acidosis in medical practice. Lactic acid is a weak acid

(pKa � 3.8) and is therefore almost completely dissociated

at physiological pH. Lactate is a carbohydrate anion and the

normal concentration in blood is 1±2 mmol.l21. Lactate

may be produced or consumed by all cells, but skeletal

muscle, the gut, the brain and erythrocytes are the main

producers (10±20 mmol.kg21.day21 in adults).

Lactate is an intermediary in carbohydrate metabolism.

Glucose is catabolised in a series of steps to pyruvate by

the Embden-Meyerhof pathway. Pyruvate in non-gluco-

neogenic organs has four potential fates: conversion to

acetyl coenzyme A by pyruvate dehydrogenase; transa-

mination by alanine aminotransferase with glutamate to

alanine and a-ketoglutarate; carboxylation to oxaloacetate

or malate; reduction by nicotinamide adenine dinucleo-

tide (NAD)H to lactate and NAD1 catalysed by lactate

dehydrogenase. Lactate can be used as a source of energy

but the process is very inefficient and it is normally

transported from the peripheral tissues back to the liver

(Cori cycle) where it is removed from the blood by

gluconeogenesis. Up to 70% of lactate is metabolised in

this way. The other 30% is metabolised by oxidation in the

liver and kidneys.

Lactate concentration in the cell is regulated by the

pyruvate concentration, the redox state of the cell and

hydrogen ion concentration in the cytosol. One step in

the Embden-Meyerhof pathway is essentially irreversible

and is catalysed by phosphofructokinase. In metabolic

acidosis, this enzyme is inhibited and lactate production is

decreased, whereas in metabolic alkalosis, phosphofruc-

tokinase is stimulated and lactate production is increased.

Causes of lactic acidosis;

Lactic acidosis was originally classified into two categories,

Type A and Type B. In Type A lactic acidosis, there is an

imbalance between oxygen supply and demand, and lactate

is generated by anaerobic metabolism. In Type B lactic

Table 4 Causes of lactic acidosis.

Type A Type B

Decreased oxygen supply Severe hypoxiaShockSevere anaemiaCongestive cardiac failure

Congenital errors of metabolism Glucose 6-phosphate dehydrogenasedeficiencyFructose 1,6 diphosphate deficiencyType 1 glycogen storage disease

Excessive oxygen demand ShiveringHyperpyrexiaStrenuous exerciseSeizures

Acquired conditions Drugs: phenformin, ethanol, methanol,paracetamol, salicylates,catecholaminesDiabetic ketoacidosis (decreasedpyruvate dehydrogenase activity)SepticaemiaNeoplastic diseaseParenteral nutrition(excess fructose/sorbitol)Vitamin deficiency (thiamine, biotin);Liver failure (metabolises 50%of daily lactate production)Renal failure (metabolises 25±30%daily lactate production)



acidosis, tissue hypoxia is irrelevant and abnormalities in

pyruvate metabolism are probably the cause. The causes of

lactic acidosis are listed in Table 4.

Significance of lactic acidosis

Although lactate per se is not detrimental and high levels

are found during severe exercise in healthy adults, it is

associated with a poor prognosis in critically ill patients

[121]. It is the trend rather than any single measurement

that is associated with a high mortality [122]. However,

therapies that have been aimed directly at lowering serum

lactate have failed to produce a significant impact on this

mortality rate [123]. Lactate has been cited as a marker of

tissue hypoxia for over 30 years [124]. This is now being

questioned because it is recognised that there are multiple

mechanisms through which it may increase in the

critically ill [125±127]. It is thought that it is the inability

of non-survivors to increase oxygen consumption that is

at fault [128], and lactate remains high in this group as a

result. The exact origin of lactic acidosis, in particular the

anatomical site of lactate production in sepsis, has yet to

be elucidated. The lung is thought to be a significant

producer of lactate in acute lung injury [129].

It has been shown that the understanding of the

purpose and metabolism of lactate in Hartmann's solution

is lacking [130]. It was first added to an intravenous fluid

preparation because it was non-irritant and acted as a

source of bicarbonate and glucose after lactate metabo-

lism. Therefore, it would be prudent to restrict the

volume of Hartmann's solution used in the fluid manage-

ment of both septic and diabetic patients.

It is reassuring to note that anaesthesia does not affect

serum lactate despite the associated haemodynamic

effects, presumably because an adequate oxygen supply

is maintained throughout. This is the case for both general

[131] and regional anaesthesia [132].

Treatment of lactic acidosis

Although in patients with serum lactate concentrations

. 5 mmol.l21, mortality exceeds 51% at 3 days after ICU

admission [121], therapy that successfully addresses the

cause can result in a successful outcome despite the

absolute lactate level. The acute increases in serum lactate

that are seen peri-operatively, after major vascular surgery

or when tourniquets are used, do not result in increased

mortality, as the aetiology is usually self-limiting [133].

Oxygen delivery must be optimised, which may require

artificial ventilation, measurement of cardiac index and

the rational use of inotropes. Aiming for supranormal

haemodynamic targets has not always been successful in

changing outcomes [128].

The use of bicarbonate has not been shown to

influence outcome in septic patients despite improve-

ments in pH. Its use cannot be recommended at present

[126], although it is necessary as the buffer in lactate-free

haemodialysate. Some success has been reported in the

treatment of combined renal failure and lactic acidosis

with the use of continuous haemofiltration using lactate

free dialysate [134]. This treatment does not mask lactate

overproduction [135] and, in the face of sustained

hyperlactataemia, an underlying diagnosis of fulminant

hepatic failure or gangrenous bowel should be considered.

Dichloroacetate stimulates pyruvate dehydrogenase,

thereby reducing lactate with an increase in bicarbonate.

It has been studied extensively but its use does not

decrease mortality and has not found much support [121].

Anions and ion channel receptors

The reversible nature of electrostatic bonds is central to

the proper functioning of ion channels whereby they are

able to mediate fast transmission throughout the central

nervous system (CNS). The intracellular influx of cations

into nervous tissue causes depolarisation and excitation,

whereas anions cause hyperpolarisation and inhibition.

Anions may be either the activating ligands, e.g. gamma-

aminobutyric acid (GABA) and glutamate, or the ions

that pass through the channels, e.g. chloride and

bicarbonate.

Gamma-aminobutyric acid is the principal fast inhibi-

tory neurotransmitter in the CNS. It acts on the GABA

receptor that belongs to a family of ligand-gated ion

channels that include the acetylcholine receptor, glycine

and 5HT3 receptors. There are three recognised receptor

subtypes, GABA-A, GABA-B and GABA-C. It is the

GABA-A receptor subtype that is pivotal to the action of

anaesthetic, anxiolytic and anticonvulsant drugs. The

structure of the GABA-A receptor is reviewed regularly as

more is learned about its diversity [136±138].

Activation of the GABA-A receptor increases the

chloride conductance of the neuron. This chloride influx

hyperpolarises the neuron and prevents an excitatory

postsynaptic potential from being transmitted. The action

of GABA can be enhanced by any of the following:

potentiating the binding of GABA to its own receptor;

increasing the frequency and/or duration of opening of

the ionophore; acting directly on the channel itself in high

concentrations. Barbiturates and neuro-active steroids

[139] have been shown to act via all three mechanisms.

Benzodiazepines, in contrast, increase the frequency of

channel opening but do not act directly on it. Their

enhancement of the affinity of GABA for its receptor is

also limited and their clinical effects are dependent on

receptor occupancy. Propofol increases GABA receptor



binding in a concentration-dependent manner and acts

synergistically with benzodiazepines [140]. This, com-

bined with absence of reversal with flumazenil [141],

suggests that propofol acts at a separate site. Volatile

anaesthetic agents also have been shown to act through

GABA potentiation, again at different sites from intrave-

nous agents [142, 143]. Evidence is increasingly in favour

of there being a protein site of action for general

anaesthetics [144].

There are three major subtypes of glutamate receptors:

N-methyl d-aspartate (NMDA), dl a-amino-3-hydroxy-

5-methylisoxazole-4-propionate (AMPA) and kainate.

The NMDA receptor is of particular importance for

anaesthetists because it is the known site of action of

ketamine [145]. It is involved in long-term potentiation

that is widely regarded as an experimental analogue for

the mechanism of learning and memory in the brain

[146]. This has implications for the control not only of

chronic pain syndromes [147], such as phantom limb pain

[148], but also for preventing awareness during surgery

under general anaesthesia. The associated calcium influx is

thought to be the principal mediator of neuronal cell

death during anoxia or stroke [149]. This has led to the

development of specific antagonists such as dizocilpine

(MK-801), with the aim of neuroprotection.

Conclusions

Anions play many important physiological and pharma-

cological roles that are of interest to the anaesthetist. Their

ability to accept a proton makes them the logical choice

for buffer systems, e.g. bicarbonate, urate, glutamate and

phosphate. They provide the power behind cellular

functions (phosphate). They are also involved in gas

exchange (bicarbonate) and transport functions, e.g.

glucose2lactate and albumin. The halogen group is

responsible for making the working environment safer

by decreasing the explosive risk of volatile agents. Because

of the reversible and surmountable nature of the ionic

bond, they are the perfect choice for the receptor±agonist

interactions that are now thought to underpin the cellular

mechanisms of anaesthesia.

Acknowledgments

We thank Miss Kelly Barber and Mrs Margaret Johnson

for their help with the preparation of this manuscript.

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