The normal value for the anion gap depends on the type of biochemical analyser used and whilst the upper limit of normal has been commonly quoted as 18, the mean range with some modern analysers is only 5–12.³ In the normal resting state the serum ionic proteins account for most of the anion gap, with a lesser contribution from other ‘unmeasured’ anions such as PO₄⁻ and SO₄⁻. In pathological conditions where there is an increase in the concentration of unmeasured anions, an anion-gap metabolic acidosis results. The anions responsible for the increase in the anion gap depend on the cause of the acidosis. Lactic acid is the predominant anion in hypoxia and shock, PO₄⁻ and SO₄⁻ in renal failure, ketoacids in diabetic and alcoholic ketoacidosis, oxalic acid in ethylene glycol poisoning and formic acid in methanol poisoning.

Of the causes of an anion-gap metabolic acidosis, lactic acidosis is the most commonly encountered in the ED and is defined as a serum lactate of >2.5 mmol/L. The presence of lactic acidosis is determined by the balance between lactate production and metabolism. In the seriously ill patient, it is common for increased production and decreased metabolism to be present simultaneously. Tissue hypoxia of any cause decreases oxidative phosphorylation and results in the increased conversion of pyruvate to lactate. This commonly occurs in major haemorrhage and in the presence of severe cardiorespiratory disease. An alternative cause for increased lactate production may be the uncoupling of oxidative phosphorylation following exposure to toxins, such as cyanide, salicylates, metformin and iron. Severe thiamine deficiency may result in a marked increase in lactate production known as warm beriberi. A mild metabolic acidosis is common in acute ethanol intoxication and is associated with an elevated anion gap in 80% of cases; however, it is multifactorial in origin. Metabolism of lactic acid occurs in the liver and kidney, and is reduced when these organs are diseased or in the presence of alkalosis, hypothermia and diabetes mellitus.

It is important to realize that, in many conditions, a variety of factors may produce the acidosis, and that multiple anions may be involved in the production of an anion-gap acidosis. For example, in a patient with severe diabetic ketoacidosis, poor tissue perfusion, renal failure, increased lactic and ketoacid production, decreased SO₄⁻ and PO₄⁻ elimination and decreased lactic acid metabolism may all be present. Lactic acidosis is generally considered to be severe if serum lactate is >4 mmol/L.

Respiratory acidosis

Respiratory acidosis is defined as an elevation of the arterial partial pressure of carbon dioxide (PCO₂) and is due to alveolar hypoventilation. The effects of mild-to-moderate hypercarbia are usually confined to its effect on decreasing the alveolar partial pressure of oxygen (see alveolar gas equation). With more significant elevations, sweating, tachycardia, confusion and mydriasis occur. When the PCO₂ is greater than 80 mmHg, the level of consciousness is usually depressed. There are many possible causes of alveolar hypoventilation. Central nervous system causes include severe hypotension, drugs with respiratory depressant effects (especially opioids and sedatives), cerebrovascular events, tumours, infections, neurotrauma and metabolic derangements. Ventilatory drive may also be reduced by high partial pressures of oxygen in patients with chronic obstructive airways disease (COAD) and chronic CO₂ retention. Lesions of the spinal cord, such as tumours, infections, trauma or demyelination, may also result in alveolar hypoventilation if the lesion is above the level of C4. Lower in the afferent limb of respiratory muscle innervation, lesions of peripheral nerves such as Guillain–Barré syndrome or trauma to both phrenic nerves may also be causative. Neuromuscular junction dysfunction following postsynaptic destruction of acetylcholine receptors in myaesthenia gravis, inactivation of cholinesterase in organophosphate poisoning or the effects of spider or snake venoms and muscle relaxant drugs may also cause ventilatory failure. Aminoglycoside antibiotics may also precipitate ventilatory failure in susceptible patients. Muscular dystrophy, myopathies and severe electrolyte disorders may cause muscular weakness, and lesions of the chest wall, such as flail chest, severe kyphoscoliosis or arthritis, may also impair effective ventilation.

Pleural abnormalities, such as tension pneumothorax, massive haemothorax/pleural effusion, pulmonary conditions, such as severe fibrosis, pulmonary oedema or pneumonia, and severe airway obstruction due to severe croup, asthma or the inhalation of a foreign body are additional causes. In the intubated patient, causes such as the improper connection of the anaesthetic circuit, mechanical ventilator failure and the use of inappropriate equipment in small children should be considered.

Treatment

The treatment of respiratory acidosis is directed towards reversal of the causative factors. Ventilatory assistance is usually indicated in the presence of severe hypoxia, depressed level of consciousness or an acute elevation of PCO₂ of greater than 80 mmHg.

Alkalosis

Alkalosis is defined as a decrease in [H⁺] in the blood. Its physiological effects are the same as those of the administration of HCO₃ except that it does not cause hyperosmolarity. In very severe cases altered mental state, seizures and respiratory depression may also occur. The most common symptoms of metabolic alkalosis are related to a decrease in the concentration of ionized calcium, and are more commonly present in respiratory alkalosis due to anxiety, than from other causes. Reduced levels of ionized calcium may cause neurological symptoms such as light headedness, dizziness, chest tightness and difficulty swallowing. On examination, the respiratory rate is elevated, muscular tremor is often present and, if severe, carpopedal spasm may also be observed. Chovstek’s and Trousseau’s signs may also be present.

Metabolic alkalosis

This is caused by loss of acid from the GIT or kidney, or the addition of exogenous alkali. Upper GIT acid losses as a result of severe and prolonged vomiting are the most common cause encountered in the ED. Other causes, such as hyperaldosteronism, Bartter’s and Gitelman’s syndromes and severe hypokalaemia, result in the loss of H⁺ in the urine due to increased H⁺−K⁺ exchange in the distal convoluted tubule. Diuretics may also induce alkalosis by the same mechanism; however, the pH is rarely raised to >7.5.

Alkali may be added to the body in the form of citrate by red cell transfusion, intravenous NaHCO₃ administration or as urinary alkalinizers. The milk alkali syndrome may occur as a result of the chronic ingestion of more than 2 g of calcium salts each day (commonly in conjunction with vitamin D).⁸ The metabolic derangement known as post-hypercapnic alkalosis is caused by the decrease of a chronically elevated PCO₂ to normal levels, when relative hyperventilation occurs. In such patients the HCO₃⁻ is usually elevated as a result of chronic hypercarbia, and when the PCO₂ is acutely lowered to normal levels the appearance on blood gas analysis is that of a metabolic alkalosis, rather than that of a relative respiratory alkalosis. The most common example of this in the ED occurs in a patient who has chronic CO₂ retention with an acute exacerbation of COAD. The ingestion of strong alkali is almost never a cause of systemic alkalosis.

The causes of metabolic alkalosis can be further classified according to their response to intravenous saline (which is also related to the urinary chloride concentration). If the urinary Cl is <10 mmol/L, this is considered to be saline responsive and is usually caused by GIT losses, diuretics or the acute correction of chronic hypercapnia. If the urinary Cl is >10 mmol/L, the metabolic alkalosis is considered to be saline resistant and is usually caused by mineralocorticoid excess, oedema states or renal failure.

The treatment of metabolic alkalosis should be directed primarily towards correction of the underlying cause. In the presence of upper gastrointestinal fluid losses, intravenous fluids with high chloride content (such as 0.9% saline) should be used initially for rehydration, and correction of hypokalaemia may also be required.

Respiratory alkalosis

This is the only acid–base disturbance in which compensation may be complete. In a fully compensated chronic respiratory alkalosis the pH returns to 7.4 in approximately 4 days, and the reduction in serum HCO₃⁻ that occurs results in an increase in the anion gap.

Common causes of respiratory alkalosis in the general population include exercise, altitude-elated hypoxia and stimulation of the medullary respiratory centre by progesterones during pregnancy. In the ED setting, causes such as hypoxia, early sepsis, cerebral oedema, hepatic cirrhosis, mechanical ventilation, anxiety and salicylate, theophylline and carbon monoxide toxicity should be considered.⁹ Treatment is directed towards correction of the underlying cause and the treatment of hypokalaemia or hypocalcaemia as required. Hydrochloric acid can be administered to correct the metabolic abnormality, but it is rarely required. A dose of 1–3 mmol/kg of hydrochloric acid can be given through a central venous line at a rate of no faster than 1 mEq/min.¹⁰

Controversies

Whilst it was previously thought that, due to levels decreasing rapidly following sampling, serum lactate needed to be measured by immediate assay of arterial blood, more recent evidence has challenged this assumption with one study failing to demonstrate any significant difference in lactate levels measured at 15 min after sampling.¹¹

References

1 Natalini G, Seramondi V, Fassini P, et al. Acute respiratory acidosis does not increase plasma potassium in normokalaemic anaesthetized patients. A controlled randomized trial. European Journal of Anaesthesiology. 2001;18(6):394-400.

2 Herr RD, Swanson T. Pseudometabolic acidosis caused by underfill of vacutainer tubes. Annals of Emergency Medicine. 1992;21(2):177-180.

3 Paulson WD, Roberts WL, Lurie AA, et al. Wide variation in serum anion gap measurements by chemistry analyzers. American Journal of Clinical Pathology. 1998;110(6):735-742.

4 Cooper DJ. Bicarbonate does not improve haemodynamics in critically ill patients who have lactic acidosis: a prospective controlled clinical study. Annals of International Medicine. 1990;112:492-498.

5 Mathieu D, Neviere R, Billard V, et al. Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Critical Care Medicine. 1991;19(11):1352-1356.

6 Okuda Y, Adrogue HJ, Field JB, et al. Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis. Journal of Clinical Endocrinology and Metabolism. 1996;81(1):314-320.

7 Australian Resuscitation Council, Medications in cardiac arrest, February 2006.

8 Whiting SJ, Kim K, Wood R. Calcium supplementation. Journal of the American Academy of Nurse Practitioners. 1997;9(4):187-192.

9 Laffey JG, Kavanagh BP. Hypocapnia. New England Journal of Medicine. 2002;347(1):43-53.

10 Adrogue HJ, Madias NE. Management of life-threatening acid base disorders. New England Journal of Medicine. 1998;338(2):107-111.

11 Jones AE, Leonard MM, Hernandez-Nino J, et al. Determination of the effect of in vitro time, temperature, and tourniquet use on whole blood venous point-of-care lactate concentrations. Academic Emergency Medicine. 2007;14:587-591.

12.2 Electrolyte disturbances

John Pasco

ESSENTIALS

1 Sodium disorders are relatively common in hospitalized patients and elderly people.

2 The brain is most at risk from hyponatraemia because the osmotically expanded intracellular volume may induce increased intracranial pressure (hyponatraemic encephalopathy).

3 Treatment of hyponatraemia needs to be carefully individualized because of the risk of osmotic myelinolysis.

4 Hypernatraemia has a high in-hospital mortality rate, which often reflects severe associated medical conditions.

5 Although usually benign, hypokalaemia may cause cardiac arrhythmias and rhabdomyolysis. Oral replacement is usually sufficient, except where there is severe myopathy or cardiac arrhythmias.

6 Electrocardiogram changes in the presence of hyperkalaemia require urgent potassium-lowering measures and myocardial protection with calcium.

7 Management of severe hypercalcaemia includes enhancement of renal excretion of calcium, inhibition of osteoclast activity and treatment of the underlying condition.

8 Acute symptomatic hypocalcaemia should be treated with i.v. calcium.

9 Hypomagnesaemia is difficult to diagnose because its symptoms are non-specific and the serum level often does not reflect the true magnesium status of the patient. It usually exists as a ‘deficiency triad’ with hypokalaemia and hypocalcaemia.

10 Hypermagnesaemia is often iatrogenic, particularly in elderly patients or patients with renal impairment and/or chronic bowel conditions receiving magnesium therapy.

Hyponatraemia

Introduction

Hyponatraemia, defined as serum sodium concentration of less than 130 mmol/L, is a common condition. The prevalence is estimated at 2.5% in hospitalized patients, of which two-thirds develop the condition whilst in hospital.¹

Pathophysiology

Hyponatraemia is almost always associated with extracellular hypotonicity, with an excess of total body water relative to sodium. The exceptions are:

• Normotonic hyponatraemia (pseudohyponatraemia): an artefactually low sodium measurement seen in hyperlipidaemia and hyperproteinaemia. It is rarely seen now because of the routine use of direct ion-selective electrodes to measure sodium.

• Hypertonic hyponatraemia: a dilutional lowering of the measured serum sodium concentration in the presence of osmotically active substances, most commonly glucose, but also mannitol, glycerol and sorbitol. In the presence of hyperglycaemia the true serum sodium can be estimated by adjusting the measured serum sodium upwards by 1 mmol/L for each 3 mmol/L rise in glucose.

Hyponatraemia causes cellular swelling as water moves down an osmotic gradient into the intracellular fluid. Most of the symptomatology of hyponatraemia is produced in the central nervous system (CNS) by the swelling of brain cells within the rigid calvarium, causing raised intracranial pressure (hyponatraemic encephalopathy). As intracranial pressure rises, adaptive responses come into play. Initially there is a reduction of the cerebral blood and cerebrospinal fluid (CSF) pools. Later, neuronal intracellular osmolality is reduced by extrusion of potassium, followed within hours to days by organic solutes such as amino acids, phosphocreatine and myoinositol. These processes return brain volume towards normal and restore cellular function.

Patients become symptomatic when hyponatraemia develops rapidly and the adaptive responses have not had time to develop, or when the adaptive responses fail.

Aetiology and classification

Hypotonic hyponatraemia may be classified according to the volume status of the patient (hypovolaemic, euvolaemic or hypervolaemic).

Hypovolaemic hyponatraemia

These patients have deficits in both total body sodium and total body water, but the sodium deficit exceeds the water deficit. Causes include renal and extra-renal fluid losses, and are listed in Table 12.2.1. Determination of the urinary sodium concentration can differentiate these two groups. Extrarenal losses are associated with low urinary sodium concentrations (<20 mmol/L) and hyperosmolar urine. The exception is with severe vomiting and metabolic alkalosis, where bicarbonaturia obligates renal sodium loss and urinary sodium is high (>20 mmol/L), despite volume depletion. However, urinary chloride, a better indicator of extracellular fluid (ECF) volume, is low.

Table 12.2.1 Causes of hypovolaemic hyponatraemia

Renal losses (urinary [Na] >20 mmol/L)

Diuretics

Mineralocorticoid deficiency—Addison’s disease

Salt-losing nephropathy

Ketonuria

Osmotic diuresis—glucose, mannitol, urea

Bicarbonaturia with metabolic alkalosis

Extrarenal losses (urinary [Na] <20 mmol/L)

Vomiting—self-induced, gastroenteritis, pyloric obstruction

Diarrhoea

Excessive sweating

Blood loss

Third-space fluid loss—burns, pancreatitis, trauma

Drugs (ADH analogues, potentiation of ADH release, unknown mechanisms)

Psychoactive agents: phenothiazines, SSRIs, TCAs, MAOIs, ‘ecstasy’

Oxytocin

Anticancer agents: cyclophosphamine, vincristine, vinblastine

NSAIDs

Carbamazepine

SIADH

TURP, transurethral resection of prostate; ADH, antidiuretic hormone; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; MAOI, monoamic oxidase inhibitor; SIAOH, syndrome of inappropriate antidiuretic hormone secretion.