Renal, metabolic and endocrine systems

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TOPIC 6 Renal, metabolic and endocrine systems

Assessment of renal function: Serological tests 97

Test: Serum creatinine 97

Test: Serum urea measurement 100

Assessment of renal function: urinalysis 101

Test: Urine dipstick 101

Test: Urine microscopy 101

Test: Laboratory assay of urine sodium, osmolality, urea, creatinine and specific gravity 102

Assessment of renal function: Measurement of glomerular filtration rate 104

Test: Radioisotope assay 104

Test: Inulin clearance 105

Test: Creatinine clearance 105

Assessment of renal function: Radiological 106

Test: Renal ultrasound 106

Investigation of salt and water disturbance 119

Test: Serum osmolality 119

Assessment of thyroid function 120

Test: Serum thyroid hormones measurement 120

Assessment of glycaemic control 121

Test: Serum glucose 121

Test: Glycosylated haemoglobin (HbA1C) 124

Investigation of the hypothalamic–pituitary axis 124

Test: Short synacthen test 124

Measurement of hormones: Phaeochromocytoma 125

Test: Plasma and urine catecholamines and their metabolites 125

Measurement of hormones: Carcinoid tumours 127

Test: Urinary 5-hydroxyindole acetic acid (5-HIAA) 127

Investigation of allergic reactions 127

Test: Serum mast cell tryptase measurement 127

Test: Serum and urine histamine assay 128

Assessment of renal function: Serological tests

Test: Serum creatinine

Indications

1. Assessment of renal function.

2. Suspected or proven rhabdomyolysis.

3. As part of routine preoperative assessment for certain patients/procedures (see NICE guidelines available at http://www.nice.org.uk/CG003).

Data presented as

Numerical value: units (μmol/L).

Interpretation

Physiological principles

• Creatinine is a basic compound that is formed mainly in skeletal muscle from phosphorylcreatine.

• Except in rhabdomyolysis, production of creatinine is fairly constant; thus creatinine levels in the serum are a useful reflection of renal function as its elimination is entirely renal.

Normal range

• 60–130 μmol/L. Normal values vary according to gender and ethnic origin.

Abnormalities and management principles

• Serum creatinine increases slowly with a reduction in glomerular filtration rate (GFR) down to 40 mL/min; thereafter, creatinine rises sharply with small reductions in GFR, reducing its usefulness as a measure of renal function at high values (Fig. 6.1).

Fig. 6.1 Serum creatinine versus renal function.

Renal failure/impairment

• Renal failure may be acute or chronic. Identification of the cause of renal failure can only be achieved using a combination of history taking and clinical evaluation, in conjunction with further investigations.

• The RIFLE criteria (Fig. 6.2) are an evidence-based guide to aid classification of the degree of renal dysfunction, based on serum creatinine and urine output.

Fig. 6.2 The RIFLE criteria for classification of renal dysfunction.

(Adapted from Bellomo et al. (2004) Crit Care Med 8:R204-R212, with permission.)

The acronym RIFLE encompasses three levels of renal dysfunction (‘risk of renal dysfunction’, ‘injury to kidney’ and ‘failure of renal dysfunction’) and two outcomes of renal dysfunction (‘loss’ and ‘end-stage renal disease’). The inclusion of these two separate outcomes acknowledges the important adaptations that occur in end-stage renal disease (ESRD) that are not seen in persistent acute renal failure (ARF). Persistent ARF (loss) is defined as need for renal replacement therapy (RRT) for more than 4 weeks, whereas ESRD is defined by need for dialysis for longer than 3 months.

Acute renal failure

See Table 6.1 for causes.

Table 6.1 Causes and classifications of acute renal failure

Classification		Example of causes
‘Pre-renal’	Pre-renal failure causing renal hypoperfusion and acute tubular necrosis	Circulating volume depletion: dehydration, haemorrhage, etc Low cardiac output of any origin Sepsis Drugs causing reduction in renal perfusion (e.g. NSAIDs, ACE inhibitors)

‘Intrinsic renal’ Acute glomerulonephritis and vasculitis

ANCA-positive vasculitis (e.g. Wegener’s)

Goodpasture’s disease

Systemic lupus erythematosus

Disruption of renal vasculature

Large vessel occlusion (renovascular disease)

Small vessel occlusion (DIC, haemolytic-uraemic syndrome; thrombotic thrombocytopenic purpura; pre-eclampsia)

Toxic acute tubular necrosis

Drugs (e.g. gentamicin)

Contrast nephropathy

Myoglobinuria from rhabdomyolysis

Interstitial nephritis

Idiopathic/autoimmune

Drug-induced hypersensitivity

Myeloma/tubular cast nephropathy ‘Post-renal’ or ‘obstructive’ Urinary tract obstruction Prostatic disease; renal stones

Prerenal uraemia versus acute tubular necrosis

• Both caused by renal hypoperfusion and ischaemia.

• In prerenal uraemia, renal function is salvageable with restoration of perfusion; in ATN, disruption of physiological mechanisms such as the renin-angiotensin system necessitate renal replacement therapy.

Management principles

• Identification and management of underlying cause.

• Treatment of fluid overload, acidosis and hyperkalaemia, using renal replacement therapy if required.

Chronic renal failure

See Table 6.2 for causes.

Table 6.2 Causes of chronic renal failure

Intrinsic causes	Obstructive causes
Diabetic nephropathy	Post-obstructive nephropathy
Chronic glomerulonephritis	Nephrolithiasis
Renovascular disease	Multiple myeloma
Chronic reflux nephropathy
Polycystic kidney disease
Amyloidosis
Post-acute renal failure
Chronic interstitial nephritis
Analgesic nephropathy

Other causes of a raised creatinine, without a concomitant rise in urea

• Drugs: cimetidine, trimethroprim, aspirin.

• Other: liver failure, racial variations, rhabdomyolysis (before onset of associated renal failure).

Management principles

• Identification and treatment of underlying aetiology.

• Renal replacement therapy with dialysis or transplantation when end-stage renal failure reached.

Limitations and complications

There is considerable inter-individual variation in normal serum creatinine due to muscle mass, age and diet. Thus, only serial measurements will provide a useful indication of changes in renal function.

Test: Serum urea measurement

Indications

1. Investigation of renal function.

2. As part of routine preoperative assessment for certain patients/procedures (see NICE guidelines).

Data presented as

Numerical value: units mmol/L.

Interpretation

Physiological principles

• Urea (NH₂CONH₂) is a product of the hepatic metabolism of amino acids, produced from the hydrolysis of arginine in the urea cycle.

• It is freely filtered by the glomerulus; approximately 50% is subsequently reabsorbed in the proximal tubule and contributes to the counter-current exchange mechanism.

• The remainder is excreted in the urine, accounting for over 80% of the body’s daily nitrogen excretion.

Normal range

2.5–7.0 mmol/L.

Management principles

See under ‘Serum creatinine’.

Assessment of renal function: urinalysis

Test: urine dipstick

Indications

1. Bedside investigation of renal function.

2. Screening for diabetes.

3. Screening for urinary tract infection.

How it is done

• A reagent stick is dipped into a urine sample.

• The various reagents change colour according to the presence of various constituents of the sample.

Data presented as

Reagent stick colour changes compared to standardized colour chart.

Abnormalities and management principles

A few causes of an abnormal urine dipstick are listed in Table 6.3.

Table 6.3 Causes of abnormal urine dipstick

Finding	Causes
Glycosuria	Diabetes mellitus
	Tubular dysfunction
	Pregnancy
Proteinuria	Glomerular dysfunction, e.g. pre-eclamptic toxaemia
	Orthostatic proteinuria (benign; occurs after prolonged standing)
	Fever
	Severe exercise
	Lower urinary tract infection
	Nephrotic syndrome
High pH	Distal renal tubular acidosis (renal bicarbonate losses)
Low specific gravity	Diabetes insipidus
Red cells	Rhabdomyolysis
	Urinary tract infection
	Glomerulonephritis
Leucocytes	Urinary tract infection
Nitrites	Gram-negative bacterial urinary tract infection
Bilirubin/increased urobilinogen	Conjugated bilirubin appears in presence of obstructive jaundice

Limitations and complications

Urine dipstick is a very nonspecific test and further investigation will always be required in the presence of an abnormal result.

Test: Urine microscopy

Indications

• Investigation of abnormal renal function.

• Suspected urinary tract infection.

How it is done

Microscopic laboratory analysis of a fresh urine sample.

Data presented as

Written report detailing presence or absence of cells, crystals and casts.

Interpretation

Physiological principles

Cells, crystals and casts are not usually found in the urine and their presence may indicate the presence of intrinsic renal pathology or infection.

Abnormalities and management principles

See Table 6.4 for explanation of various findings.

Table 6.4 Findings in the urine on microscopy

Finding	Causes
Red cells	Glomerular bleeding or dysfunction
	Infection
	Traumatic catheterization
White cells	Infection
	Some cases of glomerular disease
	Some cases of interstitial nephritis
Crystals	Renal calculi
	Gout (uric acid crystals)
Casts
Hyaline casts	Normal
Granular casts	Nonspecific
Tubular cell casts	Acute tubular necrosis or interstitial nephritis
Red cell casts	Glomerulonephritis or glomerular bleeding
Leucocyte casts	Acute tubular necrosis or pyelonephritis

Limitations and complications

Sample contamination may affect the result. This is a fairly nonspecific test, and further investigations will be required to make a diagnosis if an abnormal result is found.

Test: Laboratory assay of urine sodium, osmolality, urea, creatinine and specific gravity

Indications

Differentiation between prerenal oliguria and acute tubular necrosis.

Interpretation

Physiological principles

• In prerenal uraemia an acute hypoperfusion insult to the kidney has occurred, but there is preservation of physiological mechanisms within the kidney (such as stimulation of the renin-angiotensin-aldosterone system) which maintain normal sodium and water handling within the nephron.

• In the case of acute tubular necrosis, kidney damage has occurred, impairing normal solute and water handling; in the oliguric patient, urinalysis may differentiate between these two disorders and guide management.

Normal ranges

Table 6.5 Normal ranges for urine laboratory findings

Investigation	Prerenal oliguria	Acute tubular necrosis
Urine sodium (mmol/L)	<20	>40
Specific gravity	>1.020	<1.010
Urine osmolality (mosmol/kg)	>500	<350
Urine: plasma osmolality ratio	>2	<1.1
Urine: plasma urea ratio	>20	<10
Urine: plasma creatinine ratio	>40	<20
Fractional sodium excretion^*	<<1%	>1%

* Percentage of sodium filtered at the glomerulus (normally 1000 mmol/hour), which actually appears in the urine (normally 6 mmol/hour; i.e. 0.6%).

Abnormalities and management principles

Patients with prerenal oliguria may have their renal function salvaged by aggressive haemodynamic and fluid resuscitation. In patients with established ATN, renal replacement therapy is likely to be required.

Limitations and complications

These values will be affected by the use of diuretics. In clinical practice, it would be unusual for clinical decision making to be based on urinalysis alone.

Assessment of renal function: Measurement of glomerular filtration rate

Test: Radioisotope assay

Indications

‘Gold standard’ laboratory assessment of renal function.

How it is done

A precalculated dose of a radiolabelled isotope such as ⁵¹chromium-EDTA or ⁹⁹technetium-DTPA is injected intravenously into the patient. The clearance of the isotope is calculated using the formula:

Data presented as

Numerical value: units mL/min.

Interpretation

Physiological principles

Glomerular filtration rate (GFR) is the volume of fluid (in mL) filtered from the renal glomerular capillaries into the Bowman’s capsule per unit time (minutes). This is a measure of renal function.

The radioisotope is cleared entirely renally, thus its clearance will correlate with GFR.

Normal range

Male: 97–137 mL/minute

Female: 88–128 mL/minute

Abnormalities and management principles

Glomerular filtration rate is reduced by:

1. Any cause of renal impairment

2. Age: GFR reduces by approximately 1 mL/minute/year over the age of 30.

Glomerular filtration rate may be increased by:

Limitations and complications

• Not accurate in patients with significant oedema, as the expanded extracellular volume will influence the disappearance of the plasma tracer.

• Isotope assay is a relatively time-consuming and invasive technique. In clinical practice, creatinine clearance is usually preferred to isotope assay in the assessment of renal dysfunction.

Test: Inulin clearance

Indications

Laboratory assessment of renal function.

How it is done

Inulin, a chemically inert substance, is administered to the patient by a constant infusion and the plasma and urine concentrations measured. GFR is calculated using a variation on the clearance formula.

Physiological principles

• Measurement of glomerular filtration rate is possible by measuring the clearance of a substance that is metabolically inert, does not interfere with renal function, is neither bound nor excreted by an extrarenal route and is freely filtered by the glomerulus without being secreted or reabsorbed elsewhere in the nephron.

• Inulin fulfils all the above criteria. Prior to the development of radioisotope assays, it was used as the ‘gold standard’ for measuring glomerular filtration rate.

Limitations and complications

Inulin clearance is rarely used now as it has been superseded by isotope assays. It is a relatively invasive and complicated investigation, and in the bedside assessment of GFR, measurement or calculation of creatinine clearance (see below) is preferred as a simpler, less time-consuming and more practical method.

Test: Creatinine clearance

Indications

Bedside assessment of renal function.

Data presented as

Numerical value.

Units: mL/minute for 24 hours creatinine clearance and Cockroft-Gault and mL/minute/1.73 m² for abbreviated MDRD Study equation.

Limitations and complications

• Creatinine secretion in the tubule may be a cause of a small error; not generally clinically relevant.

• Drugs that reduce tubular creatinine secretion may cause inaccuracies, e.g. cimetidine, certain antibiotics and quinidine.

Assessment of renal function: Radiological

Test: Renal ultrasound

Indications

1. Investigation of renal impairment/failure.

2. Preoperative assessment for live related kidney donors.

How it is done

Abdominal ultrasound examination.

Data presented as

Radiological imaging, with measurement of kidney size.

Limitations and complications

• Operator dependent.

• Difficult in patients with large body habitus.

Serological measurement of electrolytes

Test: Serum sodium measurement

Indications

1. Preoperative biochemistry profile according to NICE guidelines.

2. Critical illness, renal or hepatic failure.

3. Disordered water homeostasis of any cause including suspected diabetes insipidus or syndrome of inappropriate ADH secretion (SIADH).

4. Adrenal disorders.

How it is done

Radioimmunoassay.

Interpretation

Physiological principles

• Sodium is the predominant extracellular cation and principal osmotically active solute in plasma and interstitial fluid; it is vital for membrane potentials and action potentials.

• It is actively absorbed from the small intestine and colon under the influence of aldosterone; freely filtered at the glomerulus and then actively reabsorbed in the proximal convoluted tubule, utilizing Na,K-ATPase.

• Lost predominantly in urine (150 mmol/day); some loss from sweat, faeces and saliva (10 mmol/day each).

• Sodium balance is regulated via:

– osmoreceptors, which monitor extracellular sodium concentration then influence the renin-angiotensin-aldosterone system

– Baroreceptors, which monitor changes in extracellular volume so influencing antidiuretic hormone and atrial natriuretic hormone secretion as well as the renin-angiotensin-aldosterone system.

Normal range

135–145 mmol/L.

Abnormalities and management principles

Hyponatraemia

Causes

Hyponatraemia may be divided into three categories:

1. ‘Real’ hyponatraemia (hypo-osmolar plasma)

2. Pseudo-hyponatraemia (i.e. presence of high levels of triglycerides or proteins with a normal serum osmolality)

3. Dilutional hyponatraemia: hyperosmolar plasma due to water shift from intracellular to extracellular compartments, e.g. due to the presence of ethanol, hyperglycaemia or mannitol administration.

Assessment of total body fluid status and the measurement of urinary sodium are both crucial to identifying the cause of hyponatraemia. Causes of ‘real’ hyponatraemia may be classified as in Table 6.6.

Table 6.6 Causes of ‘real’ hyponatraemia

Urine sodium (mmol/L)	Eu or hypervolaemia with oedema	Hypovolaemia
>20	Renal failure SIADH Hypothyroidism Drugs with antidiuretic effect (e.g. oxytocin, chlorpropamide)

Salt-losing nephropathy

Renal tubular acidosis

Post-relief of urinary obstruction

<10

Excessive water intake:

• Sodium deficient Intravenous Infusion (IVI)

• Trans Urethral Resection of the Prostate (TURP) syndrome

• Excessive drinking

Congestive cardiac failure

Liver cirrhosis

Nephrotic syndrome

Diarrhoea and vomiting

Acute pancreatitis

Other fluid loss

Clinical features

• Depend on the underlying cause.

• In true hyponatraemia, features of dehydration and hypovolaemia predominate.

• In hypervolaemic hyponatraemia, symptoms occur with serum sodium levels of <120 mmol/L and are predominantly neurological, including headache, nausea and confusion. If untreated, this may progress to convulsions and coma.

• Osmotic intracellular movement of water may lead to permanent neurological deficit.

Management principles

• Identification and treatment of underlying cause.

• In severe cases of sodium and water deficiency, correction with hypertonic saline.

• Avoid rapid correction (risk of pontine myelinolysis, subdural haemorrhage or cardiac failure).

• Suggested correction rate: 2 mmol/L/hour until serum sodium reaches 120 mmol/L thereafter a maximum correction rate of 5–10 mmol/L/day.

• Calculation of total sodium deficit may assist in correction; assuming normal sodium distribution throughout total body water, sodium deficit may be calculated:

Hypernatraemia

The causes of hypernatraemia can be classified as in Table 6.7, paying attention to the urinary sodium concentration.

Table 6.7 Causes of hypernatraemia

Urine sodium	Examples
>20 mmol – true hypernatraemia	Iatrogenic (e.g. administration of hypertonic saline or sodium bicarbonate solutions)
	Cushing’s syndrome
	Conn’s syndrome (hyperaldosteronism)
<20 mmol – sodium depletion with greater water depletion	Renal loss from osmotic diuresis (e.g. hyperglycaemia, uraemia, administration of mannitol)
<10 mmol – sodium depletion with more severe water depletion	Adrenocortical insufficiency
	Increase in insensible losses – e.g. from sweating or suppurating wounds
	Diarrhoea and vomiting
Variable urinary sodium – pure water depletion	Renal water loss from diabetes insipidus
Variable urinary sodium – pure water depletion	Dehydration from insufficient water intake

Clinical features

• Those of dehydration, if present: thirst, and progressive neurological obtundation.

• If severe, cerebral dehydration may occur, leading to intracerebral haemorrhage from vessel disruption.

Treatment

• Identify and manage underlying cause

– History, examination and urine sodium measurement.

– Urine and serum cortisol measurements and plasma ACTH will reveal Cushing’s syndrome.

• Rehydration with enteral water where possible; if not, use 0.9% saline IV.

• Hypotonic saline may be used in severe salt and water deficiency.

• Careful slow correction required to prevent cerebral oedema and convulsions.

Limitations and complications

Serum sodium measurement can be inaccurate in uraemia or hyperbilirubinaemia.

Test: Serum potassium measurement

Indications

1. Preoperative assessment according to NICE guidelines.

2. Renal impairment.

3. Critical illness.

4. Diuretic therapy.

5. Cardiac dysrhythmias.

6. Intravenous or enteral nutrition.

How it is done

Spectophotometric assay of serum sample.

Interpretation

Physiological principles

• Potassium is the principal intracellular cation; essential to the electrical excitability of cells and the maintenance of membrane potentials.

• It is freely filtered at the glomerulus and then reabsorbed, predominantly in the proximal convoluted tubule.

• Actively secreted in the distal tubule under the influence of aldosterone, in exchange for sodium and hydrogen ions.

Normal range

3.5–4.5 mmol/L.

Abnormalities and management principles

Hypokalaemia

Classification of the causes of hypokalaemia can be made according to the urinary potassium excretion and plasma renin activity (Table 6.8).

Table 6.8 Causes of hypokalaemia

Potassium excretion <30 mmol/day	Potassium excretion >30 mmol/day with low plasma renin activity	Potassium excretion >30 mmol/day with high plasma renin activity
Gastrointestinal losses Low intake: e.g. due to parenteral fluid therapy without potassium supplementation Previous diuretic usage Movement of potassium into cells: e.g. due to alkalosis or drugs such as insulin and catecholamines

Conn’s syndrome (primary hyperaldosteronism) and other disorders of the renin-angiotensin system

Renal tubular acidosis

Salt-wasting chronic renal failure

Diuretic phase of acute renal failure

Accelerated hypertension

Renovascular disease

Cushing’s syndrome

Bartter’s syndrome

Renin-secreting tumours

Treatment

• Replacement: either orally (up to 200 mmol/day) or intravenously (up to a maximum of 40 mmol/hour).

• Too high a concentration of intravenous potassium may cause necrosis of small veins; if significant replacement is required, a central line is recommended.

• Too rapid a correction will result in ventricular fibrillation; if quick correction is required, cardiac monitoring is indicated.

Hyperkalaemia

Causes of hyperkalaemia can be divided into those that result from increased intake, decrease output or transcellular movement into the plasma (Table 6.9).

Table 6.9 Causes of hyperkalaemia

Increased intake	Decreased renal output	Movement of potassium out of cells
Rapid blood transfusion Inappropriate intravenous replacement therapy Some dietary products contain high amounts of potassium, including chocolate and certain fruit (e.g. bananas)

Addison’s (adrenocortical insufficiency)

• ACE inhibitors

• Potassium sparing diuretics

• Ciclosporin

Muscle breakdown or disruption e.g. rhabdomyolysis, crush syndromes, trauma or malignant hyperthermia

Suxamethonium (will cause a rise of approximately 0.5 mmol/L, but this is exaggerated in patients with extra-junctional ACh receptors, such as burns patients or those with long-term immobility

Familial periodic paralysis

Clinical features

• General symptoms such as muscle weakness and gastrointestinal upset.

• Myocardial depression and a spectrum of cardiac conduction problems, both atrial and ventricular.

• ECG changes such as peaked T waves, widened QRS complexes and slurring of ST segments into T waves.

• Plasma level >7 mmol/L may lead to ventricular dysrhythmias including ventricular fibrillation, and diastolic cardiac arrest.

Limitations and complications

• Serum potassium samples may read artefactually high if the sample is haemolyzed or if there is a severe leucocytosis.

• The ratio of intracellular to extracellular potassium concentration is of more clinical relevance than an isolated plasma level.

Test: Serum magnesium

Indications

1. Preoperative biochemistry profile.

2. Renal failure.

3. Cardiac dysrhythmias.

4. Critical illness.

5. During therapeutic magnesium replacement therapy, e.g. for pregnancy-induced hypertension.

How it is done

Spectophotometric assay of serum sample.

Abnormalities and management principles

Hypomagnesaemia

Hypomagnesaemia is often found in association with hypocalcaemia and hypokalaemia (Table 6.10). It may be asymptomatic, but may present with the following clinical features:

• General: weakness and anorexia

• Cardiovascular: dysrhythmias (especially ventricular), prolonged QT interval, flattened T waves, short ST interval (occasionally)

• Neurological: ataxia, tremor, carpopedal spasm, hyper-reflexia, hallucinations, convulsions.

Table 6.10 Causes of hypomagnesaemia

Cause	Examples
Gastrointestinal loss	Diarrhoea and vomiting; malabsorption syndromes; malnutrition; small bowel disorders; chronic alcoholism
Gastrointestinal loss	Acute pancreatitis (magnesium sumps form in areas of fatty necrosis)
Renal loss	Loop and thiazide diuretics; acute alcohol intake; diabetic ketoacidosis; hypercalcaemia
Loop of Henle disorders	Acute tubular necrosis; renal transplantation; post-obstructive diuresis
Nephrotoxicity	Amphotericin B; aminoglycosides; ciclosporin A; cisplatin; pentamidine; digoxin
Other	SIADH; hyperaldosteronism

Treatment

Identify cause and replace with oral or IV supplementation.

Hypermagnesaemia

True hypermagnesaemia is rare. It is usually due to renal insufficiency or exogenous ingestion (Table 6.11).

Table 6.11 Causes of hypermagnesaemia

Cause	Examples
Renal	Renal failure of any aetiology
Exogenous administration	Purgatives (e.g. magnesium sulphate)
	Antacids (e.g. magnesium trisilicate)
	Therapeutic magnesium infusions/enemas
Drugs	Lithium
Drugs	Theophylline toxicity
Other	Adrenal insufficiency

Clinical features of hypermagnesaemia may occur at levels greater than 3–4 mmol/L and include:

1. Neurological: lethargy, drowsiness, areflexia, paralysis

2. Cardiovascular: hypotension, heart block, cardiac arrest.

Treatment with intravenous calcium may temporarily reverse toxic effects.

Limitations and complications

Serum levels are a poor reflection of total body magnesium as it is a predominantly intracellular ion.

Test: Serum calcium

How it is done

• A number of studies have found free (ionized) calcium measurement to be a more clinically useful measurement of metabolic calcium disturbances than the commonly used total serum calcium measurement, which needs to be adjusted for serum albumin levels.

• Free (ionized) calcium can be measured either in the laboratory or in a blood gas analyzer using an ion-sensitive electrode technique.

Interpretation

Physiological principles

• Calcium is involved in coagulation, neuromuscular conduction, skeletal mineralization and the integrity of the cell membrane and transmembrane transport.

• 99% of the body’s store of calcium is contained within bone and these stores buffer changes in serum calcium. Serum calcium content is divided equally between:

– Bound calcium (i.e. bound to proteins and other ions)

– Free ionized calcium.

• Calcium homeostasis is inextricably linked with that of phosphate and vitamin D and regulated by parathyroid hormone and calcitonin.

Normal range

1. Bound calcium (2.12–2.65 mmol/L; adjusted according to plasma protein levels – corrected by adding 0.02 mmol/L calcium for each g/L albumin below 40 g/L or by subtracting the same value for each g/L above albumin level 40 g/L.

2. Ionized calcium (0.8–1.1 mmol/L).

Abnormalities and management principles

Hypercalcaemia

Hypercalcaemia is due to either hyperparathyroidism or malignancy in over 90% of cases (Table 6.12).

Table 6.12 Causes of hypercalcaemia

Increased calcium absorption	Increased bony release	Miscellaneous
Increased dietary/exogenous intake of calcium Increased dietary/exogenous intake of vitamin D

Primary hyperparathyroidism

Tertiary hyperparathyroidism

Hyperthyroidism

Addison’s disease

Phaeochromocytoma

Drugs: Thiazide diuretics, lithium, theophylline toxicity

Clinical features

• Muscle weakness, malaise/depression, lethargy, confusion.

• Nephrolithiasis, nephrogenic DI, distal Renal Tubular Acidosis (RTA), renal failure.

• Peptic ulceration (due to excessive gastrin secretion), pancreatitis, constipation.

• Short QT syndrome; diabetes insipidus.

Management principles

1. Identifying and treating the cause.

2. Rehydration therapy (3–4 L crystalloid solution per day minimum) and loop diuretics.

3. Intravenous bisphosphonate therapy.

Treatment is usually mandatory for total serum corrected calcium levels above 3 mmol/L.

Hypocalcaemia

Commonest causes:

• Renal failure (due to increased serum phosphate levels)

• Hypoparathyroidism

• Vitamin D deficiency.

Other causes are listed in Table 6.13.

Table 6.13 Hypocalcaemia

Decreased calcium absorption	Hyperphosphataemia (causing reduced ionized calcium levels)	Miscellaneous
Hypoparathyroidism Vitamin D deficiency Sepsis Hypomagnesaemia Fluoride poisoning

Exogenous phosphate administration

Tumour lysis syndrome

Hungry bone syndrome

Acute respiratory alkalosis

Management

1. Identification and treatment of the underlying cause.

2. PO or IV replacement dependent on clinical situation.

3. Vitamin D supplementation in hypoparathyroidism, vitamin D deficiency or renal failure.

Limitations and complications

• Laboratory serum calcium levels may be misinterpreted with hypo- or hyperproteinaemia.

• Ionized calcium levels, as measured on arterial blood gas machines, will increase with acidosis and decrease with alkalosis. Thus, the use of a tourniquet for venous sampling or the presence of heparin, as in a blood gas syringe, may both cause an artefactual acidaemia and so an inaccurate ionized calcium result.

Test: Serum phosphate

Indications

1. Known disorder of phosphate metabolism.

2. Renal failure.

3. Patients on parenteral feeding.

4. Re-feeding syndrome.

5. Acid-base disturbance.

6. Malabsorption syndromes.

7. Rhabdomyolysis.

How it is done

Spectophotometric assay of serum sample.

Interpretation

Physiological principles

• Predominantly intracellular ion; forms part of the structure of cell membranes and plays essential roles in acid-base buffering, oxygen transport systems, energy storage and enzyme regulation.

• Regulated by renal excretion.

• Reduced phosphate excretion occurs in response to reduced intake, growth and thyroid hormones.

Normal range

Inorganic serum phosphate: 0.8–1.4 mmol/L.

Abnormalities and management principles

Hyperphosphataemia

Causes

The commonest cause of hyperphosphataemia is renal failure. Others are listed in Table 6.14.

Table 6.14 Hyperphosphataemia

Acute phosphate loading	Increased tubular re-absorption of phosphate
Exogenous phosphate intake Rhabdomyolyis Lactic acidosis Ketoacidosis

Hypoparathyroidism

Bisphosphonate treatment

Hypophosphataemia

Causes

Causes are listed in Table 6.15.

Table 6.15 Causes of hypophosphataemia

Reduced intake/intestinal absorption	Increased renal excretion	Internal redistribution
Reduced dietary intake, e.g. alcoholism Total parenteral nutrition Magnesium or aluminium-containing antacids Chronic diarrhoea or steatorrhoea Re-feeding syndrome

Primary hyperparathyroidism

Secondary hyperparathyroidism (nonrenal)

Osmotic and thiazide diuretics

Acute plasma expansion

Vitamin D deficiency

Acute respiratory alkalosis

Hyperinsulinaemia

Clinical features

• Asymptomatic unless <0.6 mmol/L; may be associated with confusion, heart failure and even coma at extremely low levels.

• Muscle weakness, particularly of the respiratory muscles; may impair ventilatory weaning on the ICU.

• If the serum concentration <0.3 mmol/L, a reactive rhabdomyolysis may occur.

Test: Serum chloride

Indications

1. Metabolic acidosis.

2. Patients on intravenous fluid replacement therapy.

3. Patients on total parenteral nutrition.

4. Severe vomiting.

How it is done

Chloride ion-sensitive electrode (uses the same reference electrode as that used for pH measurement).

Interpretation

Physiological principles

• The body’s predominant extracellular anion.

• Maintains electroneutrality, mainly as a counter to sodium; serum chloride generally increases and decreases with serum sodium.

Normal range

96–106 mmol/L.

Management principles

Identification and management of the underlying cause.

Test: Serum lactate

Indications

1. Metabolic acidosis.

2. Suspected or proven hypoperfusion (either generalized or specifically to the liver and/or intestinal tract).

How it is done

• Laboratory analysis using a venous or arterial blood sample.

• Lactate is oxidized by L-lactate peroxidase, producing hydrogen peroxide.

• This is then passed to a platinum electrode, which oxidizes the hydrogen peroxide, producing a current, the size of which is proportional to the lactate concentration.

Interpretation

Physiological principles

• Lactate is a by-product of anaerobic metabolism of pyruvate.

• Lactate levels may also rise as a result of reduced gluconeogenesis. Lactate is metabolized by the liver to bicarbonate, so a failure of this metabolism may also cause a rise in serum lactate.

• If a rise in serum lactate is also accompanied by a metabolic acidosis this is termed lactic acidosis.

Normal range

0.6–1.8 mmol/L.

Abnormalities

The causes of lactic acidosis are classified as either Type A (associated with tissue hypoxia) or Type B (without tissue hypoxia) (Table 6.16).

Table 6.16 Causes of lactic acidosis

Type A (tissue hypoxia)	Type B (no tissue hypoxia)
Hypoxaemia Anaemia Hypoperfusion of any origin (e.g. haemorrhage, sepsis, hypovolaemia) Cardiac failure Ischaemic bowel

Hepatic failure

Diabetes mellitus

Drug-induced: e.g. salicylate overdose, biguanides, alcohols

Total parenteral nutrition

Inborn errors of metabolism

Glycogen storage disorders

Management principles

• Management of lactic acidosis predominantly involves identification and treatment of the underlying cause.

• Initial supportive management includes optimization of tissue oxygen delivery with adequate oxygenation, cardiac output and haemoglobin concentration.

Test: Serum bicarbonate

Indications

Any suspected acid-base disturbance.

How it is done

Calculated from the plasma pH and PCO₂, as measured by the pH and Severinghaus electrodes in a blood gas analyzer.

Interpretation

Physiological principles

• Bicarbonate is an anion that is a major component of the body’s predominant buffer system.

• It is formed from the dissociation of carbonic acid as a part of a three-stage chemical reaction, which is catalyzed by carbonic anhydrase.

• Bicarbonate is completely filtered in the glomerulus and then reabsorbed, predominantly in the proximal tubule, via the formation of carbonic acid; the degree of this reabsorption is determined by total body acid-base balance.

Normal range

24–33 mmol/L.

Abnormalities and management principles

Limitations and complications

Investigation of salt and water disturbance

Test: Serum osmolality

Indications

1. Renal impairment.

2. Serum sodium derangement.

3. Suspicion of diabetes insipidus or SIADH.

How it is done

1. Estimation using the formula:

Plasma osmolality = [Glucose] + [urea] + 2 × [sodium]

(mosmol/kg) (mmol/L) (mmol/L) (mmol/L)

2. Laboratory determination of depression of freezing point.

3. Laboratory measurement of osmotic pressure.

4. Laboratory determination of serum ionic concentrations using flame photometry.

Data presented as

Numerical data: units mosmol/kg solvent.

In the case of plasma, the solvent is water.

Interpretation

Physiological principles

• Osmolality – the number of osmoles per kilogram solvent.

• Osmolarity – the number of osmoles per litre of solution

where osmole refers to the molecular weight of a substance divided by the number of freely moving particles in solution.

• In the plasma, the presence of proteins and fats mean that the values for osmolarity and osmolality are slightly different.

• In health, plasma osmolality is maintained within a narrow range by a number of homeostatic mechanisms involving osmoreceptors, which respond to changes by the stimulation of antidiuretic hormone.

Normal range

280–305 mosmol/kg.

Abnormalities and management principles

Diabetes insipidus (DI)

This causes a high serum osmolality and presents with polyuria and polydipsia associated with reduced ADH activity.

This may be due to:

• Cranial DI: hyposecretion of ADH – e.g. due to head injury, brain tumours, neurosurgery or, rarely, familial cranial DI

• Nephrogenic DI: renal unresponsiveness to the effects of ADH – e.g. related to drugs such as lithium, demeclocycline and gentamicin. Patients are unable to concentrate their urine in response to water deprivation.

Treatment

Depends on the cause.

• Cranial DI is treated with desmopressin, a synthetic ADH analogue.

• Nephrogenic DI is treated with thiazide diuretics.

Limitations and complications

• Pathologically high levels of alcohols, proteins, triglycerides and mannitol will make the calculation of osmolality using the above formula inaccurate, as these molecules are not accounted for.

• Urine osmolality should also be measured to confirm diagnosis of SIADH or DI.

Assessment of thyroid function

Test: Serum thyroid hormones measurement

Indications

Investigation of thyroid function.

How it is done

Serological immunoassay of thyroxine, thyronine and thyroid-stimulating hormone.

Abnormalities and management principles

Hyperthyroidism

Causes

The commonest causes are characterized by an overactive gland and thus normal or increased radio-iodine uptake; these are Graves’ disease, toxic (hot) nodule and toxic multinodular goitre administration. Drugs that can induce hyperthyroidism include amiodarone and oestrogens.

Clinical features are listed in Table 6.17.

Table 6.17 Clinical features of hyperthyroidism

Cardiovascular	Dyspnoea; atrial fibrillation; high-output cardiac failure
Musculoskeletal	Proximal myopathy, periodic paralysis; osteoporosis; hypercalcaemia
Blood	Leucopenia; microcytic anaemia

It is characterized by an increase in serum T4 measurements; TSH may or may not be suppressed depending on the cause.

• Medical management is with carbimazole or propyluracil, which prevent formation of thyroid hormones.

• Iodine therapy temporarily inhibits hormone release and is often given for 2 weeks before thyroidectomy.

• Beta adrenoceptor antagonists have dual effect, by reducing the conversion of thyroxine to the active tri-iodothyronine, and also by counteracting the systemic effects of hyperthyroidism.

• Surgical removal of the thyroid gland requires adequate preoperative medical control of hyperthyroidism, in order to prevent precipitation of a thyroid crisis.

Hypothyroidism

Causes

• Total or partial thyroidectomy.

• Drugs – e.g. amiodarone, aspirin, phenytoin, interferon, frusemide, lithium.

• Autoimmune diseases are 10 times more common in females, and the incidence increases with age.

• It is characterized by a reduction in T4/T3 levels, and will be accompanied by a high TSH if the hypothyroidism is due to intrinsic thyroid disease or drugs affecting the thyroid.

• It may rarely be caused by pituitary disease, in which case the TSH will also be low.

Clinical features are listed in Table 6.18.

• Hypothyroidism may present as a medical emergency in the form of a myxoedema coma.

• It is treated with oral thyroxine replacement or, in the emergency setting, with intravenous T3.

Table 6.18 Clinical features of hypothyroidism

General	Serous effusions (ascites, pleural, pericardial or joint effusions); hypothermia
Cardiovascular	Hypercholestrolaemia and ischaemic heart disease; bradycardia; cardiomegaly
Cardiovascular	ECG changes include low-voltage complexes and T wave flattening/inversion
Respiratory	Hypoventilation
Musculoskeletal	Muscular chest pain; muscular cramps; raised creatinine kinase
Blood	Macrocytic anaemia; microcytic anaemia in context of menorrhagia in women

Assessment of glycaemic control

Test: Serum glucose

Indications

1. Diabetes mellitus.

2. Any acute or critical illness, in particular, sepsis, acute pancreatitis.

3. Reduced level of consciousness.

4. Glycogen storage diseases.

How it is done

Laboratory assay

Several methods exist. In one such method D-glucose is oxidized in the presence of glucose oxidase, producing hydrogen peroxide and glucono-δ-lactone. Hydrogen peroxide is then passed to a platinum electrode, where it is oxidized; the magnitude of the resultant current is proportional to the glucose concentration.

Glucose reagent sticks

The same oxidation reaction is employed, producing hydrogen peroxide. In the case of reagent sticks, the hydrogen peroxide then oxidizes a dye, which produces a colour change that can be compared against a chart.

Interpretation

Physiological principles

In health, blood sugar is maintained within a narrow range by various neuroendocrine response systems including the sympathetic nervous system, insulin and glucagon.

Normal range

Fasting blood glucose: 4.1–7 mmol/L.

Abnormalities and management principles

Hyperglycaemia

Hyperglycaemia is defined as fasting plasma glucose greater than 7.0 mmol/L. Causes are listed in Table 6.19.

Table 6.19 Causes of hyperglycaemia

Causes	Examples
Pancreatic insufficiency	Diabetes mellitus (types 1 and 2) Acute or chronic pancreatitis or pancreatectomy Sepsis Cystic fibrosis

Neuroendocrine response causing increased circulating catecholamines, growth hormone, glucocorticoids, glucagon

Trauma, burns, critical illness

Stress response to surgery

Insulin resistance

Type 2 diabetes mellitus

Polycystic ovary syndrome

Acromegaly, Cushing’s syndrome or glucagonomas

Phaeochromocytoma

Exogenous administration of glucose Total parenteral nutrition (TPN), enteral nutrition Drugs Steroids, thiazide diuretics, octreotide

Acute hyperglycaemia

• Diabetic ketoacidosis is frequently precipitated by a concomitant illness.

• Hyperosmolar nonketotic coma is a more common presentation of hyperglycaemia in elderly patients. Progressive dehydration due to polyuria results in a very high plasma osmolality accompanying severe hyperglycaemia, but with little or no ketonuria.

• Management of both conditions involves slow correction of fluid, glycaemic and electrolyte abnormalities.

Acute hypoglycaemia

• Hypoglycaemia in diabetic patients may occur in those treated with either insulin or oral sulphonylureas.

• Hypoglycaemia in nondiabetic patients is rare, but can occur in association with hepatic disease, alcohol, hypoadrenalism and certain tumours (e.g. insulinomas, IGF-2 secreting tumours).

• Postprandial hypoglycaemia is well documented in patients post gastrectomy.

Tight glycaemic control

• Evidence from several major studies has found there to be outcome benefit, both in terms of morbidity and mortality from controlling blood glucose in surgical critically ill patients.

• There is still some debate over whether ‘tight’ glycaemic control is more beneficial than ‘moderate’ glycaemic control; however, most studies use a target blood glucose range of 4–8 mmol/L.

Limitations and complications

1. Glucose reagent sticks tend to be less accurate at lower glucose levels.

2. Falsely high glucose results may occur due to contamination of the testing sample, for example, with glucose-containing contaminants on the skin from where a blood sample is obtained.

Test: Glycosylated haemoglobin (HbA1C)

Indications

Monitoring of long-term glycaemic control.

Data presented as

A percentage of glycosylated haemoglobin relative to red cell haemoglobin.

Interpretation

Physiological principles

• Red cell haemoglobin is nonenzymatically glycated at a rate that relates to overall level of glucose.

• It has been found to correlate well with the risk of microvascular complications and so is a valuable tool in the assessment of long-term glycaemic control.

Normal range

There is no standardized assay of HbA1C and interpretation should be made in conjunction with local guidelines.

Abnormalities and management principles

• The commonest cause of a high HbA1C is poor glycaemic control secondary to diabetes mellitus of any aetiology.

• However, abnormalities in HbA1C may occasionally be due to some haemoglobinopathies and disorders of red cell metabolism.

Investigation of the hypothalamic–pituitary axis

Test: Short synacthen test

Indications

Suspected adrenocortical insufficiency:

1. Sepsis/critical illness

2. Addison’s disease

3. Long-term steroid usage

4. Pituitary disease or surgery.

How it is done

1. Baseline serum sample for cortisol assay.

2. Intravenous administration of 250 μg synthetic adrenocorticotrophin (ACTH) – tetracosactrin.

3. Serum cortisol assay at 30 minutes following ACTH administration.

Serum cortisol samples are laboratory analyzed by radioimmunoassay.

Data presented as

Numerical value for cortisol assay; units nmol/L.

Interpretation

Physiological principles

The administered dose of tetracosactrin should maximally stimulate the adrenal cortex. In the case of adrenal insufficiency, the adrenal cortex is unable to respond to this stimulus, resulting in a subnormal rise in serum cortisol levels.

Normal range

Post-ACTH administration cortisol level >500 nmol/L.

Abnormalities

The causes of adrenocortical insufficiency may be divided into:

1. Primary adrenal failure (Addison’s disease). This may have a variety of aetiologies including autoimmune (most common), infiltration from TB, malignancy or amyloidosis, critical illness, haemorrhage or infarction. Autoimmune Addison’s may be associated with other autoimmune disorders.

2. Secondary adrenal failure. Most commonly due to either abrupt withdrawal of long-term steroid therapy, ACTH deficiency due to pituitary disease or surgery.

Adrenal insufficiency as demonstrated by an inadequate increment in serum cortisol in response to a short synacthen test may result in a variety of clinical, biochemical and haematological abnormalities. The clinical features differ in acute and chronic adrenocortical insufficiency (Table 6.20).

Table 6.20 Acute versus chronic adrenocortical insufficiency

Acute	Chronic
Clinical features • Abdominal and muscular pain • Hypotension • Psychosis

Clinical features

• Malaise and muscle weakness

• Weight loss

• Diarrhoea and vomiting

• Postural hypotension

• Increased susceptibility to infection

Haematological features

• Eosinophilia

• Lymphocytosis

• Normocytic anaemia

Biochemical features

• Raised serum urea

• Hyponatraemia

• Hypoglycaemia

• Hyperkalaemia

• Hypercalcaemia

• Hypochloraemia

Management principles

• Severe acute adrenocortical insufficiency may present with circulatory collapse.

• Longer term management involves steroid replacement therapy, initially with intravenous hydrocortisone, and then subsequently with oral prednisolone if required.

Measurement of hormones: Phaeochromocytoma

Test: Plasma and urine catecholamines and their metabolites

Indications

Known or suspected phaeochromocytoma.

How it is done

1. Plasma assays

Laboratory assay of venous blood sample for plasma epinephrine and norepinephrine levels.

2. Urine assays

Laboratory assay of 24-hour urine sample for urinary epinephrine, norepinephrine and dopamine levels. Their urinary metabolites, vanillymandelic acid (VMA), metanephrine and normetanephrine, may also be measured.

Interpretation

Physiological principles

• Phaeochromocytomas are rare tumours of the sympathetic nervous system that are found in either the adrenal medulla or on sympathetic ganglia.

• They may secrete one or a combination of epinephrine, norepinephrine and dopamine; extraadrenal tumours do not secrete epinephrine.

• Symptoms include headache, sweating, palpitations, psychosis. Other symptoms or signs of hypertension, and sometimes hypotension, including postural hypotension, especially if the tumour secretes epinephrine.

• Patients may also present with signs or symptoms of glucose intolerance and cardiomyopathy.

Management principles

Resection of phaeochromocytomas involves careful anaesthetic preparation.

1. Complete preoperative alpha-blockade using phentolamine or phenoxybenzamine.

2. Subsequently, complete beta-blockade.

3. Prevention of intraoperative hypertension using vasodilators such as GTN, sodium nitroprusside or magnesium sulphate, and intraoperative tachy-arrhythmias using beta-blockers or amiodarone.

4. Goal-directed fluid resuscitation, particularly after tumour resection.

5. Postoperative high-dependency unit (HDU)/intensive care unit (ICU) admission.

Limitations

• Plasma catecholamine levels may be normal or only slightly elevated in up to a third of patients with phaeochromocytoma.

• Slight elevations of urinary and serum catecholamines and their metabolites may occur in a number of patients with poorly controlled systemic hypertension that is not due to phaeochromocytoma.

• False-positive urinary VMA results may occur because of concurrent therapy with methyldopa, levodopa or labetolol. It may also occur in patients with clonidine withdrawal, hypoglycaemia, raised intracranial pressure and after strenuous exercise.

• Various medications may cause false-positive results in urinary and serum catecholamine and metanephrine levels.

A variety of physiological stresses and pathophysiological processes may also cause false-positive urinary catecholamine and plasma catecholamine and metanephrine levels including the stress response to surgery, myocardial infarction, critical illness and depression.

Further investigations

• Clonidine suppression testing (i.e. the measurement of plasma free normetanephrine before and after administration of clonidine) may aid in the diagnosis.

• Preoperative tumour localization is carried out using CT scanning, radioactive meta-iodobenzyl guanidine (MIBG) scintigraphy and/or selective venous catheterization.

Measurement of hormones: Carcinoid tumours

Test: Urinary 5-hydroxyindole acetic acid (5-HIAA)

Indications

Known or suspected carcinoid tumour or carcinoid syndrome.

How it is done

Laboratory assay of 24-hour urine samples using high-performance liquid chromatography with electrochemical detection.

Interpretation

Physiological principles

• Carcinoid tumours are common, being an incidental finding in 1% of post-mortems. 85% of carcinoid tumours are found in the terminal ileum; they are rarely found outside the GI tract, in the lungs and gonads.

• Carcinoid tumours secrete serotonin and kinins but remain asymptomatic until hepatic metastases are present, resulting in carcinoid syndrome, which is a rare diagnosis. The presence of hepatic metastases impair serotonin metabolism, resulting in a variety of symptoms and signs, including flushing in association with wheezing, sweating, vasodilatation and resultant hypotension. They may also cause episodic diarrhoea and commonly lead to weight loss.

• Right-sided cardiac failure may result from endocardial fibrosis of the tricuspid and pulmonary valves (left-sided cardiac failure may occur in the presence of bronchial carcinoid or an Atrial Septal Defect (ASD)).

Normal range

3–15 mg/day. There is a correlation between tumour mass and 5-HIAA production.

Management principles

Anaesthetic management of carcinoid resection

• Cardiostable induction and maintenance with invasive arterial and central venous pressure monitoring.

• Consider cardiac output monitoring using oesophageal Doppler or similar.

• Intraoperative management revolves around the prevention of hypo- or hypertension, and bronchospasm.

• Postoperative ICU/HDU management.

Limitations

• Bananas, kiwi fruit, pineapples and a variety of nuts, all of which are serotonin rich, may cause false-positive results.

• Certain drugs, including salicylates, paracetamol and L-dopa may also affect the assay.

Further investigations

• Preoperative tumour localization is carried out using CT, MRI or PET scanning.

• Echocardiography is recommended if there are signs of cardiac involvement.

Investigation of allergic reactions

Test: Serum mast cell tryptase measurement

Indications

Suspected anaphylactic or anaphylactoid reaction.

How it is done

Enzyme immunoassay.

Interpretation

Physiological principles

Tryptase is a neutral protease that is found almost exclusively in mast cells. It exists in two structural forms (α and β); β–tryptase is normally involved in airway homeostasis, vascular contraction and relaxation, gastrointestinal motility and smooth muscle activity and in coagulation. Unlike histamine, tryptase remains elevated in the plasma for some hours after an anaphylactic reaction.

Normal range

Abnormalities and management principles

• Anaphylaxis (a type I immune reaction) and anaphylactoid reactions (involving complement released as well as mast cell degranulation) both lead to the release of histamine, serotonin, kinins and leukotrienes amongst other vasoactive substances.

• An important clinical difference between the two types of reaction is that anaphylaxis requires prior exposure and thus sensitization to the culprit agent, whereas anaphylactoid reactions do not.

• The management of suspected anaphylactic and anaphylactoid reactions is outlined in guidelines published by the Association of Anaesthetists of Great Britain and Ireland (AAGBI).

Limitations and complications

• At least three serial mast cell tryptase samples are required to be able to diagnose anaphylaxis, looking for an initial high value followed by serial decay.

• Mast cell tryptase assay does not distinguish between anaphylactic and anaphylactoid reactions.

Test: Serum and urine histamine assay

Indications

Suspected anaphylactic or anaphylactoid reaction.

How it is done

Enzyme immunoassay of either a 2-mL blood sample (non-EDTA bottle), 5 mL urine sample or 24-hour urine collection.

Data presented as

Numerical value. Units: ng/mL for random urine and blood sample; μg/24 hours for 24-hour urine collection.

Interpretation

Physiological principles

Histamine is a low-molecular-weight molecule produced by the decarboxylation of histidine. It is actively released from mast cells and basophils as part of anaphylactic and anaphylactoid reactions, but is also found throughout many body tissues and organs. Peak levels occur within 10 to 20 minutes of exposure, and then rapid decay to baseline occurs within 60–90 minutes. Thereafter, histamine may be detected in the urine.

Normal range

• Whole blood: 20–200 ng/mL.

• Random urine: 0–88 ng/mL.

• 24-hour urine: 0–118 μg/24 hours.

Abnormalities and management principles

See under mast cell tryptase.

Limitations and complications

Histamine assay does not differentiate between anaphylactic and anaphylactoid reactions.

Related

Anaesthesiology Churchills Ready Reference