Metabolic effects of poisoning

Complications of poisoning

Metabolic effects of poisoning

What’s new? • The traditional approach to acid–base abnormalities relies heavily upon the use of the carbonic acid/ bicarbonate buffer system using the Henderson– Hasselbalch equation, together with anion gaps to explain and interpret disorders. This approach may have shortcomings in describing the complexities which arise in critically ill patients in an intensive care setting

Alan Jones

• The physiochemical approach originally described by Stewart has some benefits in such patients and is increasingly used in the intensive care literature

Abstract Biochemical abnormalities due to disturbed metabolic processes are common in severely poisoned patients. These may be of diagnostic value, but most importantly their recognition and treatment are impor­ tant in the management of these patients. Acid–base abnormalites, par­ ticularly respiratory and metabolic acidoses, are common. Respiratory acidoses due to central nervous system depression or pulmomary toxi­ city, and metabolic acidoses due to lactic acidaemia or derangements of intermediary metabolism are particular features of poisoning. Plasma electrolyte abnormalities, particularly hyper- or hypokalaemia are found commonly in poisoned patients, most often due to redistribution of ­potassium across cell membranes. Hypoglycaemia is most frequently due to drug overdose.

Metabolic acidosis Acidaemia (pH <7.35 or H+ >45 nmol/L with low standard bicarbonate (<21 mmol/L) or a base deficit (<–2.3 mmol/L) indicates metabolic acidosis. pCO2 is also usually low (<4.6 kPa, 35 mm Hg) as a result of compensatory hyperventilation (Kussmaul’s breathing). Metabolic acidosis arises either through the accumulation of non-volatile acids or, less commonly, loss of bicarbonate. These may be differentiated by the measurement of the plasma anion gap by the laboratory.1,2 The electrostatic charge of the plasma cations must balance that of the anions, but conventional laboratory profiles do not measure all of the anions. Hence, there is an apparent deficiency of anions (the gap) that represents these unmeasured plasma anions (Figure 1). • The anion gap is increased when metabolic acidosis is caused by accumulation of acids (the conjugate anions of which contri­ bute to the gap). • The anion gap is normal when metabolic acidosis is caused by loss of bicarbonate. Bicarbonate loss is balanced by retention of chloride to maintain the electroneutrality of the plasma. Such acidoses are also described as ‘hyperchloraemic’. High anion gap metabolic acidoses are more common than those with a normal gap in all critically ill patients. The differential diagnosis of high anion gap metabolic acidosis is shown in Table 1. Simple biochemical measurements of urea/creatinine, glucose and blood pO2/oxygen saturation (which lead to lactic acidosis) should be performed and if these are excluded the cause of the acidosis is likely to be due to poisoning with aspirin, or alcohols/glycols. Lactic acidosis most commonly arises through impaired oxidative metabolism of pyruvate as a result of tissue hypoxia (type A lactic acidosis).3 Pyruvate is normally oxidized aerobically within mitochondria. In hypoxia pyruvate is reduced to lactate, which re-generates nicotinamide adenine dinucleotide (NAD) and allows energy production by anaerobic glycolysis to proceed. Lactate is released from the cell and in excess causes a lactic acidosis (Figure 2). A low blood pO2 or oxygen saturation is good presumptive evidence that metabolic acidosis is caused by accumulation of lactic acid, but the plasma lactate measurement confirms the diagnosis and is now often measured by modern blood gas analysers. Lactic acidosis (lactate conventionally >5 mmol/L) is associated with a poor prognosis.

Keywords acid–base disturbances; anion gap; hyperkalaemia; ­ ypoglycaemia; hypokalaemia; metabolic acidosis; osmolal gap; h ­respiratory acidosis; rhabdomyolysis

Metabolic abnormalities are common in critically ill patients. In poisoned patients metabolism may be disturbed by either: • a primary effect of the poison on a biochemical pathway • a secondary effect of the dysfunction of one or more organs which have been damaged by the poison. Biochemical disturbances may be of diagnostic or prognostic value, and their recognition and management is an essential part of the care of severely poisoned patients.

Acid–base disturbances Acid–base disturbances are common and may develop/or change rapidly. Major abnormalities are likely to impair cell and organ function. Ready access to a blood gas analyser and an ability to interpret these analytical data are essential.

Alan Jones MA DPhil FRCP FRCPath is Consultant Physician, Chemical Pathologist and Director of Laboratory Medicine at the Heart of England Foundation Trust, Birmingham, UK, and Consulting Clinical Toxicologist at the National Poisons Information Service (Birmingham Unit). He qualified from the University of Cambridge, and trained in Leicester and Birmingham. His research interest is metabolic medicine. Competing interests: none declared.

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Complications of poisoning

Formation of lactic acidosis

Measurement of the anion gap Ca2+/Mg2+

Unmeasured anions – the anion gap

K+

Glucose

NAD+

Pyruvate

NADH

Lactate

HCO3– Na+ Pyruvate

Cl–

CO2 + H2O Cations

Figure 2

Anions

Anion gap = Σ Measured cations – Σ Measured anions = ([Na+] + [K+] + [Ca2+] + [Mg2+]) – ([HCO3–] + [Cl–]) Mean = 12 mmol/L Range = 8–16 mmol/L

Type B lactic acidosis occurs despite normal tissue oxygenation. Poisons that directly inhibit the mitochondrial respiratory chain (e.g. cyanide, hydrogen sulphide) prevent normal oxidative metabolism of pyruvate. The liver normally takes up lactate from plasma, which after conversion to pyruvate, is either used to synthesize glucose by gluconeogenesis or oxidized within the mitochondria. Clinically significant hepatic dysfunction impairs these processes, and leads to a lactic acidosis and hypoglycaemia. Thus type B lactic acidosis may arise in severe paracetamol poisoning as a result of hepatic dysfunction. Acidaemia in paracetamol overdose has important prognostic significance; about 90% of such patients die.4 Poisonings – in the absence of uraemia, ketoacidosis and lactic acidosis, high anion gap metabolic acidosis should prompt ­consideration of certain poisonings (Table 1). Such acidoses may be caused by ingestion of acids, or of neutral compounds that are subsequently metabolized to strong acids. In poisoning with methanol or ethylene glycol, formation of formic or glycolic acid ­respectively follows sequential oxidation of the parent compound to the respective aldehyde and then acid by hepatic alcohol and aldehyde dehydrogenases. The clinical course is dominated by progressive development of severe metabolic acidosis. Normal anion gap metabolic acidosis usually reflects inappropriate renal loss of bicarbonate or, occasionally, loss of bicarbonate from the bowel, and is uncommon in poisoned patients. Certain nephrotoxic drugs (e.g. amphotericin) and carbonic anhydrase inhibitors (e.g. acetazolamide) cause renal tubular acidosis with loss of bicarbonate in the urine, but acidosis usually occurs only on prolonged use, and overdose of these drugs is uncommon. Abuse of volatile solvents (particularly toluene) can cause renal damage with loss of bicarbonate and potassium, and acute presentations with hypokalaemic paralysis and acid­ osis have been described.5

Figure 1

In poisoned patients, type A lactic acidoses may occur as a result of: • cardiorespiratory depression (e.g. in β-blocker or calcium channel-blocker poisoning) • repeated convulsions (e.g. in theophylline or tricyclic anti­depressant poisoning) • impaired oxygen-carrying capacity of the blood; for example, in patients who have inhaled carbon monoxide (carboxyhaemo­ globinaemia) or ingested oxidizing agents that oxidize haemoglobin (methaemoglobinaemia).

Causes of high anion gap metabolic acidosis • Uraemia • Ketoacidosis • Lactic acidosis Type A – hypoxic Type B – non-hypoxic • Poisoning Salicylate Methanol Ethylene glycol Table 1

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Complications of poisoning

Treatment of metabolic acidosis must be directed at the underlying cause to prevent further generation of acids. Administration of bicarbonate provides only a temporary buffer and large quantities contain excessive amounts of sodium, with the risk of extracellular fluid (ECF) volume overload and pulmonary oedema.

Plasma osmolality is largely dependent on sodium concentration. It can be measured in the laboratory and also calculated from routine electrolyte/glucose/urea measurements (Figure 3). Disparity between calculated and measured osmolalities is termed the ‘osmolal gap’; a gap of more than 10 mOsmol/kg indicates that an unmeasured, osmotically active solute (usually an ­alcohol) is present. An increased osmolal gap in a patient with high anion gap metabolic acidosis suggests poisoning with methanol or ethylene glycol.8,9 Plasma potassium disturbances are common in overdose.10 Potassium concentration is determined by redistribution between the intracellular fluid (ICF) and ECF spaces, and by net body balance, which is determined largely by renal function. Redistribution of plasma potassium is of greater short-term importance; it is influenced by the activity of the membrane Na+–K+ pump, by membrane integrity and by acid–base status. Hypokalaemia in overdose is caused by movement of potassium from ECF to ICF. It is common in theophylline and β2-agonist poisoning. Hyperkalaemia is caused by movement of potassium from ICF to ECF. It occurs specifically with: • agents that inhibit the membrane ion pumps (e.g. digoxin) • acidosis • impaired intracellular energy metabolism (e.g. in hypoxaemia). • rhabdomyolysis. Rhabdomyolysis may occur in unconscious patients, and is particularly common following overdose with drugs that appear to have a direct myopathic effect (e.g. opiates, theophylline, amfetamines, substituted amfetamine derivatives such as MDMA).11 Measurement of serum creatine kinase activity is essential following overdose with these drugs.

Metabolic alkalosis Metabolic alkalosis is indicated by the presence of systemic alkalosis (pH >7.45 or H+ <35 nmol/L) with high standard bicarbonate (>25 mmol/L) and a base excess (>+2.3 mmol/L). Normally, excess plasma bicarbonate is excreted renally. A metabolic alkalosis implies renal retention of bicarbonate, which occurs as a result of continued renal tubular excretion of hydrogen ion and a paradoxical aciduria (i.e. the blood is alkaline but the urine is acid). Most commonly, this occurs with ECF volume depletion which leads to secondary hyperaldosteronism. This metabolic alkalosis responds to ECF volume repletion, therefore it is known as a ‘saline-responsive’ or ‘contraction’ (of the ECF) alkalosis. Metabolic alkalosis is a common ­abnormality and is likely to occur in poisonings in which hypovolaemia has occurred. In aspirin poisoning significant ECF volume depletion occurs, and the aciduria may prevent therapeutic attempts to alkalinize the urine to increase renal excretion of salicylate. In such poisonings, restoration of euvolaemia is a prerequisite before the urine can be rendered alkaline by infusion of sodium bicarbonate. Acute respiratory acidosis Acute respiratory acidosis, with high pCO2 (>6 kPa, 45 mm Hg) and normal standard bicarbonate and base excess, occurs in overdoses with sedatives that lead to hypoventilation (opiates, tricyclic antidepressants and, now uncommonly, barbiturates) and in drug ‘cocktails’ including alcohol and benzodiazepines. Exposure to inhalational agents that cause pulmonary oedema (‘choking agents’ – chlorine, phosgene, nitrogen oxides, perfluoro-isobutylene and military smokes) can lead to respiratory acidosis. A concomitant hypoxaemia results in type A lactic ­acidosis.

The osmolal gap Osmolal gap Glucose Urea

Calculated osmolality

Acute respiratory alkalosis Aspirin and theophylline are central nervouse system respiratory centre stimulants. In overdose, they cause inappropriate hyperventilation, and hence hypocapnia and respiratory alkalosis.

Electrolyte and osmolality disorders Hypernatraemia and hyponatraemia are usually caused by deficiency and excess of total body water respectively. They are uncommon in overdose. Hypernatraemia can be caused by ingestion of saline and is well recognized as a non-accidental injury in children. Urine sodium concentration is elevated in salt poisoning, but this finding does not exclude hypernatraemia caused by dehydration; measurement of the fractional excretion of sodium and water is needed to distinguish the two causes.6 Hyponatraemia is a recognized complication of the use of ‘Ecstasy’ (MDMA) and is probably caused by inappropriate secretion of antidiuretic hormone, which impairs renal water excretion. This is often exacerbated with the excess intake of hypotonic fluids by such patients.7

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2 x [Na+ + K+]

Measured osmolality Osmolal gap = measured osmolality – calculated osmolality (2 x [Na+ + K+] + [Urea] + [Glucose])

Figure 3

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Complications of poisoning

Rhabdomyolysis may also result from ‘compartment syndrome’, which is sometimes seen in overdose in comatose patients with muscle damage caused by pressure on a muscle compartment. Urgent surgical referral is indicated in suspected cases. Hyperkalemia due to impaired renal function (resulting from poor glomerular perfusion or intrinsic renal damage) may also occur. Hypocalcaemia resulting from hypoalbuminaemia is common in critically ill patients, but in such cases the ‘corrected’ calcium concentration, adjusted for serum albumin ­concentration, is normal. Genuine hypocalcaemia is a specific feature of ethylene glycol and hydrogen fluoride poisoning, in which calcium is deposited as insoluble oxalate and hydroxyapatite crystals respectively. Hypophosphataemia is often observed in paracetamol overdose, and appears to reflect nephrotoxicity with phosphaturia.12

7 Hall AP, Henry JA. Acute toxic effects of ‘Ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth 2006; 96: 678–85. 8 Jacobsen D, Bredesen JE, Erde I, Ostberg J. Anion and osmolal gaps in the diagnosis of methanol and ethylene glycol poisoning. Acta Med Scand 1982; 21: 17–20. 9 Krahn J, Khajuna A. Osmolal gaps: diagnostic accuracy and long term variability. Clin Chem 2006; 52: 737–39. 10 Bradberry SM, Vale JA. Disturbances of potassium homeostasis in poisoning. J Toxicol Clin Toxicol 1995; 33: 295–310. 11 Coco TJ, Klasner AF. Drug induced rhabdomyolysis. Curr Opin Pediatr 2004; 16: 206–10. 12 Jones AF, Harvey JM, Vale JA. Hypophosphataemia and phosphaturia in paracetamol poisoning. Lancet 1989; 2: 608–9. 13 Seltzer HS. Drug-induced hypoglycaemia. A review of 1418 cases. Endocrinol Metab Clin North Am 1989; 18: 163–83. 14 Klonoff DC, Baarrett BJ, Nolte MS, Cohen RM, Wyderski R. Hypoglycaemia following inadvertent and factitious sulfonylurea overdosages. Diabetes Care 1995; 18: 563–67. 15 Service FT. Diagnostic approach to adults with hypoglycemic disorders. Endocrinol Metab Clin North Am 1999; 28: 519–32.

Glucose homeostasis Hyperglycaemia is not a common feature of overdose, but hypoglycaemia may be. Plasma glucose should not decrease below 2.8 mmol/L on fasting, and drugs are the most likely cause of hypoglycaemia. Sulphonylureas, insulin and ethanol are implicated in most cases, but hypoglycaemia may occur in paracetamol poisoning, in which hepatic damage impairs gluconeogenesis.13,14 Blood glucose is usually measured by a point of care testing device, and although it is imperative to treat hypoglycaemia promptly, samples should be sent to the laboratory for glucose, insulin and C-peptide assay; otherwise, a valuable diagnostic opportunity is lost.15 ◆

Further reading Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 2000; 162: 2246–51. Gluck SL. Acid-base. Lancet 1998; 352: 474–79. Halperin ML, Kame KS. Potassium. Lancet 1998; 352: 135–40. Nairns RG, Emmett M. Simple and mixed acid–base disturbances: a practical approach. Medicine (Baltimore) 1980; 59: 161–87.

Practice points

References 1 Emmett M, Nairns RG. Clinical use of the anion gap. Medicine (Baltimore) 1977; 56: 38–54. 2 Enger E. Acidosis, gaps and poisoning. Acta Med Scand 1982; 212: 1–3. 3 Kreisburg RA. Lactate homeostasis and lactic acidosis. Ann Intern Med 1980; 92: 227–37. 4 Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002; 359: 558–63. 5 Jone CM, Wu AH. An unusual case of toluene-induced metabolic acidosis. Clin Chem 1988; 34: 2596–99. 6 Coulthard MG, Haycock GB. Distinguishing between salt poisoning and hypernatraemic dehydration in children. BMJ 2003; 326: 157–60.

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• Acid–base, blood gas and serum potassium disturbances are common in severe overdose • Metabolic acidosis unexplained by renal function, plasma glucose, pO2 or oxygen saturation should prompt consideration of poisoning • Hypoglycaemia in adults is usually caused by a drug • Metabolic factors predict outcome in paracetamol poisoning – systemic metabolic acidosis (pH <7.3) or prothrombin time >100 seconds plus serum creatinine >300 μmol/litre plus hepatic encephalopathy grade 3/4 is associated with mortality of 80–90%

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