POISONOUS SUBSTANCES

Poisoning by alcohols and Key points

glycols C Alcohols are subject to oxidative metabolism in the liver by
alcohol dehydrogenase, which gives rise to metabolites that
William Stephen Waring can cause metabolic acidosis and renal failure

C After ingestion of toxic alcohols, the development of metabolic

Abstract acidosis and severe toxicity are typically delayed for several
Ethanol intoxication is commonly encountered and can cause hours
hypotension, hypoglycaemia, lactic acidosis, seizures and coma.
Isopropyl alcohol and its metabolite acetone cause profound C Fomepizole is a specific alcohol dehydrogenase antagonist
depression of the central nervous system with rapid onset. Toxic that prevents formation of toxic metabolites
alcohols include methanol, ethylene glycol and diethylene glycol;
these can cause severe metabolic acidosis, acute renal failure and, C Where there is a clinical suspicion of toxic alcohol ingestion,
for methanol, severe visual disturbance. Toxicity is attributable to fomepizole should be administered early, even before confir-
metabolites and there is a characteristic delay between ingestion matory laboratory concentrations are available
and the occurrence of severe toxicity. Assessment of the extent
of exposure requires laboratory confirmation of toxic alcohol concen- C Haemodialysis may be needed to remove circulating metabo-
trations, which conventionally involves specialized laboratory assays lites of toxic alcohols in patients who present late where there
that are not always readily available. Management strategies include is severe metabolic acidosis
assessment of toxic alcohol exposure, early administration of
fomepizole to prevent formation of metabolites and, in patients with
established poisoning, haemodialysis to remove metabolites.
Ethanol
Keywords Anion gap; blindness; diethylene glycol; ethanol; ethylene
glycol; fomepizole; haemodialysis; isopropyl alcohol; metabolic acidosis; Ethanol (CAS 64-17-5, ethyl alcohol) is widely consumed in
methanol; MRCP; osmolality; renal failure alcoholic beverages in Westernized society. Beer and cider typi-
cally contain 4e8% alcohol by volume, and wine around 10%,
although it can vary from 7% to 18%. Spirits are distilled to
increase the ethanol content, and typically contain concentra-
Alcohols tions around 40e60%.
Alcohols are a group of organic chemicals characterized by a
hydroxyl group bound to a carbon atom; the carbon that binds Pharmacokinetics of ethanol: ethanol is rapidly absorbed after
the hydroxyl group is known as the carbinol carbon. Where the oral consumption, with 80e90% absorbed within 1 hour, and
carbinol carbon binds a single carbon, this is known as a primary absorption is normally complete within 2 hours. Ethanol rapidly
alcohol, if two carbons are attached this is a secondary alcohol, distributes in the water component of tissues, is not fat soluble
and with three carbons attached this is a tertiary alcohol. and does not bind to proteins. Ethanol is subject to metabolism
The simplest primary alcohols are methanol (CH3OH), by certain alcohol dehydrogenase (ADH) isoenzymes and by
ethanol (C2H5OH) and propanol; the most basic secondary P450 oxidation within the liver at 100e125 mg/kg body weight
alcohol is isopropyl alcohol, and the simplest tertiary alcohol is per hour. There is significant interindividual variation and, for
tert-butanol (CH3)3COH (Figure 1). The hydroxyl group permits example, regular drinkers have upregulated liver enzyme activity
hydrogen bonding, meaning that simple alcohols are highly including cytochrome P450 2E1, so ethanol clearance is more
miscible in water; the lengthening alkyl chain of more complex rapid than in alcohol-naive individuals.
alcohols is associated with decreasing solubility. The rate and extent of ethanol metabolism generally increase
Alcohols do not adsorb to activated charcoal but are effectively according to ethanol concentration. At a sufficiently high ethanol
cleared from the circulation by haemodialysis. Therefore, concentration, enzyme systems become saturated and zero-order
administration of oral activated charcoal is ineffective in alcohol elimination kinetics occurs; this means that small increases in
poisoning. The term ‘alcohol’ is informally accepted as referring alcohol intake beyond this point can cause a large increase in the
to ethanol, whereas ‘toxic alcohols’ is generally used to describe circulating ethanol concentration. The rate of ethanol elimination
methanol, ethylene glycol and isopropyl alcohol. Toxic alcohols from the circulation from high values is said to range between
account for only around 0.5% of poisoning cases but represent 10 mg/dl/hour and 35 mg/dl per hour.
3e5% of enquiries to the UK National Poisons Information
Service. Pharmacodynamics of ethanol: ethanol is capable of disrupting
the phospholipid component of neuronal cell membranes. In
addition, it exerts neurological effects by altering the function of
specific proteins including membrane-bound ligand-gated ion
William Stephen Waring PhD FBPhS FRCP is a Consultant Physician at
York Teaching Hospitals NHS Foundation Trust, UK and Honorary channels and voltage-dependent ion channels, and the activity of
Senior Lecturer at Hull York Medical School, UK. Competing second-messenger proteins. This includes increased activity of g-
interests: none declared. aminobutyric acid (GABA) type A and glycine receptors, and

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 POISONOUS SUBSTANCES

Figure 1

inhibition of activity of N-methyl-D-aspartate and 5- Management of ethanol toxicity e care should be taken to
hydroxytryptamine type 3 receptors. Enhanced GABA neuro- protect the airway, especially in patients with reduced conscious
transmission appears to depend on ethanol concentration and is level or vomiting. If the patient is drowsy or unconscious,
closely linked to the effects of acute exposure and to alcohol- intravenous dextrose should be administered initially using 10%
seeking behaviour. e20% dextrose and intravenous glucose titrated administered
according to response. Glucagon can be considered but it is often
Ethanol toxicity: toxicity is predominantly related to its ineffective in individuals who have chronic alcoholism because
depressant effect on the central nervous system (CNS), with a of depleted liver glycogen stores. Heart rate, blood pressure,
correlation between blood ethanol concentrations and toxicity conscious level, respiratory rate and temperature should be
(Table 1). The legal limit for driving in Scotland and many Eu- monitored. Intravenous thiamine should be considered to pre-
ropean countries is 50 mg/dl in blood, or 22 micrograms/dl in vent development of Wernicke encephalopathy in individuals
breath; in England, Wales and Northern Ireland the corre- considered to be at risk of deficiency.
sponding legal limits are 80 mg/dl and 35 micrograms/dl. Where reduced consciousness persists despite normoglycae-
In severe ethanol toxicity, there can be respiratory acidosis mia, consider cerebral oedema, co-ingestion of sedative medica-
caused by hypoventilation, and hypothermia and hypotension tions, seizures and hepatic encephalopathy. Blood ethanol
caused by peripheral vasodilation.1 Ethanol metabolism causes concentration can help to determine the severity of poisoning,
the accumulation of reduced nicotinamide adenine dinucleotide particularly the cause of persisting coma. Haemodialysis can be
(NADH), and the subsequent increase in NADH:NAD ratio im- considered in patients with severe ethanol intoxication, particu-
pairs gluconeogenesis and increases the ratio of lactate to pyru- larly with blood ethanol concentrations >450 mg/dl, liver damage
vate; individuals can therefore exhibit hypoglycaemia and lactic or metabolic acidosis that persists despite conservative measures.
acidosis. Alcoholic ketoacidosis is a recognized complication of
binge alcohol consumption, particularly in malnourished Methanol
individuals.
Methanol (CAS 67-56-1, methyl alcohol, wood alcohol) is present
The fatal dose in adults is around 6e10 ml/kg body weight of
in commercial and domestic antifreeze solutions and certain
ethanol, with significant individual variation, for example ac-
windscreen washer fluids. Methanol is also encountered as a
cording to patterns of chronic consumption. Deaths have
congener in some foodstuffs and alcoholic beverages, particu-
occurred in patients with blood ethanol concentrations of
larly spirits; significant amounts can be found where there are
250 mg/dl, whereas survival has been reported despite concen-
poor quality preparation techniques, for example in illicitly
trations of 1500 mg/dl.
distilled beverages.

Clinical effects at various ethanol concentrations vary Methanol toxicity: methanol is a rare cause of human poisoning.
between individuals In health, small quantities of methanol (from gut bacterial
metabolism), formaldehyde (from methanol metabolism) and
Blood ethanol Clinical effects
formate (from mitochondrial conversion of serine to glycine) are
(mg/dl)
present. It is readily absorbed from the gastrointestinal tract
<50 Disinhibition, excitation and euphoria after oral administration, and subject to hepatic metabolism
50e100 Impaired reaction times, poor judgement, (Figure 2).
diminished motor skills, dysarthria, Methanol absorption from the gastrointestinal tract can take 1e2
incoordination hours, giving rise to a high osmolal gap. Thereafter, methanol
101e200 Blurred vision, disorientation, ataxia, stupor, metabolism is associated with a decline in methanol concentrations
vomiting and osmolal gap, and progressively worsening metabolic acidosis
>200 Diplopia, severe incoordination, coma, owing to the formation of formaldehyde and formate. There is a
hypotension, hypoglycaemia, cardiac arrhythmia, characteristic latent period during the first 24 hours after ingestion
respiratory depression, seizures during which the metabolic acidosis is initially compensated and
then becomes progressively more severe; a severely poisoned
Table 1 patient can initially have a normal pH. Representation of the

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 POISONOUS SUBSTANCES

Figure 2

osmolal gap (broken line) and anion gap (solid line) after ingestion conscious level or vomiting. Gastric aspiration can be considered
of toxic alcohol is shown in Figure 3. if there is a strong clinical suspicion that a life-threatening
Toxicity is largely attributable to the effects of formate rather quantity of methanol has been ingested within the previous 1
than to the alcohol itself. Formate inhibits cytochrome C oxidase hour. Blood glucose, electrolytes, renal function and acidebase
in the mitochondrial electron transport chain. Formate concen- status should be assessed. The methanol concentration should
trations correlate with the risk of visual impairment after meth- be checked and, if the analysis could be delayed, an urgent
anol ingestion. Soon after methanol consumption there can be osmolality and ethanol concentration determined in the interim
transient inebriation, similar to the effects of ethanol intoxica- to allow calculation of the osmolal gap. Treatment often has to be
tion, with nausea, vomiting and mild depression of CNS function. administered before confirmatory laboratory data are available.
Thereafter, features of severe toxicity include reduced conscious Fomepizole is a selective ADH inhibitor that prevents the
level, coma, impaired vision including complete blindness, metabolism of methanol to formate, so methanol is subject to
cardiorespiratory arrest, hyperglycaemia and raised amylase. renal elimination without further metabolism. Fomepizole
Management of methanol toxicity e care should be taken to should normally be administered when there is a reasonable
protect the airway, especially in patients with a reduced clinical suspicion of methanol ingestion, especially in individuals

Time dependent changes in osmolal gap (blue broken line) and anion
gap (red solid line) after toxic alcohol ingestion

40 30
35
25
Osmolal gap (mOsm)

30
Anion gap (mEq/l)

20
25
20 15

15
10
10
5
5
0 0
0 2 4 6 8 10 12 14 16
Time after ingestion (hours)

Figure 3

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 POISONOUS SUBSTANCES

who present early. This prevents the formation of toxic metab- be assessed; urinalysis should be performed, and microscopy for
olites, while the alcohol is eliminated unchanged by the kidneys. calcium oxalate crystals can be considered.
An alternative approach is to administer ethanol, which The ethylene glycol concentration should be urgently
competitively inhibits methanol metabolism by ADH. It is checked. The assay is not always readily available, and antidote
cheaper to use ethanol but the administration rate requires treatment with fomepizole should be considered before confir-
careful titration against blood ethanol concentrations, it can be matory laboratory tests if there is a reasonable clinical suspicion
less effective in preventing formate production, and can be of ingestion. Novel assays, for example assays based on glycerol
associated with hazardous adverse effects. dehydrogenase, appear to offer a rapid means of confirming the
In individuals presenting late after methanol poisoning, presence of ethylene glycol but are not yet routinely available.2
fomepizole and ethanol administration can be less effective Where a delay is anticipated, osmolality and ethanol concen-
because patients already have high circulating formate concen- trations should be urgently determined to allow calculation of the
trations. Haemodialysis can reduce the elimination half-life of osmolal gap, which can provide evidence of the presence of a toxic
methanol from around 6e8 hours to around 2e3 hours and alcohol. As with methanol poisoning, treatment often has to be
should be considered a means of enhancing methanol and commenced before confirmatory laboratory data become available.
formate clearance, particularly in patients with severe metabolic The main strategy for minimizing toxicity is to prevent the
acidosis. Folinic acid is a co-factor in formate metabolism that formation of toxic metabolic intermediaries by the administration
may enhance its clearance. of fomepizole. If there is a delay in obtaining fomepizole,
administration of ethanol as a competitive substrate for the
enzyme can be considered but fomepizole appears to be a more
Ethylene glycol
effective strategy, particularly in patients with high ethylene
Ethylene glycol (CAS 107-21-1, ethane-1,2-diol) is a colourless glycol concentrations.3
liquid with a sickly sweet taste. Depression of freezing point is Haemodialysis is effective in enhancing the removal of ethylene
maximal at concentrations of around 70%, and commercially glycol and its toxic metabolites, and may allow the correction of
available formulations normally contain 5%e70%. Vehicle metabolic disturbances, although evidence of outcome benefits is
antifreeze solutions are often brightly coloured from added dye, limited. For example, haemodialysis can reduce the elimination
for example a characteristic bright green hue resulting from so- half-life of ethylene glycol from around 10e12 hours to around 3e4
dium fluorescein. Other constituents include silicates and inor- hours. Haemodialysis should be considered for patients with se-
ganic salts including sodium borate and sodium phosphate. vere poisoning, for example if ethylene glycol concentrations are
>50 mmol/litre, or the osmolal gap is >50 mOsm, there is severe
Ethylene glycol toxicity: ethylene glycol can be ingested acci- metabolic acidosis or there are severe clinical features including
dentally or intentionally, sometimes as a substitute for ethanol by seizures, coma or acute kidney injury.4
alcoholic individuals. The lethal dose is around 1.5 ml/kg body
weight. Ethylene glycol is rapidly absorbed from the gastroin-
Diethylene glycol
testinal tract within 1e4 hours after ingestion, and there can be
an early inebriation phase, giving similar clinical features to mild Diethylene glycol (CAS 111-46-6, ethylene diglycol) is used as a
or moderate ethanol intoxication. coolant and a constituent of hydraulic fluids and brake fluids. It
Ethylene glycol is subject to hepatic metabolism (Figure 2). is a colourless and odourless hygroscopic fluid, with a slight
After a latent period, there can be progressive metabolic acidosis sweet taste.
arising from the accumulation of acidic metabolites, renal failure
and rhabdomyolysis. Late clinical features at 12e36 hours after Diethylene glycol toxicity: poisoning with diethylene glycol is
ingestion can include tachypnoea, pulmonary oedema, seizures, comparatively rare, and exposure can occur after intentional or
coma, oliguric renal failure and progressive multiorgan failure. unintentional ingestion, or from transdermal absorption after
Glycolate is the main toxic metabolite that gives rise to contact with broken skin. Peak circulating concentrations occur
metabolic acidosis and is capable of inhibiting cellular respira- within 30e120 minutes after ingestion. There have been out-
tion, producing lactic acidosis. Oxalate chelates with calcium, breaks of mass poisoning with diethylene glycol from contami-
thereby causing hypocalcaemia and rhabdomyolysis. Formation nation of medicines.
of calcium oxalate crystals is a recognized cause of cerebral Diethylene glycol is metabolized by ADH to form toxic
oedema and renal failure; crystals can be demonstrated in the intermediaries: 2-hydroxyethoxyacetaldehyde, 2-hydroxyethoxy-
urine within 4e8 hours after ingestion. CNS depression is acetate and diglycolic acid. These give rise to metabolic acidosis,
observed within 6e12 hours after ingestion, when metabolites acute renal failure and neuropathy. Patients can present with
are likely to be at their highest concentrations. symptoms of nausea and vomiting, abdominal pain and reduced
Management of ethylene glycol toxicity e supportive mea- conscious level within a few hours of exposure, although delayed
sures should be adopted with appropriate monitoring for seizures onset of symptoms up to 24 hours after ingestion can occur when
and renal failure. Care should be taken to protect the airway, there has been ethanol co-ingestion.
particularly in patients with reduced conscious level or vomiting. Within 24e48 hours of ingestion, there can be progressively
Gastric aspiration should be considered if there is a strong clin- worsening metabolic acidosis and oliguric renal failure; features
ical suspicion that a life-threatening quantity of ethylene glycol include hypotension, acute pancreatitis, hyperkalaemia and
has been ingested within the previous 1 hour. Blood glucose, hepatitis. Within 1e5 days after exposure, a variety of neurop-
electrolytes, renal function, calcium and acidebase status should athies have been reported, including facial palsies, optic neuritis

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 POISONOUS SUBSTANCES

and sensorimotor limb neuropathies. Respiratory weakness can Both isopropanol and acetone cause CNS depression. Other
cause respiratory failure, and invasive ventilator support may be features of isopropanol intoxication include headache, dizziness,
needed. ataxia, miosis, reduced conscious level, coma and seizures. Iso-
In individuals surviving the acute toxic effects, there can be propanol is a gastrointestinal irritant and can cause abdominal
delayed recovery of neurological function or permanent injury, and pain, vomiting, diarrhoea and haematemesis. Other features
patients can also require prolonged renal replacement therapy.5 include hypotension and organ hypoperfusion with secondary
Management of diethylene glycol toxicity e management renal impairment and lactic acidosis.
consists of supportive care. Patients should be monitored for Management of isopropanol toxicity e this consists of sup-
renal failure, respiratory failure and metabolic disturbance. portive care including the protection of the airway in patients
Administration of fomepizole should be considered to prevent with reduced conscious level, monitoring for vomiting or
the formation of toxic intermediaries by ADH, or ethanol can be gastrointestinal bleeding, administration of intravenous fluids to
administered to competitively inhibit formation. Haemodialysis allow correction of hypotension and hypoglycaemia, and moni-
should be considered in patients with severe metabolic acidosis, toring of electrolytes and acidebase status. Haemodialysis is
declining renal function or severe electrolyte disturbances. rarely required but can be considered if patients have severe
features of intoxication including refractory hypotension and
Isopropanol seizures. A
Isopropanol (CAS 67-63-0, isopropyl alcohol, propan-2-ol, rub-
bing alcohol) is a clear, colourless liquid that emits an acetone- KEY REFERENCES
type odour. It is widely found in hand sanitizer products in 1 Wilson E, Waring WS. Severe hypotension and hypothermia
concentrations of around 70%. caused by acute ethanol toxicity. Emerg Med J 2007; 24: e7.
2 Filip AB, Farnsworth CW, Mullins ME, et al. Accuracy of a glycerol
Isopropanol toxicity: young children can be subject to accidental dehydrogenase assay for ethylene glycol detection. J Med Toxicol
exposures, and adults can have intentional exposure related to 2023; 19: 362e7.
self-harm intent or seeking an ethanol substitute, sometimes in a 3 Beaulieu J, Roberts DM, Gosselin S, et al. Treating ethylene glycol
healthcare setting. Isopropanol is rapidly absorbed from the poisoning with alcohol dehydrogenase inhibition, but without
gastrointestinal tract, producing effects within 30 minutes. Iso- extracorporeal treatments: a systematic review. Clin Toxicol 2022;
propanol is subject to metabolism by ADH to acetone, which is 60: 784e97.
primarily eliminated in urine, and a small amount excreted via 4 Ghannoum M, Gosselin S, Hoffman RS, et al. EXTRIP Workgroup.
inhalation, giving rise to a characteristic ‘fruity’ breath odour. Extracorporeal treatment for ethylene glycol poisoning: systematic
The half-life of isopropanol is around 3e8 hours, but this can review and recommendations from the EXTRIP workgroup. Crit
be prolonged to around 16e18 hours in individuals co-ingesting Care 2023; 27: 56.
ethanol. High acetone concentrations are normally encountered 5 Conklin L, Sejvar JJ, Kieszak S, et al. Long-term renal and neuro-
in the setting of diabetic ketoacidosis; detection of acetone in the logic outcomes among survivors of diethylene glycol poisoning.
absence of acidosis can raise suspicion of isopropanol or acetone JAMA Intern Med 2014; 174: 912e7.
ingestion.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 What is the most important next step in management?

A 46-year-old man presented as an emergency after suspected A Haemodialysis
ingestion of antifreeze. On examination: drowsy, slurred speech, B Intravenous fomepizole
heart rate 112 per minute, blood pressure 130/75 mmHg, respi- C Intravenous naloxone
ratory rate 24 per minute, oxygen saturations 96% on air. D Intravenous sodium bicarbonate
E Oral activated charcoal
Investigations
 pH 7.21 Question 2
 Serum bicarbonate 6 mmol/litre (22e32) A 51-year-old motor mechanic presented as an emergency
 Plasma glucose 6.8 mmol/litre (3.0e6.0) 30 minutes after accidentally ingesting brake fluid that had been
 Ethanol undetectable contained in a drinks bottle. On examination: fully conscious and
 Serum osmolality 328 mosmol (275e295) alert, heart rate 86 per minute, blood pressure 146/88 mmHg,

MEDICINE 52:6 362 Ó 2024 Published by Elsevier Ltd.

 POISONOUS SUBSTANCES

and respiratory rate 14 per minute. Investigations showed Investigations

normal renal function and electrolytes.  Serum potassium 6.5 mmol/litre (3.5e4.9)
 Serum creatinine 278 micromol/litre (60e110)
Which of the following features would most strongly suggest a  Plasma glucose 4.8 mmol/litre (3.0e6.0)
significant ingestion of toxic alcohol?  Serum bicarbonate 2 mmol/litre (20e28)
A Blood ethanol 12 milligrams/dl  pH 7.23
B Corrected serum calcium 2.86 mmol/litre  Osmolar gap 4 mosmol (<10)
C Serum osmolar gap 44 mosmol
D Serum glucose 13 mmol/litre
What is the most important management step to consider?
E Serum ketones 2.2 mmol/litre
A Haemodialysis
B Intravenous ethanol infusion
Question 3 C Intravenous fomepizole
A 28-year-old woman presented with abdominal pain, D Intravenous hydration
retching and vomiting. She had a past history of alcohol abuse, and E Oral activated charcoal
a friend said that in the previous 2e3 days she had been drinking
methylated spirits. On examination, she was drowsy.

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