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A 25-year-old woman had been working at a bar where she was seen to
collapse. Police at the scene started cardiopulmonary
resuscitation shortly afterwards. An ambulance arrived several
minutes later and she was defibrillated according to ambulance
protocol, with a total of 12 defibrillation attempts. She arrived at
the emergency department in ventricular fibrillation and was
resuscitated according to advanced cardiac life support guidelines
for a further 20 minutes. At no stage did she regain a spontaneous
cardiac output.
Further history (which became available later) indicated that the
patient had been diagnosed with mitral valve prolapse. She had been
referred to a cardiologist because of palpitations. He had raised the
issue of caffeine intake, and she had agreed to limit this to a cup of tea
daily. Her previously recorded resting electrocardiogram was
normal, with no evidence of QT prolongation.
On the day of her death she had been given a 55 mL squirt bottle of "Race
2005 Energy Blast with Guarana and Ginseng", which she had nearly
emptied. Other staff working at the bar had also been given bottles of
Race 2005. She had not consumed other caffeine-containing
substances.
At autopsy, the patient was found to have sclerosis and myxoid change
of the mitral valve leaflets. A toxicological screen for all common
prescribed and non-prescribed drugs (including opiates, cannabis,
amphetamines, and cocaine metabolites) was performed. Assay
methods included gas chromatography and mass specrometry (GC-MS)
and immunoassay. Caffeine was detected by GC-MS; the toxicology
screen was negative for other substances. High pressure liquid
chromatography revealed a caffeine concentration of 19 mg/L
(non-preserved) in aortic blood. The caffeine concentration in the
bottle of Race 2005 Energy Blast was assayed at the Chemistry Centre of
Western Australia and yielded a level of 10 g/L, which is more than 60
times the concentration of caffeine in cola beverages (see
Box).4 A similar bottle was later
shown to have a caffeine concentration of 19 g/L.
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The wide availability and toxicology of "natural" tonics and
remedies and the regulation of such substances has been the subject of
vigorous debate in both the lay press and the medical
literature.6-10 Guarana is produced from the seeds of the guarana plant (Paullina
cupana), a creeping Amazonian shrub. The seeds are black "like an
eye" and contain 3.6%-5.8% caffeine.11 The substance is named
after the Guarani Amazonian tribe, who originally used the seeds to
brew a drink.11 In Brazil, guarana is
commonly used as an astringent, a flavouring, and as a stimulant, and
it is increasingly being used in similar products internationally.
Such products are widely available at pharmacies and natural food
outlets, and are marketed as natural sources of energy.
Caffeine is a natural alkaloid methylxanthine. Ninety-nine per cent
is absorbed after oral ingestion, the blood concentration peaks
1-1.5 hours after ingestion, and its half-life in adults is 3-6 hours.
Caffeine is metabolised by the P450 hepatic enzyme
system.12 The pharmacodynamic
profile of caffeine is similar to that of theophylline, another
methylxanthine, in that it inhibits the adenosine receptor and acts
as a phosphodiesterase inhibitor.12 At high serum levels,
enzyme saturation occurs, and elimination follows zero-order
kinetics, with constant elimination regardless of serum
level.12 Caffeine increases
intracellular calcium concentrations, causes noradrenaline
release and sensitises dopamine receptors. The pharmacological
effects of caffeine include central nervous system (CNS) and cardiac
stimulation, as well as coronary vasodilatation. It relaxes smooth
muscle, stimulates skeletal muscle, has a weak diuretic action, and
its metabolic effects include hypoglycaemia.
While toxicity generally occurs at serum levels over 25 mg/L, the
correlation between concentration and clinical effects is
poor.4 The measured concentration
of 19 mg/L in our patient may reflect postmortem changes in drug level,
or an enhanced sensitivity to caffeine toxicity in this patient. The
measured concentration is the equivalent of what would result from
drinking approximately 15-20 cups of coffee.4 The toxic effects of
caffeine include vomiting and abdominal pain followed by CNS
symptoms, including agitation, altered conscious state, rigidity
and seizures.4 Cardiovascular effects
include supraventricular and ventricular tachyarrhythmias, and
significant metabolic disturbances may occur, including
hypokalaemia and hyperglycaemia.
Suggested management for caffeine toxicity, in addition to general
supportive measures, includes multidose charcoal therapy, and
extracorporeal elimination by charcoal
haemoperfusion.13 One proposed mechanism
for the seizures and cardiac arrhythmias is the blockade of adenosine
receptors.12 Thus, there is a
theoretical rationale for the use of adenosine in this setting,
particularly if seizures are refractory to benzodiazepine
agents.14 Likewise, as there is
adrenergic stimulation, parenteral  -blocker
therapy (propranolol or esmolol) should be considered for treating
ventricular arrhythmias.15
Most deaths associated with caffeine intoxication have occurred
after overdose with diet pills and stimulants, and most have occurred
in young patients without known underlying heart disease or variant
of normal, such as mitral valve prolapse. At least two case reports
document sudden death in patients who "walked" into an emergency
department.14
After the death of our patient, the Western Australian Coroner
recommended that Race 2005 Energy Blast be removed from the local
market, and the product was recalled nationally by letter to
distributors in August 1999. However, many other products
containing guarana (eg, "energy" tablets containing 35 mg of
caffeine each, as well as a variety of energy drinks) remain available
Australia-wide. With the growing use of guarana-based products
containing high levels of caffeine, there is an obvious potential for
lethal overdose.
Our patient had a relatively common cardiac abnormality, present in
2.4% of the population.16 While mitral valve
prolapse has been associated with sudden death, the risk of this is
low.17 Malignant arrhythmias
may occur in the absence of cardiac stimulants, but the association of
arrhythmia with drugs that increase cardiac irritability is well
known. The role of caffeine in this woman's death is supported by her
history of palpitations associated with caffeine ingestion, a
history that had prompted her cardiologist to advise her to limit her
caffeine intake. In this patient's case the Coroner found that the
high level of caffeine was associated with the development of an
intractable arrhythmia.
This case highlights the need for more careful regulation of
"natural" products, including warnings for patients with
underlying health problems, and clear labelling to document the
presence of any constituents with potentially toxic effects. It also
shows the need for medical practitioners to be familiar with the more
widely used "natural"-remedy substances, and their toxicological
profile.
Acknowledgements: We thank Dr Julian Stella and Dr
Peter Sprivulis for their assistance in the preparation of this
manuscript.
Disclosure: We did not receive any financial or other
support for this work, and have no financial or professional
relationships that may pose a conflict of interest.
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Department of Emergency Medicine, Fremantle Hospital, Fremantle,
WA.
Marianne E Cannon, MB BS, FACEM, Emergency Medicine Staff
Specialist.
PathCentre, QEII Medical Centre, Nedlands, WA.
Clive T Cooke, BMedSci, FRCPA, Forensic Pathologist.
University of Western Australia, Department of Medicine, Fremantle
Hospital, Fremantle, WA.
James S McCarthy, MB BS, FRACP, Senior Lecturer.
Reprints will not be available from the authors.
Correspondence: Dr M
E Cannon, Department of Emergency Medicine, Fremantle Hospital,
Fremantle, WA 6959.
mariannecannonAThotmail.com
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