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Subject: Toxico: bloqueur calcique
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Martin.
CASE REPORT
Delayed asystolic cardiac arrest after diltiazem overdose; resuscitation
with high dose intravenous calcium
G K Isbister
Discipline of Clinical Pharmacology, University of Newcastle
and Department of Clinical Toxicology and Pharmacology, Newcastle Mater
Misericordiae Hospital, Australia
Correspondence to:
Dr G K Isbister, Discipline of Clinical Pharmacology,
Level 5, Clinical Sciences Building, Newcastle Mater Hospital, Edith Street,
Waratah, NSW 2298, Australia;
[EMAIL PROTECTED]
Accepted for publication
31 January 2002
ABSTRACT
A 51 year old man took a mixed overdose including 1.83.6
g of diltiazem, paracetamol, aspirin, isosorbide nitrate, and
alcohol. He initially presented to hospital after six hours
with mild hypotension and was treated with activated charcoal
and intravenous fluids. Eighteen hours after the overdose he
had two generalised tonic-clonic seizures. The patient remained
unresponsive with junctional bradycardia, unrecordable blood
pressure, and then became asystolic. He was resuscitated with
high dose (13.5 g) intravenous calcium and adrenaline (epinephrine).
He required inotropic support and temporary pacing over the
next 48 hours. This case suggests there is a role for aggressive
high dose intravenous calcium therapy in severe diltiazem overdose,
particularly with the onset of asystole. It should be considered
early in cases of cardiac arrest after diltiazem overdose. The
case also highlights the problems with delayed toxicity when
whole bowel irrigation is not administered.
Keywords: drug overdose; resuscitation; cardiac arrest
Abbreviations: CCB, calcium channel blocker; BP, blood pressure;
HR, heart rate
Calcium channel blocker (CCB) overdose is relatively uncommon,
but has a higher mortality and morbidity compared with other
drug overdoses.1
Diltiazem overdose has been reported previously, mainly as case
reports28
and in a few case series.1,9
In particular, overdose of its slow release formulations may
lead to severe toxicity if appropriate decontamination is not
started.3
There remains considerable controversy about the treatment of
severe CCB overdose, particularly with the use of intravenous calcium.1013
Here is reported an overdose of slow release diltiazem causing
delayed asystolic arrest, and successful resuscitation with
rapidly administered, high dose calcium gluconate.
CASE REPORT
A 51 year old white man took a mixed overdose comprising diltiazem
1.83.6 g (slow release preparation), paracetamol, aspirin,
isosorbide nitrate, and alcohol. He presented to hospital six
hours after the overdose complaining of nausea, vomiting, weakness,
and lethargy. He had a past history of ectatic coronary arteries
and cardiomyopathy, asthma, bipolar mood disorder, and alcohol
misuse.
Examination on presentation revealed: heart rate (HR) 80 bpm and
blood pressure (BP) 90/40 mm Hg. He was orientated and cooperative.
Cardiovascular, respiratory, and neurological examinations were
normal. An electrocardiograph (ECG) showed sinus rhythm. He
was treated with 50 g activated charcoal, 3 litres of intravenous
crystalloid solution, and 1 g of calcium gluconate. BP improved
to 100/50. Salicylate and paracetamol concentrations were not
in the toxic range. Whole bowel irrigation was not undertaken.
Over the next 12 hours he remained alert and well, with no significant
decrease in BP or HR.
Eighteen hours after the overdose, he had two generalised tonic-clonic
seizures and remained unresponsive with a junctional bradycardia,
HR 43, BP unrecordable. He then became asystolic with no palpable
pulses. He was intubated and ventilated while cardiopulmonary
resuscitation was started. Over a period of 12 minutes he was
given 10 g calcium gluconate as 1 g boluses and 9 mg of adrenaline
(epinephrine). He responded with HR 54 (junctional bradycardia)
and BP 137/80 mm Hg. Five minutes later, he had a second asystolic
cardiac arrest and was given a further 2.5 g calcium gluconate
and 1 mg adrenaline (total of 12.5g of calcium gluconate given
over 28 minutes). An external pacemaker was attached, and an
adrenaline infusion (6 mg/100 ml at 5 ml/h) and a calcium gluconate
infusion of 1 g in 100 ml/h were started.
After one hour, calcium was stopped but high dose noradrenaline
(norepinephrine) and dobutamine were required to maintain blood
pressure, and a temporary pacing wire was necessary to maintain
rhythm. There was no response in haemodynamic parameters to
glucagon. Severe metabolic acidosis (pH 6.83 base excess 26)
and acute renal failure were treated with a bicarbonate infusion
and 24 hours of continuous veno-venous haemofiltration. Insulin
was required for hyperglycaemic control.
Over 48 hours inotropes were weaned, the acidosis resolved, renal
function improved, and pacing was stopped (table 1
presents serial blood parameters). The only other complication
was pulmonary oedema. This was initially treated as aspiration
pneumonia with antibiotics and oxygen therapy, but radiographical
findings were more consistent with pulmonary oedema. The patient
was discharged from intensive care on day 5 and discharged himself
against medical advice eight days after presentation. On subsequent
attendances to the emergency department, he had a normal neurological
examination, normal chest radiograph, ECG, and creatinine.
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Table 1 Serial biochemical parameters
including corrected serum calcium concentrations; 13.5 g calcium gluconate
given 18 hours after the overdose |
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DISCUSSION
This case illustrates the potentially life threatening effects
of slow release diltiazem overdose and the problems with delayed
toxicity if decontamination is incomplete or not undertaken.
The clinical effects in the patient described were consistent
with CCB overdose. The spectrum of CCB toxicity includes hypotension
(combination of vasodilatation and negative inotropic effects),
bradycardia, conduction abnormalities (sinus node depression
and AV conduction block), pulmonary oedema, metabolic effects
(hyperglycaemia and metabolic acidosis), and neurological symptoms
(lethargy, coma, seizures).17,9,14
The pharmacokinetics and mechanism of toxicity have been reviewed
previously.5,14
Whole bowel irrigation is being used increasingly in poisoning
with slow release formulations.15
Similar to most treatment modalities in clinical toxicology,
the evidence for the use of whole bowel irrigation in slow release
CCB overdose is based on case reports alone. There is a reported
case of two patients who took similar doses of slow release
verapamil, where one patient had whole bowel irrigation and
developed only minimal toxicity, while the other patient, who
did not receive whole bowel irrigation, developed severe toxicity.16
Although whole bowel irrigation has not been proved effective
in controlled trials of slow release CCB overdoses, the seriousness
of this poisoning and the effectiveness of whole bowel irrigation
in previous case reports,16
make it an important consideration for decontamination, until
clinical trials are undertaken.
The patient had two generalised tonic-clonic seizures minutes before
the asystolic arrest. Seizures have been reported uncommonly with
calcium channel overdoses.17
Quezado et al also reported a generalised seizure before
asystole in a verapamil overdose.17
It may be hypothesised that the seizures precipitated asystole
by causing acidosis and increasing the amount of ionised drug
available for channel blockade.
There is disagreement about the use of intravenous calcium in CCB
overdose.1013
Recently published Toxicologic-Oriented Advanced Cardiac Life
Support guidelines recommend the use of 1 g3 g of intravenous
calcium as a slow intravenous bolus, only after shock is refractory
to other treatments.12
However, there is some evidence that intravenous calcium is
a useful first line therapy.16,18
There is one report of an asystolic arrest after diltiazem overdose
responding to 2 g of calcium gluconate alone.6
In situations of severe haemodynamic compromise, such as asystole,
larger doses may be beneficial.13,16
In the case reported here, much larger doses were administered
rapidly, and then repeated after a second episode of asystole,
with good response. High dose intravenous calcium, that is,
greater than 3 g, has been reported in a number of cases of
CCB overdose,13,16,18
but not previously in diltiazem overdose.5
In contrast, in cases of CCB poisoning reporting failure of intravenous
calcium, the dose was 1 g3 g.3,4,8
Failure of high dose intravenous calcium seems to occur less
commonly,19
suggesting that a higher dose may be more appropriate in severe
poisoning. Proponents of high dose calcium suggest that in cases
of failure, the overdose is often refractory to all treatment.1
No serious side effects have been reported despite transient
high serum calcium (up to 4.8 mmol/l).13,16,18
Multicentre clinical trials will be required to test the hypothesis
that high dose intravenous calcium is beneficial in CCB poisoning
because it is an uncommon poisoning.
Although the severe delayed toxicity in this case most probably
resulted from inadequate decontamination, his pre-existing cardiac
disease may have exacerbated it. However, good outcomes with
severe CCB toxicity have been reported in patients with a history
of coronary artery disease,6,8
and poor outcomes have been reported in otherwise healthy persons.16,20
It is unclear if continuing the calcium infusion postcardiac
arrest would have reduced the amount and time inotropes were
required. Previous case reports have suggested that continuing
a calcium infusion is beneficial,7,16,18
but a controlled trial would be required to test this hypothesis.
This case suggests there is a role for aggressive intravenous calcium
therapy in severe diltiazem (and other CCB) overdose, particularly
with the onset of asystole. It should be considered early in
cases of cardiac arrest after CCB overdose. The case also highlights
the problems with delayed toxicity when whole bowel irrigation
is not administered.
ACKNOWLEDGEMENTS
Thanks to Dr Patricia McGettigan and Ms Corrine Balit for reading
the manuscript. Thank you to Associate Professors Ian Whyte
and Andrew Dawson for their comments on the manuscript.
Contributors
Geoffrey Isbister attended the patient in the emergency department,
wrote and revised all manuscripts and will be guarantor for
the paper. Ian Whyte and Andrew Dawson discussed the idea and
focus of the case report with the author, but did not read the
manuscript. Patricia McGettigan and Corrine Balit read and commented
on the manuscript.
