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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.
View this
table:
[in
this window]
[in a new window]
|
Table 1 Serial biochemical
parameters including corrected serum calcium concentrations;
13.5 g calcium gluconate given 18 hours after the
overdose | |
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.
