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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:
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this window]
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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 | |
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.
