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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 1.8�3.6 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
reports2�8
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.10�13
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 1.8�3.6 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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Table 1 Serial biochemical
parameters including corrected serum calcium concentrations;
13.5 g calcium gluconate given 18 hours after the overdose
| |
DISCUSSIONThis 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).
1�7,9,14
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.10�13
Recently published Toxicologic-Oriented Advanced Cardiac Life
Support guidelines recommend the use of 1 g�3 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 g�3 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.
