Download The use of glucagon and other antidotes in a case of beta

Hong Kong Journal of Emergency Medicine
The use of glucagon and other antidotes in a case of beta-blocker and
calcium channel blocker overdose
β
HT Fung
, CH Lai
, OF Wong
, KK Lam
, CW Kam
We report a case of metoprolol and nifedipine overdose complicated by hypotension which responded to
intravenous boluses of calcium chloride and glucagon. The blood pressure was subsequently stabilised by
continuous glucagon infusion with the aid of an insulin-dextrose drip. The discussion is focused on the role
of antidotes and catecholamine inotropes in the management of beta-blocker and calcium channel blocker
poisoning. (Hong Kong j.emerg.med. 2007;14:113-118)
β
Keywords: Adrenergic beta-antagonists, antidotes, calcium channel blockers, glucagon, overdose
β
Case
A 45-year-old female with hypertension, diabetes mellitus,
hyperlipidaemia and renal impairment was brought to
the emergency department (ED) in September 2006 for
drowsiness after drug overdose. The history obtained from
the patient and her sister suggested ingestion of 60 tablets
of metoprolol, slow-release nifedipine and prazosin 10
hours ago. She had a Glasgow Coma Scale (GCS) of
14/15, blood pressure (BP) 79/54 mmHg, pulse rate
55/min, respiratory rate 18/min, SpO2 98% on room air
and blood glucose 8.6 mmol/L. The ECG showed sinus
bradycardia and first-degree heart block with PR interval
Correspondence to:
Fung Hin Tat, MRCP, FRCSEd, FHKAM(Emergency Medicine)
Tuen Mun Hospital, Accident & Emergency Department, Tsing
Chung Koon Road, Tuen Mun, N.T., Hong Kong
Email: [email protected]
Lai Cing Hon, MBBS, MRCSEd, FHKAM(Emergency Medicine)
Wong Oi Fung, MBChB, MRCSEd
Lam Ka Keung, MBBS, MRCSEd, FHKAM(Emergency Medicine)
Kam Chak Wah, MRCP, FRCSEd, FHKAM(Emergency Medicine)
of 226 msec. Two hundred millilitres of normal saline
were administered as intravenous bolus but the BP 30
minutes later was 75/57 mmHg. After receiving
intravenous glucagon 3 mg over 5 minutes, her BP
increased to 88/63 mmHg. With a second dose of
glucagon at 6 mg and 10 ml of 10% calcium chloride
administered 17 minutes later, the BP rose to 107/78
mmHg and she vomited twice. Calcium chloride 1 g was
repeated and glucagon infusion at 9 mg/h was
commenced. Actrapid HM 6 IU/h based on an estimated
body weight of 60 kg and dextrose 6 g/h were
subsequently added in view of a BP of 92/63 mmHg at
the end of the first hour of glucagon infusion. The blood
pressure at one hour after placing on insulin-dextrose
alone was 95/57 mmHg and then glucagon infusion at
9 mg/h was reintroduced after the arrival of the pharmacy
stock. One hour post-glucagon resumption the BP was
114/79 mmHg. In the rest of the ED stay, the BP readings
were all above 100/60 mmHg, ranging from 110/70 to
120/80 mmHg most of the time, except for one occasion
of 97/61 mmHg half-an-hour after an inadvertent
interruption of the glucagon infusion.
Hong Kong j. emerg. med. „ Vol. 14(2) „ Apr 2007
114
Her GCS improved to 15/15 eight hours after the ED
attendance. The pulse rate was stable between 60 and
70/min. The PR interval, 226 ms on arrival, reached a
peak of 238 ms (Figure 1) 7 hours later but was
normalised to 184 ms 25 hours post-attendance. There
was no hypoglycaemic episode and the blood glucose
during insulin therapy varied between 7 and 17 mmol/L.
One hour after the two doses of calcium chloride, the
serum albumin adjusted calcium was 3.11 mmol/L,
falling spontaneously to 2.62 mmol/L after 18 hours.
The renal function was deranged with urea 13.2 mmol/L
and creatinine 173 umol/L on presentation. The
creatinine was corrected 18 hours later to 118 umol/L,
identical to that four months previously.
The glucagon and insulin dextrose infusions were
gradually tapered down in response to the
haemodynamic improvement. The duration of
glucagon infusion was 20 hours and the cumulative
dose inclusive of the first two boluses was 109 mg.
The hyperinsulinaemic euglycaemia therapy was
tapered off after 23 hours. Other drug treatments
undertaken were 1 L of normal saline over 23 hours
and 4 doses of 50 g activated charcoal. The treatments
offered were summarised in Table 1. After regaining
full consciousness, she admitted that she had taken 30
tablets of hypnotics and other medications with an
estimated amount of 4,200 mg of metoprolol,
1,120 mg of slow-release nifedipine, 84 mg of prazosin,
Figure 1. ECG showing sinus bradycardia and first-degree heart block.
Table 1. Summary of the treatment given to the patient
Treatment
Total dose
Duration
Glucagon
109 mg (including 9 mg of loading dose)
20 hours
Calcium
26 mmol (in 2 doses)
Dextrose-insulin drip
Maximum rate of Actrapid HM 6 IU/h and dextrose 6 g/h
23 hours
Normal saline
1L
23 hours
Activated charcoal
50 g for 4 doses
Fung et al./Beta-blocker and calcium channel blocker overdose
2,240 mg of gliclazide and 280 mg of fluvastatin. She
developed dizziness about one hour later but she
managed to go home for sleep. Awareness of the
surroundings was present only after ED arrival. She
was discharged on the next day from the ED following
psychiatric consultation.
115
calcium administration hypercalcaemia in poisoning
settings, there is a paucity of experience so far. Our
case's serum calcium level was 3.11 mmol/L after
26 mmol of intravenous calcium but there were no
obvious symptoms and signs of hypercalcaemia. The
hypercalcaemia of 4.8 mmol/L in a verapamil-poisoned
patient treated with 30 g of calcium gluconate dropped
to normal after four days with no sequela.6
Discussion
In overdose of beta-blockers, metoprolol is second to
propranolol in the occurrence of cardiovascular
morbidity which is aggravated by cardiovascular coingestants, primarily calcium channel blockers, cyclic
antidepressants and neuroleptics. 1 The different
receptor selectivity in the heart and vasculature of
different calcium channel blockers may be lost in the
overdose situation. Hypotension, dysrhythmia and
sinus node depression develop equally commonly in
poisoning of verapamil, diltiazem and nifedipine but
verapamil accounts for more frequent and more severe
atrioventricular node conduction block.2 Overdose of
prazosin, a post-synaptic alpha-1-adrenergic receptor
antagonist, causes hypotension and tachycardia.3,4 The
bradycardia in our case could be ascribed to metoprolol
with or without nifedipine whereas the first-degree
atrioventricular block was more likely due to
metoprolol. Onset of symptoms and signs may help
differentiate metoprolol from slow-release nifedipine
poisoning as the former usually has an earlier onset.
However the early dizziness in this patient may be
explained by both the hypnotic effect and the
metoprolol-induced hypoperfusion. Moreover the
haemodynamic status was unknown in the many hours
before the ED presentation.
Both calcium channel blockers and beta-blockers
hinder calcium entry through the L-type calcium
channels in myocytes and vascular smooth muscle cells.
Calcium administration improves BP and cardiac
conduction in calcium channel blocker intoxication.2
It was reported to restore palpable pulses in a case of
atenolol-induced electromechanical dissociation. 5 A
dose response relationship probably exists but the
optimal dose has not been determined yet. 2,6
Concerning possible detrimental effects of post-
The binding of glucagon on myocardial glucagon
receptor, as demonstrated by 125I-glucagon studies,
bypasses the beta-adrenergic receptor and increases the
intracellular calcium available for actin-myosin
coupling through Gs protein mediated adenylate
cyclase activation, phosphodiesterase inhibition and
arachidonic acid release.7-10 The optimal chronotropic
action of glucagon relies on normal serum calcium level
according to rat studies. 11 The post-calcium therapy
hypercalcaemia in human case reports was
inconsequential, but attenuation on glucagon's action,
if any, remains to be determined.
In animal models of propranolol overdose, glucagon
consistently augments the heart rate but the benefits
on BP, cardiac output and survival rate are less clear.
Glucagon appears to increase the heart rate and cardiac
output and circumvent the atrioventricular block in
animals overdosed with calcium channel blocker.
However it does not significantly affect the mean
arterial pressure and mortality rate. The implication
of many of these animal studies was limited by
insufficient glucagon dosage, unblinded design and
small number of animals. 12 Studies on the role of
glucagon in human poisoning are lacking. Glucagon
was noticed reversing hypotension within two minutes
in a nifedipine poisoned patient failing calcium
chloride treatment.13 Glucagon requirement of 108 mg
over 33 hours and 120 mg over 24 hours had been
observed in two cases poisoned by nifedipine and
propranolol respectively. 14,15 In a case of mixed
amlodipine and atenolol overdose, the patient
recovered fully after receiving 264 mg of glucagon in
52 hours. 16 The favourable outcome in these cases
could not be completely attributed to glucagon because
of the co-administration of other inotropes. Our
patient was given calcium chloride in the first hour of
Hong Kong j. emerg. med. „ Vol. 14(2) „ Apr 2007
116
in calcium channel blocker and beta-blocker
intoxication. Insulin administration promotes cellular
glucose uptake and restores calcium influx. Though
not always effective, hyperinsulinaemia and
euglycaemia treatment is successful in many case
reports of calcium channel blocker overdose and one
case of combined calcium channel blocker and betablocker overdose. In the 16 aforementioned cases, the
maximum infusion rate of insulin and glucose was
1 IU/kg/h and 75 g/h respectively.16,19 The insulin dose
for our case was initiated at only 0.1 IU/kg/h because
at that juncture the BP was marginally low at 92/63
mmHg whilst on 9 mg/h of glucagon and it was
clinically judged to be the appropriate dose to start
with. While under insulin dextrose alone, the drop of
BP to 97/61 mmHg during the 30 minutes period of
interruption of glucagon infusion suggests that the
insulin-dextrose dose was suboptimal for our patient.
ED attendance. In the following period, she was
maintained on infusions of glucagon and insulin-dextrose.
The absence of inotropes and the transient BP drop
during interruption of glucagon infusion suggested
glucagon was the principal agent in stabilising the
haemodynamic status throughout her ED stay beyond
the first hour of presentation. Owing to the limited
experience of the outcome of the post-calcium
hypercalcaemia as well as the expected efficacy and safety
profile of glucagon, glucagon is a reasonable choice over
calcium as continuous infusion in our case. Glucagon's
clinical action is peaked in 5 to 10 minutes and disappears
by 30 minutes.17 It is recommended to be given in 3 to
5 mg as initial dose, followed by higher doses up to 10
mg in case of poor response. The subsequent infusion
rate should begin at the 'response dose' per hour.18 The
first two doses in our case were 17 minutes apart and the
therapeutic effect of them might have overlapped.
Therefore we decided the 'response dose' to be the sum
of the initial two doses. The only adverse effect of glucagon
detected in our case was transient vomiting.
Catecholamine support in beta-blocker overdose
produces mixed successful and failed results. By means
of competing for the beta-receptors, the dose of betaagonist may need to be excessively high and pure betaagonists like isoproterenol in considerable amount may
Switching of fatty acid utilisation to carbohydrate in
the myocardium and insulin secretion inhibition occur
Table 2. A general guide for the specific treatment of poisoning of beta-blockers and calcium channel blockers (The sequence and
choice may need individualised adjustment. Closed monitoring and supportive care are always important.)2,16,18-23
Beta-blocker
Calcium channel blocker
Asymptomatic
1. Decontamination
1. Decontamination
Mild toxicity (mild hypotension or mild bradycardia)
1. Decontamination
2. Fluid bolus
3. Atropine for bradycardia
1. Decontamination
2. Fluid bolus
3. Atropine for bradycardia
Moderate toxicity (Failure of the above treatment or severe hypotension or severe bradycardia or hypoperfusion)
1.
2.
3.
4.
5.
6.
Decontamination
Fluid bolus
Glucagon
Calcium for hypotension
Atropine for bradycardia
Insulin-dextrose (delayed onset)
1.
2.
3.
4.
5.
6.
7.
Decontamination
Fluid bolus
Calcium mainly for hypotension
Glucagon
Atropine for bradycardia
Catecholamine
Insulin-dextrose (delayed onset)
Severe toxicity (Failure of the above treatment or cardiogenic shock)
1. The above
2. Catecholamine (high dose needed)
3. Electromechanical support
1. The above
2. Electromechanical support
Fung et al./Beta-blocker and calcium channel blocker overdose
cause undue peripheral vasodilatation. The potential
deleterious effects on the microcirculation and
unopposed alpha-receptor stimulated hypertension of
mixed alpha and beta-adrenergic medications such as
epinephrine, dopamine and norepinephrine should also
be recognised.20,21
A review suggested that glucagon, effective in 86% of
cases in increasing the heart rate and BP, should be
the agent of choice in managing haemodynamically
compromised patients poisoned by beta-blockers. The
other agents in descending order of effectiveness are
epinephrine, pacemaker, isoproterenol, dopamine and
atropine.22
Given the close similarities of antidotal and supportive
treatments in poisoning of beta-blockers and calciumchannel blockers, a suggested guide on their uses is
formulated in Table 2.2,16,18-23 As evidence is limited in
some aspects and clinical parameters are not always
identical among individuals, clinicians should exercise
modifications if needed.
Conclusion
Despite the long-standing utilisation of calcium and
glucagon, as well as increasing recognition of insulindextrose as antidotes for beta-blocker and calcium
channel blocker intoxication, there is a paucity of
human trials evaluating their efficacies often
because of ethical concerns in poisoning settings.
Our case and the up-to-date evidence favour glucagon
as an effective and safe agent. The role of glucagon
relative to the conventional catecholamine vasopressors
as maintenance therapy in drug overdose deserves
consideration.
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4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
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