Download A case of fatal hydroxychloroquine overdose

Hong Kong Journal of Emergency Medicine
A case of fatal hydroxychloroquine overdose
, KK Lam
HT Fung
, OF Wong
, B Lau
, CW Kam
A 28-year-old woman ingested 20 g of hydroxychloroquine sulphate for suicidal attempt. She developed
hypotension, cardiac conduction disturbance, hypokalemia and hypoglycemia. Despite treatment with
mechanical ventilation, epinephrine, sodium bicarbonate, diazepam and potassium replacement, she
succumbed 10 hours post-overdose. Previous case reports of hydroxychloroquine overdose are summarised
and the therapeutic choices are discussed. (Hong Kong j.emerg.med. 2007;14:53-57)
28
20
10
Keywords: Diazepam, hydroxychloroquine, hypoglycemia, hypokalemia, overdose
Case
A 28-year-old woman having systemic lupus
erythematosis and history of attempted suicide, presented
to the emergency department in August 2006,
about one hour after ingesting 100 tablets of 200 mg
hydroxychloroquine sulphate (each tablet containing
155 mg hydroxychloroquine base). At presentation, she
had Glasgow Coma Score (GCS) 3/15, blood pressure
(BP) 46/21 mmHg, pulse rate 68/min, respiratory rate
22/min, blood glucose 2.6 mmol/L, serum potassium
3.6 mmol/L and ECG of QRS 152 ms and QTc 428 ms
(Figure 1). Twenty grams of dextrose given intravenously
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]
Lam Ka Keung, MBBS, MRCSEd, FHKAM(Emergency Medicine)
Wong Oi Fung, MBChB, MRCSEd
Lau Bun, MBBS, MRCSEd
Kam Chak Wah, MRCP, FRCSEd, FHKAM(Emergency Medicine)
brought her GCS to 15/15 and blood glucose to
13.4 mmol/L. The BP was improved to 80/50 mmHg
after infusion of 1 L of normal saline. Gastrointestinal
decontamination was performed with 50 g of oral
activated charcoal but gastric lavage was not done.
She was later transferred to the Intensive Care Unit. She
remained conscious but the BP and central venous
pressure were 57/35 mmHg and 26 cmH2O respectively.
She was intubated and put on synchronised intermittent
mandatory ventilation mode of mechanical ventilation.
The medications given included intravenous diazepam
60 mg followed by infusion of 2 mg/h, epinephrine
20 µg/min and sodium bicarbonate 100 mmol. The
serum potassium three hours after the overdose was
1.5 mmol/L. Potassium chloride of 20 mmol was given
over one hour followed by a maintenance infusion of
1.6 mmol/h.
Her BP was sustained well above systolic 100 and
diastolic 60 mmHg one hour after starting the
epinephrine drip. At six hours post-overdose, the QRS
Hong Kong j. emerg. med. „ Vol. 14(1) „ Jan 2007
54
Figure 1. The ECG on emergency department arrival. Arm lead reversal was present.
and QTc were shortened to 110 ms and 379 ms
respectively while the blood results were: pH 7.32,
HCO 3 1 9 . 6 m m o l / L , p O 2 2 4 . 3 k Pa , s o d i u m
153 mmol/L and potassium 2.4 mmol/L. There was
no more hypoglycemic episode under a 10% dextrose
infusion. Echocardiographic imaging revealed poor
global ventricular contractility with an ejection fraction
of 35%. She developed pulseless ventricular tachycardia
9.5 hours post-ingestion and was certified dead half
an hour later. Post-mortem examination was waived.
Discussion
Hydroxychloroquine is synthesised by adding a
hydroxyl group to an N-ethyl group of chloroquine
rendering it 2-4 times less toxic.1 As hydroxychloroquine
and chloroquine share similar str uctural and
pharmacological properties, and there is relatively
richer experience with chloroquine toxicity, most of
the following discussions are based on studies of
chloroquine poisoning.
Hydroxychloroquine poisoning is rarely reported. From
a literature search, there were 20 cases but a few were
in abstract form or non-English languages. Information
of doses, clinical presentations and treatments were not
always available. The features of all these cases are
depicted in Table 1. 2-16 Many of them suffered from
hypotension, widened QRS and hypokalemia. The
overall mortality was 25%. One case presented with a
blood glucose level of 3.4 mmol/L with GCS of 15/15.11
Another presented with slurred speech, drowsiness,
blood glucose of 3.2 mmol/L and blood pressure of
63 mmHg by palpation. She was resuscitated with fluid
boluses and dopamine. Four hours later, the blood
pressure was 100/74 mmHg. She was drowsy but
oriented, and she complained of nausea. She was
haemodynamically stable over the next three days but
further description of her sensorium was not available.
Repeat blood glucose measurement was not reported
and no dextrose replacement was mentioned. According
to the contents of the case report, she remained drowsy
over the first four hours after arrival but minor
improvement of consciousness might exist as judged
Fung et al./Fatal hydroxychloroquine overdose
55
appeared. The drop in the mortality of rats
administered LD 50 chloroquine correlated with
increasing diazepam doses up to 20 mg/kg. Doses
greater than 20 mg/kg increased the mortality as a
result of respiratory depression.17 In a prospective study
of more than 5 g chloroquine ingestion utilising
historical control, 10 of the 11 study patients receiving
immediate mechanical ventilation and administration
of diazepam (2 mg/kg followed by 1-2 mg/kg/day for
2-4 days) and epinephrine (0.25 µg/kg/min with
increments of 0.25 µg/kg/min until systolic BP ≥100
mmHg) survived whereas only 1 of the 11 controls
survived.18 However inotropes other than epinephrine
were often co-administered and treatment details
of the historical controls were not described.
A retrospective uncontrolled trial was carried out
by other relevant parameters. As no dextrose replacement
was given, it was likely that the clinicians did not
consider she was suffering from hypoglycemia. From a
retrospective view, the BP correction might account
for the consciousness improvement, if any, but we
cannot rule out that she was under a minor hypoglycemic
attack up to four hours post-arrival.13 Our case is one
of the two ingesting the second largest dose and the
first one with hypoglycemia and precise documentation
of the GCS and blood glucose response to intravenous
dextrose.
In the 1970s, toxic dose chloroquine ingestion was
observed in a patient with diazepam co-ingestion,
producing no intoxication.17 Since then, studies of the
protective effect of diazepam on chloroquine poisoning
Table 1. Summary of the case reports of hydroxychloroquine overdose
Ref. Age
Dose BP
QRS QTc Arrhythmia Glucose
K+
Diazepam
(g)
(mmHg) (ms) (ms)
(mmol/L) (mmol/L)
2
Adult ? 7.2 40/?
3
16
10.8
4
16
12
5
42
6
29
4
7
2.5
12
8
30
4
9
27
12
104/86
10
30
11
18
20
67/34
105
12
24
12
48/?
160
13
16
76/32
140
14
16
26
41
47
29
16
4
3.9
4
14
3.6
115/45
120/90
104/90
60/?
88/37
110/66
85
90
15
17
22
54/23
16
19
6
Our 28
case
Other
inotropes
Y
NaHCO3
Death
N
Y
Y
Y
6.4
Y
Y
N
Y
N
Y
81/45
20
Epinephrine
N
N
160
>200
100
564 Y
3.4
152
3.2
27.5 mg
140 mg
5-10 µg/min
then 4 mg/h
2.1
N
Y
N
N
Y
N
Y
N
N
N
N
N
1050 mmol Y
N
3.4
Y
2.9
2
3.9
180 mg
600 Y
3.1
N
Y
120 mmol N
60 mg then 20 µg/min
2 mg/h
N
150 mmol Y
428 Y
1.5
2.6
Empty boxes mean clinical data unavailable or unmentioned.
N = no; Ref = reference; Y = yes
2.7
1.8
80 mg then
6 mg/h
Y
46/21
N
1.5
N
56
evaluating various therapies including the combination
of mechanical ventilation, high dose diazepam and
epinephrine in acute chloroquine intoxication. Among
the 167 patients studied, 87% received at least one of
the combination treatment modalities. All the 14 dead
were given the full combination treatment regimen.
While the 'antidotal' aspect of any particular single or
combination therapy was impossible to be confirmed,
a <10% mortality rate was achieved with an approach
comprising aggressive early use of epinephrine and
diazepam, early mechanical ventilation, as well as
attention to the fundamental principles of intensive
care. 19 Nineteen patients of mild to moderate severity
of chloroquine overdose (dose between 2 and 4 g,
systolic BP >80 mmHg, QRS width <120 ms and
absence of arrhythmia) received a diazepam loading
dose of 0.5 mg/kg with subsequent infusion of 1 mg/kg
over 24 hours were enrolled in a prospective doubleblind placebo controlled study. There was no difference
in evolution of the systolic BP, QRS duration and QT
interval over 24 hours between the two groups.20
The mechanism of action of diazepam in chloroquine
intoxication is not well understood. The possible
antiarrhythmic properties could be due to a decrease
of sympathetic output in the central nervous system
and peripheral benzodiazepine receptor mediated
regulation of the cardiac calcium channels.21,22 Being a
potent vasoconstrictor and inotrope, the therapeutic
mechanism of epinephrine is more easily understood
and it was demonstrated to enhance the rate and
amplitude of the ECG in chloroquine-poisoned dogs.23
In the four reviewed cases (inclusive of our case) of
hydroxychloroquine overdose using high dose
diazepam therapy, the mortality was 50%. The case
ingesting the greatest dose of 22 g survived without
utilising any diazepam. Further studies on the benefits
of high dose benzodiazepine therapy have yet to be
done.
The hypokalemia is thought to be secondary to
potassium channel blockage causing over-dominant
intracellular potassium distribution. Overzealous
replacement may cause subsequent hyperkalemia. 24
Tw o c a s e s o f p o s t - p o t a s s i u m r e p l a c e m e n t
hyperkalemia, one of 6.7 mmol/L but asymptomatic,
Hong Kong j. emerg. med. „ Vol. 14(1) „ Jan 2007
another of 5.8 mmol/L associated with ventricular
fibrillation, had been reported.11,16
By extrapolating the experience of other membrane
stabilising cardiotoxins, sodium bicarbonate should
have a role in correcting the cardiac conduction block
of hydroxychloroquine or chloroquine poisoning
although it has not been formally evaluated in these
two particular medications. The possible worsening
of hypokalemia warrants close serum potassium
monitoring during the use of sodium bicarbonate.
Therapeutic dose of hydroxychloroquine causing
hypoglycemia in a diabetic patient on insulin was
reported. Hydroxychloroquine stimulates insulin
release and somatostatin analogue, which suppresses
insulin secretion, has been reported to reverse
intravenous quinine-induced hypoglycemia. 2 5
However, somatostatin analogues should only be
considered in refractory cases of hypoglycemia.
The last serum potassium measurement in our case was
performed approximately three hours before the cardiac
arrest. In light of the strong potassium channel
blockade of hydroxychloroquine and the potassium
replacement given, life-threatening hypokalemia or
hyperkalemia may develop within a short period of
time. It was not sure whether more meticulous
monitoring and correction of the serum potassium
would affect her outcome. Besides the maintenance of
normokalemia, the correction of the widened QRS was
another difficult issue in clinical management. One
had to take great caution in administering agents like
sodium bicarbonate and hypertonic saline in the
presence of her hypokalemia and hypernatremia.
Conclusion
Hydroxychloroquine poisoning is rare but may result
in hypotension, negative inotropy, cardiac conduction
abnormalities, hypoglycemia and marked hypokalemia.
Treatment options include early intubation,
gastrointestinal decontamination, epinephrine, sodium
bicarbonate, careful potassium replacement and
correction of hypoglycemia by glucose or somatostatin
Fung et al./Fatal hydroxychloroquine overdose
analogue. The role of high dose diazepam is not well
established but most authors still recommend its use
for serious cases.
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