Download Overdose of Dologesic with a fatal outcome: a case report

Hong Kong Journal of Emergency Medicine
Overdose of Dologesic with a fatal outcome: a case report
CY Man
Dologesic is a commonly prescribed analgesic in accident and emergency department. Yet report of overdose
with this drug is not common. We report a case in which the patient developed cardiac arrest within an
hour of ingestion. Dextropropoxyphene, a component of the drug Dologesic, used to be a common cause
of fatalities after drug overdose in the seventies. It is highly toxic in overdose and therefore caution should
be exercised when prescribing this drug. (Hong Kong j.emerg.med. 2001;8:207-211)
Keywords: Arrthmias, cardiac arrest, dextropropoxyphene, naloxone, sodium bicarbonate
Case history
Our patient was a 41 years lady who had a quarrel
with her husband on the day of admission. She rang
her relatives subsequently, saying that she had taken
many painkillers with alcohol, with the intention to
commit suicide. Forty-five minutes after making the
phone call, she was discovered unconscious by the
relatives. When the ambulance arrived 7 minutes later,
she was found to be in cardiac arrest. Basic life support
was started immediately.
On arrival at the Accident and Emergency department,
she was in asystole. Advanced cardiac life support was
instituted. A total of 5 mg of adrenaline was given (in
5 shots) and the patient regained pulse. The first blood
pressure was 113/72 mmHg with pulse rate of 143
per minute, which gradually dropped to 66/41 mmHg
with pulse rate of 110 per minute. Adrenaline infusion
was started with good response (BP113/55 mmHg,
pulse 106/min). The first ECG after restoration of
heart beat showed wide-complex tachycardia. (Figure
1) Naloxone was not given.
Correspondence to:
Man Chi Yin, MRCP, FRCSEd, FHKAM(Emergency Medicine)
Prince of Wales Hospital, Accident & Emergency Department,
Shatin, New Territories, Hong Kong
Email: [email protected]
On physical examination, her general condition was
poor. The temperature was 37.6 degrees Celsius
(tympanic). She was comatose with the Glasgow Coma
Score of 3/15. Her pupils were fixed and dilated. There
was no spontaneous respiration. The chest air entry
was satisfactory with artificial ventilation and was
equal on both sides. Examination of her heart was
normal.
Gastric lavage was then performed followed by
instillation of 50 g activated charcoal. The arterial
blood gas (post-cardiac arrest) showed pH 6.9,
PCO 2 9.1 kPa, PO 2 26.6 kPa (on 100% oxygen),
HCO 3 15.2 mmol/L, Base excess -17.1 mmol/L.
Plasma sodium and potassium were 146 mmol/L
a n d 5 . 9 m m o l / L r e s p e c t i v e l y. T h e b l o o d
glucose was 8.5 mmol/L and the haemoglobin
was 13.9 g/dL.
The remains of the four drugs suspected to have been
taken by the patient were sent to the government
forensic laboratory for analysis. They were
subsequently confirmed to contain the following: drug
1 contains paracetamol and salicylamide, drug
2 contains paracetamol, chlorpheniramine and
diphenhydramine, drug 3 contains oxybutynin, and
drug 4 contains paracetamol and propoxyphene. This
patient had a mixed drug overdose and the amount of
the individual drugs taken unknown. There was also
Hong Kong j. emerg. med.
208
„
Vol. 8(4) „ Oct 2001
associated alcohol intake. She was admitted to the
intensive care unit (ICU) for further management.
serum osmolality of 341 mOsm/Kg and urine osmolality
of 244 mOsm/Kg which required DDAVP for control.
Serum paracetamol level at 4 hours was 1.07 mmol/L.
Serum salicylate level was 0.09 mmol/L which was in
the therapeutic range (<1.80 mmol/L). The serum urea
was 4.5 mmol/L, creatinine 102 umol/L, chloride
108 mmol/L, lactate 4.6 mmol/L, total protein
71 g/L, albumin 36 g/L, total bilirubin 2 umol/L,
alkaline phosphatase 60 IU/L, ALT 34 IU/L, albuminadjusted calcium 2.33 mmol/L, amylase 107 U/L,
phosphate 0.50 mmol/L, and magnesium 0.66 mmol/L.
Plasma ethanol level was <2 mmol/L. Serum and urine
propoxyphene levels were not checked. Haemoglobin was
13.8 g/dL, platelet count 205x10E9 /L, and total white
cell count was 13.3x10E9/L. Her INR was 1.11 and
APTT 28.0 seconds.
She remained in metabolic acidosis which required
treatment with sodium bicarbonate.
Chest X-ray showed left lower zone haziness suggestive
with aspiration pneumonitis. CT brain was performed
and was normal.
While in the ICU she required mechanical ventilation
and inotrope infusion. N-acetylcysteine infusion was
started and activated charcoal was given through the
nasogastric tube at regular intervals. Intravenous
cefuroxime and metronidazole were given. She
subsequently developed myoclonus requiring sodium
valproate for control, as well as diabetes insipidus with
Twenty-four hours after admission to the ICU, she
suddenly developed ventricular fibrillation which was
refractory to treatment and she finally succumbed.
Post-mortem report showed bilateral aspiration
pneumonia, pulmonary edema and focal myocardial
necrosis.
Subsequent toxicology analysis confirmed that the
patient's blood (taken after admitting to ICU)
contained the following drugs: paracetamol (subtherapeutic level), lignocaine (therapeutic level),
propoxyphene (therapeutic level) and metronidazole
(sub-therapeutic level).
Discussion
Although the exact cause of her cardiac arrest at home
was not known, the most likely cause was probably
due to dextropropoxyphene (DXP) toxicity, as inferred
from the presence of propoxyphene in the patient's
blood. It is highly unlikely that paracetamol overdose
Figure 1. Electrocardiogram of the patient showing wide-complex tachycardia.
Man/Overdose of Dologesic with a fatal outcome: a case report
have contributed to her cardiac arrest within an hour
of ingestion. The lignocaine and metronidazole from
the toxicological studies were probably administered
after admission while the paracetamol and
propoxyphene were taken by the patient. Furthermore,
the fact that the propoxyphene in the blood of the
patient was still at therapeutic level after admission
suggested that the highest level was actually above the
therapeutic level contributing to her cardiac arrest. It
is unlikely that the other suspected drugs would cause
cardiac arrest within 1 hour after ingestion. This is
further supported by their absence in the patient's
blood on toxicological analysis.
The drug Dologesic, a very commonly prescribed
drug for pain relief locally, contains paracetamol
325 mg and dextropropoxyphene 32.5 mg.
Dextropropoxyphene (DXP) is an optical isomer of
propoxyphene and it is this isomer that contains
analgesic properties. Of the constituents of DXPparacetamol preparations, DXP has a far more
immediate and dangerous effect than paracetamol. 1
Ever since its launch in the market in the early sixties,
reports of death have occurred within a year. But it
was not until the late seventies and early eighties that
there has been a large increase of DXP poisonings in
many countries. 2-7 In Sweden for example, DXP
used to be one of the most prescribed analgesic
compounds, 8 and the frequency of fatal poisoning by
DXP ingestion was constantly high. 9 In UK during
that period, it was suggested that many doctors were
unaware of the danger of DXP in overdose and the
problem of DXP poisoning had not been fully
appreciated.10 It was also alleged by some authors that
under-reporting of DXP fatalities may increase the
risk that knowledge of its toxicity will not reach the
population consuming this drug. 8 After reports of
deaths from this drug and stricter regulation on the
prescription, there was a decline in the incidence of
DXP poisonings. 4,11-13
DXP is a highly toxic and lethal drug when taken
in overdose. Its toxicity is highly potentiated by
alcohol.2,4 The fatal dose may be as small as 15 tablets
or possibly less in the DXP 32.5 mg and paracetamol
209
325 mg combination 4 (as in Dologesic). Blood
propoxyphene concentrations of 0.2 mg/dl were found
to be fatal. 14 Since the two drugs, paracetamol and
DXP, have a fixed ratio in the compound preparation
of Dologesic, the dose of the DXP (the effective lethal
agent) can be inferred from the paracetamol dose
calculated by its volume of distribution. 3
Many of the cases of poisoning are fatal at the time of
discovery, and if patients survive, serious sequelae are
extremely rare. 15 However, optic atrophy after DXP
overdose was reported in 1982.16 In comparison with
other drug fatalities, death characteristically occurs
rapidly, as little as 1 hour after ingestion and usually
before hospital treatment can be initiated. 4,14 It was
suggested that the rapid death may be due to the
predominant narcotic effects of DXP. 10 However,
because of the high tissue concentrations and
s l ow e l i m i n a t i o n o f a c t i v e D X P m e t a b o l i t e s
( e . g . n o r p r ox y p h e n e ) , s u d d e n u n p re d i c t a b l e
deterioration may occur up to 24 hours. 14 This was
the case with our patient. Therefore, continued and
intensive monitoring after resuscitation is essential.
Other patients may be unconscious, in severe
respiratory depression, moderate circulatory failure,
and quinidine-like changes in the ECG within 1 hour
of ingestion. 17 In fact, because of the rapidity of
deterioration, 40% of patients sustain irreversible
cerebral damage before reaching resuscitation
facilities. 18 In another study of 222 consecutive
patients with DXP poisoning, 73% had neurological
symptoms, 10% had convulsions on admission, 45%
were in respiratory failure, and 48% had impaired
circulation. The mortality was 8%.19
The cardiotoxic effects of DXP has been widely
studied. The cardiovascular failure was found to
respond flavourably to dopamine infusion. 20,21 Two
cases of improvement of DXP-induced cardiovascular
depression after naloxone infusion were reported by
Hantson et al in 1995. 22 The occurrence of cardiac
complications also appeared to be reduced by
mechanical hyperventilation which induces
hypocapnia. 23 In 1983, Heaney described the
occurrence of left bundle branch block after acute
DXP overdosage.24 It was transient and associated with
Hong Kong j. emerg. med.
210
no permanent sequelae. Like tricyclic antidepressants,
beta-adrenergic antagonists and chlorpromazine, DXP
possesses membrane stabilising activity. It was
suggested that this property, although regarded as
being of little importance in therapeutic use, may be
responsible for death in more that 30% of fatal
poisonings.25 In 1989, it was found that the marked
QRS widening and sodium channel blockage induced
by DXP could be reversed with lignocaine. 26 From
their animal experiments the authors found that both
drugs (DXP and lignocaine) compete for a common
receptor during the polarising phase. The more rapid
dissociation of lignocaine during the recovery period
leads to less blockage when both lignocaine and DXP
were present than when exposure was due to DXP
alone. In 1995, Stork et al first reported a case of DXPinduced wide complex arrhythmia that was responsive
to sodium bicarbonate therapy. 27 In their case, the
initial ECG showed a regular rhythm of 84 bpm, no
discernable P-waves and a QRS duration 160 msec.
The initial arterial pH was 7.16 and the bicarbonate
16 mmol/L. A total of 200 mmol of sodium
bicarbonate was given via intravenous push followed
by a continuous infusion of sodium bicarbonate
(22.5 mmol/h). After the bicarbonate bolus, the QRS
complex rapidly narrowed within 1 minute to 110
msec and the rhythm converted to normal sinus. The
patient survived and the authors suggested sodium
bicarbonate therapy may be a valid option for patients
who develop wide complex arrhythmia after DXP
overdose. Although the post arrest ECG is difficult to
interpret and cannot be confidently attributed to DXP
poisoning in our patient, it could serve to remind us
of the possibility of DXP-induced ventricular
arrhythmia. Our patient's pH remained low and a
higher dose of sodium bicarbonate could have been
given earlier on and subsequent deterioration of
ventricular fibrillation might have been prevented. The
importance of early diagnosis and treatment has been
stressed by some authors in view of the potentially
lethal complications of DXP overdose.28 In fact, it was
claimed that half of the patients who arrived at medical
facility in asystole could be resuscitated without
sequelae.19 This makes early and aggressive treatment
of DXP poisoning particularly relevant and mandatory.
„
Vol. 8(4) „ Oct 2001
Other treatment modalities have also studied.
Plasmapheresis, has been reported to be effective in
improving the conscious level of the patients, and of
six patients heavily intoxicated by DXP treated with
this method, 5 survived and only one died.29 On the
other hand, there was a case report of DXP poisoning
failing to respond to therapeutic doses of naloxone.
When 20 times of the manufacturer's recommended
dosage was given, the patient responded immediately.30
The authors suggested that if there is no response
within two minutes of the initial 0.01 mg/kg dosage
of naloxone hydrochloride, a second dose 0.1 mg/kg
(ten times the manufacturer's recommended dose) be
given. Our patient, however did not received any
naloxone.
In conclusion, our patient had mixed drug overdose
with alcohol which was fatal and the dextropropoxyphene in Dologesic was the mostly likely cause
of death. Dologesic is a commonly prescribed analgesic
in current medical practice. Death after drug overdose
is rare nowadays and the rapid deterioration to cardiac
arrest within one hour of ingestion is even rarer.
Hopefully this will alert physicians to the potential
lethality of this common drug and consequently to
exercise due caution when prescribing.
References
1.
2.
3.
4.
5.
6.
Sengupta A, Peat MA. Propoxyphene overdosage: a
study of cases involving analgesic. Arch of Toxicol 1977;
37(2):123-33.
Jonasson U, Jonasson B, Saldeen T. Middle-aged mena risk category regarding fatal poisoning due to
dextropropoxyphene and alcohol in combination. Prev
Med 2000;31(2 Pt 1):103-6.
Obafunwa JO, Busuttil A, al-Oqleh AM.
Dextropropoxyphene-related deaths-a problem that
persists? Int J Legal Med 1994;106(6):315-8.
Whittington RM. Dextropropoxyphene deaths:
coroner's report. Hum Toxicol 1984;3 Suppl:175S-185S.
Whittington RM, Barclay AD. The epidemiology of
dextropropoxyphene (Distalgesic) overdose fatalities in
Birmingham and the West Midlands. J Clin Hosp
Pharm 1981:6(4):251-7.
Simonsen J. Accidental fatal drug poisoning with
particular reference to dextropropoxyphene. Forensic Sci
1977;10(2):127-32.
Man/Overdose of Dologesic with a fatal outcome: a case report
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Rejent TA, Michalek RW, Lehotay JM. Propoxypheneassociated deaths: methods, post-mortem levels in blood
and liver. Clin Toxicol 1977;11(1):43-51.
Jonasson U, Jonasson B, Saldeen T. The manner of
death among fatalities where dextropropoxyphene
caused or contributed to death. Forensic Sci Int 1998;
96(2-3):181-7.
Jonasson U, Jonasson B, Saldeen T. Correlation between
prescription of various dextropropoxyphene
preparations and their involvement in fatal poisonings.
Forensic Sci Int 1999;103(2):125-32.
Carson DJ. Fatal dextropropoxyphene poisoning in
Northern Ireland. Review of 30 cases. Lancet 1977;1
(8017):894-7.
Segest E, Harris CN, Bay H. Dextropropoxyphene
deaths in Denmark from the health authority point of
view. Med Law 1993;12(1-2):141-51.
Jonasson U, Jonasson B, Saldeen T. Suicides may be
overreported and accidents underreported among
fatalities due to dextroporpoxyphene. J Forensic Sci
1999;44(2):334-8.
Jonasson U, Jonasson B, Holmgren R, et al. The
prevalence of dextroporpoxyphene in autopsy blood
samles. Forensic Sci Int 1998;96(2-3):135-42.
Yo u n g R J . D e x t r o p r o p o x y p h e n e o v e rd o s a g e .
Pharmacological considerations and clinical
management. Drugs 1983;26(1):70-9.
Segest E. Poisoning with dextropropoxyphene in
Denmark. Hum Toxicol 1987;6(3):203-7.
Weiss IS. Optic atrophy after propoxyphene overdose:
report of a case. Ann Ophthalmol 1982;14(6):586-7.
Elonen E, Neuvonen PJ. Mixed dextropropoxyphene
poisoning: concentration-effect relationships and effect
of naloxone. Int J Clin Pharmacol Ther Toxicol 1984;
22(1):16-9.
Young RJ, Lawson AA. Distalgesic poisoning- cause for
concern. Br Med J 1980;289(6220):1045-7.
Sloth Madsen P, Str om J, Reiz S, et al. Acute
propoxyphene self-poisoning in 222 consecutive
patients. Acta Anaesthesiol Scand 1984;28(6):661-5.
211
20. Krantz T, Thisted B, Strom J, et al. Sorensen MB. Severe
acute propoxyphene overdose: plasma concentrations
of propoxyphene and norpropoxyphene and the effect
of dopamine on circulatory failure. Acta Anaesthesiol
Scand 1986;30(4):271-6.
21. Krantz T, Thisted B, Strom J, et al. Severe, acute
propoxyphene overdose treated with dopamine.
J Toxicol Clin Toxicol 1985;23(4-6):347-52.
22. Hantson P, Evenepoel M, Ziade D, et al. Adverse
cardiac manifestations following dextroporpoxyphene
overdose: can naloxone be helpful? Ann Emerg Med
1995;25(2):263-6.
23 Schou J, Angelo H, Dam W, et al. Pharmacokinetics
of dextropropoxyphene in acute poisoning. Arch Toxicol
Suppl 1978;(1):343-6.
24. Heaney RM. Left bundle branch block associated with
propoxyphene hydrochloride poisoning. Ann Emerg
Med 1983;12(12):780-2.
25. Henry JA, Cassidy SL. Membrane stabilising activity:
a major cause of fatal poisoning. Lancet 1986;1(8495):
1414-7.
26. Whitcomb DC, Gilliam FR, Starmer CF, et al. Marked
QRS complex abnormalities and sodium channel
blockade by propoxyphene reversed with lidocaine.
J Clin Invest 1989;84(5):1629-36.
27. Stork CM, Redd JT, Fine K, et al. Propoxypheneinduced wide QRS complex dysrhythmia responsive to
sodium bicarbonate- a case report. J Toxicol Clin Toxicol
1995;33(2):179-83.
28. Lawson AA, Northridge DB. Dextropropoxyphene
overdose. Epidemiology, clinical presentation and
management. Med Toxicol Adverse Drug Exp 1987;2
(6):430-44.
29. Thamdrup B, Ostergaard OV, Clausen E. Plasma
exchange in the treatment of propoxyphene
intoxications. Int J Clin Pharmacol Ther Toxicol 1986;
24(7):379-80.
30 Moore RA, Rumack BH, Conner CS, et al. Naloxone:
underdosage after narcotic poisoning. Am J Dis Child
1980;134(2):156-8.