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Benzodiazepine (BZD) Overdose (OD) in
Emergency Department
Abstract
Benzodiazepines are commonly prescribed
drugs and although ingestions are
relatively common, fatalities from
Benzodiazepines alone are rare. The
clinical findings of pure BZD overdose
are usually those of mild CNS
depression, rarely causing coma alone.
The specific Benzodiazepine antagonist
flumazenil is useful in the differential
diagnosis of coma in the Emergency
Department, when BZD overdose alone is
suspected. Our Department diagnosed a
few patients with BZD OD. The antidote
flumazenil was used in three comatosed
patients without any side effects.
Key words :Benzodiazepines, Overdose, Management of, Flumazenil
Case 1 :
A 40 year old female was brought to the
Emergency Department by her family.
History was taken from her husband who
gave a history of increased sleepiness
for one day before the admission. She
was sleepy and drowsy the day before the
presentation, she was then awake for a
few hours only, then went back to sleep
and did not regain full consciousness
after that. On examination the lady was
drowsy, difficult to arouse Glasgo Coma
Scale (G.C.S.) was 11, not responding to
verbal stimuli, and was not aware of the
surrounding, her pupils mid-sized
reacting to light. Her other general
examination was unremarkable including a
normal BP of 120/80 mmHg and HR 80. A
working diagnosis of Post-ictal state
was reached, CBC, Biochemistry, Arterial
Blood Gas (ABG), ECG, C.T. Brain were
requested and were all normal. The
husband was then interviewed again and
she denied any history of drug ingestion
and no previous illnesses or Psychiatric
disorders. With further questioning he
admitted she had taken some sedatives in
the past to help her sleep, but that was
more than a year ago. Benzodiazepine OD
was suspected and the antidote
Flumazenil 0. 2 mg was given I.V. Within
two minutes she showed a good recovery
but then deteriorated quickly. Another
0.2mg of Flumazenil was given IV then
she regained full consciousness, which
lasted for about five minutes. She
denied any history of drug ingestion but
we had to give her more doses of
Flumazenil up to 1mg (total dose) and
admitted her to the Hospital. After
making a full recovery she discharged
her self from the hospital against
medical advice.
Case
2 :
A 45 year old lady suffering from anxiety was admitted to the Emergency
Department observation area for about 10
hours. History was taken from her son
and daughter didnصt reveal anything of
significance apart from Diabetus
Mellitus which was well controlled by an
oral hypoglycaemic agent . We asked
specifically about history of drug
ingestion, or convulsions but they
denied any related significant history.
They only mentioned that their mother
had gone to the toilet and collapsed
there. Surprisingly, the husband did not
attend the hospital to visit or
accompany, his wife. On examination she
was laying flat in bed with G.C.S. about
(9) but her vitals were normal including
BP 110/80, H.R. 70/min regular, R.R. of
10/min., and over R. Blood sugar was 8
mml on presentation and was maintained
between 6-8 mml during her hospital
stay. Her pupils were equal in size,
sluggish in reaction to light, with
about 4mm in size. Her other general
examination was unremarkable. Her
investigations showed normal CBC,
Biochemistry, ECG, CXR, Liver enzymes,
Blood sugar, and C.T. Brain. Her
Arterial Blood Gas (ABG) showed slight,
hypercapnia ( sign of early Respiratory
depression). Blood levels for toxicdogy were negative for barbiturates
and cyclic anti-depressants.
Benzodiazepines overdose was suspected
and Flumazenil 0. 2 mg was given I.V.,
she showed some recovery but she made a
good recovery after another 0. 2mg I.V.
After a few minutes she needed another
0.4 mg of flumazenil in divided doses
where she regained full consciousness
and walked out of the hospital refusing
the admission. Again she denied any drug
ingestion or any Psychiatric disorder.
Case
3 :
An 18 year old man was brought to Emergency Department by his family complaining
of drowsiness and deterioration of his
conscious level since (6) hours. On
examination he was drowsy, disoriented
GSC of 11, pupils equal/reacting. Other
systemic examination was unremarkable.
The initial results of CBC, Biochemistry
and CXR, were all normal. Taking the
history from his sister, she said the
previous night he had severe footache
and could not sleep because of the pain,
so she had to give her brother some
sleeping tablets, she gave him (4)
tablets all together. The tablets were
prescribed to her by the psychiatrist
for adjacment disorder after a
bereavement. Benzodiazepines overdose
was suspected and the antidote
Flumazenil 0.2 mg was given I.V. He
regained consciousness in a few minutes
and made a full recovery. After the
second dose of 0.2mg, he was then
discharged home after a few hours of
observation.
Historical Perspective:
Prior to 1950, treatment of anxiety was limited, then a modified barbiturate,
Meprobamate was synthesized. Aultimately
proved no safer than the barbiturate but
its commercial success inspired the
development of other non barbiturate
anxiolytics. The first BZD,
chlordiazepoxide was first introduced in
1960 and diazepam soon followed. The BZD
have distrinct advantages over The
barbiturates namely cardiac effects and
fatalities from pure BZD overdose are
rare, respiratory depression less
pronounced than with barbiturate, and
they cause minimal drug-metabolizing
enzymes (ie, cytochrome P450)
stimulation and result in very few
adverse drug-to-drug interactions.
Benzodiazepines remain among the most
widely prescribed drugs of any class
with nearly 50 types available world
wide. BZD are the most common
prescription drugs used by individuals
attempting drug-assisted suicide.
Principles Of Disease :
BZD produce sedative, hypnotic anxiolytic, and
anticonvulsant effects by enhancing the
inhibitory actions of GABA. Binding of a
BZD to a specific BZD receptor
potentiates GABA effects on the chloride
channel at the GABA, receptor increasing
intercellular flux of chloride ions and
hyperpolarizing the cell. The net effect
is a diminished ability of the nerve
cell to initiate an action potential,
resulting in inhibition of neural
transmission. Three groups of BZD
receptor ligands have been identified:
(1) agonists (classic) produce the
therapeutic effects. (2) Inverse
agonists ( beta-carbolines) cause
effects opposite to those of the
agonists. (3) Antagonists (Flumazenil)
competitively inhibit the effects of
both the agonists and inverse agonists.
Flumazenil may reverse hepatic
encephalopathy in patients with liver
failure. Recent studies have shown the
presence of BZD-like substances that
enhance GABA ergic activity in patients
with hepatic encephalopathy. Flumazenil
appears to inhibit the binding of theses
substances. There are also
peripheral-type BZD receptors in a
variety of organs but their role is not
clear.
Pharmacokinetics
Oral BZD are rapidly absorbed. Intramuscular chordiazopoxide and diazepam
is limited by erratic eruption,but both
lorazepam and midazolam are predictably
absorbed intramuscularly. BZD are highly
protein-bound, distribute easily in the
tissues after absorption, and penetrate
easily the blood brain barrier because
of their highly lyophilize structure.
BZD metabolism occurs in the liver. Some
of them Oxazepam, Temazepam, and
Larazepams are directly conjugated to an
inactive water-soluble glucuronide
metabolite that is excreted by the
kidney. Other BZD must first be
metabolically converted by the hepatic
cytochrone p450 system. Coingestion of
drugs that use cytochrom p450
metabolism,i.e. Cimetidine, Ethanol may
prolong the half-lives of these BZD;
however, the clinical significance of
these interactions is unclear. In the
elderly, and in liver disease,
cytochrome p450 processes may be
significantly impaired leading to
prolonged elimination of some of the BZD.
Several BZD are metabolized to or more
active metabolites, which either slowly
or rapidly conjugate and are excreted.
Clinical Features:
The clinical findings of pure BZD
poisoning are usually those of mild CNS
depression: lethargy, drowsiness, and
short-term memory loss. Coma is rare
after pure BZD ingestion. Respiratory
depression may be seen with large oral
overdoses. Physical signs include
tachycardia, altered level of
consciousness, hyporeflexia,
hypereflexia, hypothermia, dysartria,
seizures, ataxia, nystagmus,
hallucination, and, rarely, hypotension
and hyperthermia. Death with BZD
overdose is rare, laxity of the
pharyngeal muscles that can result in
obstructive sleep apnoea and aspiration
(1) Pressure necrosis of skin and
muscles may occur, Rhabdomyolysis has
been reported in mixed ingestion,(2)
especially with psychotropic drugs.
Laboratory Evaluation :
Laboratory Evaluation: Qualitative
immunoassays of BZD in the urine is
available and may be useful to confirm
the presence of BZD, particularly if the
history is unreliable. Many of these
tests detect only BZD that are
metabolized to oxazepam glucuronide.
Serum drug concentrations are not
routinely available on an emergent basis
and do not correlate with clinical
severity and outcome.(3)
Differential considerations :
The signs and symptoms of BZD intoxication are nonspecific, atypical and usually
mild. The presence of profound coma,
marked hypotension and significant
respiratory depression may suggest
coingestion with alcohol, opiate, major
tranquilizes, sedative-hypnotics
(barbiturates), or tricyclic
antidepressants. The contribution of
opiates to the overdose state can be
determined by the use of naloxone. The
BZD antagonist Flumazenil is useful in
the differential diagnosis of coma in
the emergency department.(4,5) Any
suspicion of concomitant tricycle
overdose contraindicates Flumazenil use.
(6,7)
Management:
BZD OD usually requires only supportive
care ( activitaed charcoal
administration 1gm/Kg). This can be
repeated ( 15-20gm every 2-4 hours) in
high risk patients with COPD , liver
cirrhosis, multiple drug ingestion,
children, and the elderly. (5) As with
any serious OD, secure the airway,
monitor breathing and circulation, and
check the blood sugar. Use Naloxone if
indicated. Respiratory depression many
not be completely reversed by
Flumazenil,(8) and it may need assisted
ventilation. Hypotension not responding
to IV fluids ( ie, 2L Normal saline or
Ringers lactate), either dopamine or
norepinephine should be titrated to
maintain the systolic blood pressure
above 90mm Hg
Antidote:
Flumazenil is a specific BZD respecter antagonist and has been shown to be
effective in reversing BZD induced
sedation and coma. (4,5,9,10) There are
reports of reversal of hypotension with
Flumazenil.(11,12) Seizures and
dysrhythmias can occur with Flumazenil
administration. (13,14,15,16)
Coingestion of drugs with proconvulsant
properties is associated with an
increased risk of seizures, because of
the loss of the BZD's protective
anticonvulsant effect when the
antagonist is administrated. Combined OD
of BZD with cyclic antidepressants
accounts for 50% of these seizures. (14)
Coingestants with carbamazepine, or
chloral hydrate may increase the chance
of arrhythmias by a similar percentage.
For Indications/Contraindications of
Flumazenil please refer to Table (1) The
initial adult dose of Flumazenil is
0.2mg I.V. over 30 seconds, with
subsequent dose of 0.3-0.5mg q1 min. up
to a total of 3mg. Recovery is usually
rapid within 5 minutes, even after the
ingestion of large quantities of BZD.
Flumazenils half-life is approximately 1
hour, so patients who ingested longer
acting BZD may require multiple doses or
continuous infusions.(4) The rate of an
infusion is 0.1-0.2mg/hr
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Table 1 : Use of Flumazenil |
Sever withdrawal reaction in chronic BZD
users may be induced after Flumazenil,(14)
so it is suggested initial small doses
be used with additional incremental
doses given as needed. BZD withdrawal
symptoms, please refer to Table (2)
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Table 2 : Benzodiazepine
withdrawal symptoms |
Conclusion
The specific BZD antidote
Flumazenil is useful in the differential
diagnosis of coma in the ED, if
coingestion of other drugs are excluded.
In Hamad General Hospital, in Doha, the
Emergency Department (ED) receives an
average of 800 patients every 24 hours,
so we expect to see more of sedative and
drug misuse. As we had approached our
patient, Flumazenil is relatively safe
if given in highly suspect cases of BZD
OD alone without coingestion, started
with small doses provided the ECG
( Q.T.
interval) is normal. This will reduce
the time spent by the patient in the ED,
and reduce the load on admissions where
we have a shortage of beds most of the
time, especially for the monitored beds.
If coingestion with cyclic
antidepressants is suspected, blood
levels can be determined before giving
any BZD antidote. The availability of
BZD qualitative assay in urine may be
useful to confirm the presence of BZD.
Coingestion of BZD with alcohol is rare
in our society because of the religious
background (Islam forbids drinking
alcohol). We suggest further studies be
conducted to see the scale of the mixed
drug abuse, in comparison with a single
drug misuse in our society. In summary,
Flumazenil should be used for selected
patients with significant symptoms from
a known benzodiazepine overdose and not
routinely used in patients with altered
mental status.
References
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