Article

Human and Experimental Toxicology

2017, Vol. 36(3) 311–316
The effects of intravenous ª The Author(s) 2016
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aminophylline on level DOI: 10.1177/0960327116646619
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of consciousness in acute intentional
benzodiazepines poisoning
in comparison to flumazenil

A Aghabiklooei1 and J Sangsefidi2

Abstract
Aim: Acute intentional benzodiazepine poisoning is marked by a significant loss of consciousness, aspiration
pneumonia, and increased rates of mortality and morbidity, especially in older patients with underlying heart or
lung disease. These patients may need flumazenil to reverse the respiratory effects of benzodiazepines. The
positive effects of aminophylline on respiration and neonatal apnea improvement have been shown previously.
However, its possible effects on increasing the level of consciousness have never been evaluated.
Methods: In a placebo-controlled study, we assessed the effectiveness of aminophylline on increasing the level
of consciousness.
Results: Time to full awakening was significantly shorter in those who received aminophylline (72 min vs.
881 min, p ¼ 0.001), compared to those who received a placebo.
Conclusion: When ‘‘flumazenil’’ is contraindicated or unavailable, intravenous aminophylline can be used as
a second choice.

Keywords
Aminophylline, poisoning, benzodiazepines, consciousness, flumazenil

Introduction effect duration. It is also a bronchodilator and

Acute intentional benzodiazepines (BZDs) poisoning
is a common drug poisoning in emergency depart-
ment (ED). The most prominent symptom is loss of
consciousness (LOC). BZDs poisoning may also lead
to respiratory depression, apnea, or death in high
doses or in older patients especially with underlying
cardiopulmonary diseases.1 BZDs augment activity of
g-aminobutyric acid (GABA) and inhibit reuptake of
adenosine in the brain leading to LOC.2 Caffeine and
theophylline antagonize the inhibitory effect of ade-
nosine and have stimulatory effects on CNS.3,4 Ade-
nosine antagonists like aminophylline inhibit BZDs
binding to GABA receptors.4 Studies on rats have
shown that prescription of adenosine antagonists
increase BZDs withdrawal symptoms.5 Aminophyl-
line as a non-specific antagonist of adenosine recep-
tors and an inhibitor of esterase is a central nervous
system (CNS) and cardiac stimulator. It has short
increases secretion of gastric acid.
Prolonged hospital stay due to BZDs poisoning
may cause complications such as nosocomial pneu-
monia and/or exacerbation of underlying diseases
especially in older patients. It seems increasing con-
sciousness can reduce these complications and their
morbidity. BZDs-intoxicated patients with severe
LOC (Glasgow Coma Score (GCS) < 8) with or with-
out respiratory depression may need administration
1
Department of Legal Medicine and Toxicology, Firouzgar Hospi-
tal, Iran University of Medical Sciences, Tehran, Iran
2
Tehran University of Medical Sciences, Tehran, Iran
Corresponding author:
A Aghabiklooei, Department of Legal Medicine and Toxicology,
Firouzgar Hospital, Iran University of Medical Sciences, Valiasr Sq.,
Valadi Ave, Tehran, Iran.
Emails: aghabikloo@yahoo.com; aghabikloo.a@iums.ac.ir
312
of flumazenil, although use of this antidote may not
be beneficial in terms of risk to benefit ratio6 and has
many limitations in use such as possibility of seizure
in BZD-dependent patients or in those with concomi-
tant head trauma.7 However, sometimes it is practi-
cally impossible to use flumazenil in many cases of
BZDs toxicity in underdeveloped countries because
of its high cost and unavailability.
The effects of aminophylline as a stimulator of
central respiratory center in improvement of dia-
phragm contraction and increase of the minute venti-
lation have been shown.8 Some researches introduced
aminophylline as an antagonist of BZDs in 1985.9–11
Aminophylline could reverse the depressive affects of
BZDs on the brain in patients who were iatrogenically
overdosed during medical procedures like endo-
scopy.9,11,12 Although the efficacy of aminophylline
on improvement of respiration and treatment of neo-
natal apnea has been shown, its effectiveness on
increasing consciousness in patients who have inten-
tionally ingested a large amount of benzodiazepines
has not been investigated. In this prospective placebo-
controlled study, we assessed the effectiveness of
aminophylline on increasing consciousness of
BZDs-poisoned patients.
Materials and methods
This was a placebo-controlled single blind study.
Suicidal patients aged between 14 and 60 years who
presented to poisoning ED of Baharloo Hospital in
Tehran with diagnosis of acute pure BZDs poisoning
and LOC were randomly divided into intervention
and control groups (by drawing lots from a dark bag
containing 25 labels of A for intervention group and
25 labels of B for control group). Diagnosis of BZDs
toxicity was made clinically (history of the name and
dose of the ingested drug, signs of toxicity, and pos-
itive urine tests for BZDs). Urinary screening test was
also sent for other drugs such as opioids, salicylate,
Human and Experimental Toxicology 36(3)
over 30 min (placebo). Serum was administered by
trained ED nurses who were blind to the study. After
emergency management, all patients were admitted to
toxicology ward or intensive care unit (ICU) and
underwent cardiac, respiratory, and pulse-oximetry
monitoring. Our patients were also blind to the aims
and process of the study.
Level of consciousness was evaluated by the GCS
scoring system on arrival and during admission at 1th,
2nd, 4th, 6th, and 8th h post hospitalization. The time
of full consciousness recovery was also recorded. We
used term of ‘‘awaking time’’ when our patient
became fully alert, awake, and oriented to time, place,
and person. Our main outcome measure was increas-
ing the level of consciousness.
Similarly, respiratory status, respiratory rate, oxy-
gen saturation, heart rate, and blood pressure were
measured and recorded on admission and every 2 h,
afterward. Other data including age, gender, type and
dose of the drug used, patient’s place of admission
(ward versus ICU), hospital stay period, and charac-
teristics of arterial blood gas (ABG) analysis were
also checked.
Informed consents were obtained from patients’
relatives and legal guardians. Costs incurred, includ-
ing drugs, were reimbursed to patients. This research
was approved by ethical committee on research of
faculty of medicine of Tehran University with number
92/D/130/184 on October 26th, 2015.
Exclusion criteria
Cases of multiple drug toxicity (all those who had
positive test results for drugs other than BZDs in urine
screening test or mentioned ingestion of other medica-
tions), those with concomitant head trauma associated
with toxicity, cases with hypoglycemia, patients with
history of underlying diseases including peptic ulcer,
chronic renal or hepatic failure, chronic lung diseases,
and cardiac diseases especially dysrhythmia, positive
phenothiazines, and tricyclic antidepressant (TCA)
for all patients on admission to rule out mixed drug
toxicity. Serum level of glucose was checked for all
patients on arrival using dipstick test.
On ED admission, patients received emergency
management if needed and those with respiratory fail-
ure and/or GCS < 8 underwent tracheal intubation.
Patients in intervention group received a single dose
of intravenous aminophylline with dose of 5 mg/kg in
100 cc of dextrose 5% over 30 min and patients in
control group only received 100 cc of dextrose 5%
history of allergy to agonists of -adrenergic receptors
such as theophylline, age over 60 and below 14 years,
and those whose relatives refused this treatment and
did not sign the consent form were excluded.
Results
Of 50 intoxicated patients who were brought to poi-
soning ED with diagnosis of acute pure benzodiaze-
pine toxicity, 5 were excluded (4 patients became
fully awake after receiving aminophylline and left the
hospital after signing the refusal consent form as well
Aghabiklooei and Sangsefidi 313

Table 1. The patients data in both intervention and control group.

Intervention G Control G
No.: 21 No.: 24
Sex Female 14/(67%) 14/(58%)
male 7/(33%) 10/(42%)
Age (years) Mean + SD 28 + 9 30 + 9
The time taken to arrive hospital (h) Mean + SD 5.3 + 4.2 5.5 + 2.1
Kinds of drug led to toxicity Chlorodiazepoxide 3/(14.3%) 1/(4.2%)
Diazepam 3/(14.3%) 3/(12.5%)
Clonazpam 6/(9.5%) 7/(29.2%)
Alprazolam 12/(57%) 10/(41.7%)
Iorazepam 1/(4.8%) 3/(12.5%)

Table 2. Consciousness and vital signs of patients in both intervention and control groups.
Intervention G Control G
Signs Checking timea No.: 21 (mean + SD) No.: 24 (mean + SD) p Value
Level of consciousness (GCS) On arrival time 11.5 + 0.8 11.3 + 1.1 0.62
At the end of 1th h 14.6 + 0.8 12.5 + 1.0 <0.01
At the end of 2nd h 14.0 + 0.7 12.79 + 0.8 <0.01
At the end of 4th h 13.6 + 0.8 13.3 + 0.7 0.174
Respiratory rate (per min) On arrival time 14.6 + 1.7 17.0 + 3.3 0.62
At the end of 1th h 15.0 + 1.7 14.8 + 1.7 0.75
At the end of 2nd h 15.2 + 1.8 15.6 + 1.8 0.75
At the end of 4th h 14.4 + 2 15.7 + 2.0 0.557
Pulse rate (per min) On arrival time 91 + 16 84 + 18 0.214
At the end of 1th h 95 + 12 85 + 11 0.192
At the end of 2nd h 90 + 11 84 + 14 0.192
At the end of 4th h 89.66 + 10.56 84 + 15 0.141
Systolic blood pressure (mm/Hg) On arrival time 112.61 + 2.64 112.95 + 2.48 0.928
At the end of 1th h 108.95 + 2.47 116.00 + 2.3 0.134
At the end of 2nd h 112.85 + 2.40 116.20 + 2.24 0.055
At the end of 4th h 112.04 + 3.00 109.54 + 2.81 0.524
Awaking timeb (min) 72.61 + 13.20 880 + 35 <0.01
Mean hospital staying (h) 76.1 77.6 0.75
a
The time that LOC assessed after finishing the intravenous infusion of aminophylline.
b
The time at which the patients became awake, alert, and oriented.

as another patient who did not give reliable history).
Finally, 45 patients were enrolled: 21 in intervention
group and 24 in control group. Twenty-eight (62%)
were female and 17 (37%) were male. Patients were
between 15 and 52 years old with a mean age of 29
years (Table 1). Alprazolam was the most common
ingested drug in 22 (49%) cases. Other drugs used
included chlordiazepoxide (9%), diazepam (13%),
clonazepam (20%), and lorazepam (9%). In total, one
patient from intervention group and three from con-
trol group were admitted to ICU because of severe
LOC (GCS < 8), and the remainder was hospitalized
in the poisoning ward. The shortest hospital stay was
1.7 days (40.8 h) in a patient in intervention group
who received aminophylline. Generally, there were
no significant differences between the two groups in
terms of hospital stay (p ¼ 0.11).
Status of consciousness
Time taken to regain consciousness (awaking time)
after taking one dose of intravenous aminophylline
was recorded in minutes. Awaking time was between
15 and 260 min (mean 72 +53 min) in the interven-
tion group and 240 and 1740 min in the control group
(mean 885 + 352 min; p < 0.01) (Table 2). Mean
314
GCS on admission was 11.52 + 0.82 in the interven-
tion group and 11.37 + 1.13 in the control group (p ¼
0.62). This number was 13.8 + 0.92 and 13.7 + 0.8
on the 8th-h post admission (p ¼ 0.697), respectively.
The difference was significant on the 1st and 2nd and
insignificant on the 4th- to 8th-h post admission
(Table 2). No significant difference was observed
between the two groups in heart rate, respiratory rate,
or blood pressure before and after administration of
drug or during hospitalization.
Discussion and conclusion
We had several limitations including: First, we did not
record the patients’ level of consciousness 30 min
after finishing the infusion of aminophylline, and the
first record was done 1 h later; Second, we could only
detect the BZDs qualitatively and were not able to
check their serum concentration due to laboratory
limitations; third, four patients (one in intervention
and three in control group) had severe LOC and
underwent tracheal intubation; however, 42 patients
had GCS > 8 and did not need tracheal intubation.
There was a significant difference between inter-
vention and control groups in awaking time after
administration of aminophylline (72.6 min vs.
885 min, respectively). This showed effectiveness of
aminophylline in faster regain of consciousness in the
intervention group. There was also a significant dif-
ference between the two groups in GCS at the end of
the 1st h after finishing administration of aminophyl-
line (14.6 vs. 12.5, respectively). At the end of the 4th
h, GCS dropped in the intervention group and was
nearly equal to that in the control group. We believe
that this regression of GCS is due to decreasing the
serum aminophylline concentration confirming our
hypothesis that aminophylline is effective on raising
consciousness in cases of BZDs toxicity. This also
means that one dose of aminophylline is able to keep
patients conscious for at least 2 h.
There was no significant difference between the
two groups in duration of hospital stay. This means
that administration of a single dose of aminophylline
did not reduce hospital staying. There were no signif-
icant differences between the two groups in other vital
signs.
As discussed, adenosine has a physiologic role in
inducing sleep and sedation. With administration of
adenosine antagonists to a patient with BZDs poison-
ing, increased consciousness is expected as our results
confirm it. Recent studies on the mechanism of action
Human and Experimental Toxicology 36(3)
of BZDs suggest an antagonistic action on adenosine
receptor sites in the brain and an increasing extracel-
lular adenosine level possibly by blocking adenosine
reuptake into neuronal and glial cells. 1,11 Many
researches introduced methylxanthines such as ami-
nophylline as an antagonist of adenosine receptors.9–11
Philips et al. showed that 1 mg/kg of intravenous
aminophylline could antagonize the effects of BZDs
and clinically reverse BZDs-induced somnolence.3,13
Aminophylline has also been used to improve ventila-
tion in neonatal apnea and to abolish Cheyne–Stokes
respiration.9 Aminophylline can stimulate the medul-
lary respiratory center and can be effective in rever-
sing BZDs-induced sedation in low dose. This action
has been widely used in treatment of apneic attack in
neonates.14–19 The other important effect of amino-
phylline as a stimulator of central respiratory center is
improvement of diaphragm contraction and increase
in the minute ventilation.8
This study showed that in cases of acute BZDs toxi-
city, aminophylline can increase the consciousness
level and reduce the need for tracheal intubation and
aspiration pneumonia. This is especially important in
the elderly or in cases of advanced underlying cardio-
pulmonary diseases. Although aminophylline cannot
quickly reverse drowsiness or respiratory depression
of BZDs in comparison to flumazenil, it can be used
when access to flumazenil is impossible or when flu-
mazenil is prohibited in high-risk patients with
unstable vital signs, dependency to BZDs, concomitant
use of seizure-inducing drugs such as TCAs, and his-
tory of seizures.6,7,20 Moreover, against flumazenil,
aminophylline does not increase intracranial pressure
especially in patients with concomitant head trauma.
Our findings showed that aminophylline as an ade-
nosine antagonist could improve the CNS depressant
effects of BZDs in the brain as mentioned in the pre-
vious studies 19,21,22 that showed theophylline
reversed sedative effects of propofol on adenosine
receptors. Another study by Krintal et al.23 showed
effectiveness of aminophylline on improving con-
sciousness in patients sedated for surgery with drugs
other than BZDs like barbiturates. The important clin-
ical point of this study was that aminophylline could
improve the CNS depressant effects of BZDs for at
least 2 h. However, CNS depression may return if
aminophylline is not readministered. Thus, further
studies to find maintenance dosage of this drug are
warranted.
Our study showed that aminophylline can be a sub-
stitute for flumazenil specially when there are
Aghabiklooei and Sangsefidi
limitations for flumazenil use20 such as probability of
seizure (dependent patient to BZDs) or in cases of
acute BZDs toxicity who have concomitantly ingested
other drugs that can lead to seizure. This study also
showed that some complication of acute BZDs
toxicity such as aspiration pneumonia and compli-
cations of tracheal intubation can be prevented by
aminophylline therapy. Despite our expectation, use
of aminophylline did not lead to less hospital stay
which we think is due to the fact that we prescribed
only one dose of aminophylline and did not continue
the maintenance dose. Aminophylline resulted in
complete awaking in all patients in intervention group
with no adverse events. Seizure and dysrhythmia did
not occur in any of our patients. Therefore the authors
believe that aminophylline use is probably safe and
effective in acute BZDs toxicity and improves the
patients’ outcome.
The authors recommend aminophylline use in
BZDs overdose setting if the electrocardiogram is
normal and GCS is less than 8 to prevent intubation,
decrease the use of mechanical ventilation, and
decrease the rate of aspiration pneumonia. Admission
of the patients to ICU for sole monitoring is not cost-
effective and early awaking of these patients with
administration of aminophylline may obviate the need
for ICU admission in most of BZDs-intoxicated cases.
Prolonged hospital stay due to BZDs poisoning may
also cause complications like nosocomial pneumonia
or exacerbation of underlying diseases especially in
older patients who have chronic medical problems
and do not tolerate major stressors without significant
complications. It seems that trying to increase con-
sciousness can reduce these complications and their
morbidity. Based on our results, the authors believe
that in severe cases of BZDs toxicity such as suicidal
cases with ingestion of large amounts of BZDs
associated with significant LOC, administration of
aminophylline can lead to increased consciousness.
It can also reduce the need for tracheal intubation,
the probability of aspiration pneumonia, and decrease
the morbidity and mortality rates especially in the
elderly or those with advanced underlying cardio-
pulmonary diseases. Although iatrogenic BZDs over-
dose rarely induces respiratory arrest, possibility of
apnea increases in intentional poisoning cases with
large amounts of ingestion or in old patients with
underlying cardiopulmonary diseases.
However, flumazenil is still the first choice in
respiratory depression and apnea following medical
procedures where patients are iatrogenically and
315
severely sedated by BZDs20 except for when it is
contraindicated or unavailable. We recommend a
dose of theophylline in suicidal BZDs-poisoned
patients to reverse their LOC while we also recom-
mend future research on use of multiple dose or con-
tinuous infusion of aminophylline.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest
with respect to the research, authorship, and/or publication
of this article.
Funding
The author(s) declared the following potential conflicts of
interest with respect to the research, authorship, and/or
publication of this article: The authors had support from
both Tehran University and Iran University of medical
sciences for this research. There are no financial relation-
ships with any organizations in the previous 3 years.
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