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 = 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.
Introduction
Acute intentional benzodiazepines (BZDs) poisoning is a common drug poisoning in emergency department (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 γ-aminobutyric acid (GABA) and inhibit reuptake of adenosine in the brain leading to LOC. 2 Caffeine and theophylline antagonize the inhibitory effect of adenosine and have stimulatory effects on CNS. 3,4 Adenosine 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 Aminophylline as a non-specific antagonist of adenosine receptors and an inhibitor of esterase is a central nervous system (CNS) and cardiac stimulator. It has short effect duration. It is also a bronchodilator and increases secretion of gastric acid.
Prolonged hospital stay due to BZDs poisoning may cause complications such as nosocomial pneumonia and/or exacerbation of underlying diseases especially in older patients. It seems increasing consciousness can reduce these complications and their morbidity. BZDs-intoxicated patients with severe LOC (Glasgow Coma Score (GCS) < 8) with or without respiratory depression may need administration of flumazenil, although use of this antidote may not be beneficial in terms of risk to benefit ratio 6 and has many limitations in use such as possibility of seizure in BZD-dependent patients or in those with concomitant head trauma. 7 However, sometimes it is practically 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 diaphragm contraction and increase of the minute ventilation 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 endoscopy. 9,11,12 Although the efficacy of aminophylline on improvement of respiration and treatment of neonatal apnea has been shown, its effectiveness on increasing consciousness in patients who have intentionally 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 positive urine tests for BZDs). Urinary screening test was also sent for other drugs such as opioids, salicylate, 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 failure 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% 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 increasing the level of consciousness.
Similarly, respiratory status, respiratory rate, oxygen 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 characteristics of arterial blood gas (ABG) analysis were also checked.
Informed consents were obtained from patients’ relatives and legal guardians. Costs incurred, including 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 medications), 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 history of allergy to agonists of β-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 poisoning ED with diagnosis of acute pure benzodiazepine toxicity, 5 were excluded (4 patients became fully awake after receiving aminophylline and left the hospital after signing the refusal consent form as well 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 control 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 = 0.11).
The patients data in both intervention and control group.
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 intervention group and 240 and 1740 min in the control group (mean 885 ± 352 min; p < 0.01) (Table 2). Mean GCS on admission was 11.52 ± 0.82 in the intervention group and 11.37 ± 1.13 in the control group (p = 0.62). This number was 13.8 ± 0.92 and 13.7 ± 0.8 on the 8th-h post admission (p = 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.
Consciousness and vital signs of patients in both intervention and control groups.
aThe time that LOC assessed after finishing the intravenous infusion of aminophylline.
bThe time at which the patients became awake, alert, and oriented.
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 intervention 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 difference between the two groups in GCS at the end of the 1st h after finishing administration of aminophylline (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 significant 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 poisoning, increased consciousness is expected as our results confirm it. Recent studies on the mechanism of action of BZDs suggest an antagonistic action on adenosine receptor sites in the brain and an increasing extracellular adenosine level possibly by blocking adenosine reuptake into neuronal and glial cells. 1,11 Many researches introduced methylxanthines such as aminophylline 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 ventilation in neonatal apnea and to abolish Cheyne–Stokes respiration. 9 Aminophylline can stimulate the medullary respiratory center and can be effective in reversing 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 aminophylline 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 toxicity, 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 cardiopulmonary 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 flumazenil is prohibited in high-risk patients with unstable vital signs, dependency to BZDs, concomitant use of seizure-inducing drugs such as TCAs, and history 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 adenosine antagonist could improve the CNS depressant effects of BZDs in the brain as mentioned in the previous 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 consciousness in patients sedated for surgery with drugs other than BZDs like barbiturates. The important clinical 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 substitute for flumazenil specially when there are limitations for flumazenil use 20 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 complications 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 consciousness 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 cardiopulmonary diseases. Although iatrogenic BZDs overdose 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 severely sedated by BZDs 20 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 recommend future research on use of multiple dose or continuous infusion of aminophylline.
Footnotes
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 relationships with any organizations in the previous 3 years.