sign in sign up
<<
Home , Benzodiazepine overdose, Induced coma

Critical Care Issue: Volume 24(2), February 1996, pp 199-206 Copyright: © Williams & Wilkins 1996. All Rights Reserved. Publication Type: [Clinical Investigation] ISSN: 0090-3493 Accession: 00003246-199602000-00004

[Clinical Investigation] Use of in the treatment of : A double-blind and open clinical study in 110 patients Weinbroum, Avi MD; Rudick, Valeri MD; Sorkine, Patrick MD; Nevo, Ygal MD; Halpern, Pinchas MD; Geller, Eran MD; Niv, David MD

Author Information From the Departments of and Critical Care Medicine (Drs. Weinbroum, Rudick, Sorkine, Nevo, and Niv), and Emergency Room (Dr. Halpern), Tel-Aviv- Elias Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel, and the Surgical (Dr. Geller), Palo Alto Veterans Administration Medical Center and the Stanford University School of Medicine, Palo Alto, CA. This study was supported, in part, by institutional departmental funds. Address requests for reprints to: Avi Weinbroum, MD, Department of Anesthesiology and Critical Care Medicine, Tel-Aviv-Elias Sourasky Medical Center, 6 Weizman Street, Tel-Aviv 64239, Israel. Abstract

Objectives: To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of -induced (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness.

Design: A two-phase study: a controlled, randomized, doubleblind study followed by a prospective, open study.

Setting: An 800-bed, teaching, university-affiliated hospital.

Patients: Unconscious patients (n equals 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine . The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol.

Interventions: All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder . ,

electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious.

Measurements and Main Results: Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 plus minus 0.3 (SD) mg vs. one of 14 placebo patients (p less than .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 plus minus 0.6 to 0.4 plus minus 0.5 (p less than .01) after the injection of 0.7 plus minus 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested remained awake for 72 plus minus 37 mins after flumazenil administration; 40% relapsed into coma after 18 plus minus 7 mins and various central drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for less than equals 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and were encountered. There were 27 mildly unpleasant ``waking'' episodes, such as , restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in - intoxicated patients.

Conclusions: Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.

(Crit Care Med 1996; 24:199-206)

KEY WORDS: coma; overdose; intoxication, drug; benzodiazepines; ; flumazenil; tricyclic antidepressive agents

Since their discovery in the early 1960s, the use of benzodiazepines has seen an enormous expansion world- wide [1-3]. Their anxiolytic, , , and properties have led to frequent and sometimes inappropriate use. In the early 1980s, benzodiazepines were reported to be implicated in 40% to 60% of all suicide attempts [4-7], while the use of the potent benzodiazepine, , has recently been reported to be popular among youths around the globe. Pure benzodiazepine overdoses are usually not fatal [8-10]. However, the newer, short-acting, but potent derivatives (e.g., flunitrazepam, ) may greatly increase the frequency of complications [11-13], especially when benzodiazepines are combined with other - depressant drugs [13-15], or when aged or debilitated patients are involved [16,17]. Flumazenil (Anexate Registered Trademark in Europe, Romazicon Registered Trademark in the United States, Hoffmann-La Roche, Basel, Switzerland), a specific competitive central benzodiazepine receptor antagonist, has been increasingly used during the last decade in the treatment of benzodiazepine overdoses [15,18,19].

In the present study, we prospectively evaluated the clinical efficacy of flumazenil, both as a diagnostic and as a therapeutic tool in drug-intoxicated patients.

MATERIALS AND METHODS

Patients and Grouping.

The study group was comprised of 110 consecutive comatose patients, who were admitted to the emergency room or to the intensive care unit (ICU) between January 1, 1987 and January 1, 1992. Patients suspected of having ingested an overdose of drugs, based on history, physical examination, or information obtained from accompanying persons, were enrolled into the study. Patients less than 18 yrs of age, pregnant women, and individuals who had suspected brain trauma were excluded from the study. The study was approved by the Institutional Human Studies Committee and written informed consent was obtained from the next of kin.

The study was conducted in two phases. The initial phase (31 patients) was performed in a randomized, controlled, double-blind fashion. The remaining 79 consecutive patients were studied in an open-design protocol. The change to the open study was prompted by the efficacy of flumazenil in reversing coma due to benzodiazepine overdose in the first double-blind phase, making it unethical in the authors' view to withhold or delay the administration of the drug from such patients.

On arrival to the emergency room or ICU, patients received supplemental oxygen by mask if they were breathing spontaneously. Endotracheal intubation was performed whenever deemed necessary, and synchronized intermittent mandatory ventilation was initiated as required. Each patient was connected to an electrocardiogram monitor. A peripheral intravenous cannula was inserted, through which a solution of 5% dextrose in 0.45% sodium chloride was infused. Indwelling arterial and urinary bladder catheters were also introduced in all patients. A central venous was inserted and vasoactive drugs (e.g., , ephedrine) were administered whenever blood pressure was below normal despite adequate fluid load, or when urine output was less than 0.5 mL/kg/min. Blood pressure, heart rate, respiratory rate, and end-tidal CO2, as well as core temperature, were continuously recorded on paper (Cardiocap Registered Trademark, Datex Corporation, Helsinki, Finland). Whenever it was available, the patients were monitored by a two-channel, computerized, online spectral analysis electroencephalogram, displaying left and right hemispheric electrical activity (Cerebro Trac 2500 Trademark, SRD, Shorashim, Israel).

Depth of coma was graded according to the Matthew and Lawson scale [20]: 0 equals patient fully conscious; 1 equals patient drowsy but reawakens to verbal commands; 2 equals asleep, awakens to skin stimulation; 3 equals asleep, reactive to mild painful stimulation; and 4 equals patient comatose, does not react to maximal painful stimulation. Patients with a coma grade of 0 to 1 were not admitted into the study. Hemodynamic and respiratory variables were measured upon the individual's entry into the trial and at 5, 10, 15, 30, 45, 60, and 90 mins later, as well as hourly after the start of the study for as long as treatment continued. All patients underwent with tap water through a nasogastric tube, which was introduced only when a gag reflex was demonstrably active or when airways were secured by an endotracheal tube with an inflated cuff. They then received 30 g of activated charcoal every 4 hrs until fully awakened. Sodium bicarbonate was administered for alkalization of the blood in patients with tricyclic overdose, and alkalization of the urine in cases of intoxication with long-acting barbiturates.

Biochemical and hematologic profiles were obtained before test drug administration, and the arterial blood gases and acid-base balance were assessed and corrected if necessary. At the same time, samples of blood and urine were taken for drug screening (Emit Tox Trademark serum tricyclic antidepressants, benzodiazepine, and barbiturates assays, Syva, San Jose, CA, for drug tracing in blood, and gas chromatography for urine screening). Drug serum concentrations measured by this assay are the result of the total of all derivatives belonging to the same class of drugs. For example, if different benzodiazepines had been used by one patient, all were combined and expressed as the equivalent only (therapeutic sedative concentrations of 0.3 to 0.5 ng/mL). Barbiturates were combined and expressed as the secobarbital equivalent (therapeutic anticonvulsant serum concentration ranges of 0.5 to 2 ng/mL). Tricyclic antidepressant agents were combined and expressed as nortriptyline (effective antidepressant activity less than 800-ng/mL therapeutic values).

Double-Blind, Controlled Phase.

The first consecutive 31 patients were studied in a randomized, double-blind fashion. The contents of coded 10-mL ampules were injected intravenously at a rate of 1 mL every 30 secs. Ampules contained either 1 mg/10 mL of flumazenil (Anexate in Europe, Romazicon in the United States, Hoffmann-La Roche) or saline. The test drug was injected until either spontaneous awakening occurred or a total of 10 mL was reached. Patients who regained consciousness after flumazenil injection but who later relapsed into coma, as well as those patients who did not awaken at all, were further treated with flumazenil in the open-design phase. Data from both the double-blind and the open-phase groups were pooled together for analysis.

Open, Uncontrolled, Design Study.

Seventy-nine consecutive patients were treated with flumazenil in an open, prospective manner. Another 16 patients, previously treated according to the double-blind, controlled protocol and who remained unconscious, were added to this group. Flumazenil was injected intravenously in doses of 0.1 mg every 30 secs until full consciousness was regained, or until no improvement in depth of coma could be detected, despite the administration of 2.5 mg. Additional doses (1 mg) could be given only if the patient's level of consciousness changed after the 2.5 mg flumazenil cumulative dose. This ceiling dose was based on the authors' and others' experiences [15,19]. If deep sedation or coma recurred (coma grade of more than equals 2), either repeated doses of flumazenil were administered according to the abovementioned mode of injection, or, after an effective bolus of flumazenil, a continuous infusion was instituted at preestablished ranges of 0.1 to 1 mg/hr, titrated thereafter to prevent resedation [21,22]. Patients were randomly assigned to receive flumazenil in boluses or by infusion on a ratio basis of 2:1. The infusion was discontinued every 6 hrs, as long as the patient's coma score did not increase to more than equals 2, thereby determining the need for further flumazenil administration. After treatment was terminated, patients remained under close observation for the next 12 hrs and then were transferred to an internal ward.

Patients were extubated when fully awake, when they obeyed verbal commands, and when they communicated with the medical staff, and all hemodynamic and respiratory parameters were within normal ranges. Most importantly, extubation was performed after active gag reflex could be demonstrated in patients who were either intubated only or intubated and mechanically ventilated. Extubation was also performed after active gag reflex in those patients who had received intubation due to respiratory insufficiency (respiratory rate of less than equals 6 breaths/min, PaCO2 of more than 45 torr [more than 6.0 kPa], or tidal volume of less than 5 mL/kg, or lack of gag reflex). All of these extubated patients remained under continuous of all for 12 hrs thereafter.

All side effects, both local and systemic, were recorded.

Results are expressed as mean plus minus SD. Data regarding drug administration and central nervous system status were compared by the Mann-Whitney U test. Changes in physiologic variables, before and after flumazenil administration, were analyzed using Student's t-test, multiple analysis of variance, or the chi-square test, as appropriate. The level of significance was chosen as.05.

RESULTS

Demographic and general data and the coma scores of all 110 patients are summarized in Table 1. Forty-five percent of the study group was more than equals 65 yrs of age. No patient had biochemical or hematologic values that were abnormal enough to explain the state of coma. Ten patients had received naloxone from first aid teams before the administration of flumazenil, but this drug had no effect on the state of unconsciousness.

Table 1. Demographic and general data (mean plus minus SD)

Controlled, Double-Blind Phase.

Data for this group are presented in Table 2. Full awakening was achieved by 14 of 17 flumazenil patients, with a cumulative single dose of 0.8 plus minus 0.3 mg within 2.5 plus minus 1.3 mins, whereas only one placebo patient out of 14 regained consciousness (p less than .001). Immediately after test-drug injection, five flumazenil- treated patients were safely extubated and endotracheal intubation could be avoided in three other patients. No patient in the placebo group could be safely extubated after test drug administration. Six flumazenil patients vs. one patient in the placebo group experienced mild, transient, side effects (p less than .05) which, however, did not necessitate specific treatment Table 3.

Table 2. Double-blind phase, demographic and general data

Table 3. Side effects Results in Both Phases.

The data presented reflect all 110 patients. The initial depth of coma of 63% of the patients was rated as being 3 or 4. Eighty-three (75%) patients (group R), including 11 placebo patients, successfully regained full consciousness after a cumulative single dose of 0.7 plus minus 0.3 mg of flumazenil. In 27 (25%) of the nonresponders (group NR), the depth of coma remained unchanged after a mean cumulative intravenous dose of 2.4 plus minus 1.6 mg of flumazenil. Five patients in group NR, although not regaining consciousness, showed evidence of an increase in spontaneous movements, slightly improved respiration, and sympathetic nervous system stimulation after 2.5 mg of flumazenil. The additional 1 mg prescribed in such cases did not ameliorate the patients' conditions.

In the responders (group R), the effect of flumazenil was fully manifest within 2.4 plus minus 1.7 mins from the start of injection. Patients remained fully awake for a mean period of 45 plus minus 38 mins. The majority (82%) then became resedated to various degrees. However, in 66% of patients, the coma worsened (scale 3 to 4) to the point that additional flumazenil treatment was required. Continuous infusion was administered to 35% of the responders at a mean rate of 0.3 plus minus 0.2 mg/hr, for a mean duration of 21 plus minus 39 hrs. The remaining patients were given boluses of flumazenil as required. Flumazenil dosing data are detailed in Table 4.

Table 4. Flumazenil dosing (mean plus minus SD)

Group R was further divided into two subgroups, according to the duration of sustained wakefulness obtained with the first effective dose of flumazenil Figure 1. This categorization was not initially planned. The time cutoff point used to assign patients into the two subgroups of group R was 30 mins. Group R1 consisted of 49 patients (59% of group R). Fifteen patients of group R1 remained awake after the first flumazenil dose, without the need for further treatment, while the other 34 patients relapsed into moderate sleep (coma grade 2) within 72 plus minus 37 mins of the first injection Figure 1. Nevertheless, these latter patients were easily reawakened by further small doses (0.2 to 0.5 mg) of flumazenil. Almost all R1 patients regained full consciousness after the administration of less than equals 1 mg of flumazenil Table 4. The second R subgroup was comprised of 34 (41%) patients (group R2). All R2 patients relapsed into coma (score 3 to 4) within 18 plus minus 6.5 mins (p less than .01 vs. R1) from the time of awakening and required significantly higher amounts of flumazenil than did the R1 patients to avoid resedation (0.6 to 2.0 mg, p less than .05) Table 4. Administrations of further boluses of flumazenil to R2 patients were progressively less effective in reversing coma, as expressed by the duration of wakefulness that became gradually shorter and the fewer number of patients regaining consciousness after subsequent boluses Figure 1.

Figure 1. Differential responsiveness to flumazenil. Resedation in all responders (shaded bars) and the R1 group (stippled bars) after consecutive cumulative injections of flumazenil occurred after a similar lapse of time. In contrast, R2 patients (striped bars) relapsed into coma significantly sooner, and the duration of wakefulness became progressively shorter after each additional cumulative flumazenil injection. Furthermore, the number of R2 patients (within bars) responding to subsequent flumazenil injections became statistically lower, starting from the third injection onward. #p less than .05 vs. time to resedation in R and R1 groups. *p less than .05 vs. the number of R2 patients reawakening after the first and second flumazenil cumulative dose. Data are expressed as mean plus minus SD. R1 group, patients who regained consciousness for more than 30 mins, with few episodes of An uneven response of R1 and R2 patients to flumazenil was also observed with continuous infusion. relapse into coma. R2 group, patients who relapsed into coma within 30 mins. Flumazenil was infused in 35% of patients in group R (27 patients), in 32% of patients in group R1, and in 38% of patients in group R2 patients (NS). In group R1, a mean total infusion dose of 0.2 plus minus 0.1 mg/hr successfully maintained all patients in a wakeful state (coma score during the infusion 0.5 plus minus 0.6). In R2 patients, the same infusion rate prevented relapse into deep unconsciousness, but the patients were sleepier (coma score of 1.8 plus minus 0.8; p less than .02). Clinically, there was little benefit from the treatment in this subgroup, even at infusion rates as high as 1 mg/hr.

The majority (85%) of the responders tested positive for benzodiazepines, while no benzodiazepines were found in 40% of the nonresponders. Pure benzodiazepine overdose was common in group R1 (63%) and absent in groups R2 and NR. Additional drugs identified in the whole study group included tricyclic antidepressants (71%), barbiturates (53%), phenothiazines (8%), opiates (6%), salicylates (5%), ethanol (three patients), and acetaminophen (three patients). Detailed toxicological data are reported in Table 5.

Flumazenil produced only minor changes in respiratory variables. The spontaneous respiratory rate increased slightly during the first 30 mins of treatment, but PaCO2 did not decrease significantly. Among the 57 intubated patients, 14 (25%) patients could be extubated safely after receiving flumazenil, while the preparation for endotracheal intubation that had been ordered by the attending physician was revoked in 12 instances (nine R1 vs. three R2 patients) after the administration of flumazenil Table 6. None of these patients required subsequent respiratory assistance.

Table 5. Toxicological data: Drug serum concentration (mean plus minus SD)

Table 6. Respiratory data

Hypothermia (temperature range 28 degrees to 35.5 degrees C) was recorded in 18% of the patients. None of these hypothermic patients developed cardiac dysrhythmia before or after flumazenil administration, and the response to flumazenil was similar to that response assessed in the normothermic patients.

Most of the 26 patients from whom electroencephalograms were obtained demonstrated bilateral, regular, low-to-medium voltage, with predominance of theta and delta waves. Reawakening in the benzodiazepine comatose patients was accompanied by the reappearance of distinct alpha activity and an increase in amplitude of medium-to-high voltage (8 to 10, 13 to 20 mu V), symmetrically distributed. Among the patients treated with flumazenil, five patients had neurologic signs suggestive of a cerebrovascular event that could have caused the coma. Thus, computerized axial tomography was recommended by the attending neurologist. Flumazenil administration, while correctly establishing the etiology of benzodiazepine-induced coma, also obviated the need for computerized axial tomography since all of these patients later confirmed having undergone a cerebrovascular accident in the past.

The side effects noted after flumazenil administration are detailed in Table 3. No withdrawal symptoms, such as convulsions or dysrhythmias, were observed. Withdrawal symptoms were most noticeably absent in patients with increased serum tricyclic antidepressant concentrations. The patients generally demonstrated mild, transient (10- to 15-min) emotional reactions that required no treatment. Three patients showed increases in blood pressure of 23% to 25% and two patients (non-tricyclic intoxicated) had transient (120 beats/min) after flumazenil administration; all blood pressure and heart rate values returned to normal within 15 to 30 mins. The only fatality was an elderly patient who developed acute myocardial infarction and bilateral pneumonia before test drug treatment.

DISCUSSION

This double-blind and open study, while confirming the clinical efficacy of flumazenil in pure benzodiazepine overdose, establishes dosing guidelines based on the response to flumazenil, distinguishing between pure, mixed, and nonbenzodiazepine overdose. The avoidance or withdrawal of airway support in patients receiving flumazenil treatment is also described. Most importantly, the study demonstrated the safety of the benzodiazepine antagonist in the wide range of doses given, even among patients with considerable tricyclic antidepressant intoxication.

Although previous double-blind studies [15,23-28] have shown similar results regarding the regaining of consciousness with the use of flumazenil, precise toxicological data are now presented. These data establish a consistent linkage between the serum concentration of the intoxicating drug(s) and the quality (as well as the duration) of coma reversal achieved by flumazenil injections/infusion. Consequently, the present study shows, for the first time, that the prompt response to flumazenil differentiates at the bedside between patients in whom benzodiazepines are the main cause of coma (prolonged wakefulness after less than equals 1 mg of flumazenil) and those patients in whom nonbenzodiazepine drugs are the predominant cause of coma (short-lived wakefulness) as well as coma due to other causes (no effect after 2.5 mg of flumazenil). Since drug screening is not always available on a fulltime basis, and given that there are seldom state-of-the-art techniques, this mode of treatment is a safe and rapid diagnostic procedure to follow in cases of coma, which would well serve the first aid medical team and the physician in the emergency room or ICU. This drug will also save time and resources by reducing the need for electroencephalagram or computerized axial tomography.

The identification of two distinct subgroups (R1 and R2) of comatose patients based on different clinical patterns of the effect of flumazenil has not previously been described. Brief descriptions of small numbers of patients responding differently to flumazenil have appeared in the literature [4,15,19,24,29], but these reports lacked specific toxicological data, and the phenomenon was not addressed in depth. It was characteristic of our R2 patients to show a progressively shorter duration of wakefulness after repeated doses of flumazenil, and to need increasingly higher doses of flumazenil to achieve an effective response similar to the response shown in R1 patients. This clinical distinction was later supported by toxicological data: all patients in group R2 had mixed-drug overdose and the nonbenzodiazepine serum concentrations were also higher than in R1 patients. The distinction between the two subgroups has an important clinical relevance, in that after the initial dose of flumazenil, it becomes possible to identify those patients in whom further treatment would result in minimal or no gain of consciousness and, therefore, those patients who are expected to need prolonged life-support measures. However, full wakefulness after flumazenil administration does not obviate the need for patients to have their stomachs lavaged and for activated charcoal to be instilled to remove as much drug material as possible and stomachs lavaged and for activated charcoal to be instilled to remove as much drug material as possible and prevent progression of enteric absorption.

Resedation in patients intoxicated with benzodiazepines alone occurred among some of the R patients, probably due to the short half-life of flumazenil (approximate 1 hr) [30] compared with the half-life of the most commonly used benzodiazepines. In mixed drug intoxication, recurrent central nervous system depression occurs earlier. The synergistic activity of benzodiazepines and nonbenzodiazepine depressant drugs may account for the more rapid resedation, as we have documented [31]. Flumazenil has been shown to lack agonistic effects, even when administered either alone or in combination with [32] at doses as high as 7 to 15 times those doses generally recommended [15,21,22]. Based on our experience and the experience of others [27,33], a continuous infusion of flumazenil (0.3 to 0.5 mg/hr) should be started immediately after the second bolus dose to prevent further resedation. Patients who become resedated rapidly after the initial dose and who do not respond adequately either to the second bolus or to an infusion at a rate of 0.5 to 0.7 mg/hr will not benefit from flumazenil administered in any mode. It should be stressed that patients treated with flumazenil should have their respiratory and cardiovascular systems monitored in the event of recurring coma.

Important new data in this study include the beneficial effect of flumazenil on the respiratory system. This effect has two aspects. The first and more important aspect is the return of protective airway reflexes and upper airway muscle tone, thus securing airway patency after the patient's reawakening. The lack of such reflexes and/or the presence of upper airway obstruction probably constitute the major risks to these patients and are the most common indications for intubation of drug-intoxicated patients. Ventilatory or hypoxemic comprises the second indication for intubation. In 49% of the double-blind phase of our study and in 24% of all patients, flumazenil improved the mortality rate by lowering the need for and facilitating extubation. However, the effects of flumazenil on alveolar ventilation were unimpressive in this study and in other studies [23,31,34-36], and only one study [26] noted a mean decrease of only 4 torr (0.5 kPa) in PaCO2 after flumazenil was given to intoxicated patients. No significant increase in alveolar ventilation could be discerned in our study, even when subjects with hypercapnia (PaCO2 of more than 45 torr [more than 6.0 kPa]) were evaluated separately. Since the majority of our patients had mixed drug intoxication, and since many of them were mechanically ventilated at the time flumazenil was administered (with some patients given sodium bicarbonate as necessary), this general lack of improvement in respiratory parameters is probably not surprising. One should keep these observations in mind when managing patients with severe respiratory depression and hypoxemia induced by drugs, and give priority to the establishment and maintenance of upper airway patency, oxygenation, and ventilatory support before the administration of flumazenil.

Hypothermia was not associated with any decrease in the efficacy of flumazenil, nor were there any side effects. This finding is of great importance, given that a prolonged period of unconsciousness is invariably accompanied by decreased body temperature, most notably in the elderly who are prone to respiratory and general complications. No previous data regarding this issue are available, except for one flumazenil study [37] in which hypothermic patients were excluded. Our conclusions are that hypothermia, at ranges such as those reported herein, does not seem to be a contraindication to flumazenil administration.

Data from the present study show that the durations of mechanical ventilation and stay in the ICU were shorter in awake patients than in the nonresponders Table 1 and Table 6. Treatment with flumazenil may result in a shorter stay of patients in the ICU compared with nontreated patients [7,24,29]. However, no definite conclusions regarding the latter issue can be drawn on the basis of the present data.

No serious complications due to flumazenil were observed in this study. Previous publications [15,19,29], although dealing with smaller numbers of patients, support the present results. Clinically important side effects were reported in earlier studies [30,38] when flumazenil was used in high doses (less than equals 10-mg bolus) and/or administered rapidly (within 1 to 2 mins). Flumazenil has been shown to be safe hemodynamically, even in patients with clinically important coronary artery or valvular heart disease [39]. Most studies have documented the absence of any serious system arousal after flumazenil administration [40]. In this study, the three episodes of increased systolic blood pressure were of no clinical importance. In most patients, there was a mild, transient increase in systolic and diastolic blood pressures and heart rate. Since these changes were brief, they may be attributable to sudden awakening. Several other studies [15,25,36,41,42] have demonstrated similar mild hemodynamic effects. Shivering, nausea, anxiety, and restlessness were uniformly transient in our patients and required no special intervention. Furthermore, isolated, serious, untoward events, such as convulsions or intractable myocardial dysrhythmias, which have been reported in the literature to follow flumazenil administration in patients intoxicated with combinations of benzodiazepines and tricyclic antidepressants or [25,28,42-47], were not encountered in this study. Two reviews [48,49], one from Europe and the other from the United States, detailed severe side effects, including convulsions and arrhythmias in flumazenil-treated patients. Two deaths also occurred when patients intoxicated with benzodiazepines and high doses of tricyclics were given a 0.5-mg flumazenil bolus [50,51]. In the present study, a much higher proportion of patients than previously reported had concomitant tricyclic drug intoxication (71%) and was given the drug with no specific side effects being noted in these patients. This absence of side effects is possibly related to the slow, incremental mode of flumazenil injection. We recommend that flumazenil always be administered cautiously, especially to patients with a history of seizure disorders or jerking movements, or with hemodynamic instability, electrocardiogram signs of tricyclic overdose, or evidence of the ingestion of very high doses of tricyclics [15,48]. electrocardiogram signs of tricyclic overdose, or evidence of the ingestion of very high doses of tricyclics [15,48].

Because of the potential risk of inducing a benzodiazepine withdrawal syndrome, the advisability of administering flumazenil to chronic benzodiazepine users has been questioned by some authors [25,52]. In our study, 27 (25%) patients had been using benzodiazepines chronically, yet no withdrawal symptom was observed. In a French study [35], 32 patients receiving chronic benzodiazepine treatment were also given flumazenil, with no physical or mental side effects. Those data suggest that the titration of flumazenil to a clinical end point, which resulted in a relatively small total dose, preferably combined with infusion mode, can probably ensure the absence of withdrawal signs in such patients.

In conclusion, flumazenil has proved in this study to be an effective, reliable, and safe drug when used to antagonize drug-induced coma. This drug is clinically helpful in differentiating coma due to benzodiazepine overdose from coma caused by other drugs or having organic origins. Regardless of the specific benzodiazepine involved or the dose ingested, titration of small doses (to a maximum of 1 mg) of flumazenil is highly effective in reversing coma for more than 30 mins without causing clinically important, untoward effects. Flumazenil is safe hemodynamically and helpful in assisting patients to withdraw from mechanical ventilation. This study also demonstrates that the drug is safe in patients who are intoxicated with both benzodiazepines and tricyclic anti- . Patients poisoned primarily by psychotropic drugs other than benzodiazepines will not benefit from flumazenil.

REFERENCES

1. Greenblatt DJ, Shader RI: Drug therapy: Benzodiazepines. N Engl J Med 1974; 291:1011-1015 ExternalResolverBasic Bibliographic Links [Context Link]

2. Balter MB, Manheimer DI, Mellinger GD, et al: A cross-national comparison of anti-anxiety/sedative drug use. Curr Med Res Opin 1984; 8:5-20 [Context Link]

3. Bergman Y, Dahlstrom M: Anxiety and antianxiety drug use in Sweden. Workshop: ``Treating of Anxiety,'' Drug Information Committee, National Board of Health and Welfare, Sweden, 1987 [Context Link]

4. Hojer J, Baehrendtz S: The effect of flumazenil (RO 15-1788) in the management of self-induced benzodiazepine . Acta Med Scand 1988; 224:357-365 ExternalResolverBasic Bibliographic Links [Context Link]

5. Proudfoot AT, Park J: Changing pattern of drugs used for self-poisoning. BMJ 1978; 1:90-93 ExternalResolverBasic Bibliographic Links [Context Link]

6. Willox DGA: Self poisoning. A review of patients seen in the Victoria Infirmary, Glasgow. Scott Med J 1985; 30:220-224 ExternalResolverBasic Bibliographic Links [Context Link]

7. Hojer J, Baehrendtz S, Gustafsson L: Benzodiazepine poisoning: Experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med 1989; 226:117-122 ExternalResolverBasic Bibliographic Links [Context Link]

8. Ashton CH: Benzodiazepine overdose: Are specific antagonists useful? BMJ 1985; 290:805-806 ExternalResolverBasic Bibliographic Links [Context Link]

9. Greenblatt DG, Woo E, Allen MD, et al: Rapid recovery from massive diazepam overdose. JAMA 1978; 240:1872- 1874 ExternalResolverBasic Bibliographic Links [Context Link]

10. Divoll M, Greenblatt DJ, Lacasse Y, et al: Benzodiazepine overdosage: Plasma concentrations and clinical outcome. Psychopharmacology 1981; 73:381-383 ExternalResolverBasic Bibliographic Links [Context Link]

11. Heyndrickx B: Fatal intoxication due to flunitrazepam. J Anal Toxicol 1987; 11:278 ExternalResolverBasic Bibliographic Links [Context Link]

12. Mignee C, Garnier R, Conso F: Intoxication aigue par le flunitrazepam. (Abstr. in English) Therapie 1980; 35:581- 589 [Context Link]

13. Greenblatt DJ, Allen MD, Noel BJ, et al: Acute overdosage with benzodiazepine derivatives. Clin Pharmacol

Ther 1977; 21:497-514 ExternalResolverBasic Bibliographic Links [Context Link]

14. Vale JA, Meredith TJ: Epidemiology of poisoning in the UK. In: Poisoning Diagnosis and Treatment. Vale JA, Meredith TJ (Eds). London, Update Books, 1981, pp 1-8 [Context Link]

15. Weinbroum A, Halpern P, Geller E: The use of flumazenil in the management of acute drug poisoning--A review. Intensive Care Med 1991; 17:S32-S38 ExternalResolverBasic Bibliographic Links [Context Link]

16. Castleden CM, George CF, Marcer D, et al: Increased sensitivity to in old age. BMJ 1977; 1:1-12 ExternalResolverBasic [Context Link]

17. Greenblatt DJ, Allen MD, Shader RI: of high dose in the elderly. Clin Pharmacol Ther 1977; 21:355-361 ExternalResolverBasic Bibliographic Links [Context Link]

18. Scollo-Lavizzari G: First clinical investigation of the benzodiazepine antagonist Ro 15-1788 in comatose patients. Eur Neurol 1983; 22:7-11 ExternalResolverBasic Bibliographic Links [Context Link]

19. Geller E, Niv D, Weinbroum A, et al: The use of flumazenil in the treatment of 34 intoxicated patients. 1988; 16:S57-S62 ExternalResolverBasic Bibliographic Links [Context Link]

20. Matthew H, Lawson AAH: Acute poisoning: A review of two years' experience. Q J Med 1966; 35:539- 552 ExternalResolverBasic Bibliographic Links [Context Link]

21. Ricou B, Forster A, Bruckner A: Clinical evaluation of a specific benzodiazepine antagonist (RO 15-1788). Br J Anaesth 1986; 58:1005-1011 ExternalResolverBasic Bibliographic Links [Context Link]

22. Allone E, Baitella L, Hossli G: Double-blind study of the reversal of midazolam-supplemented general anesthesia with Ro 15-1788. Br J Anaesth 1987; 59:455-458 ExternalResolverBasic Bibliographic Links [Context Link]

23. Lheureux P, Askenasi R: Specific treatment of benzodiazepine overdose. Hum Exp Toxicol 1988; 7:165-170 [Context Link]

24. O'Sullivan GF, Wade DN: Flumazenil in the management of acute drug overdosage with benzodiazepines and other agents. Clin Pharmacol Ther 1987; 42:254-259 ExternalResolverBasic Bibliographic Links [Context Link]

25. Aarseth HP, Bredesen JE, Grynne B, et al: Benzodiazepine-receptor antagonist, a clinical double blind study. Clin Toxicol 1988; 26:283-292 ExternalResolverBasic Bibliographic Links [Context Link]

26. Hojer J, Baehrendtz S, Matell G, et al: Diagnostic utility of flumazenil in coma with suspected poisoning: A double blind, randomized controlled study. BMJ 1990; 301:1308-1311 ExternalResolverBasic Bibliographic Links [Context Link]

27. Hojer J, Baehrendtz S, Magnusson A, et al: A placebo-controlled trial of flumazenil given by continuous infusion in severe benzodiazepine overdosage. Acta Anaesthesiol Scand 1991; 35:584-590 ExternalResolverBasic Bibliographic Links [Context Link]

28. Lheureux P, Askenasi R: Double-blind study of Anexate in benzodiazepine intoxication. Eur J Anaesthesiol 1988; 39(Suppl 2):300-304 ExternalResolverBasic [Context Link]

29. Lheureux P, Askenasi R: Agonism and antagonism at the benzodiazepine-receptor: New concept for new approach of common drug poisoning. Acta Anaesthesiol Belg 1989; 40:23-28 ExternalResolverBasic Bibliographic Links [Context Link]

30. Amrein R, Leishman B, Bentzinger C, et al: Flumazenil in benzodiazepine antagonism: Actions and clinical use in intoxication and anaesthesiology. Med Toxicol Adv Drug Exper 1987; 2:411-429 [Context Link]

31. Weinbroum A, Geller E: The respiratory effects of reversing midazolam sedation with flumazenil in the presence or absence of narcotics. Acta Anaesthesiol Scand 1990; 34(Suppl):S65-S69 ExternalResolverBasic [Context Link]

32. Forster A, Grettenand G, Klopfenstein CE, et al: Absence of effects of high-dose flumazenil on ventilation and psychometric performance in human volunteers. Anesth Analg 1993; 77:980-986 Ovid Full Text ExternalResolverBasic Bibliographic Links [Context Link]

33. Winkler E, Almog S, Kriger D, et al: Use of flumazenil in the diagnosis and treatment of patients with coma of unknown etiology. Crit Care Med 1993; 21:538-543 Ovid Full Text ExternalResolverBasic Bibliographic Links [Context Link]

34. Cuvier C, Amiot JF, Haegel A, et al: Use of flumazenil in , prehospital, multi-center study. Rev Samu 1988; 6:247-253 [Context Link]

35. Pollard BJ, Master AP, Bunting P: The use of flumazenil (Anexate, Ro 15-1788) in the management of drug overdose. Anaesthesia 1989; 44:137-138 ExternalResolverBasic Bibliographic Links [Context Link]

36. Freye E, Hartung E: Der spezifische Antagonist ``Flumazenil'' bei benzodiazepine-Intoxikation. (Abstr. in English) Dtsch Arztebl 1988; 85:2025-2027 [Context Link]

37. Herve C, Gaillard M, Gandouin JM, et al: Indications and limits of the antagonist benzodiazepine pre-hospital use in self poisoning. (Abstr. in English) Conv Med 1988; 7:163-167 [Context Link]

38. Hofer P, Scollo-Lavizzari G: Benzodiazepine antagonist Ro 15-1788 in self-poisoning: Diagnostic and therapeutic use. Arch Intern Med 1985; 145:663-664 ExternalResolverBasic Bibliographic Links [Context Link]

39. Geller E, Halpern P, Chernilas J, et al: Cardiorespiratory effects of antagonism of diazepam sedation with flumazenil in patients with cardiac disease. Anesth Analg 1991; 72:207-211 Ovid Full Text ExternalResolverBasic Bibliographic Links [Context Link]

40. Marty J, Joyon D: Haemodynamic responses following reversal of benzodiazepine-induced anaesthesia or sedation with flumazenil. Eur J Anaesthesiol 1988; (Suppl 2):167-171 [Context Link]

41. Knudsen L, Lonka L, Sorensen BH, et al: Benzodiazepine intoxication treated with flumazenil (Anexate, Ro 15- 1788). Anaesthesia 1988; 43:274-276 ExternalResolverBasic Bibliographic Links [Context Link]

42. Prischl F, Donner A, Grimm G, et al: Value of flumazenil in benzodiazepine self-poisoning. Med Toxicol Adv Drug Exper 1988; 3:334-339 [Context Link]

43. Short TG, Maling T, Galletly DC: Ventricular arrhythmia precipitated by flumazenil. BMJ 1988; 296:1070-1071 ExternalResolverBasic Bibliographic Links [Context Link]

44. Salib P, Baud FJ, Bismuth C, et al: Utilisation d'un antagoniste le flumazenil dans l'intoxication volontaire par benzodiazepines; valeur diagnostique et therapeutique d'une dose unique: Etude sur 40 cas. Abstr. Ann Fr Anesth Reanim 1987; 6:R200 ExternalResolverBasic [Context Link]

45. Passeron D, Peschaud JL, Kienlen J, et al: Etude preliminaire d'un antagoniste des benzodiazepines (flumazenil) en toxicologie. (Abstr. in English) Ann Fr Anesth Reanim 1987; 5:26A [Context Link]

46. Feldman R, Szajewski J: Flumazenil (Anexate) in the treatment of acute benzodiazepine poisoning. A preliminary report. (Abstr. in English) Pol Arch Med Wewn 1988; 79:233-237 [Context Link] preliminary report. (Abstr. in English) Pol Arch Med Wewn 1988; 79:233-237 [Context Link]

47. Mordel A, Winkler C, Almog S, et al: Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic antidepressant overdose. Crit Care Med 1992; 20:1733-1734 [Context Link]

48. Geller E, Crome P, Schaller MD, et al: Risks and benefits of therapy with flumazenil (Anexate) in mixed drug intoxications. Eur Neurol 1991; 31:241-250 ExternalResolverBasic Bibliographic Links [Context Link]

49. Miller RD (Ed), Flumazenil Study Group: U.S. clinical trials of flumazenil, a benzodiazepine antagonist. Clin Ther 1992; 14:978-995 [Context Link]

50. Burr W, Sandham P: Death after flumazenil. BMJ 1989; 298:1713 [Context Link]

51. Marchant B, Wray R, Leach A, et al: Flumazenil causing convulsions and ventricular tachycardia. BMJ 1989; 299:860 ExternalResolverBasic Bibliographic Links [Context Link]

52. Lheureux P, Askenasi R: Treatment of benzodiazepine overdose with Ro 15-1788. Arch Intern Med 1986; 146:1241 [Context Link]

IMAGE GALLERY

Select All Export Selected to PowerPoint

Table 3

Table 1

Table 2

Table 4 Figure 1

Table 5

Table 6 Back to Top

Copyright (c) 2000-2011 Ovid Technologies, Inc. Terms of Use Support & Training About Us Contact Us Version: OvidSP_UI03.04.00.01.101, SourceID 54407