Auditory and electroencephalographic effects of midazolam and alpha-hydroxy-midazolam in healthy subjects.

AIMS: Whereas cortical EEG effects of benzodiazepines are well characterized, information about benzodiazepine effects in other areas of the central nervous system is sparse. This study investigated the action of midazolam and its active metabolite alpha-hydroxy-midazolam on different parts of the auditory pathway in six healthy volunteers in a randomized, double-blind, three-way cross-over study. METHODS: Acoustically evoked short (SLP) and middle (MLP) latency potentials, transitory evoked otoacoustic emissions (TEOAE), and EEG power spectra were analysed after short i. v. injections of placebo, or 0.15 mg kg-1 midazolam, or alpha-hydroxy-midazolam, respectively. RESULTS: All subjects fell asleep during the 4 min infusion of active drug. SLP showed a significant transient increase of Jewett wave V 10 min after injection for midazolam and alpha-hydroxy-midazolam while the latency of wave I was unchanged. Both benzodiazepines induced a marked and long-lasting MLP amplitude decrease for 240 min with slow recovery over the following 360 min. No changes of TEOAE were observed. In agreement with earlier reports, increases in EEG beta activity and decreases in alpha activity were observed after administration of either drug. CONCLUSIONS: Systemically administered benzodiazepines modulate the auditory pathway above the level of the cochlea. While SLP changes were closely associated with sedation and high plasma benzodiazepine concentrations, MLP effects persisted for hours after sedation even at low benzodiazepine plasma levels. Evoked potentials may therefore be more sensitive than EEG as a tool to monitor benzodiazepine effects.

[Syncopes from the neurologic viewpoint]. / Synkopen aus neurologischer Sicht.

A syncope is defined as a sudden, temporary loss of consciousness, associated with loss of postural tone with spontaneous recovery. The incidence is high and the differential diagnosis broad; therefore, the first observations are essential for the management of the patient. In this review diseases will be described which manifest themselves with syncopes that fall under the auspices of either internal medicine or neurology. First, the etiologies of syncopes are discussed in the strict sense of the word, i.e. due to a global cerebral ischemia such as in orthostatic hypotension and vasopressor syncopes. Thereafter, a discussion concerning the differential diagnosis of syncopes will be introduced, including mainly psychogenic and epileptic seizures as well as vertebrobasilar hypoperfusion. Depending on the reason of the loss of consciousness, it can be a common benign disorder or a severe life-threatening disease. The personal history or witness account of the incidence provides the most useful information concerning diagnosis. The cardiological diagnostic procedures are discussed elsewhere. In some instances an EEG can further help with the diagnosis. In many cases an etiology can't be found, even if extensive investigations have been performed.

Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study.

BACKGROUND: Portal systemic encephalopathy (PSE) is a complex neuropsychiatric syndrome associated with hepatic failure. Small scale studies have shown the benzodiazepine receptor antagonist flumazenil to be effective in ameliorating PSE. AIMS: To determine the efficacy of flumazenil in patients with non-comatous mild to moderate PSE (stages I to III) due to severe chronic liver disease. PATIENTS: 49 male and female adults without symptoms of severe bleeding and sepsis and who screened negative for benzodiazepine in both blood and urine, were included in the study. METHODS: Patients were randomised to receive either three sequential bolus injections of flumazenil (0.4, 0.8, and 1 mg) or placebo at one minute intervals, followed by intravenous infusions of either flumazenil (1 mg/h) or placebo for three hours. Clinical PSE grading and vital signs were assessed hourly during baseline and post-treatment periods and half hourly during treatment. The main outcome measures were improvement in group average PSE score and reduction of two points in individual PSE score (clinically relevant improvement). RESULTS: The mean average improvement in the PSE score in the subjects treated with flumazenil was not statistically significantly different from placebo. However, for patients showing clinically relevant improvement, the difference between flumazenil and placebo was statistically significant (seven of 28 v none of 21; p = 0.015). Flumazenil was well tolerated. CONCLUSIONS: A subgroup of patients with PSE resulting from chronic liver disease may benefit from the administration of flumazenil.

Effect of flumazenil on the electroencephalogram of patients with portosystemic encephalopathy. Results of a double blind, randomised, placebo-controlled multicentre trial.

The efficacy of the benzodiazepine antagonist flumazenil has been assessed clinically in a double blind, randomised, placebo-controlled multicentre study in patients with grade I-III portosystemic encephalopathy. In an ancillary study reported here the effect of flumazenil on the electroencephalogram (EEG) was analysed in 32 patients who had EEG grading according to protocol. Following the baseline observation period, patients were randomised to receive (at 1 min interval) 3 sequential bolus injections of flumazenil (0.4, 0.8 and 1 mg) or placebo followed by infusions of flumazenil (1 mg/h) or placebo for 3 h. Patients were monitored for 5 h after infusion. A positive response was defined as 1 point improvement in EEG grade. After independent analysis of the EEG gradings 5 out of 17 (29%) flumazenil treated patients showed an improvement in EEG grading (3 after bolus, 2 during follow-up) compared to 2 out of 15 (13%) placebo treated patients (1 after bolus, 1 during follow-up) (95% confidence interval of difference: -12% to + 50%). Of the 5 EEG responders after flumazenil, 3 also had an improvement in clinical PSE grading (none after bolus, 2 during infusion, 1 during follow-up), compared to neither of the 2 EEG responders after placebo. EEg responders did not differ from non-responders with respect to Child-Pugh score, basal EEG, PSE grade and positivity for benzodiazepines. In conclusion, treatment perspectives for flumazenil in portosystemic encephalopathy appear to be present for only a minority of patients; however, this study yields no support for a major role of benzodiazepine antagonists in the treatment of hepatic encephalopathy.

Prolonged sedation due to accumulation of conjugated metabolites of midazolam.

Midazolam is a short-acting benzodiazepine routinely used in intensive-care medicine. Conjugates of its main metabolite, alpha-hydroxymidazolam, have been shown to accumulate in renal failure but have not previously been related to the prolonged sedative effects commonly observed in critically ill patients. We report five patients with severe renal failure who had prolonged sedation after administration of midazolam. In all five patients, the comatose state was immediately reversed by the benzodiazepine-receptor antagonist flumazenil. Serum concentration monitoring showed high concentrations of conjugated alpha-hydroxymidazolam when concentrations of the unconjugated metabolite and the parent drug were below the therapeutic range. In-vitro binding studies showed that the affinity of binding to the cerebral benzodiazepine receptor of glucuronidated alpha-hydroxymidazolam was only about ten times weaker (affinity constant 16 nmol/L) than that of midazolam (1.4 nmol/L) or unconjugated alpha-hydroxymidazolam (2.2 nmol/L). Conjugated metabolites of midazolam have substantial pharmacological activity. Physicians should be aware that these metabolites can accumulate in patients with renal failure.

[Therapy of epilepsy: trends and effectiveness of new anticonvulsants]. / Epilepsie-Therapie: Trends und Stellenwert von neuen Antiepileptika.

New antiepileptic drugs such as vigabatrin, lamotrigine, gabapentin, oxcarbazepine and felbamate have been lately marketed. This article provides an overview, showing known modes of action, pharmacokinetics, efficacy, tolerability, interactions and indications. A table showing selected data of antiepileptic drugs is included.

[Sodium valproate--still a current antiepileptic agent?]. / Natriumvalproat--ein noch aktuelles Antiepileptikum?

In Switzerland valproate is in use as an anticonvulsant drug since 25 years. On this occasion we present a synopsis of the state of knowledge about its mechanism of action, pharmacokinetics, clinical efficacy, side effects, drug interactions, and administration with respect to special clinical situations.

Computed tomography and magnetic resonance imaging in epileptic seizures.

In epileptic seizures, the sensitivity of CT and MRI depends on different underlying pathologies and varies according to the age of the patient and the type of seizure. The different modalities are discussed in detail.

[Epilepsy in middle and older age]. / Epilepsien des mittleren und höheren Lebensalters.

Single fits and epileptic illness are more frequent in advanced age; their occurrence reaches the same frequency as in the neonatal period. Their origin and the possibilities of treatment are tightly connected to the process of ageing, a fact that requires special consideration. The main reasons for new epileptic attacks in the group of age 65 or more are structural changes, i.e. ischemic infarctions, tumors and atrophic involution. For certain patients, the use of antiepileptic drugs may be limited by unavoidable side effects. Complete cure of the attacks in advanced age is rare, but with a well selected treatment sufficient control is often possible.

[Confusional states following administration of short-acting benzodiazepines (midazolam/triazolam)]. / Dämmerzustände nach Einnahme von kurzwirkenden Benzodiazepinen (Midazolam/Triazolam).

The authors report about six patients, who after the intake of Midazolam or Triazolam suffered from an oneiroid-confusional state in which they carried out complex acts and for which an anterograde amnesia existed. In addition to these drugs, one female patient was under the influence of alcohol and one male patient of Bromazepam. Two of the patients suffered of emotional conflicts. The possibility of disinhibition of suicide and other impulses is named. The authors recommend caution in prescribing these benzodiazepines of ultrashort action.

Risks and benefits of therapy with flumazenil (Anexate) in mixed drug intoxications.

Flumazenil, the first specific benzodiazepine (BZD) antagonist, is one of the most innovative drugs to become available within the last few years. Flumazenil is indicated for the reversal of the centrally depressant effects of BZDs, in BZD-induced anaesthesia, in BZD sedation in intensive care and in patients comatose after drug overdoses including BZDs. A conference of experts experienced in the treatment of mixed drug overdoses by various means, including flumazenil, was held in order to try to reach a consensus regarding the safe use of flumazenil in this indication. From the knowledge and experience gained to date, it was concluded that flumazenil may be useful and safe in the treatment of suspected BZD and mixed drug overdoses, provided that the appropriate precautions are observed.

[Diagnostic and therapeutic aspects of the initial epileptic seizure]. / Diagnostische und therapeutische Aspekte des erstmaligen epileptischen Anfalls.

We present the concept of an 'epileptic syndrome' which is important for prognostic statements and the application of appropriate therapeutic measures. We then discuss the epileptic seizure and the assessment of suspected seizure, indications for admission to a hospital, diagnostic measures (EEG, CT scan, laboratory tests, lumbal puncture, MRI scan, PET scan, angiography), therapy and procedures for imminent status epilepticus. Finally, we try to answer the question whether anticonvulsant medication should be instituted after a first epileptic seizure.

Use of flumazenil in intoxicated patients with coma. A double-blind placebo-controlled study in ICU.

In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.

Computed tomography, electroencephalography, and clinical features in the differential diagnosis of senile dementia. A prospective clinicopathologic study.

The accuracy of computed tomography, electroencephalography, and clinical features in the differential diagnosis of senile dementia was studied prospectively. Out of 50 demented patients, autopsy revealed 32 cases with either senile dementia of the Alzheimer's type (SDAT), multi-infarct dementia (MID), or a combination of both. Eighteen patients had dementia caused by other diseases. Based on a combination of computed tomography, electroencephalography, and clinical features, senile dementia of the Alzheimer's type was differentiated from all 50 patients, with a specificity of 83% and a sensitivity of 80%. Focusing on senile dementia of the Alzheimer's type, multi-infarct dementia, or a combination of both, specificity decreased to 65% and sensitivity to 47%. Comparing the different methods, multi-infarct processes were diagnosed with a higher sensitivity by the clinical features (73%) than by computed tomography (18%) or electroencephalography (18%). None of the methods validly differentiated multi-infarct dementia from a combination of multi-infarct dementia and senile dementia of the Alzheimer's type.

[Epilepsy yesterday, today and tomorrow]. / Epilepsie gestern, heute und morgen.

In this overview the current state of knowledge concerning epilepsy is presented: diagnosis, classification, etiology, pathogenesis and therapy. The change in these aspects during the past epochs of medical history is described. Suggestions as to future prospects are discussed.

Flumazenil (Anexate) in severe intoxication with carbamazepine (Tegretol).

In addition to the benzodiazepine antagonism we report, as a first observation, the effect of flumazenil on carbamazepine intoxication, where a mechanism other than benzodiazepine receptor antagonism must be supposed.

The clinical anti-convulsant effects of flumazenil, a benzodiazepine antagonist.

The clinical anti-convulsant effect of flumazenil in epilepsy has been demonstrated: (i) by acute i.v. administration under EEG control in an epileptic patient who had been previously heavily sedated with diazepam; (ii) in patients undergoing pharmaco-EEG studies whereby spike and wave counts were diminished following oral administration of 10 mg of flumazenil; and (iii) in a series of 27 epileptic patients treated chronically for periods of up to 42 months with flumazenil as monotherapy or as addition to basic therapy. The daily dose ranged from 10-90 mg. Before treatment all patients presented with frequent seizures and had an abnormal EEG. In these patients the anti-convulsant effect was good or very good in 70% of the previously untreated (naive) patients and in about half of the patients who had epilepsy of long duration and had been treated already with standard anti-convulsants. Side-effects with flumazenil were generally mild in nature and rarely led to discontinuation. About one-third of the patients expressed a feeling of well-being while under therapy with flumazenil. A possible mechanism of action is discussed.

[Value of the EEG in the prognosis of post-anoxic coma following cardiocirculatory arrest]. / Der Wert des EEG zur Prognose bei postanoxischen Komata nach kardiozirkulatorischem Stillstand.

The EEGs of 26 patients who remained at least 6 hours in coma after cardiovascular arrest were analyzed. The first EEG was recorded within few days after reanimation, classified in a 5-grade scale of increasingly severe impairment and compared with the final clinical outcome. On the basis of the present study and of a review of 408 EEG findings reported in similar investigations in the literature we conclude that the EEG can be useful in predicting the outcome of patients in postanoxic coma states: the EEG should be recorded at earliest 8-12 hours but within 2 days after reanimation, a barbiturate intoxication and hypothermia should be excluded. The classification of the recordings in a 5-grade scale has proven to be helpful and accurate in predicting the outcome: Grade I EEG findings imply a very good prognosis, a complete remission can be expected in most cases. Grade II and III findings have no definite prognosis: the EEG should be repeated one or two days later, a favorable outcome is to be expected only with rapid improvement of the tracing. Grade IV and Grade V findings have a very serious prognosis: complete recovery has been described episodically, most in the pediatric population and with findings of alpha-coma.

Prognostic value of EEG in post-anoxic coma after cardiac arrest.

The authors themselves studied 26 patients. The EEGs were classified in terms of increasing severity in 5 categories. Incorporating over 400 cases from the literature, the authors correlated the initial EEG findings with the clinical outcome following cardiac arrest. Grade I EEG findings (normal alpha with theta-delta activity) imply a very good prognosis. A complete remission can be expected in most cases. Grade II (dominant theta-delta activity with detectable normal alpha) and grade III (dominant theta-delta activity without detectable normal alpha) findings have no definite prognosis. Grade IV [low-voltage delta, possibly with short isoelectric intervals; dominant, monomorphic, non-reactive alpha-activity (alpha coma); periodic generalized phenomena (spikes, sharp waves, slow waves with very low background activity)] and grade V (very flat to isoelectric EEG) findings have a very serious prognosis.