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To evaluate the impact of human milk and different neonatal variables on tidal breathing flow-volume loop (TBFVL) parameters within three months' corrected age (CA) in infants born ≤32 wks or weighing1500 g.We retrospectively studied 121 infants with gestational age (GA) ≤ 32 weeks or birth weight (BW) 1500 gr who had lung function assessment within three months' CA by TBFVL analysis between June 2009 and April 2018. We investigated the impact of GA, gender, being Small for GA (SGA), sepsis, days of mechanical ventilation (MV) and human milk feeding (HMF) on later respiratory function, both in the entire group and according to BW ( ≤1000 g and1000 g).The mean(SD) z-score for tidal volume (Vt) and time to peak expiratory flow to expiratory time (tPTEF/tE) were respectively -4.3 (2.5) and -0.8 (2.0) for the overall population with no significant differences between infants1000 g or ≥1000 g. The mean(SD) Vt standardized for body weight was 6.2(2.0) ml/kg. Being female was associated with better Vt/Kg, whereas longer MV or being born SGA were associated with worst tPTEF/tE. For infants with BW 1000 gr, tPTEF/tE was positively associated with HMF.An early TBFVL assessment within three months' CA already reveals lung function alteration in preterm infants. Being female is associated with better Vt/Kg, while longer duration of MV or being born SGA negatively affect tPTEF/tE. The positive association between HMF and better tPTEF/tE in infants with BW1000 g has emerged, which deserves further investigation.

Background Current criteria for surfactant administration assume that hypoxia is a direct marker of lung-volume de-recruitment. We first introduced an early, non-invasive assessment of lung mechanics by the Forced Oscillation Technique (FOT) and evaluated its role in predicting the need for surfactant therapy. Objectives To evaluate whether lung reactance (Xrs) assessment by FOT within 2 h of birth identifies infants who would need surfactant within 24 h; to eventually determine Xrs performance and a cut-off value for early detection of infants requiring surfactant. Methods We conducted a prospective, observational, non-randomized study in our tertiary NICU in Milan. Eligible infants were born between 27+0 and 34+6 weeks’ gestation, presenting respiratory distress after birth. Exclusion criteria: endotracheal intubation at birth, major malformations participation in other interventional trials, parental consent denied. We assessed Xrs during nasal CPAP at 5 cmH2O at 10 Hz within 2 h of life, recording flow and pressure tracing through a Fabian Ventilator for off-line analysis. Clinicians were blinded to FOT results. Results We enrolled 61 infants, with a median [IQR] gestational age of 31.9 [30.3; 32.9] weeks and birth weight 1490 [1230; 1816] g; 2 infants were excluded from the analysis for set-up malfunctioning. 14/59 infants received surfactant within 24 h. Xrs predicted surfactant need with a cut-off − 33.4 cmH2O*s/L and AUC-ROC = 0.86 (0.76–0.96), with sensitivity 0.85 and specificity 0.83. An Xrs cut-off value of − 23.3 cmH2O*s/L identified infants needing surfactant or respiratory support > 28 days with AUC-ROC = 0.89 (0.81–0.97), sensitivity 0.86 and specificity 0.77. Interestingly, 12 infants with Xrs 2O*s/L (i.e. de-recruited lungs) did not receive surfactant and subsequently required prolonged respiratory support. Conclusion Xrs assessed within 2 h of life predicts surfactant need and respiratory support duration in preterm infants. The possible role of Xrs in improving the individualization of respiratory management in preterm infants deserves further investigation.

The coronavirus disease 2019 (COVID-19) pandemic has predominantly affected adults of higher age groups, and the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on infants and neonates appears to be small. While we are gathering emerging evidence on the exact SARS-CoV-2 disease process, intrauterine or perinatal transmission of SARS-CoV-2 remains ambiguous and vertical transmission has yet to be proven although viral RNA by reverse transcription polymerase chain reaction has been found in placental membranes and breast milk. [...]

Background: The COVID-19 pandemic threatens global newborn health. We describe the current state of national and local protocols for managing neonates born to SARS-CoV-2-positive mothers. Methods: Care providers from neonatal intensive care units on six continents exchanged and compared protocols on the management of neonates born to SARS-CoV-2-positive mothers. Data collection was between March 14 and 21, 2020. We focused on central protocol components, including triaging, hygiene precautions, management at delivery, feeding protocols, and visiting policies. Results: Data from 20 countries were available. Disease burden varied between countries at the time of analysis. In most countries, asymptomatic infants were allowed to stay with the mother and breastfeed with hygiene precautions. We detected discrepancies between national guidance in particular regarding triaging, use of personal protection equipment, viral testing, and visitor policies. Local protocols deviated from national guidance. Conclusions: At the start of the pandemic, lack of evidence-based guidance on the management of neonates born to SARS-CoV-2-positive mothers has led to ad hoc creation of national and local guidance. Compliance between collaborators to share and discuss protocols was excellent and may lead to more consensus on management, but future guidance should be built on high-level evidence, rather than expert consensus. Impact: At the rapid onset of the COVID19 pandemic, all countries presented protocols in place for managing infants at risk of COVID19, with a certain degree of variations among regions.A detailed review of ad hoc guidelines is presented, similarities and differences are highlighted.We provide a broad overview of currently applied recommendations highlighting the need for international context-relevant coordination.

To investigate, in infants born preterm with or without bronchopulmonary dysplasia (BPD), the trajectory of tidal breathing flow-volume (TBFV) parameters in the first 2 years of life; the association between TBFV parameters and perinatal risk factors; and the predictive value of TBFV parameters for rehospitalizations due to respiratory infections and wheeze.We retrospectively analyzed TBFV measurements performed at 0-6, 6-12, and 12-24 months of corrected age in 97 infants32 weeks of gestation and1500 g. We assessed the association between TBFV parameters and perinatal risk-factors using linear regressions and the predictive capacity for subsequent respiratory morbidity using logistic regressions. We used the area under the curve and likelihood ratio test (LRT) to compare nested models.Time to peak tidal expiratory flow/expiratory time ratio (tPTEF/tE) was lower than normal for the first 2 years of corrected age. Longer duration of oxygen supplementation, intubation, and respiratory support were associated with reduced tPTEF/tE at all time points. For each z-score increase in tPTEF/tE, the OR for rehospitalizations decreased by 0.70. tPTEF/tE added significantly to BPD classifications alone in predicting rehospitalizations (area under the receiver operating characteristic curve = 0.81 vs 0.76, P value for LRT = .0012), and wheeze (area under the receiver operating characteristic curve = 0.76 vs 0.71, P value for LRT.001).Infants born preterm, with and without BPD, display persistent airway obstruction during the first 2 years of life. tPTEF/tE may identify infants at greater risk of severe respiratory morbidity.

Objective We aimed to measure lung mechanics at birth by the forced oscillation technique (FOT) for assessment of the initial degree of lung aeration and the short-term aeration changes after applying different respiratory support strategies. Methods Eighteen preterm infants (gestational age = 29-36 week) were randomized to receive either continuous positive airway pressure (CPAP) at 5 cmH2 O only or combined with a sustained inflation (SI; 15 seconds at 25 cmH2 O after 5 seconds of CPAP) at birth. We assessed the respiratory system reactance at 5 Hz (X5; increases with lung volume recruitment at a given distending pressure) at 2, 40, and 150 seconds after initiation of CPAP. k-Means clustering of the initial X5 value (X5,i ) stratified newborn into either infants with lower (lowerX5,i ; X5 -240 cmH2 O*s/L) initial degree of lung volume recruitment. Results Initial values were highly heterogeneous. In the LowerX5,i group, X5 increased with time, with SI-patients showing significantly higher values at 150 seconds than the non-SI group (X5 = -89 ± 27 cmH2 O vs -274 ± 58 cmH2 O). In the higherX5,i group, X5 did not improve with time, regardless of the respiratory strategy, suggesting a lack of lung recruitment. Moreover, 75% of infants receiving SI in the higherX5,i group experienced a transient loss of aeration after the maneuver. Conclusions Preterm newborns present initially with highly heterogeneous lung aeration at birth that significantly impacts the effectiveness of the subsequent lung volume recruitment strategy. FOT may represent a valuable tool for individualizing a respiratory resuscitation at birth as it is noninvasive and may be applied simultaneously to respiratory support.

Objectives: To determine the short-term tolerance, efficacy, and lung deposition of supraglottic atomized surfactant in spontaneously breathing lambs receiving continuous positive airway pressure. Design: Prospective, randomized animal study. Setting: Animal research laboratory. Subjects: Twenty-two preterm lambs on continuous positive airway pressure (132 +/- 1 d gestational age). Interventions: Animals receiving continuous positive airway pressure via binasal prongs at 8 cm H 2 O were randomized to receive atomized surfactant at approximately 60-minute of life (atom; n = 15) or not (control; n = 7). The atom group received 200 mg/kg of poractant alfa (Curosurf; Chiesi Farmaceutici SpA, Parma, Italy) over 45 minutes via a novel atomizer located in the upper pharynx that synchronized surfactant delivery with the inspiratory phase. Measurements and Main Results: Arterial blood gas, regional distribution of tidal ventilation (electrical impedance tomography), and carotid blood flow were recorded every 15 minutes until 90 minutes after stabilizing on continuous positive airway pressure. Gas exchange, respiratory rate, and hemodynamic variables, including carotid blood flow, remained stable during surfactant treatment. There was a significant improvement in arterial alveolar ratio after surfactant delivery in the atom group (p < 0.05; Sidak posttests), while there was no difference in Paco 2. Electrical impedance tomography data showed a more uniform pattern of ventilation in the atom group. In the atom group, the median (interquartile range) deposition of surfactant in the lung was 32% (22-43%) of the delivered dose, with an even distribution between the right and the left lungs. Conclusions: In our model of spontaneously breathing lambs receiving CPAP, supraglottic atomization of Curosurf via a novel device was safe, improved oxygenation and ventilation homogeneity compared with CPAP only, and provided a relatively large lung deposition suggesting clinical utility.

OBJECTIVE: To provide a non-invasive approach to monitoring lung function in spontaneously breathing lambs, from birth to five months of life, by the forced oscillation technique (FOT). This report describes the experimental set-up, data processing, and identification of normal predicted values of resistance (Rrs) and reactance (Xrs) of the respiratory system, along with normal bronchodilator response for bronchial reversibility testing. APPROACH: Rrs and Xrs at 5, 11, and 19 Hz were measured monthly for five months in 20 normal term lambs that breathed spontaneously. In seven lambs, repeated measurements also were made within the first month of life (at 3, 7, 14, and 21 d of life). We determined the repeatability and reproducibility of the measurements and characterized the relationship between lung mechanics and age, sex, and body dimensions, using regression analysis, and measured changes in lung mechanics in response to inhaled bronchodilator. MAIN RESULTS: The measurements provided repeatable and reproducible data. Rrs decreased, whereas Xrs increased, with growth from birth through the first two months of life, after which no statistically significant differences were detected. We identified normal value equations for Rrs and Xrs and for each of the measured anthropometric variables. Respiratory system mechanics were not affected by the bronchodilator. SIGNIFICANCE: The FOT provides reliable non-invasive measurement of respiratory system mechanics in spontaneously breathing term lambs from birth to five months of age. The methods and normal reference values defined in this study will facilitate testing of the pathophysiological consequences of preterm birth and prolonged respiratory support on respiratory system mechanics.

To describe the interrelationship between antenatal steroids, exogenous surfactant, and two approaches to lung recruitment at birth on oxygenation and respiratory system compliance (Cdyn) in preterm lambs.Lambs (n = 63; gestational age 127 ± 1 d) received either surfactant at 10-min life (Surfactant), antenatal corticosteroids (Steroid), or neither (Control). Within each epoch lambs were randomly assigned to a 30-s 40 cmH2O sustained inflation (SI) or an initial stepwise positive end-expiratory pressure (PEEP) open lung ventilation (OLV) maneuver at birth. All lambs then received the same management for 60-min with alveolar-arterial oxygen difference (AaDO2) and Cdyn measured at regular time points.Overall, the OLV strategy improved Cdyn and AaDO2 (all epochs except Surfactant) compared to SI (all P0.05; two-way ANOVA). Irrespective of strategy, Cdyn was better in the Steroid group in the first 10 min (all P0.05). Thereafter, Cdyn was similar to Steroid epoch in the OLV + Surfactant, but not SI + Surfactant group. OLV influenced the effect of steroid and surfactant (P = 0.005) on AaDO2 more than SI (P = 0.235).The antenatal state of the lung influences the type and impact of a recruitment maneuver at birth. The effectiveness of surfactant maybe enhanced using PEEP-based time-dependent recruitment strategies rather than approaches solely aimed at initial lung liquid clearance.

A sustained first inflation (SI) at birth may aid lung liquid clearance and aeration, but the impact of SI duration relative to the volume-response of the lung is poorly understood. We compared three SI strategies: 1) variable duration defined by attaining volume equilibrium using real-time electrical impedance tomography (EIT; SIplat); 2) 30 s beyond equilibrium (SIlong); 3) short 30-s SI (SI30); and 4) positive pressure ventilation without SI (no-SI) on spatiotemporal aeration and ventilation (EIT), gas exchange, lung mechanics, and regional early markers of injury in preterm lambs. Fifty-nine fetal-instrumented lambs were ventilated for 60 min after applying the allocated first inflation strategy. At study completion molecular and histological markers of lung injury were analyzed. The time to SI volume equilibrium, and resultant volume, were highly variable; mean (SD) 55 (34) s, coefficient of variability 59%. SIplatand SIlongresulted in better lung mechanics, gas exchange and lower ventilator settings than both no-SI and SI30. At 60 min, alveolar-arterial difference in oxygen was a mean (95% confidence interval) 130 (13, 249) higher in SI30vs. SIlonggroup (two-way ANOVA). These differences were due to better spatiotemporal aeration and tidal ventilation, although all groups showed redistribution of aeration towards the nondependent lung by 60 min. Histological lung injury scores mirrored spatiotemporal change in aeration and were greatest in SI30group ( P < 0.01, Kruskal-Wallis test). An individualized volume-response approach to SI was effective in optimizing aeration, homogeneous tidal ventilation, and respiratory outcomes, while an inadequate SI duration had no benefit over positive pressure ventilation alone.

Aerosolization of exogenous surfactant remains a challenge. This study is aimed to evaluate the efficacy of atomized poractant alfa (Curosurf) administered with a novel atomizer in preterm lambs with respiratory distress syndrome.Twenty anaesthetized lambs, 127 ± 1 d gestational age, (mean ± SD) were instrumented before birth and randomized to receive either (i) positive pressure ventilation without surfactant (Control group), (ii) 200 mg/kg of bolus instilled surfactant (Bolus group) at 10 min of life or (iii) 200 mg/kg of atomized surfactant (Atomizer group) over 60 min from 10 min of life. All lambs were ventilated for 180 min with a standardized protocol. Lung mechanics, regional lung compliance (electrical impedance tomography), and carotid blood flow (CBF) were measured with arterial blood gas analysis.Dynamic compliance and oxygenation responses were similar in the Bolus and Atomizer groups, and both better than Control by 180 min (all P0.05; two-way ANOVA). Both surfactant groups demonstrated more homogeneous regional lung compliance throughout the study period. There were no differences in CBFConclusion:In a preterm lamb model, atomized surfactant resulted in similar gas exchange and mechanics as bolus administration. This study suggests evaluation of supraglottic atomization with this system when noninvasive support is warranted.

The purpose of this investigation was to collect information regarding rhinovirus (RV) circulation in children with lower respiratory tract infections (LRTIs) in Burundi, Central Africa. We enrolled all of the children aged between 1 month and 14 years who were admitted to the hospital of Kiremba, North Burundi, with fever and signs and symptoms of LRTI (i.e., cough, tachypnea, dyspnea or respiratory distress, and breathing with grunting or wheezing sounds with rales) between 1 November 2010 and 31 October 2011, and obtained nasopharyngeal swabs for RV detection by means of polymerase chain reaction (PCR). The VP4/VP2 region of the positive samples was sequenced to determine the species of RV (A, B, or C). Four hundred and sixty-two children were enrolled: 160 (34.6 %) with bronchitis, 35 (7.6 %) with infectious wheezing, and 267 (57.8 %) with community-acquired pneumonia (CAP). RV infection was demonstrated in 186 patients [40.3 %; mean age ± standard deviation (SD) 1.77 ± 2.14 years]. RV infection was detected in 78 patients aged12 months (40.0 %), 102 aged 12-48 months (44.3 %), and six aged48 months (16.7 %; p 0.01 vs. the other age groups). The most frequently identified RV was RV-A (81 cases, 43.5 %), followed by RV-C (47, 25.3 %) and RV-B (18, 9.7 %); subtyping was not possible in 40 cases (21.5 %). RV-A was significantly associated with bronchitis and CAP (p 0.01) and RV-C with wheezing (p 0.05). In Burundi, RVs are frequently detected in children with LRTIs. RV-A seems to be the most important species and is identified mainly in patients with bronchitis and CAP.

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.

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.

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 afterbolus, 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.

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.

An EEG study was carried out in 4 epileptic patients. In each case, Ro 15-1788 caused the disappearance or marked reduction of the epileptic potentials. In 1 case the patient had been pretreated with diazepam; in the other cases there had been no prior benzodiazepine treatment. In the first case, it is possible that Ro 15-1788 acted by abolishing a paradoxical effect of diazepam; in the other cases, we postulate an intrinsic anticonvulsant effect of Ro 15-1788. This investigation would suggest further study of Ro 15-1788 in epileptic patients for clarification of its anticonvulsant properties. In addition, evaluation of its action on the sedation caused by benzodiazepine antiepileptic medication is suggested.

Computerized transaxial tomography was carried out on 112 patients with partial seizures with complex symptomatology. Structural abnormalities were defined in 33% of their studies: tumors in 8 patients, diffuse cerebral atrophy in 2, focal cortical atrophy in 27 and vascular abnormality in 1 case.

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.

In medical practice a number of antagonists which are capable of abolishing the effect of endogenous substances are available. The discovery of the benzodiazepine antagonist Ro 15-1788 has opened up new possibilities in the treatment and diagnosis of comas of different aetiology. This compound makes it possible to shorten the duration of unconsciousness and to eliminate selectively the effect of the benzodiazepine in an organism which has been intoxicated by different substances. The benzodiazepine antagonist Ro 15-1788 occupies the benzodiazepine receptors in the brain and, without influencing the receptor itself, prevents an active benzodiazepine from binding to this site and from exercising its pharmacological effect. On the basis of 9 clinical examples in special situations, the efficacy of treatment using the benzodiazepine antagonist is presented and discussed.

Six cases of psychotic episodes are described which in some way or another resemble petit mal status, but differ from it in their time courses and in exhibiting focal epileptic discharge besides the b

SUMMARY Two unusual cases of sensory precipitation of epileptic attacks are presented and briefly discussed. One patient had suffered from tonic and clonic seizures in her right arm for 11 years. The seizures were induced by touching this arm or even by carrying a heavy object. She never had a generalized seizure. The other patient had petit mal-like attacks when taking food, sometimes provoked by the mere sight of it. In both cases the epileptic nature was confirmed by the EEG and by successful anticonvulsant treatment. RESUME Deux cas inhabituels de declanchement sensoriel d'attaques epileptiques sont presentes et brievement discutes. L'un concerne une patiente souffrant de crises tonico-cloniques de son bras droit, depuis 11 ans, a l'exclusion de toute generalisation. Les crises etaient induites par le simple contact decebras, ou lorsqu'elle soulevait un objet lourd. L'autre patient avait des crises de type petit mal lorsqu'il absorbait de la nourriture ou meme parfois a la simple vue de celle-ci. Dans les deux cas, la nature epileptique a ete confirmee par l'E.E.G. et par les bons resultats d'une therapeutique anticonvulsivante.

In the present work, on the basis of an unselected collection of patients suspected of epilepsy, the diagnostic value of waking and sleep recordings each after 24 h sleep deprivation are compared with one another. Indicative findings of epilepsy were found in 16.7% of the cases in the waking EEG after sleep deprivation. In the sleep EEG after sleep deprivation this amounted to 57.1%. These figures speak for the advantage of the second method. The result is highly significant with a chi2 value of 13.01 (p less than 0.01).

In 1983, we reported on the excellent efficacy of the benzodiazepine antagonist RO 15-1788 in cases of acute intoxication with diazepam in intensive care medicine. Upon observing a positive effect in a patient who had taken alcohol as well as diazepam a study aiming at establishing the beneficial effect of RO 15-1788 in alcoholic intoxication was started. In the meantime, we discovered a significant amelioration of the cerebral disturbance in patients suffering from hepatic coma by the same benzodiazepine antagonist. The preliminary results of a multicenter study reflecting the beneficial effect of RO 15-1788 in cases of alcohol intoxication will be presented.

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 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.

Repeated administration of diazepam in two ventilated patients had caused drug cumulation and coma over several days. In both cases central nervous depression could be demonstrated by the benzodiazepin antagonist Ro 15-1788 which induced reversal of coma. Estimation of plasma concentrations in a 70-year-old female patient 150 hours after the last administration showed a diazepam concentration of 437 ng/ml and a desmethyl-diazepam concentration of 483 ng/ml. The calculated elimination half-life of these substances were 109 and 403 hours. In the second case benzodiazepin could be demonstrated in urine for 10 days after withdrawal of medication. These observations suggest that diazepam is not a suitable drug for prolonged sedation in artificially ventilated patients. The benzodiazepin antagonist Ro 15-1788 represents a valuable diagnostic aid in ascertained or suspect cases of benzodiazepin intoxications. It can also be used therapeutically for reversal of central nervous depression.

7 adult cases with petit mal status are described; most of these patients had clinical recurrences of petit mal seizures after time intervals ranging from 15 to 50 years. Electroencephalography (EEG) and computerized transverse axial tomography (CT) findings are described and correlated. All CT studies showed frontal lobe abnormalities. When speaking of absence status in the adult, it is useful to distinguish between such an event within the course of primary generalized epilepsy and its reactivation after a very long seizure-free period at an older age. Such reactivations occur preferentially in women. CT supplies more structural information on the living brain and thus we could identify a dysplastic configuration of the skull and hemispheres in a 28-year-old patient and frontocortical and moderate subcortical lesions in the older age-group. The role of the frontal lobe in releasing spike-and-wave discharges of different degrees of generalization appears to be a new aspect worthy of further investigation.

A 24-year-old female with gastrointestinal disturbances, nausea and vomiting, had a convulsion with loss of urine and bitten lips on the 5th day of hospitalization. A significant decrease of sodium and potassium levels and lowered osmolality of the serum as well as urinary hyperosmolality permitted the diagnosis of the so-called syndrome of inappropriate antidiuretic hormone release (SIADH) of unknown aetiology, described by Schwartz-Bartter. Twice short tests for porphyria were negative; then the elevated porphyrin precursors collected in 24 h urine indicated the existence of an acute intermittent porphyria. A clinical follow-up and improvement were demonstrated by the EEG findings. Since animal experiments and pathohistological findings indicate that porphyrin metabolites such as delta-amino laevulinic acid and porphobilinogen may influence inhibitory and neurosecretory structures in central nervous tissue and interfere with GABA, cerebral hyperexcitability as well as disturbance of electrolytes may be explained. Finally, the question of whether the EEG changes are due to the significant electrolyte disturbances or are typical signs of acute intermittent porphyria is discussed.

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.

This paper reports on 294 patients with presumptive symptoms of epilepsy but no noteworthy, or only suspicious, EEG findings. With recording during sleep after 24-27 h of sleep deprivation, 138 persons showed definite epilepsy potentials. The remainder of the group showed no noteworthy findings. Nevertheless, on the basis of clinical observations and the course of the patient's illness, epilepsy was diagnosed in 27 patients of this second group. Neurophysiological aspects of the electroencephalographic provocation method are discussed.

193 patients with epilepsy were investigated by EEG and by computerized tomography (C.T.). 55.5% of the pathological C.T. scans were found in partial seizures with elementary symptomatology. In patients with generalized seizures the diagnosis of symptomatic epilepsy could be made in 40 cases (35.7%) with the help of computerized tomography. In 38 EEG there was a continual delta-wave focus, 18 of these with epileptogenic activity. Of these 38 patients, 34 showed a pathological result in computerized tomography. 19 tumors or metastases, 11 cases of atrophy (10 local and one diffuse) as well as one case of encephalitis could be diagnosed. The remaining 3 patients showed indefinate findings with C.T. 19 EEG showed intermittent theta-wave foci. Computerized tomography gave 5 pathological scans in these patients. If one compares the results of computerized tomography and EEG in cases of tumor, the agreement between positive tomography and the pathological EEG is very high (95%): 64 positive C.T. compared with 61 positive EEG. Our investigations with computerized tomography show organic findings in 67 of 193 epilepsies, that is about 35%.

All-night sleep electroencephalograms were recorded in healthy adults in order to perform spectral analysis in different sleep stages. From each subject 13 EEG samples of 40 sec length were selected f

Depakine® sodium di-n-propylacetate is a new anti-epileptic drug. Its action may be related to inhibition of GABA-transaminase. We report our results with Depakine treatment in 33 patients with Petit

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.

• Thirteen patients with benzodiazepine overdosage received the specific benzodiazepine antagonist Ro 15-1788. Intravenous administration of 1.5 to 10 mg reversed the central nervous system depression induced by different benzodiazepine compounds within one to two minutes of injection. These case reports indicate that Ro 15-1788 may be an effective tool in the primary management of self-poisoning. ( Arch Intern Med 1985;145:663-664)