Real world experience reflecting current guidelines

Background: In case of suspected acute coronary syndrome (ACS), international guidelines recommend to obtain a 12-lead ECG as soon as possible after first medical contact, to administrate platelet aggregation inhibitors and antithrombins, and to transfer the patient as quickly as possible to an emergency department. Methods: A German emergency care service database was retrospectively analysed from 2014 to 2016. Data were tested for normal distribution and the Mann-Whitney test was used for statistical analysis. Results are presented as medians (IQR). Results: A total of 1424 patients with suspected ACS were included in the present analysis. A 12-lead ECG was documented in 96% of patients (n = 1369). The prehospital incidence of ST-segment elevation myocardial infarction (STEMI) was 18% (n = 250). In 981 patients (69%), acetylsalicylic acid (ASA), unfractionated heparin (UFH), or ASA and UFH was given. Time in prehospital care differed significantly between non-STEMI (NSTEMI) ACS (37 [IQR 30, 44] min) and STEMI patients (33 [IQR 26, 40] min, n = 1395, p < 0.0001). Most of NSTEMI ACS and STEMI patients were brought to the emergency care unit, while 30% of STEMI patients were directly handed over to a cardiac catheterization laboratory. Conclusions: Prehospital ECG helps to identify patients with STEMI, which occurs in 18% of suspected ACS. Patients without ST-elevations suffered from longer prehospital care times. Thus, it is tempting to speculate that ST-elevations in patients prompt prehospital medical teams to act more efficiently while the absence of ST-elevations even in patients with suspected ACS might cause unintended delays. Moreover, this analysis suggests the need for further efforts to make the cardiac catheterization laboratory the standard hand-over location for all STEMI patients.Einführung: Internationale Leitlinien empfehlen die umgehende Ableitung eines 12-Kanal-Elektrokardiogramms bei Patienten mit akuter Angina-pectoris-Symptomatik. Ebenfalls wird die präklinische Gabe von Azetylsalizylsäure, Heparin sowie der sofortige Transport in ein Krankenhaus mit der Möglichkeit einer koronarinvasiven Diagnostik empfohlen. Methoden: Es wurden die Einsatzprotokolle einer Rettungsstellendatenbank retrospektiv für den Zeitraum von 2014–2016 auf diese Merkmale untersucht. Die Daten wurden auf Normalverteilung getestet und für die statistische Analyse wurde ein Mann-Whitney-Test verwendet. Die Ergebnisse sind als Mediane (Interquartilsabstand, IQR) dargestellt. Ergebnisse: Es wurden 1424 Patienten mit Angina-pectoris-Symptomatik eingeschlossen. In 96 % (n = 1369) der Fälle wurde ein 12-Kanal-Elektrokardiogramm aufgezeichnet. Präklinisch wurden 250 Patienten (18 %) mit ST-Strecken-Hebungs-Infarkt (STEMI) diagnostiziert. Insgesamt 981 Patienten (69 %) erhielten Azetylsalizylsäure bzw. Heparin oder Azetylsalizylsäure und Heparin. Die präklinischen Zeiten unterschieden sich signifikant zwischen Patienten mit akutem Koronarsyndrom ohne Ischämiezeichen im Elektrokardiogramm (NSTEMI ACS; 37 min [IQR 30,44]) und Patienten mit ST-Hebungen (STEMI; 33 min [IQR 26,40]). Der Großteil der Patienten wurde in der Notaufnahme übergeben, während 30 % der STEMI-Patienten direkt in das Herzkatheterlabor transferiert wurden. Schlussfolgerung: Die Inzidenz von ST-Hebungen liegt im präklinischen Bereich bei Patienten mit Angina-pectoris bei 18 %. Patienten ohne Ischämiezeichen wurden langsamer einem Krankenhaus zugeführt als Patienten mit STEMI. Dieses Ergebnis kann auf die geltenden Leitlinien zurückzuführen sein, da bei STEMI-Patienten die Zeit von Diagnosestellung bis zur koronarinvasiven Diagnostik <120 min betragen soll

Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices

The benzodiazepine midazolam is widely used in critical care medicine. Midazolam has a clinically active metabolite, 1-hydroxymidazolam. The contribution of 1-hydroxymidazolam to the effects of midazolam is controversial. The aim of the current study was to compare the actions of midazolam and 1-hydroxymidazolam on network activity of cortical neurons. Midazolam depressed neuronal activity at a low concentration of 5 nM. When midazolam concentration was increased, it depressed neuronal discharge rates in a biphasic manner. In comparison, 1-hydroxymidazolam did not depress the cortical network activity at low nanomolar concentrations. Higher concentrations of 1-hydroxymidazolam consistently inhibited neuronal activity. Moreover, midazolam shortened cortical up states at low, but not at high concentrations, while the opposite effect was observed with 1-hydroxymidazolam. The network depressant action of midazolam at low concentrations was absent in slices from GABAA receptor α1(H101R)mutant mice. The α1(H101R)mutation renders α1-subunit containing GABAA receptors insensitive towards benzodiazepines. This GABAA receptor subtype is thought to mediate sedation. As midazolam is more potent than its metabolite 1-hydroxymidazolam, the major clinical effects are thus likely caused by midazolam itself. However, 1-hydroxymidazolam could add to the effects of midazolam, especially after the application of high doses of midazolam, and in case of impaired drug metabolism

Zolpidem Activation of Alpha 1-Containing GABAA Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons

Introduction: High frequency neuronal activity in the cerebral cortex can be induced by noxious stimulation during surgery, brain injury or poisoning. In this scenario, it is essential to block cortical hyperactivity to protect the brain against damage, e.g., by using drugs that act as positive allosteric modulators at GABAA receptors. Yet, cortical neurons express multiple, functionally distinct GABAA receptor subtypes. Currently there is a lack of knowledge which GABAA receptor subtypes would be a good pharmacological target to reduce extensive cortical activity.Methods: Spontaneous action potential activity was monitored by performing extracellular recordings from organotypic neocortical slice cultures of wild type and GABAAR-α1(H101R) mutant mice. Phases of high neuronal activity were characterized using peri-event time histograms. Drug effects on within-up state firing rates were quantified via Hedges’ g.Results: We quantified the effects of zolpidem, a positive modulator of GABAA receptors harboring α1-subunits, and the experimental benzodiazepine SH-053-2′F-S-CH3, which preferably acts at α2/3/5- but spares α1-subunits. Both agents decreased spontaneous action potential activity but altered the firing patterns in different ways. Zolpidem reduced action potential firing during highly active network states. This action was abolished by flumazenil, suggesting that it was mediated by benzodiazepine-sensitive GABAA receptors. SH-053-2′F-S-CH3 also attenuated neuronal activity, but unlike zolpidem, failed to reduce high frequency firing. To confirm that zolpidem actions were indeed mediated via α1-dependent actions, it was evaluated in slices from wild type and α(H101R) knock-in mice. Inhibition of high frequency action potential firing was observed in slices from wild type but not mutant mice.Conclusion: Our results suggest that during episodes of scarce and high neuronal activity action potential firing of cortical neurons is controlled by different GABAA receptor subtypes. Exaggerated firing of cortical neurons is reduced by positive modulation of α1-, but not α2/3/5-subunit containing GABAA receptors

Sevoflurane-induced loss of consciousness is paralleled by a prominent modification of neural activity during cortical down-states.

Networks of neocortical neurons display a bistable activity pattern characterised by phases of high frequency action potential firing, so called up-states, and episodes of low discharge activity (down-states). We hypothesised that during down-states neocortical neurons are vulnerable to anaesthetic agents. To tackle this issue, it is necessary to identify analytical methods, which are sufficiently sensitive for resolving anaesthetic effects during phases of scarce neuronal activity. The local field potential was recorded in organotypic cultures (OTC) from rat neocortex under control conditions and in the presence of increasing concentrations of sevoflurane by extracellular electrodes. Epochs from down-states were cut from the local field potential and analysed using power spectrum density as well as non-linear parameters approximate entropy (ApEn) and order recurrence rate (ORR). ApEn and ORR proved to be suitable tools for analysing the actions of volatile anaesthetics on cortical down-states. During these phases of low neuronal activity, sevoflurane caused prominent changes in the local field potential. Time series analysis using ApEn showed a reduction of signal predictability in the presence of sevoflurane. Furthermore, the ORR displayed an abrupt decrease at sevoflurane concentrations corresponding to loss of consciousness in vivo, indicating a drug-induced decrease in the signal to noise ratio. The actions of volatile anaesthetics on cortical down-states have been neglected so far, perhaps due to the lack of suitable analysis tools. In the current in vitro study the non-linear parameters ApEn and ORR are introduced to characterise volatile anaesthetics actions. Sevoflurane alters cortical down-states as indicated by non-linear parameter analysis of local field potential recording from cultured neuronal networks. ORR even displays an abrupt change, i.e., a step-like behaviour indicating an increased signal complexity at concentrations of sevoflurane corresponding to loss of consciousness in humans