[Cardiogenic shock following yew needle poisoning : Digoxin immune fab, va-ECMO and albumin dialysis for the treatment of a suicidal yew leaf poisoning]. / Kardiogener Schock nach Eibennadelintoxikation : Digitalisantidot, va-ECMO und Albumindialyse in der Therapie der suizidalen Eibennadelintoxikation.

We present the case of a 46-year-old male who developed refractory bradycardia with cardiogenic shock after attempting suicide by ingestion of yew leaves. Due to delayed availability of the Digoxin immune fab, a va-ECMO was established to maintain sufficient circulation. Administration of the digoxin fab resulted in recovery of spontaneous circulation. Continuous venovenous hemodiafiltration with hemoadsorption and albumin dialysis were initiated with the intention to remove immune fab-toxin complexes and as organ support in acute kidney and liver failure. Within 5 days the patient was successfully weaned from ECMO, liver support and renal replacement and discharged without physical sequelae.

Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers.

BACKGROUND: For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug's high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 µg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. METHODS: 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 µg, 140 mL per puff), one short intravenous infusion of 50 µg fentanyl, and one lozenge with an integrated applicator (200 µg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. RESULTS: 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h ∗ pg/ml, CV% = 32.86), followed by intravenous (672 h ∗ pg/ml, CV% = 32.18) and intranasal administration (515 h ∗ pg/ml, CV% = 30.10). C max was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. t max was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. CONCLUSION: Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

[Preclinical management of cardiac arrest-extracorporeal cardiopulmonary resuscitation]. / Präklinisches Management bei Herz-Kreislauf-Stillstand ­ extrakorporale kardiopulmonale Reanimation.

BACKGROUND: The chances of surviving out-of-hospital cardiac arrest (OHCA) are still very low. Despite intensive efforts the outcome has remained relatively poor over many years. In specific situations, new technologies, such as extracorporeal cardiopulmonary resuscitation (eCPR) could significantly improve survival with a good neurological outcome. OBJECTIVE: Does the immediate restoration of circulation and reoxygenation via eCPR influence the survival rate after OHCA? Is eCPR the new link in the chain of survival? MATERIAL AND METHODS: Discussion of current study results and guideline recommendations. RESULTS: The overall survival rates after OHCA have remained at 10-30% over many years. Despite low case numbers more recent retrospective studies showed that an improved outcome can be achieved with eCPR. In selected patient collectives survival with a favorable neurological outcome is possible in 38% of the cases. CONCLUSION: Survival after cardiac arrest and the subsequent quality of life dependent on many different factors. The time factor, i.e. the avoidance of a no-flow phase and reduction of the low-flow phase is of fundamental importance. The immediate restoration of the circulation and oxygen supply by eCPR can significantly improve survival; however, large randomized, controlled trials are currently not available.

[Impact of acute normovolemic hemodilution on primary hemostasis]. / Einfluss der akuten normovolämischen Hämodilution auf die primäre Hämostase.

BACKGROUND: Acute normovolemic hemodilution (ANH) is performed with the intention to reduce the requirement for allogeneic blood transfusions. After preoperative withdrawal of whole blood, corresponding amounts of crystalloids and/or colloids are infused to maintain normovolemia. The main benefit of ANH is the availability of whole blood containing red blood cells, clotting factors and platelets for reinfusion after removal during the dilution process. Until retransfusion whole blood components are stored at the patient's bedside in the operating theatre. AIM: It was the aim of the present investigation to analyze potential changes in ex vivo induced platelet aggregation in stored blood components. MATERIAL AND METHODS: After obtaining approval 15 patients undergoing complex cardiac surgery were enrolled into this prospective observational study. Acute normovolemic hemodilution (ANH) was routinely performed in this collective based on institutional standards. Besides analyses of pH and plasma concentrations of ionized calcium and hemoglobin, hematological analyses included aggregometric measurements using multiple electrode aggregometry (MEA, Multiplate®, Roche, Grenzach, Germany). Ex vivo platelet aggregation was induced using arachidonic acid (ASPI test), as well as thrombin receptor activating peptide (TRAP test) and adenosine diphosphate (ADP test). Laboratory analyses were performed before beginning ANH (baseline), as well as immediately (T1), 30 min (T2), 60 min (T3), 90 min (T4), 120 min (T5), 150 min (T6) and 180 min (T7) after beginning of storage. The areas under the aggregation curves (AUC) in the MEA were defined as primary (ASPI test) and secondary endpoints (ADP test, TRAP test). RESULTS: As compared to baseline, arachidonic acid induced platelet aggregation was significantly reduced at T1 [77 U (68/94 U) vs. 53 U (25/86 U), p = 0.003] and each consecutive measuring point. As compared to T1 (begin of storage), arachidonic acid induced platelet aggregation was significantly reduced at T4 [26 U (14/54 U); p = 0.002], T5 [30 U (21/36 U); p = 0.007], T6 [25 U (17/40 U); p = 0.004] and T7 [28 U (17/39 U); p < 0.001]. The extent of ex vivo induced platelet aggregation in the TRAP test and ADP test remained unchanged during the study period. The pH as well as the concentrations of ionized calcium and hemoglobin remained unchanged in the blood component during storage. CONCLUSION: The results of the present study indicate that disturbances of platelet aggregation may occur during storage of whole blood components prepared for the purpose of ANH. Further investigations are needed to analyze whether the observed phenomena are of hemostatic relevance.

[Reintubation using the C-MAC videolaryngoscope. Implementation in patients with difficult airways initially managed with in situ laryngeal tubes]. / Umintubation mithilfe des C-MAC-Videolaryngoskops. Durchführung bei Patienten mit schwierigem Atemweg und einliegendem Larynxtubus.

BACKGROUND: Securing the airway with supraglottic airway devices, such as a laryngeal tube, is a regular component of most difficult airway management algorithms. It is further recommended that in emergency medicine rescuers less skilled in endotracheal intubation should use supraglottic airways as a first line device. Exchanging the laryngeal tube with an endotracheal tube can be performed with video-assisted laryngoscopy as described below. MATERIAL AND METHODS: A total of 20 adult patients with airways managed using laryngeal tubes due to actual or anticipated difficult intubation underwent endotracheal intubation using the C-MAC videolaryngoscope. After deflating the cuffs of the laryngeal tube, seeking out the glottis was done by following the constructional landmarks of the laryngeal tube, considering concordance with anatomical landmarks of the human airway. In cases of failed video-assisted endotracheal intubation, the laryngeal tube that was still in situ was reinflated to re-establish ventilation of the lungs. RESULTS: In 19 out of the 20 patients the laryngeal tube could be exchanged for an endotracheal tube with the video-assisted technique described. In one patient no laryngeal structures could be identified (Cormack and Lehane grade IV) even with the C-MAC videolaryngoscope and ventilation was continued via the laryngeal tube. No complications related to the video-assisted intubation technique were observed. CONCLUSIONS: The C-MAC videolaryngoscope is a mobile system which facilitates endotracheal intubation in patients with a difficult airway and a laryngeal tube in place. It is not only possible but recommended to leave the laryngeal tube in situ as a back-up when videolaryngoscopy fails.

Pre-filling of the extracorporeal circuit with autologous blood is safe, but not effective in optimizing biocompatibility in high-risk patients.

OBJECTIVES: Haemodilution resulting from crystalloid priming of the cardiopulmonary bypass circuit represents a major risk factor for blood transfusions in high-risk cardiac surgery patients. We designed this study to evaluate the effects of antegrade autologous priming (AAP) on reducing perioperative blood transfusion and markers of the inflammatory response in older patients (>75 years). METHODS: Seventy-two patients undergoing first-time coronary bypass and/or aortic valve replacement were prospectively randomised to a cardiopulmonary bypass (CPB) with or without AAP. AAP was performed by adding the patient's own blood to the prime solution (mean 280 ml). Perfusion and anaesthetic techniques were as usual. The haematocrit was maintained at a minimum of 21% during CPB. Patients were well matched for all preoperative variables, including established transfusion risk factors. The primary endpoint was the requirement of red cell transfusion. The surrogate endpoints were renal function, inflammatory response and ischaemic parameters. Blood samples were drawn pre- and intraoperatively and at intervals of 6 hours till POD 6. RESULTS: Current analysis shows no differences in patients receiving homologous packed red cell transfusions. Also, markers of the inflammatory response (IL6, IL8), renal function (cystatin C, creatinine) and myocardial ischaemia (troponin T, CK-MB) were comparable in both groups (p>0.05). Clinical outcomes were similar with respect to pulmonary, renal and hepatic function, length of ICU stay and hospital stay. CONCLUSION: These data suggest that antegrade autologous priming is a safe procedure, but an ineffective way for improving biocompatibility and reducing the need for blood transfusion in older patients.

Intracellular injections of lucifer yellow into lightly fixed mitral cells reveal neuronal dye-coupling in the developing rat olfactory bulb.

We report that intracellular injections of Lucifer Yellow into lightly fixed mitral cells revealed dye-coupling between mitral cells and between mitral and granule cells in the form of discrete, radially oriented cell clusters. Dye-coupling was observed in animals as early as postnatal day 10 (P10) and at least until P30. In P10 rats, a mean of 2.5 dye-coupled mitral cells and 27 granule cells were observed per column. Mean column depth and width were 169 microns and 86 microns respectively. Most of the dye-filled granule cells were found within 150 microns of the mitral cell layer. No significant changes were found at P20. By P30, the mean number of granule cells per column increased to 42 and the addition of granule cells occurred in areas proximal to the mitral cell layer. Immunocytochemical results indicate that the developing bulb contains a large concentration of the gap junction protein Connexin 43 (Cx43). Cx43-like immunoreactivity was found at all ages examined, with the most intense staining in the nerve and glomerular layers. Less intense Cx43-like immunoreactivity was found in both the mitral and granule cell layers, with Cx43-like immunoreactive puncta observed between and around cell body profiles. Freeze-fracture analysis revealed the presence of gap junction-like plaques on mitral cells, further suggesting that the dye-coupling occurred across interneuronal gap junctions. Neuronal coupling during development could provide an inter-cellular pathway for the passage of relevant developmental signals which could influence the formation and/or strengthening of synaptic contacts. The coupling could also be involved in the synchronization of neuronal activity, which may be important for olfactory coding.

Olfactory bulb granule cell aggregates: morphological evidence for interperikaryal electrotonic coupling via gap junctions.

Anaxonic interneurons of the granule cell type in the mammalian main olfactory bulb (MOB) are characterized by prominent membrane specializations, which include reciprocal, interdendritic chemical and electrical synapses; however, the latter are thought to be restricted to the external plexiform layer (EPL) and connect granule-mitral- and granule-tufted-cell dendrites (Landis et al., 1974). The present study focuses on interperikaryal membrane specializations between tangentially oriented aggregates of granule microneurons in the lamina granularis interna (IGL). Both infraprimate (Rattus norvegicus, Gerbillus perpallidus) and primate species (Callithrix jacchus) were studied using the following methods: (1) transmission electron microscopy (TEM), (2) freeze-fracture analysis, (3) light and TEM immunohistochemistry using affinity-purified antibodies directed against the connexin-32 or connexin-43 carboxy tail fragment of the gap-junction protein (GJP), and (4) intracellular Lucifer yellow injections in fixed tissue (LYF technique). Freeze-fracture replicas of the MOB-IGL showed that adjacent granule cell perikarya have numerous particle aggregates on the cytoplasmic membrane; in terms of their structure and arrangement, such particles are characteristic of gap junctions. The existence of junctional membranes was substantiated by application of antibodies against GJP demonstrating punctate immunoreactivity, frequently confined to the interperikaryal plasmalemmae of granule cells in the IGL and their dendritic processes in the EPL. Upon TEM analysis, GJP-like immunoreactivity was additionally found in membranous organelles, including Golgi apparati and associated vesicular components. In order to test the permeability of identified membrane specializations, the LYF technique was used, which resulted in bright fluorescence of the perikaryal and dendritic components of the transsomatically injected neuron and staining of neighboring neurons with similar morphology. These findings imply that small molecules can diffuse across the interperikaryal membrane specializations. The existence of gap junctions between granule cell perikarya suggests that there is a significant, low-resistance electrical transmission between aggregated granule cells. This coupling might permit synchronization of neural discharge among small aggregates of these neurons. Gap junctions between granule cells may also serve signaling functions associated with the protracted period of granule cell development.

Chemoanatomical organization of the noradrenergic input from locus coeruleus to the olfactory bulb of the adult rat.

The locus coeruleus contains noradrenergic neurons which project widely throughout the CNS. A major target of locus coeruleus projections in the rat is the olfactory bulb (Shipley et al.: Brain Res. 329:294-299, '85) but the organization of the projections within the bulb has not been systematically examined. In this study, the laminar distribution and densities of locus coeruleus-noradrenergic fibers in the main and accessory olfactory bulbs were determined with anterograde tracing and immunocytochemical techniques. Following iontophoretic injections of 1% wheat germ agglutinin-horseradish peroxidase into the locus coeruleus, the densest anterograde label in the accessory olfactory bulb was observed in the external plexiform layer, granule cell layer, and especially in the internal part of the mitral cell layer. Virtually no label was observed in the glomerular layer. In the main olfactory bulb, labelled axons were observed in the granule cell layer, in the internal and external plexiform layers, occasionally in the mitral cell layer, and least often in the glomerular layer. Noradrenergic fibers in the olfactory bulb were identified by using immunocytochemistry with an antibody to dopamine-beta-hydroxylase. Laminar patterns and densities of noradrenergic innervation were determined with quantitative image analysis. In the accessory olfactory bulb, the densest innervation was in the innermost portion of the mitral cell layer followed by the granule cell layer, the superficial part of the mitral cell layer, and the external plexiform layer. The density of fibers in the glomerular layer was least. The laminar pattern of noradrenergic fiber distribution in the main olfactory bulb was similar to that in accessory olfactory bulb. The present studies demonstrate that locus coeruleus-noradrenergic fibers terminate preferentially in the internal plexiform, granule cell, and external plexiform layers. This suggests that the major influence of the locus coeruleus input to both the main and accessory the olfactory bulbs is on the predominant neuronal element in those layers, the granule cells. Additional studies are needed to resolve how this input influences specific olfactory bulb circuits.

Persistence of the pars externa system of the anterior olfactory nucleus in a microsmatic primate, Callithrix jacchus.

The pars externa (PE) system of the anterior olfactory nucleus (AON) in a primate, Callithrix jacchus, was defined by its architecture and by its connection patterns with the main olfactory bulb (MOB) as revealed by tracing techniques. Focal, unilateral injections of wheat germ agglutinin-conjugated horseradish peroxidase into the MOB yielded ipsilaterally labelled afferent neurons in all subdivisions of the AON, with the exception of a clearly circumscribed area in the ventrolateral retrobulbar field of the basocaudal frontal lobe; in the contralateral hemisphere, this same area contained intensely stained neurons forming a horizontal flat plate of small neurons. This unique commissural connection pattern parallels the organization of the PE to MOB connection in sub-primates (Schoenfeld and Macrides, 1984, J. Comp. Neurol., 227: 121-135). Thus, despite earlier controversy (Crosby and Humphrey, 1939, J. Comp. Neurol., 71: 121-213), there appears to be a PE system in a microsmatic primate whose organization is quite similar to that in sub-primates.

Interbulbar axonal collateralization and morphology of anterior olfactory nucleus neurons in the rat.

The organizational patterns of the bilateral projections of the anterior olfactory nucleus (AON) to the main olfactory bulb (MOB) were defined in the rat with Golgi staining, HRP tracing-methods and fluorescent dyes. Three issues were addressed: (1) description of the morphology of the AON-neurons projecting to the MOB, (2) quantitative analysis of the bilateral pathways arising in different AON subdivisions and (3) ultrastructural identification of AON to MOB channels. The cytoarchitectural features of the AON as recognized in Golgi preparations were correlated with its neural architecture as revealed by retrograde HRP-tracing from the MOB. The following cell types were determined: (1) pyramidal like neurons typified by a lack of basal dendrites and a sparse covering with long spines (pars externa), (2) fusiform shaped cells with bipolar dendritic arborisations (pars medialis) and (3) densely spined fusiform, pyramidal, and polygonal neurons (pars ventroposterior, lateralis and dorsalis) with a tendency of radial orientation of their apical dendrites. In addition, in the more caudal parts of the pars ventroposterior there were neurons with tertiary dendritic processes oriented nearly parallel to the molecular layer. Quantitative analysis of AON neurons projecting to the MOB showed that the pars externa neurons project exclusively to the contralateral MOB while pars medialis neurons project almost exclusively to the ipsilateral MOB. All subdivisions of the AON which establish specific termination patterns within the MOB, participated in about equal portion in the ipsilateral projections to the MOB. The highest proportion of the bilaterally projecting neurons were found in the dorsal subdivision, followed by the lateral and ventroposterior subdivisions. The postsynaptic targets of the AON to MOB channel are the spinous processes and varicosities of the proximal and distal-most dendrites of granule cells. The boutons derived from AON projection neurons contained clear spherical vesicles and established exclusively asymmetric synaptic junctions.