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Resuscitation from haemorrhagic shock and the subsequent circulatory arrest remains a major clinical challenge in the care of trauma patients. Numerous experimental studies in sexually mature animals have shown a gender dimorphism in response to trauma and haemorrhagic shock. The first study was designed to evaluate sex differences in outcome after resuscitation from hypovolemic circulatory arrest. We intended to examine innate sex differences, and chose to study sexually immature animals. The study showed that cerebral cortical blood flow was greater, blood-brain-barrier was better preserved and neuronal injury was smaller in female as compared to male piglets. The second study demonstrated that female sex was associated with enhanced haemodynamic response, cardioprotection, and better survival. This cardioprotective effect was observed despite comparable estradiol and testosterone levels in male and female animals, indicating an innate gender-related cardioprotection. In both studies (I and II) female sex was associated with a smaller increase in the cerebral expression of inducible and neuronal nitric oxide synthase (iNOS and nNOS). Thus in the study III we tested the hypothesis that exogenously administered 17β-estradiol (E2) could improve neurological outcome by NOS modulation. The results showed that compared with the control group, animals in the E2 group exhibited a significantly smaller increase in nNOS and iNOS expression, a smaller blood-brain-barrier disruption and a mitigated neuronal injury. There was also a significant correlation between nNOS and iNOS levels and neuronal injury. A hypothesis if female-specific cardioprotection may be attributed to a smaller NOS activity was tested in study IV. The animals received methylene blue (MB) during CPR, but were otherwise treated according to the same protocol as studies I-II. The female-specific cardioprotection could be attributed to a smaller NOS activity, but NOS inhibition with MB did not improve survival or myocardial injury, although it abated the difference between the sexes.

Kreislaufstillstand in tiefer Hypothermie (KSTH) wird in der Herzchirurgie zur Korrektur komplexer angeborener Herzfehler angewendet. In den letzten Jahren zeigte sich eine Abnahme der Morbidität und Mortalität nach kardiochirurgischen Eingriffen. Es entstanden aber gleichzeitig Bedenken über eine Beeinträchtigung der neurologischen Funktion und psychomotorischen Entwicklung der operierten Kinder. Wir untersuchten das morphologische Schädigungsmuster im Gehirn nach extrakorporaler Zirkulation mit Kreislaufstillstand in tiefer Hypothermie (KSTH) in einem neonatalen Tiermodell. Zusätzlich evaluierten wir morphologisch den Einfluss einer neuroprotektiven Vorbehandlung mit systemischer und intrathekaler Applikation von Methylprednisolon (MP). Material und Methoden: 24 neugeborenen Ferkeln mit einem Alter unter 1 Woche (Gewicht: 2,1 ± 0,5 kg KG) wurden mittels eines cardiopulmonalen Bypass(CPB) bei 15 °C rektaler Körpertemperatur einem totalen Kreislaufstillstand (KSTH) von 120 Minuten ausgesetzt. Nach Reperfusion wurden die Tiere vom CPB entwöhnt und für 6 Std. überwacht. Eine Gruppe ohne Intervention mit 12 Tieren diente als Kontrollgruppe, bei 7 Tieren wurde eine systemische und bei 5 Tieren eine intrathekale Methylprednisolongabe (Urbason) präoperativ durchgeführt. Das Gehirn wurde nach Fixierung regional histologisch und immunhistochemisch untersucht. Die nekrotischen und apoptotischen Neurone wurden quantitativ in Hippocampus, Kortex, Stammganglien und Kleinhirn erfasst. Molekulargenetische Untersuchungen erfolgten im frontalen Kortex und es wurde die Genexpression mittels "Real-time PCR" für das Hitze-Schock-Protein 70 kD (HSP 70) und die apoptotischen Gene Bak, FAS und Bcl-xL erfasst. Ergebnisse: Das Schädigungsmuster nach KSTH von 120 Minuten bestand aus Nekrose der Neuronen mit einem Fokus in Hippocampus, Kleinhirn und Kortex. Zusätzlich kam es im Gyrus dentatus zum Auftreten apoptotischer Neuronenveränderungen, wobei durch die MP-Vorbehandlung die Anzahl apoptotischer Neurone zunahm. Unter der systemischen Steroidbehandlung kam es zu einer signifikanten Hyperglykämie. Molekulargenetisch zeigten sich bei systemischer Steroidvorbehandlung eine Induktion pro-apoptotischer Gene. Nach intrathekaler Steroidgabe war das Verhältniss zugunsten der anti-apoptotischen Gene signifikant verändert. Die Expression des HSP-70 war nur in der intrathekalen Gruppe signifikant erhöht und scheint im Zusammenhang mit einer geringeren neuronalen Zellschädigung zu stehen. Schlussfolgerung: Eine systemische Vorbehandlung mit MP zeigte keinen neuroprotektiven Effekt, im Gegenteil kam es zu einer Zunahme nekrotischer und apoptotischer neuronaler Zellveränderungen. Bei intrathekaler Applikation des MP und Umgehung der Blut-Hirn-Schranke kam es zu einer signifikanten Reduktion der nekrotischen Zellveränderungen im Sinne einer neuroprotektiven Wirkung. Die routinemäßige Applikation von Steroiden in der Kinderherzchirurgie sollte aufgrund dieser Ergebnisse kritisch überdacht werden. / We evaluated the mode of neuronal cell injury and the possible neuroprotective effect of pretreatment with high dose steroids in a neonatal piglet model with CPB and 120 minutes deep hypothermic circulatory arrest (DHCA). Methods: 24 neonatal piglets (age < 10 days and 2,1 ± 0,5 kg BW) were included in this study. Three groups were formed, one group without any additional pharmacological treatment (n=12) served as control group, two groups with a high dose methylprednisolone (MP) pretreatment, where 30 mg / kg/ BW MP (Urbason) was administered either systemically preoperatively (n=7), or intrathecally 4-6 hours preoperatively (n=5). All animals were anaesthetized, intubated and mechanically ventilated. After median sternotomy the animals were connected to CPB by cannulation of the aorta and right atrium. Full flow CPB (200 ml/kg/min) was initiated to achieve homogeneous systemic cooling. Circulatory arrest for 120 min. was induced when rectal temperature of 15°C was achieved. After rewarmed reperfusion and establishment of stable cardiac ejection the animals were weaned from CPB and monitored for 6-8 hours. Thereafter the animals were sacrificed and the brain was immediately removed, cut in standardized sections and fixated and frozen for further histological and immunohistochemical studies. Neuronal cells were counted in cerebral cortex, basal ganglia, hippocampal region and cerebellum in respect to apoptotic and hypoxic-necrotic neuronal cell changes in each animal. Real-time PCR was performed from frozen brain sections for analysis of expression of heat-shock-protein 70kD (HSP 70), FAS, Bak and Bcl-xl. Results: The main preliminary findings of this neonatal ischemic brain model were the quantitative evaluation of cell injury including perivascular astroglial cells and necrotic and apoptotic neuronal cell changes. The systemic application of high dose methylprednisolone lead only to a slight reduction of edema, but it produced a significant hyperglycemia and aggravation of neuronal necrosis. Intrathecal MP was effective in reducing neuronal necrosis without appearance of hyperglycemia. Application of steroids lead to an induction of neuronal apoptosis in the hippocampus. Increased pro-apoptotic gene expression were detected with steroid pretreatment. Increased expression of HSP 70 may reflect reduction in neuronal cell death. Conclusion: Systemic pretreatment with methylprednisolone seems not to be effective for neuroprotective goal during cardiac surgery with DHCA. In contrast intrathecal steroid treatment could reduce neuronal cell death significant. The pronounced apoptotic neuronal cell changes, which were seen after steroid pretreatment, raises concern with regard to the routine use of methylprednisolone during pediatric cardiac surgery.

Deep brain stimulation (DBS) is a potent symptomatic therapy for Parkinson’s disease, but it is debated whether it causes or prevents neurodegeneration. We used serum neurofilament light chain (NFL) as a reporter for neuronal damage and found no difference between 92 patients with chronic STN-DBS and 57 patients on best medical treatment. Serum NFL transiently increased after DBS surgery whereas the initiation of STN stimulation did not affect NFL levels, suggesting that DBS surgery can be associated with neuronal damage whereas stimulation itself is not.