Die vorliegende Untersuchung stellt sich die folgenden Fragen: Welchen Stand hat die Entwicklung von mechanischen Kreislaufunterstützungssystemen für Kinder, worin unterscheiden sich die eingesetzten Verfahren? Wie beeinflusst der Blutkontakt mit Fremdmaterial das Kapillarleck beim Kind? Welche Erfahrungen gibt es mit dem pulsatilen Ventrikelunterstützungssystem Berlin Heart beim Kind, welche Schwierigkeiten und Nebenwirkungen sind für das Kindesalter spezifisch? Wann profitieren Kinder von einer mechanischen Kreislaufunterstützung? Die bei Kindern am häufigsten eingesetzten Verfahren, Herzlungenmaschine (HLM), extrakorporale Membranoxygenierung (ECMO) und pneumatisch pulsatiles ventrikuläres Assist device (VAD) unterscheiden sich in Technik, Indikation, Nebenwirkung und möglicher Einsatzdauer erheblich. Die HLM dient der intraoperativen Kreislaufunterstützung. ECMO haben wir seit 1990 zur mittelfristigen Kreislaufunterstützung bei mehr als 70 Kindern für eine Dauer von ein bis zwei, selten bis zu drei Wochen eingesetzt. Mit VAD''s haben wir seit 1990 bei 56 Kindern die Herzfunktion teils monatelang ersetzt. Es bestehen multiple Unterschiede bei dem Einsatz von VAD zwischen Säuglingen, Kindern und Erwachsenen sowohl in der Indikation, Physiologie, Technik, Antikoagulation, der Familienbetreuung und hinsichtlich der Komplikationen. Bei jeder mechanischen Kreislaufunterstützung aktiviert der Fremdflächenkontakt des Blutes das Kontaktsystem, zu dem Gerinnungs- und Komplementsystem gehören. Klinische Äquivalente sind Thrombosen, Thrombozytenverlust und Kapillarleck. Insbesondere Säuglinge neigen zu diesen Komplikationen, weil das Verhältnis von Blutvolumen zu Fremdfläche ungünstig ist und der kontaktabhängige alternative Weg der Komplementaktivierung im jungen Alter vorherrscht. - Wir untersuchten prospektiv den prä- und postoperativen Verlauf von Kontakt- und Komplementsystem (C1q, C3, C4, C1-Inhibitor, Faktor B, Faktor XIIa) bei 11 herzoperierten Säuglingen ohne und 24 Säuglingen mit HLM. Es konnte nachgewiesen werden, dass obwohl bei allen Kindern eine Komplementaktivierung vorhanden war, diese signifikant ausgeprägter in der HLM-Gruppe stattfand. Die Kontaktaktivierung (Faktor XIIa, Präkallikrein) ließ sich nur in der HLM-Gruppe nachweisen, so dass belegt war, dass es nicht die Anästhesie oder die Operation an sich, sondern die HLM ist, die die inflammatorische Reaktion hervorruft. - Bei 27 mit HLM operierten Säuglingen untersuchten wir prospektiv die CLS-Entstehung und die Komplement- und Kontaktaktivierung. Bei den 10 Kindern, die im späteren Verlauf ein Kapillarlecksyndrom (CLS) entwickelten, waren bereits 30 Minuten nach HLM-Beginn die C1-INH-Konzentration und -Aktivität niedriger und Faktor XIIa, C3a und C5a höher als bei den 17 Kindern, die später kein CLS entwickelten. Die Aktivierung korrelierte mit dem Alter der Kinder und der HLM-Zeit, nicht mit der Tiefe der Hypothermie. - Retrospektiv untersuchten wir 28 Kinder (6 Tage - 16 Jahre alt), bei denen im terminalen Herzversagen nach Reanimation die Herzfunktion mit dem parakorporalen pneumatischen VAD Berlin Heart 1-98 Tage lang unterstützt wurde. Zwölf dieser Kinder wurden unter laufender Reanimation mit Herzdruckmassage in den Operationssaal gebracht. 13 Patienten erreichten eine Herztransplantation, 3 Kinder wurden mit dem eigenen Herzen vom System entwöhnt. 12 Kinder starben am System, Todesursachen waren Schock, Multiorganversagen, Sepsis und Blutungen. - Bei 95 herztransplantierten Kindern untersuchten wir retrospektiv die Verläufe in Abhängigkeit davon, ob die Kinder (I) vor der Transplantation in relativ stabilem Zustand zuhause waren (n=33), ob sie (II) kritisch krank hospitalisiert waren (n= 44), oder ob sie (III) nach Reanimation mit einem VAD kreislaufunterstützt wurden (n=18, Dauer 4-111 Tage). Die Überlebensraten nach 1Mo/1J/5J betrugen in Gruppe I 88/88/80 %, Gruppe II 88/82/79 %, Gruppe III 72/72/72 %. Der frühpostoperative Verlauf nach Transplantation war bei Gruppe III nur wenig komplizierter, was den Erfolg der Transplantation nicht minderte. - Retrospektiv untersuchten wir den Verlauf von 4 Kindern mit schwerer Myokarditis, die bei kardiogenem Schock mit biventrikulärem VAD kreislaufunterstützt wurden. Das schockbedingte Multiorganversagen und die Thrombozytopenie bildete sich während der Unterstützung mit dem VAD zurück. Drei Kinder konnten nach Erholung des Myokards vom VAD entwöhnt werden, eines wurde erfolgreich transplantiert. - Ausserdem untersuchten wir den Verlauf von 84 Kindern, die wegen Kardiomyopathie auf der Intensivstation behandelt wurden. Von den 69 (= 82 %), bei denen eine kreislaufstützende medikamentöse Therapie ausreichend war, konnten 32 herztransplantiert werden, 36 besserten sich und wurden nach Hause entlassen und ein Kind verstarb akut. Fünfzehn der 84 Kinder (= 18 %) ließen sich nicht stabilisieren und erhielten nach Reanimation eine mechanische Kreislaufunterstützung mit VAD (Dauer 1 – 98 Tage). Von diesen konnten 12 transplantiert werden. Die in dieser Habilitationsschrift ausgeführten Arbeiten haben weiterführende Fragestellungen und Grenzbereiche des mechanischen Kreislaufersatzes im Kindesalter aufgezeigt und neue Therapiestrategien dargestellt. Dadurch ist es möglich, die Überlebenschancen von Kindern mit terminalem Herzversagen erheblich zu verbessern. Sei es durch Zeitgewinn bis zur Erholung des Myokards oder zum Organangebot auf der HTx-Warteliste. Durch den Zeitgewinn, den die VAD`s den zur HTx gelisteten Kindern bieten, brauchen zur Transplantation freigegebene Kinderherzen seltener verworfen werden, mehr Kinder können überleben und die Ausnutzung der angebotenen Organe gelingt besser. / This scientific work addresses the following questions: what is the state of the art in mechanical circulatory support (MCS) in infants and children? How do the different techniques differ? How does mechanical circulatory support influence the systemic inflammatory response after cardiac surgery? What are the indications for use of the pneumatic pulsatile ventricular support system Berlin Heart in children and what do our experience and the results of its use show? The MCS systems most often used for children of all ages are cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), centrifugal pumps and the pneumatic pulsatile ventricular assist device (VAD). These systems vary in indications, results, side effects and potential supporting time. CPB is used to replace the circulation during cardiac surgery. ECMO has been used in our hospital since 1990 for circulatory support in cases of cardiac failure and of pulmonary failure and has been applied in more than 70 children over a period of 1 to 3 weeks. The VAD (Berlin Heart) has been used since 1990 in 56 children for long-term support, when the heart function had to be supported for up to several months. In VAD use there are multiple differences in indication, physiology, underlying disease, technique, anticoagulation and complications between infants, children and adults. In every case of MCS there is contact and complement activation as a reaction of the blood to foreign surfaces, resulting in capillary leak and activation of coagulation and anticoagulation systems with the risk of thrombosis or bleeding. In particular, young infants are prone to systemic inflammatory response in the form of capillary leak. In a prospective study we compared the complement activation after cardiac operations with or without CPB in 35 infants and measured serially the complement function and concentrations or activity of C1q, C3, C4, C1 esterase inhibitor, factor B, the activated split product C3a, prekallikrein and factor XIIa of the contact system. We found that complement activation occurs in all infants but is significantly higher in the group with CPB. Contact activation occurred only in patients who undergo CPB. Thus, the inflammatory response is caused by the use of a CPB circuit and to a lesser degree by surgical procedures and anesthesia. In 27 infants with CPB surgery we prospectively investigated the early clinical parameters that predict the development of capillary leak syndrome (CLS) and examined the relationship between CLS and complement and contact activation and C1 esterase inhibitor during and after bypass. We found that contact and complement activation occurs during CPB and contributes to CLS more frequently in infants of a younger age and with a prolonged bypass time. This activation and decrease in C1 esterase inhibitor was strongly expressed in the CLS group. Although MCS in intractable heart failure in children has normally been limited to centrifugal pumps and ECMO, we implanted 28 children with the pediatric sized pulsatile air-driven Berlin Heart VAD. Our aim was to keep the children alive and allow recovery from shock sequeale until later transplantation or myocardial recovery. Twelve children were brought to the operating room under cardiac massage. In total 12 children died on the system, but thirteen children were transplanted and three were sucessfully weaned from the system. Acute myocarditis appears to be a promising precondition for complete recovery during VAD support and in patients with cardiomyopathy support until transplantation is the goal for the future. We reviewed the course of 95 children who had undergone heart transplantation in our center to investigate whether previous VAD support has an impact on long-term outcome after transplantation. Three groups were compared and we found that bridging to transplantation with a pulsatile pneumatic VAD is a safe procedure in pediatric patients. After transplantation the overall survival rate is 86 % at 1 month, 82 % at 1 year and 75 % at 5 years. The survival of children previously supported with a VAD is similar to that of patients who were bridged with inotropes or who awaited heart transplantation electively. In 4 children with fulminant myocarditis and cardiogenic shock in whom all aggressive medical treatment failed we found that artificial replacement of the heart with complete unloading was followed by total recovery; 3 patients were successfully weaned from the device. No patient died and heart transplantation was necessary in only one child. Retrospectively we examined the course of 84 children who were treated at the ICU, presenting severe cardiac failure due to cardiomyopathy. In 15 of them medical treatment failed and the disease progressed so rapidly that they would have died during the waiting period before a suitable donor organ was found. After resuscitation these 15 children were supported with a VAD. Only 3 died during the waiting period and 12 (80%) underwent later heart transplantation. Progress has been rapid towards individualized choice of mechanical circulatory support systems for children of different ages and with different indications. With the Berlin Heart VAD prolonged circulatory support until myocardial recovery or until heart transplantation is effective in children and infants. It offers time to restore organ function, allows extubation, mobilization and neurological examination and increases the chances for successful transplantation. It can be used with low device-related morbidity and satisfactory results especially in the myocarditis and the cardiomyopathy groups. Complete recovery from secondary organ dysfunction should be achieved before heart transplantation is considered. We expect not only that children with end-stage heart failure will benefit from long-term VAD support, but also that fewer organs from young donors will be lost. Of particular importance is our experience with myocardial recovery in children with acute myocarditis in whom the devices could be explanted.

Introdução. A Aprotinina parece reduzir o uso de transfusões, o processo inflamatório e o dano miocárdico, pós-CEC. Material e Métodos. Estudo prospectivo randomizado em crianças de 30 dias a 4 anos de idade, submetidas à correção de cardiopatia congênita acianogênica, com CEC e divididas em dois grupos, um denominado Controle (n=9) e o outro, Aprotinina (n=10). Neste, a droga foi administrada imediatamente antes da CEC. A resposta inflamatória sistêmica e disfunções hemostáticas e multiorgânicas foram analisadas por marcadores clínicos e bioquímicos. Foram consideradas significantes as diferenças com p<0,05. Resultados. Os grupos foram semelhantes quanto às variáveis demográficas e intra-operatórias, exceto por maior hemodiluição no Grupo Aprotinina. Não houve benefício quanto aos tempos de ventilação pulmonar mecânica, permanência no CTIP e hospitalar, nem quanto ao uso de inotrópicos e função renal. A relação PaO2/FiO2 (pressão parcial de oxigênio arterial/fração inspirada de oxigênio) apresentou queda significativa com 24 h PO, no Grupo Controle. Ocorreu preservação da concentração plaquetária com a Aprotinina enquanto no grupo Controle houve plaquetopenia desde o início da CEC. As perdas sangüíneas foram semelhantes nos dois grupos. No grupo Aprotinina surgiu leucopenia significativa, em CEC, seguida de leucocitose. Fator de necrose tumoral alfa (TNF-) , Interleucinas (IL)-6, IL-8, IL-10, proporção IL-6/IL-10, troponina I cardíaca (cTnI), fração MB da creatinofosfoquinase (CKMB), transaminase glutâmico-oxalacética (TGO) e fração amino-terminal do peptídio natriurético tipo B (NT-proBNP) não apresentaram diferenças marcantes intergrupos. A proporção IL-6/IL-10 PO aumentou no grupo Controle. A lactatemia e acidose metabólica pós-CEC foi mais intensa no grupo Aprotinina. Não houve complicações com o uso da Aprotinina. Conclusão. A Aprotinina não minimizou as manifestações clínicas e os marcadores séricos de resposta inflamatória sistêmica e miocárdicos, mas preservou quantitativamente as plaquetas. / Introduction. Aprotinin seems to reduce the need for transfusion, the inflammatory process and myocardial damage after extracorporeal circulation (ECC). Material and Methods. A prospective randomized study was conducted on children aged 30 days to 4 years submitted to correction of acyanogenic congenital heart disease with ECC and divided into two groups: Control (n=9) and Aprotinin (n=10). In the Aprotinin Group the drug was administered immediately before ECC and the systemic inflammatory response and hemostatic and multiorgan dysfunctions were analyzed on the basis of clinical and biochemical markers. Differences were considered to be significant when P<0.05. Results. The groups were similar regarding demographic and intraoperative variables, except for a greater hemodilution in the Aprotinin Group. The drug had no benefit regarding time of mechanical pulmonary ventilation, permanence in the postoperative ICU and length of hospitalization, or regarding the use of inotropic drugs and renal function. The partial arterial oxygen pressure/inspired oxygen fraction ratio (PaO2/FiO2) was significantly reduced 24 h after surgery in the Control Group. Platelet concentration was preserved with the use of Aprotinin, whereas thrombocytopenia occurred in the Control Group since the beginning of ECC. Blood loss was similar for both groups. Significant leukopenia was observed in the Aprotinin Group during ECC, followed by leukocytosis. Tumor necrosis factor alpha (TNF-), interleukins (IL)-6, IL-8, IL-10, IL-6/IL-10 ratio, cardiac troponin I (cTnI), creatine kinase MB fraction (CKMB), glutamic-oxaloacetic transaminase (GOT) and the aminoterminal fraction of natriuretic peptide type B (NT-proBNP) ndid not differ significantly between groups.The postoperative IL-6/IL-10 fraction increased significantly in the Control Group. Post-ECC blood lactate concentration and metabolic acidosis was more intense in the Aprotinin Group. There were no complications with the use of Aprotinin. Conclusion. Aprotinin did not minimize the clinical manifestations or serum markers of the inflammatory, systemic and myocardial response, but quantitatively preserved the platelets.

Introdução. A Aprotinina parece reduzir o uso de transfusões, o processo inflamatório e o dano miocárdico, pós-CEC. Material e Métodos. Estudo prospectivo randomizado em crianças de 30 dias a 4 anos de idade, submetidas à correção de cardiopatia congênita acianogênica, com CEC e divididas em dois grupos, um denominado Controle (n=9) e o outro, Aprotinina (n=10). Neste, a droga foi administrada imediatamente antes da CEC. A resposta inflamatória sistêmica e disfunções hemostáticas e multiorgânicas foram analisadas por marcadores clínicos e bioquímicos. Foram consideradas significantes as diferenças com p<0,05. Resultados. Os grupos foram semelhantes quanto às variáveis demográficas e intra-operatórias, exceto por maior hemodiluição no Grupo Aprotinina. Não houve benefício quanto aos tempos de ventilação pulmonar mecânica, permanência no CTIP e hospitalar, nem quanto ao uso de inotrópicos e função renal. A relação PaO2/FiO2 (pressão parcial de oxigênio arterial/fração inspirada de oxigênio) apresentou queda significativa com 24 h PO, no Grupo Controle. Ocorreu preservação da concentração plaquetária com a Aprotinina enquanto no grupo Controle houve plaquetopenia desde o início da CEC. As perdas sangüíneas foram semelhantes nos dois grupos. No grupo Aprotinina surgiu leucopenia significativa, em CEC, seguida de leucocitose. Fator de necrose tumoral alfa (TNF-) , Interleucinas (IL)-6, IL-8, IL-10, proporção IL-6/IL-10, troponina I cardíaca (cTnI), fração MB da creatinofosfoquinase (CKMB), transaminase glutâmico-oxalacética (TGO) e fração amino-terminal do peptídio natriurético tipo B (NT-proBNP) não apresentaram diferenças marcantes intergrupos. A proporção IL-6/IL-10 PO aumentou no grupo Controle. A lactatemia e acidose metabólica pós-CEC foi mais intensa no grupo Aprotinina. Não houve complicações com o uso da Aprotinina. Conclusão. A Aprotinina não minimizou as manifestações clínicas e os marcadores séricos de resposta inflamatória sistêmica e miocárdicos, mas preservou quantitativamente as plaquetas. / Introduction. Aprotinin seems to reduce the need for transfusion, the inflammatory process and myocardial damage after extracorporeal circulation (ECC). Material and Methods. A prospective randomized study was conducted on children aged 30 days to 4 years submitted to correction of acyanogenic congenital heart disease with ECC and divided into two groups: Control (n=9) and Aprotinin (n=10). In the Aprotinin Group the drug was administered immediately before ECC and the systemic inflammatory response and hemostatic and multiorgan dysfunctions were analyzed on the basis of clinical and biochemical markers. Differences were considered to be significant when P<0.05. Results. The groups were similar regarding demographic and intraoperative variables, except for a greater hemodilution in the Aprotinin Group. The drug had no benefit regarding time of mechanical pulmonary ventilation, permanence in the postoperative ICU and length of hospitalization, or regarding the use of inotropic drugs and renal function. The partial arterial oxygen pressure/inspired oxygen fraction ratio (PaO2/FiO2) was significantly reduced 24 h after surgery in the Control Group. Platelet concentration was preserved with the use of Aprotinin, whereas thrombocytopenia occurred in the Control Group since the beginning of ECC. Blood loss was similar for both groups. Significant leukopenia was observed in the Aprotinin Group during ECC, followed by leukocytosis. Tumor necrosis factor alpha (TNF-), interleukins (IL)-6, IL-8, IL-10, IL-6/IL-10 ratio, cardiac troponin I (cTnI), creatine kinase MB fraction (CKMB), glutamic-oxaloacetic transaminase (GOT) and the aminoterminal fraction of natriuretic peptide type B (NT-proBNP) ndid not differ significantly between groups.The postoperative IL-6/IL-10 fraction increased significantly in the Control Group. Post-ECC blood lactate concentration and metabolic acidosis was more intense in the Aprotinin Group. There were no complications with the use of Aprotinin. Conclusion. Aprotinin did not minimize the clinical manifestations or serum markers of the inflammatory, systemic and myocardial response, but quantitatively preserved the platelets.

Early administration of broad-spectrum antibiotics is the first goal in sepsis treatment. Besides from bacteriostatic/bactericidal effects, some antibiotics may also modify the host´s response to infection. The novel antibiotic tigecycline may exert such properties; however, this property has not been evaluated in large-animal trials. We compared tigecycline with doxycycline and placebo in relation to anti-inflammatory, circulatory and organ dysfunction effects in a sterile pig model of sepsis. Doxycycline, but not tigecycline, reduced the inflammatory response as manifested by tumor necrosis factor alpha levels in plasma. Tigecycline, however, had a stabilizing effect on the circulation not exerted by doxycycline or placebo. To achieve rapid restoration of the circulating blood volume - another major goal in sepsis treatment - fluid bolus administration of is some-times practiced. In addition to crystalloids, albumin-containing solutions are suggested. Yet, some animal-experimental data suggests that rapid bolus administration of albumin reduces albumin’s plasma-expanding effect. We compared a rapid intravenous bolus of radiolabeled albumin with a slow infusion in a sterile pig model of sepsis. Rapid bolus of administration did not reduce plasma levels of albumin following administration and did not increase the amount of albumin that left the circulation. Inadequate oxygen delivery (DO2) by the circulation to the tissues may cause increased plasma lactate, which is the most striking effect of sepsis on the metabolism. However, experimental data and clinical trials refute this link, instead, suggesting other mechanisms, including impaired oxygen extraction, mitochondrial dysfunction and accelerated aerobic glycolysis. We investigated the impact of DO2, oxygen consumption (VO2), hemodynamic parameters and inflammatory response on plasma lactate and organ dysfunction in two experimental sepsis models. In the most severe cases of shock, with DO2, there was an increase in plasma lactate, but without a decrease in VO2, invalidating the assumption that the increase in lactate is due to anaerobic metabolism. To identify critical steps in the sepsis-induced increase in lactate, we inhibited the major energy-producing step in the electron transport chain (ETC). The combination of sepsis and ETC inhibition led to a cellular energy crisis. This finding suggests that early sepsis induces a partial mitochondrial dysfunction.