published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Sepsis neonatal temprana se define como un síndrome clínico caracterizado por signos sistémicos de infección los cuales se acompañan de bacteriemia en las primeras 72 horas de vida.La sepsis neonatal temprana en prematuros se estima que ocurre en mayor medida por transmisión vertica, esto por contacto del neonato con gérmenes en el canal vaginal, además este tipo de sepsis tiene un curso clínico grave, fulminante y multisistémico, siendo su complicación mas frecuente la neumonía. Así, en la búsqueda del diagnóstico de dicho síndrome debemos tener presente que la historia clínica materna proporciona importante información como los datos de filiación, antecedentes infecciosos en la madre, factores de riesgo obstétrico, los cuales se suman a aquellos factores de riesgo durante el parto y luego de este. De esta manera el objetivo de la presente tesis es identificar los factores determinantes asociados a sepsis neonatal temprana en prematuros en la unidad de cuidados intensivos neonatales del Hospital Nacional Docente Madre Niño San Bartolomé, que nos lleve a un diagnóstico clínico más certero. Objetivos: Identificar los factores determinantes asociados a sepsis neonatal temprana en prematuros de la unidad de cuidados intensivos neonatales del Hospital Nacional Docente Madre Niño San Bartolomé en el periodo comprendido del 01 de Enero al 31 de Diciembre del 2007. Determinar si los factores de riesgo maternos (filiación, antecedentes patológicos), de riesgo durante el parto (tipo de parto, trauma obstétrico, Apgar), de riesgo del neonato prematuro (edad, asfixia neonatal, enfermedad de membrana hialina, cateterismo, procedimientos invasivos)que se mencionan son factores determinantes de sepsis neonatal temprana en prematuros ingresados a la unidad de cuidados intensivos neonatales del Hospital Nacional Docente Madre Niño San Bartolomé en el periodo comprendido del 01 de Enero al 31 de Diciembre del 2007 Diseño: Descriptivo, retrospectivo, y transversal de casos y controles.

Sepsis affects hundreds of thousands each year in the United States alone, with an estimated 20-30% mortality rate in spite of current treatment regimens. Sepsis mortality was originally understood to be the caused by overproduction of inflammatory cytokines in response to pathogen detection by the host. However, recent studies suggest that with modern treatments, secondary infection, rather than inflammatory shock, may be of greater concern. In either case, the failure of a large number of anti-inflammatory agents to produce beneficial outcomes in sepsis treatment during clinical trial suggests that the development of a new class of immunomodulatory agents may be required for effective treatment. In experimental models, pre-treatment with sub-lethal doses of lipopolysaccharide (LPS, previously referred to as endotoxin) induces a state of "LPS tolerance" that reduces septic shock lethality. Paradoxically, LPS tolerance also results in increased antimicrobial gene expression and resistance to secondary infection in some models. Further exploration of this process may provide drug targets capable of limiting inflammation without dampening antimicrobial immunity, which could be of great benefit in the treatment of sepsis and chronic inflammatory disease. Many groups have studied signaling changes that occur during LPS tolerance. However, mediators of tolerance that can account for the changes in LPS-induced gene expression that result in increased microbial resistance are not well described. This has prevented proper testing of the physiological effects of tolerance on disease, and it remains unclear if this process could be artificially induced or is of any benefit to sepsis patients. Recent in vitro work suggests that tolerant gene expression patterns are the result of large scale changes in chromatin organization that occur in macrophages after prolonged LPS stimulation. Because microRNAs (miRNAs), a new class of gene regulator, have been found to regulate chromatin modifying complexes in other systems, LPS-induced miRNAs were screened to identify potential mediators of tolerance that could cause changes in gene expression patterns without necessarily impacting LPS signaling itself. Several tolerance-associated miRNAs were identified. One miRNA in particular, miR-222, was found to repress tumor necrosis factor (Tnf) and Brahma-related gene one (Brg1) expression. This attenuates expression of genes dependent on nucleosome remodeling, primarily affecting inflammatory genes. Consequently, miR-222 expression effectively limits septic shock lethality. However, low-level responses, as well as NF-κB signaling and the expression of a subset of antimicrobial and antiviral genes, are left intact. Thus, although miR-222 does not entirely recapitulate the tolerance response, by directing the LPS response into a less damaging expression profile, miR-222 may accelerate the onset of tolerance and be a promising target for therapeutics aiming to treat inflammatory disease without compromising host immunity.

Sepsis neonatal temprana se define como un síndrome clínico caracterizado por signos sistémicos de infección los cuales se acompañan de bacteriemia en las primeras 72 horas de vida.La sepsis neonatal temprana en prematuros se estima que ocurre en mayor medida por transmisión vertica, esto por contacto del neonato con gérmenes en el canal vaginal, además este tipo de sepsis tiene un curso clínico grave, fulminante y multisistémico, siendo su complicación mas frecuente la neumonía. Así, en la búsqueda del diagnóstico de dicho síndrome debemos tener presente que la historia clínica materna proporciona importante información como los datos de filiación, antecedentes infecciosos en la madre, factores de riesgo obstétrico, los cuales se suman a aquellos factores de riesgo durante el parto y luego de este. De esta manera el objetivo de la presente tesis es identificar los factores determinantes asociados a sepsis neonatal temprana en prematuros en la unidad de cuidados intensivos neonatales del Hospital Nacional Docente Madre Niño San Bartolomé, que nos lleve a un diagnóstico clínico más certero. Objetivos: Identificar los factores determinantes asociados a sepsis neonatal temprana en prematuros de la unidad de cuidados intensivos neonatales del Hospital Nacional Docente Madre Niño San Bartolomé en el periodo comprendido del 01 de Enero al 31 de Diciembre del 2007. Determinar si los factores de riesgo maternos (filiación, antecedentes patológicos), de riesgo durante el parto (tipo de parto, trauma obstétrico, Apgar), de riesgo del neonato prematuro (edad, asfixia neonatal, enfermedad de membrana hialina, cateterismo, procedimientos invasivos)que se mencionan son factores determinantes de sepsis neonatal temprana en prematuros ingresados a la unidad de cuidados intensivos neonatales del Hospital Nacional Docente Madre Niño San Bartolomé en el periodo comprendido del 01 de Enero al 31 de Diciembre del 2007 Diseño: Descriptivo, retrospectivo, y transversal de casos y controles.

The arterial vasodilation seen in human septic shock is conventionally attributed to increased nitric oxide (NO) production, primarily by extrapolation of animal and cellular studies. Little is known of the cellular source of NO in human septic shock. Other mediators, such as carbon monoxide (CO), may modulate NO production, and could also directly contribute to vasodilation. This study has examined the NO and CO synthetic pathways in peripheral blood mononuclear cells and mesenteric arterial smooth muscle from patients with septic shock, and from non-septic controls. Peripheral blood mononuclear cells from septic patients had increased NO production, though this was perhaps more modest than expected. The transport of arginine, the substrate for NO synthase, into these cells was increased; this was due to an increase in the activity of one transporter system, y⁺. mRNA for a protein encoding y⁺ activity, CAT2B, was increased in these cells. However, mRNA and protein for inducible and endothelial NO synthase was decreased in sepsis, while inducible heme oxygenase (the enzyme responsible for CO production) mRNA and protein was increased. NO production in arterial smooth muscle from septic patients was reduced, as was mRNA for inducible and endothelial NO synthase, and the arginine transporter CAT1. There was no increase in inducible NO synthase protein, though there were small increases in endothelial NO synthase protein and NO synthase activity. In contrast, both mRNA and protein for inducible heme oxygenase were increased. These results challenge the assumption that NO is central to the pathogenesis of human sepsis. Negative feedback systems for NO production have been demonstrated in cell models. These may be relatively more important in human sepsis. In addition to forming one of these feedback systems, it may be that CO, more than NO, is responsible for the hypotension observed in these patients.

Thesis (Ph. D.)--Georgia State University, 2009. / Title from file title page. Chun Jiang, committee chair; Walter William Walthall, Delon W. Barfuss, Deborah Baro, committee members. Description based on contents viewed July 28, 2009. Includes bibliographical references. (p. 121-143)

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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Farmacologia / Made available in DSpace on 2012-10-26T10:13:35Z (GMT). No. of bitstreams: 1 301421.pdf: 1081641 bytes, checksum: c4185c784477f7ab0b14ae0295686558 (MD5) / Sepse é uma infecção local, acompanhada de uma resposta inflamatória sistêmica e vinculada à elevada incidência e taxa de mortalidade. Apesar desta patologia ser alvo de inúmeras pesquisas, poucos estudos avaliam o papel do leito vascular renal nessa condição. Neste trabalho, avaliamos as alterações vasculares renais e o envolvimento da via Rho-A/Rho-quinase em ratos endotoxêmicos. Ratos machos Wistar, com peso de 230-280 g provenientes do Biotério Central da Universidade Federal de Santa Catarina, receberam, via intraperitoneal, PBS (1 ml/kg) ou LPS (10 mg/kg), 6 ou 24 horas antes dos protocolos experimentais. Os animais tratados com LPS apresentaram PAM reduzida, aumento da FC, hiporresponsividade à Phe, além do aumento na concentração plasmática de NO, uréia e creatinina, como descrito por vários autores, demonstrando reprodutibilidade do modelo. Na análise da reatividade vascular renal, houve hiporreatividade à Phe nos rins dos animais do grupo LPS 24 horas. No entanto, a administração de AVP no leito renal dos animais tratados com LPS revelou uma hiper-reatividade a este agente, além de uma maior sensibilidade à inibição da enzima Rho-quinase (ROCK) no grupo LPS 6 horas. A análise, in vivo, da pressão arterial e fluxo microvascular renal também revelou hiper-reatividade à AVP nos animais endotoxêmicos. Além disto, a administração de 0,1 mg/kg de Y-27632 (i.v.), um inibidor da enzima ROCK, diminuiu o efeito da AVP na PAM dos animais do grupo controle. O mesmo não foi observado nos grupos endotoxêmicos. A administração de Y-27632 não influenciou a redução do fluxo sanguíneo renal em resposta às menores doses de AVP, mas nos grupos LPS 6 e 24 h, reduziu significativamente a diminuição causada pela maior dose de AVP utilizada (30 nmol/kg). A análise de parâmetros cardíacos revelou que não há correlação entre as alterações cardíacas induzidas pelo LPS e a hiper-reatividade à vasopressina. As expressões de proteínas não se mostraram alteradas nos grupos que receberam LPS quando comparadas ao PBS. Por fim, constatamos que houve diminuição na produção inicial de urina que se reestabelece 24 horas após o choque endotoxêmico, o que pode estar relacionando a variações nos níveis de AVP plasmático durante a endotoxemia. Podemos concluir que o leito renal não apresenta hiporreatividade à AVP durante a endotoxemia, o que pode contribuir para a eficácia desse mediador em elevar a pressão arterial no choque séptico. Alterações na funcionalidade da via Rho-A/Rho-quinase parecem contribuir de forma diferenciada para os efeitos vasculares da AVP durante a sepse. Novos estudos precisam ser desenvolvidos a fim de esclarecer o potencial benéfico ou deletério dessa inter-relação. / Sepsis is a local infection, followed by systemic inflammatory response and linked to high incidence and mortality rate. Although very studied, few researches have investigated the role of renal vascular bed in this condition. In this work, we evaluated the changes in the functionality of the renal vascular bed, and the involvement of the Rho-A/Rho-kinase pathway, in endotoxemic rats. Male Wistar rats (230-280 g) received by intraperitoneal route either saline (1 ml/kg) or LPS (10 mg/kg), 6 or 24 hours before the experimental protocols. The endotoxemic animals showed reduced mean arterial pressure (MAP), increased heart rate, hyporesponsiveness to phenylephrine and high levels of plasmatic nitrate+nitrate, urea and creatinine levels, as described by several studies. In the analysis of renal vascular function, kidneys from LPS 24 group were hyporeactivity to Phe. However, the renal bed of the animals treated with LPS showed a hyper-reactivity to vasopressin (AVP). An increased sensitivity to inhibition of Rho-kinase (ROCK) was found in the groups LPS 6 hours. The effects of AVP on systemic blood pressure and renal blood flow (both measured in vivo) were also enhanced in endotoxemic rats. In addition, the administration of 0.1 mg/kg of Y-27632 (i.v.), a ROCK inhibitor, decreased the effect of AVP on MAP of control animals., but not in endotoxemic groups. The administration of Y-27632 partially avoided the reduction in renal blood flow elicited by lower doses of AVP in all experimental groups, but had no effect against the highest dose of AVP (30 nmol/kg) in groups LPS 6 and 24 h. Analysis of cardiac parameters showed no correlation between the LPS-induced cardiac changes and the increased effects of AVP. The protein expression of components of the Rho-A/Rho-kinase pathway had not been significantly impaired in kidneys from LPS-treated animals, when compared to control samples. Finally, we did observe a decreased urinary output in the first 6 h after LPS administration, that was restored between 18-24 hours of endotoxemia. Changes in diuresis may be related to variations in plasma levels of AVP during endotoxemia. We concluded that the renal bed does not present hyporeactivity to AVP in endotoxemic shock, what can contribute to the effectiveness of this mediator in raising blood pressure in septic shock. Differential changes in the functionality of the Rho-A/Rho-kinase pathway may contribute to the increased vascular effects of AVP in renal vessels during a septic state. Further studies need to be carried out to provide more evidence regarding the beneficial or deleterious importance of this relationship.

Made available in DSpace on 2016-11-30T14:53:34Z (GMT). No. of bitstreams: 2 110485_Andriele.pdf: 1263113 bytes, checksum: bd3c49919814be43251ae64701ca3977 (MD5) license.txt: 214 bytes, checksum: a5b8d016460874115603ed481bad9c47 (MD5) Previous issue date: 2014 / A sepse é uma doença de caráter heterogêneo e complexo, definida como uma resposta inflamatória sistêmica (SIRS), associada a um quadro de infecção sendo a maior causa de morbidade e mortalidade em Unidades de Terapia Intensiva (UTI). O dano cerebral contribui severamente para o aumento das taxas de mortalidade. A sepse e suas consequências podem ser exacerbadas quando associadas a um quadro de inflamação crônica, como a obesidade. Na obesidade ocorre aumento dos níveis de várias citocinas pró-inflamatórias e proteínas de fase aguda. Quando essa situação é exposta a um insulto inflamatório agudo, como a sepse, os tecidos tornam-se mais vulneráveis à lesão via inflamação exagerada. Portanto, o objetivo é avaliar a suscetibilidade a encefalopatia séptica em ratos obesos. Foram utilizados ratos machos, pertencentes à linhagem Wistar (rattus norvegicus), com idade de 60 dias, pesando entre 250-300g. Os grupos experimentais foram divididos em Sham (controle) + Eutrofia, Sham + Obesidade, CLP (ligação e perfuração cecal ) + Eutrofia e CLP + Obesidade. Durante dois meses os animais foram induzidos à obesidade através da alimentação hipercalórica e após, submetidos a sepse por CLP. A avaliação quantitativa do aumento da permeabilidade da barreira hematoencefálica (BHE) foi investigada no hipocampo, córtex e córtex pré-frontal nos tempos de 12 e 24h após a indução de sepse assim como foram quantificadas as concentrações de nitrito/nitrato, a atividade de mieloperoxidase (MPO), os parâmetros de dano oxidativo em lipídios e proteínas e a atividade da enzima superóxido dismutase (SOD) e catalase (CAT). Os dados foram avaliados por ANOVA seguido pelo teste post hoc Tukey e os resultados foram considerados significantes para p<0.05. Os dados encontrados indicam que em ratos obesos e submetidos a sepse ocorre um aumento de permeabilidade da BHE em diferentes regiões cerebrais em comparação com ratos eutróficos sépticos. Essa alteração refletiu sobre a migração de neutrófilos, concentração de nitrito/nitrato, dano oxidativo em lipídios e proteínas e um desequilíbrio das defesas antioxidantes, especialmente, 24 horas após a sepse. Conclui-se que a obesidade devido ao seu fenótipo pró-inflamatório exacerba o quadro clínico já conhecido da sepse, podendo assim agravar ou preciptar a encefalopatia séptica (ES) e contribuir para disfunção e degeneração neuronal. / Sepsis is a heterogeneous character of disease and complex, defined as a systemic inflammatory response (SIRS) associated with a frame of infection is a major cause of morbidity and mortality in intensive care units. The brain damage contributes heavily to the increase in mortality rates. Sepsis and its consequences may be exacerbated when associated with a chronic inflammatory condition, such as obesity. In obesity is an increase in the levels of several pro-inflammatory cytokines and acute phase proteins. When this situation is exposed to an acute inflammatory insult, such as sepsis, tissues become more vulnerable to damage through excessive inflammation. Therefore, the objective is to evaluate the susceptibility to septic encephalopathy in obese mice. Will be used male rats Wistar (Rattus rattus), aged 60 days, weighing 250-3000g. The experimental groups will be divided into sham (control) + Eutrophia, Sham + Obesity, CLP + Eutrophia and CLP + Obesity. For two months the animals will be induced obesity by high calorie food and sepsis by cecal ligation and puncture (CLP). The quantitative evaluation of increased permeability of the blood-brain barrier (BBB) is investigated in the hippocampus, cortex and prefrontal cortex of the 12 and 24 days after induction of sepsis as well as wiil be quantified nitrite / nitrate concentrations, myeloperoxidase activity (MPO ), the parameters of oxidative damage to lipids and proteins and the activity of superoxide dismutase (SOD) and catalase (CAT). The data were evaluated by ANOVA followed by post hoc Tukey and statistical significance will be considered for values of p <0.05. The data indicate that in obese mice and subjected to sepsis occurs an increase of BBB permeability in different brain regions compared to eutrophic septic rats. This change reflected on neutrophil migration, concentration of nitrite/nitrate, oxidative damage to lipids and proteins and an imbalance of antioxidant defenses especially 24 hours after sepsis. It follows that obesity due to its pro-inflammatory phenotype exacerbates the already known clinical sepsis and can therefore aggravate or preciptar septic encephalopathy (ES) and contribute to neuronal dysfunction and degeneration.

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2012. / Submitted by Albânia Cézar de Melo (albania@bce.unb.br) on 2013-01-07T14:14:57Z No. of bitstreams: 1 2012_JoseRobertoDeusMacedo.pdf: 839769 bytes, checksum: 88842f167deba6eea64327126652b7fd (MD5) / Approved for entry into archive by Guimaraes Jacqueline(jacqueline.guimaraes@bce.unb.br) on 2013-01-24T12:44:18Z (GMT) No. of bitstreams: 1 2012_JoseRobertoDeusMacedo.pdf: 839769 bytes, checksum: 88842f167deba6eea64327126652b7fd (MD5) / Made available in DSpace on 2013-01-24T12:44:18Z (GMT). No. of bitstreams: 1 2012_JoseRobertoDeusMacedo.pdf: 839769 bytes, checksum: 88842f167deba6eea64327126652b7fd (MD5) / A emergência de infecções graves causadas por bactérias gram-negativas multi-resistentes (MR) é uma grande preocupação em hospitais de todo o mundo, especialmente em unidades de terapia intensiva (UTI). Esta situação restabeleceu o uso das polimixinas, uma antiga classe de antibióticos catiônicos, polipeptídeo- cíclicos, com atividade contra bactérias gram-negativas selecionadas, incluindo espécies de Acinetobacter e Pseudomonas. Relatos clínicos antigos sugeriam uma alta taxa de nefrotoxicidade associada com polimixinas. Entretanto, injúria renal aguda induzida pela polimixina é ainda controvérsia, desde recentes estudos que tem mostrado menos toxicidade que o previamente relatado. O objetivo desse estudo foi avaliar a eficácia e nefrotoxicidade da administração endovenosa da polimixina B (PoliB), comparada com o tratamento (controle) com piperacilina/tazobactam (Pipe/Tazo). Realizamos um estudo observacional tipo coorte prospectiva, envolvendo pacientes críticos com pneumonia nosocomial que receberam tratamento contra bactérias gram-negativas. Um total de 100 pacientes foram envolvidos: 50 tratados com PoliB e 50 com Pipe/Tazo. Excluímos pacientes com creatinina sérica prévia ≥2 mg/dl, em diálise, em uso de amicacina, vancomicina ou anfotericina, e aqueles com aumento de creatinina sérica ≥2 vezes em menos de 72h após início antibiótico. Os pacientes foram seguidos por 14 dias após o último dia de infusão da droga. Injúria Renal Aguda (IRA) foi definida como creatinina sérica ≥2 mg/dl, aumento ≥100% da creatinina sérica basal ou diálise após início antibiótico. O nível de significância adotado foi 0,05 (alfa=5%). Não houve diferença entre os grupos PoliB e Pipe/Tazo, considerando idade, gênero, Apache II escore e Sofa escore inicial. O tempo médio de tratamento foi 9,22 (3 to 14) dias de PoliB vs 9,12 (4 to 14) dias de Pipe/Tazo, p=0,814. A incidência de IRA foi de 18% (9 pacientes), igual nos dois grupos (log-rank, p=0,998). A taxa de mortalidade foi levemente diminuída no grupo PoliB - 11 (22%) vs 12 (24%) pacientes no controle (log-rank, p=0,767). Usando regressão logística mulvariada, os fatores prognóstico independentemente associados com o desenvolvimento de IRA foram: idade OR=1,05 (CI 95% 1,01 - 1,10), p=0,021, Apache II escore OR=1,12 (CI 95% 0,95-1,32), p=0,018, e escore Sofa final OR=1,66 (CI 95% 1,20-2,30), p=0,002. Em relação a mortalidade, o único fator prognóstico identificado foi a IRA OR=4,62 (CI 95% 1,46-14,63), p=0,009. A Polimixina B é uma alternativa segura e eficaz para infecções em UTI devido bactérias gram-negativas. A incidência de IRA em pacientes em uso de polimixina B está relacionada predominantemente a sepse e síndrome de disfunção de múltiplos órgãos. De fato, são necessárias mais avaliações sobre sua segurança e eficácia em estudos prospectivos com maior número de pacientes. ______________________________________________________________________________ ABSTRACT / The emergence of serious infections caused by multidrug-resistant (MDR) gram-negative bacteria is a great concern across hospitals worldwide, especially in intensive care units (ICU). This situation has reinstated the use of polymyxins, an old class of cationic, cyclic polypeptide antibiotics, with activity against selected gram- negative bacteria, including Acinetobacter and Pseudomonas species. Older clinical reports suggested a high rate of nephrotoxicity associated with polymyxins. However, polymyxin induced renal injury is still controversial, since some recent studies have shown less toxicity than previously reported. The aim of this study was to evaluate the effectiveness and nephrotoxicity of intravenously administered polymyxin B (PolyB) compared with a piperacillin/tazobactan (Pipe/Tazo) treatment (control). We performed a observational prospective cohort study, enrolling critically ill patients with nosocomial pneumonia who received treatment against gram-negative bacteria. A total of 100 patients were enrolled: 50 were treated with PolyB and 50 with Pipe/Tazo. We excluded patients with previous serum creatinine ≥2 mg/dL, in dialysis, in use of amikacin, vancomycin or amphotericin, or those with serum creatinine that increases ≥2 fold in less than 72h after antibiotic initiation. The patients were followed during 14 days after the last day of drug infusion. Acute Kidney Injury (AKI) was defined as a serum creatinine value ≥2 mg/dL, an increase 100% of the baseline creatinine level, or dialysis after antibiotic therapy initiation. A level of significance of 0.05 (alpha=5%) was adopted. There were no difference between PolyB and PipeTazo groups considering age, gender, Apache II score and initial Sofa score. The mean time of treatment was 9,22 (3 to 14) days of PolyB vs 9,12 (4 to 14) days of Pipe/Tazo, p=0,814. The incidence of AKI was 18% (9 patients), equal in both groups (log-rank, p=0,998). Mortality rate were lightly diminished in PolyB group - 11 (22%) vs 12 (24%) patients in control (log-rank, p=0,767). Using multivariate logistic regression, the prognostic factors independently associated with AKI development were: age (OR=1,05 (CI 95% 1,01 - 1,10), p=0,021), Apache II score (OR=1,12 (CI 95% 0,95-1,32), p=0,018), and final SOFA score (OR=1,66 (CI 95% 1,20-2,30), p=0,002). With respect to mortality, removed the final Sofa, the only prognostic factor independently associated was AKI (OR=4,62 (CI 95% 1,46-14,63), p=0,009). Polymyxin B is an effective and safe alternative to infectious in ICU due to MDR gram-negative bacteria. The incidence of AKI in patients using Polymyxin B is related predominantly to sepsis and syndrome of multiple organ dysfunction. Indeed, further evaluation of its efficacy and safety in larger numbers of patients and prospective studies is required.