After Thirty Years, We Still Cannot Understand Why Methylene Blue is not a Reference to Treat Vasoplegic Syndrome in Cardiac Surgery

Abstract Vasoplegic syndrome (VS) comprises a constellation of concurrent signs and symptoms: hypotension, high cardiac index, low systemic vascular resistance, low filling pressures, the tendency to occur diffuse bleeding, and sustained hypotension. All of these parameters may persist even despite the use of high doses of vasoconstrictor amines. VS arises from vasoplegic endothelial dysfunction with excessive release of nitric oxide by polymorphonuclear leukocytes mediated by the nitric oxide synthase's inducible form and is associated with systemic inflammatory reaction and high morbimortality. The achievements regarding the treatment of VS with methylene blue (MB) are a valuable Brazilian contribution to cardiac surgery. The present text review was designed to deliver the accumulated knowledge in the past ten years of employing MB to treat VS after cardiac surgery. Considering that we have already published two papers describing acquired experiences and concepts after 15 and 20 years, now, as we achieve the 30-year mark, we compose a trilogy.

Key Points for Curbing Cardiopulmonary Bypass Inflammation

PURPOSE: Cardiopulmonary bypass (CPB) procedures are thought to activate systemic inflammatory reaction syndrome (SIRS). Strategies to curb systemic inflammation have been previously described. However, none of them is adequate, since "curbing" the extent of the inflammatory response requires a multimodal approach. The aim of the present mini-review is to discuss the main key points about the main principles in cardiopulmonary bypass curbing inflammation. METHODS: No systematic literature search (MEDLINE) and extracted data from the accumulated experience of the authors. The preconceived idea of an association between severe inflammation and coagulation disorders is reviewed. Also, some fundamental concepts, CPB inflammatory biomarkers, the vasoplegic syndrome and the need forindividual CPB protocols for children, diabetes and old patients, are discussed. CONCLUSION: The ways in which surgical technique (atraumatic vein harvest, biocompatibility and shear resistance of the circuit, monitoring, minimizing organ ischemia, minimal cross-clamping trauma, and blood management) are thought to curb SIRS induced by CPB and affect positively the patient outcome.Improved patient outcomes are strongly associated with these modalities of care, more than single or combinatorial drug strategies (aprotinin, tranexamic acid, pentoxifylline) or CPB modalities (minicircuits, heparin-coated circuits, retrograde autologous prime).

Cardiopulmonary bypass increases the risk of vasoplegic syndrome after coronary artery bypass grafting in patients with dialysis-dependent chronic renal failure / O uso da circulação extracorpórea aumenta o risco de síndrome vasoplégica em pacientes com insuficiência renal crônica hemodialítica submetidos à revascularização cirúrgica do miocárdio

AbstractObjective:Coronary artery bypass grafting is currently the best treatment for dialysis patients with multivessel coronary artery involvement. Vasoplegic syndrome of inflammatory etiology constitutes an important postoperative complication, with highly negative impact on prognosis. Considering that these patients have an intrinsic inflammatory response exacerbation, our goal was to evaluate the incidence and mortality of vasoplegic syndrome after myocardial revascularization in this group.Methods:A retrospective, single-center study of 50 consecutive and non-selected dialysis patients who underwent myocardial revascularization in a tertiary university hospital, from 2007 to 2012. The patients were divided into 2 groups, according to the use of cardiopulmonary bypass or not (off-pump coronary artery bypass). The incidence and mortality of vasoplegic syndrome were analyzed. The subgroup of vasoplegic patients was studied separately.Results:There were no preoperative demographic differences between the cardiopulmonary bypass (n=20) and off-pump coronary artery bypass (n=30) group. Intraoperative data showed a greater number of distal coronary arteries anastomosis (2.8 vs. 1.8, P<0.0001) and higher transfusion rates (65% vs. 23%, P=0.008) in the cardiopulmonary bypass group. Vasoplegia incidence was statistically higher (P=0.0124) in the cardiopulmonary bypass group (30%) compared to the off-pump coronary artery bypass group (3%). Vasoplegia mortality was 50% in the cardiopulmonary bypass group and 0% in the off-pump coronary artery bypass group. The vasoplegic subgroup analysis showed no statistically significant clinical differences.Conclusion:Cardiopulmonary bypass increased the risk for developing postoperative vasoplegic syndrome after coronary artery bypass grafting in patients with dialysis-dependent chronic renal failure.

ResumoObjetivo:O melhor tratamento atual para os pacientes dialíticos com acometimento coronariano multiarterial é a revascularização cirúrgica do miocárdio. Dentre as complicações pós-operatórias, a síndrome vasoplégica de etiopatogenia inflamatória torna-se importante pelo impacto altamente negativo no prognóstico. Considerando que esses pacientes possuem uma exacerbação intrínseca da resposta inflamatória, nosso objetivo foi avaliar a incidência e a mortalidade da síndrome vasoplégica no pós-operatório de revascularização miocárdica nesse grupo.Métodos:Estudo retrospectivo, unicêntrico, de 50 pacientes dialíticos consecutivos e não selecionados, submetidos à revascularização miocárdica, em um hospital terciário universitário, no período de 2007 a 2012. Esses pacientes foram divididos em 2 grupos, de acordo com o emprego ou não da circulação extracorpórea. A incidência e a mortalidade da vasoplegia foram analisadas nos grupos. Após a identificação dos pacientes quanto à presença de vasoplegia, este subgrupo foi estudado separadamente.Resultados:Não houve diferenças demográficas pré-operatórias entre os grupos com circulação extracorpórea (n=20) e sem circulação extracorpórea (n=30). Dados intraoperatórios demonstraram maior número de artérias coronárias revascularizadas (2,8 vs. 1,8; P<0,0001) e maior necessidade de transfusão (65% vs. 23%; P=0,008) no grupo circulação extracorpórea. A incidência de vasoplegia foi estatisticamente maior (P=0,0124) no grupo circulação extracorpórea (30%) em comparação ao grupo sem circulação extracorpórea (3%). A mortalidade dos pacientes com vasoplegia foi 50% no grupo circulação extracorpórea e 0% no grupo sem circulação extracorpórea. A análise do subgrupo vasoplégico não demonstrou diferenças clínicas estatisticamente significantes.Conclusão:O emprego da circulação extracorpórea na revascularização cirúrgica do miocárdio em pacientes com insuficiência renal crônica dialítica aumentou o risco para desenvolvimento de síndrome vasoplégica pós-operatória.

Reclassificando o espectro de pacientes septicos com o uso do lactato: sepse grave, choque criptico, choque vasoplegico e choque disoxico / Reclassifying the spectrum of septic patients using lactate: severe sepsis, cryptic shock, vasoplegic shock and dysoxic shock

Objetivo: A definição atual de sepse grave e choque séptico inclui um perfil heterogêneo de pacientes. Embora o valor prognóstico de hiperlactatemia seja bem estabelecido, ela está presente em pacientes com ou sem choque. Nosso objetivo foi comparar o prognóstico de pacientes sépticos estratificando-os segundo dois fatores: hiperlactatemia e hipotensão persistente. Métodos: Este estudo é uma análise secundária de um estudo observacional conduzido em dez hospitais no Brasil (Rede Amil - SP). Pacientes sépticos com valor inicial de lactato das primeiras 6 horas do diagnóstico foram incluídos e divididos em 4 grupos segundo hiperlactatemia (lactato >4mmol/L) e hipotensão persistente: (1) sepse grave (sem ambos os critérios); (2) choque críptico (hiperlactatemia sem hipotensão persistente); (3) choque vasoplégico (hipotensão persistente sem hiperlactatemia); e (4) choque disóxico (ambos os critérios). Resultados: Foram analisados 1.948 pacientes, e o grupo sepse grave constituiu 52% dos pacientes, seguido por 28% com choque vasoplégico, 12% choque disóxico e 8% com choque críptico. A sobrevida em 28 dias foi diferente entre os grupos (p<0,001), sendo maior para o grupo sepse grave (69%; p<0,001 versus outros), semelhante entre choque críptico e vasoplégico (53%; p=0,39) e menor para choque disóxico (38%; p<0,001 versus outros). Em análise ajustada, a sobrevida em 28 dias permaneceu diferente entre os grupos (p<0,001), sendo a maior razão de risco para o grupo choque disóxico (HR=2,99; IC95% 2,21-4,05). Conclusão: A definição de pacientes com sepse inclui quatro diferentes perfis, se considerarmos a presença de hiperlactatemia. Novos estudos são necessários para melhor caracterizar pacientes sépticos e gerar conhecimento ...

Objective: The current definition of severe sepsis and septic shock includes a heterogeneous profile of patients. Although the prognostic value of hyperlactatemia is well established, hyperlactatemia is observed in patients with and without shock. The present study aimed to compare the prognosis of septic patients by stratifying them according to two factors: hyperlactatemia and persistent hypotension. Methods: The present study is a secondary analysis of an observational study conducted in ten hospitals in Brazil (Rede Amil - SP). Septic patients with initial lactate measurements in the first 6 hours of diagnosis were included and divided into 4 groups according to hyperlactatemia (lactate >4mmol/L) and persistent hypotension: (1) severe sepsis (without both criteria); (2) cryptic shock (hyperlactatemia without persistent hypotension); (3) vasoplegic shock (persistent hypotension without hyperlactatemia); and (4) dysoxic shock (both criteria). Results: In total, 1,948 patients were analyzed, and the sepsis group represented 52% of the patients, followed by 28% with vasoplegic shock, 12% with dysoxic shock and 8% with cryptic shock. Survival at 28 days differed among the groups (p<0.001). Survival was highest among the severe sepsis group (69%, p<0.001 versus others), similar in the cryptic and vasoplegic shock groups (53%, p=0.39), and lowest in the dysoxic shock group (38%, p<0.001 versus others). In the adjusted analysis, the survival at 28 days remained different among the groups (p<0.001) and the dysoxic shock group exhibited the highest hazard ratio (HR=2.99, 95%CI 2.21-4.05). Conclusion: The definition of sepsis includes four different profiles if we consider the presence of hyperlactatemia. Further studies are needed to better characterize septic patients, to understand the etiology and to design adequate targeted treatments. .

Cirugía cardiaca con circulación extracorpórea: síndrome vasoplégico y vasopresina / Vasoplegic syndrome and its treatment with vasopressin during cardiac surgery with cardiopulmonary bypass

Cardiac surgery with cardiopulmonary bypass is associated with systemic inflammatory response. In some cases this clinical condition is characterized by severe hypotension due to low systemic vascular resistance during and after cardiopulmonary bypass. Afew ofthese cases do not respond to volume or catecholamines. This condition is known as vasoplegic syndrome. Its etiology is notfully understood today and carries associated morbidity and mortality In this syndrome, vasopressin levéis are reduced, as in septic and hypovolemic shock. Supplementary vasopressin improves blood pressure and might be considered as an alternative treatment. Severa! reports have shown benefits when used alone or in combination with catecholamines. However, further studies are necessary to find the most appropriate use ofthe drug for vasoplegic syndrome.

Methylene blue for vasoplegic syndrome treatment in heart surgery: fifteen years of questions, answers, doubts and certainties / Azul de metileno no tratamento da síndrome vasoplégica em cirurgia cardíaca: quinze anos de perguntas, respostas, dúvidas e certezas

OBJECTIVE: There is strong evidence that methylene blue (MB), an inhibitor of guanylate cyclase, is an excellent therapeutic option for vasoplegic syndrome (VS) treatment in heart surgery. The aim of this article is to review the MB's therapeutic function in the vasoplegic syndrome treatment. METHODS: Fifteen years of literature review. RESULTS: 1) Heparin and ACE inhibitors are risk factors; 2) In the recommended doses it is safe (the lethal dose is 40 mg/kg); 3) The use of MB does not cause endothelial dysfunction; 4) The MB effect appears in cases of nitric oxide (NO) up-regulation; 5) MB is not a vasoconstrictor, by blocking of the GMPc system it releases the AMPc system, facilitating the norepinephrine vasoconstrictor effect; 6) The most used dosage is 2 mg/kg as IV bolus followed by the same continuous infusion because plasmatic concentrations strongly decays in the first 40 minutes; 7) There is a possible "window of opportunity" for the MB's effectiveness. CONCLUSIONS: Although there are no definitive multicentric studies, the MB used to treat heart surgery VS, at the present time, is the best, safest and cheapest option, being a Brazilian contribution for the heart surgery

OBJETIVO: Existem fortes evidências de que o azul de metileno (AM), um inibidor da guanilato ciclase, é uma excelente opção terapêutica para o tratamento da síndrome vasoplégica (SV) em cirurgia cardíaca. O objetivo deste artigo é rever o papel terapêutico do AM no tratamento da SV. MÉTODOS: Revisão da literatura em período de 15 anos. RESULTADOS: 1) A heparina e inibidores da ECA são fatores de risco; 2) Nas doses preconizadas é droga segura (a dose letal é de 40 mg/kg); 3) O AM não causa disfunção endotelial; 4) O efeito do AM só aparece em caso de supra-regulação de óxido nítrico (NO); 5) O AM não é um vasoconstritor, pelo bloqueio do sistema GMPc ele "libera" o sistema AMPc, facilitando o efeito vasoconstritor da noradrenalina; 6) A dosagem mais utilizada é 2 mg/kg em bolus endovenosa, seguida de infusão contínua, pois a concentração plasmática decai acentuadamente nos primeiros 40 minutos; 7) Existe possível "janela de oportunidade" para efetividade do AM. CONCLUSÃO: Embora não existam estudos multicêntricos definitivos, a utilização do AM no tratamento da SV em cirurgia cardíaca é, na atualidade, a melhor, mais segura e barata opção, sendo contribuição brasileira