Hemodynamic phenotype-based, capillary refill time-targeted resuscitation in early septic shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial study protocol. / Ressuscitação direcionada ao tempo de enchimento capilar baseada em fenótipo hemodinâmico no choque séptico precoce: protocolo de estudo do ensaio clínico randomizado ANDROMEDA-SHOCK-2.

BACKGROUND: Early reversion of sepsis-induced tissue hypoperfusion is essential for survival in septic shock. However, consensus regarding the best initial resuscitation strategy is lacking given that interventions designed for the entire population with septic shock might produce unnecessary fluid administration. This article reports the rationale, study design and analysis plan of the ANDROMEDA-2 study, which aims to determine whether a peripheral perfusion-guided strategy consisting of capillary refill time-targeted resuscitation based on clinical and hemodynamic phenotypes is associated with a decrease in a composite outcome of mortality, time to organ support cessation, and hospital length of stay compared to standard care in patients with early (< 4 hours of diagnosis) septic shock. METHODS: The ANDROMEDA-2 study is a multicenter, multinational randomized controlled trial. In the intervention group, capillary refill time will be measured hourly for 6 hours. If abnormal, patients will enter an algorithm starting with pulse pressure assessment. Patients with pulse pressure less than 40mmHg will be tested for fluid responsiveness and receive fluids accordingly. In patients with pulse pressure > 40mmHg, norepinephrine will be titrated to maintain diastolic arterial pressure > 50mmHg. Patients who fail to normalize capillary refill time after the previous steps will be subjected to critical care echocardiography for cardiac dysfunction evaluation and subsequent management. Finally, vasopressor and inodilator tests will be performed to further optimize perfusion. A sample size of 1,500 patients will provide 88% power to demonstrate superiority of the capillary refill time-targeted strategy. CONCLUSIONS: If hemodynamic phenotype-based, capillary refill time-targeted resuscitation demonstrates to be a superior strategy, care processes in septic shock resuscitation can be optimized with bedside tools.

INTRODUçÃO: A reversão precoce da hipoperfusão tecidual induzida é essencial para a sobrevida no choque séptico. No entanto, falta consenso sobre a melhor estratégia de ressuscitação inicial, uma vez que intervenções destinadas a toda a população com choque séptico podem produzir administração desnecessária de líquidos. Este artigo relata a justificativa, o delineamento e o plano de análise do estudo ANDROMEDA-2, que visa determinar se uma estratégia guiada por perfusão periférica, que consiste na ressuscitação guiada pelo tempo de enchimento capilar com base em fenótipos clínicos e hemodinâmicos, está associada a uma diminuição no desfecho composto de mortalidade, tempo até a interrupção ao suporte de órgãos e tempo de internação em comparação com o atendimento padrão em pacientes com choque séptico precoce (< 4 horas do diagnóstico). METÓDOS: O estudo ANDROMEDA-2 é um ensaio clínico randomizado controlado multinacional e multicêntrico. No grupo de intervenção, o tempo de enchimento capilar será medido a cada hora, durante 6 horas. Se estiver anormal, os pacientes serão alocados em um algoritmo, começando com a avaliação da pressão de pulso. Pacientes com pressão de pulso inferior a 40mmHg serão testados quanto à capacidade de resposta a líquidos e receberão líquidos de acordo. Em pacientes com pressão de pulso > 40mmHg, norepinefrina será titulada para manter a pressão arterial diastólica > 50mmHg. Os pacientes que não normalizarem o tempo de enchimento capilar após as etapas anteriores serão submetidos à ecocardiografia de cuidados intensivos para avaliação da disfunção cardíaca e posterior manejo. Por fim, serão realizados testes com vasopressores e inodilatadores para otimizar ainda mais a perfusão. Um tamanho de amostra de 1.500 pacientes fornecerá 88% de poder para demonstrar a superioridade da estratégia direcionada ao tempo de enchimento capilar. CONCLUSÃO: Se for demonstrado que o direcionamento ao tempo de enchimento capilar é uma estratégia melhor, os processos de atendimento na ressuscitação do choque séptico podem ser otimizados com ferramentas usadas à beira do leito.

Ressuscitação direcionada ao tempo de enchimento capilar baseada em fenótipo hemodinâmico no choque séptico precoce: protocolo de estudo do ensaio clínico randomizado ANDROMEDA-SHOCK-2 / Hemodynamic phenotype-based, capillary refill time-targeted resuscitation in early septic shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial study protocol

RESUMO Introdução: A reversão precoce da hipoperfusão tecidual induzida é essencial para a sobrevida no choque séptico. No entanto, falta consenso sobre a melhor estratégia de ressuscitação inicial, uma vez que intervenções destinadas a toda a população com choque séptico podem produzir administração desnecessária de líquidos. Este artigo relata a justificativa, o delineamento e o plano de análise do estudo ANDROMEDA-2, que visa determinar se uma estratégia guiada por perfusão periférica, que consiste na ressuscitação guiada pelo tempo de enchimento capilar com base em fenótipos clínicos e hemodinâmicos, está associada a uma diminuição no desfecho composto de mortalidade, tempo até a interrupção ao suporte de órgãos e tempo de internação em comparação com o atendimento padrão em pacientes com choque séptico precoce (< 4 horas do diagnóstico). Metódos: O estudo ANDROMEDA-2 é um ensaio clínico randomizado controlado multinacional e multicêntrico. No grupo de intervenção, o tempo de enchimento capilar será medido a cada hora, durante 6 horas. Se estiver anormal, os pacientes serão alocados em um algoritmo, começando com a avaliação da pressão de pulso. Pacientes com pressão de pulso inferior a 40mmHg serão testados quanto à capacidade de resposta a líquidos e receberão líquidos de acordo. Em pacientes com pressão de pulso > 40mmHg, norepinefrina será titulada para manter a pressão arterial diastólica > 50mmHg. Os pacientes que não normalizarem o tempo de enchimento capilar após as etapas anteriores serão submetidos à ecocardiografia de cuidados intensivos para avaliação da disfunção cardíaca e posterior manejo. Por fim, serão realizados testes com vasopressores e inodilatadores para otimizar ainda mais a perfusão. Um tamanho de amostra de 1.500 pacientes fornecerá 88% de poder para demonstrar a superioridade da estratégia direcionada ao tempo de enchimento capilar. Conclusão: Se for demonstrado que o direcionamento ao tempo de enchimento capilar é uma estratégia melhor, os processos de atendimento na ressuscitação do choque séptico podem ser otimizados com ferramentas usadas à beira do leito.

ABSTRACT Background: Early reversion of sepsis-induced tissue hypoperfusion is essential for survival in septic shock. However, consensus regarding the best initial resuscitation strategy is lacking given that interventions designed for the entire population with septic shock might produce unnecessary fluid administration. This article reports the rationale, study design and analysis plan of the ANDROMEDA-2 study, which aims to determine whether a peripheral perfusion-guided strategy consisting of capillary refill time-targeted resuscitation based on clinical and hemodynamic phenotypes is associated with a decrease in a composite outcome of mortality, time to organ support cessation, and hospital length of stay compared to standard care in patients with early (< 4 hours of diagnosis) septic shock. Methods: The ANDROMEDA-2 study is a multicenter, multinational randomized controlled trial. In the intervention group, capillary refill time will be measured hourly for 6 hours. If abnormal, patients will enter an algorithm starting with pulse pressure assessment. Patients with pulse pressure less than 40mmHg will be tested for fluid responsiveness and receive fluids accordingly. In patients with pulse pressure > 40mmHg, norepinephrine will be titrated to maintain diastolic arterial pressure > 50mmHg. Patients who fail to normalize capillary refill time after the previous steps will be subjected to critical care echocardiography for cardiac dysfunction evaluation and subsequent management. Finally, vasopressor and inodilator tests will be performed to further optimize perfusion. A sample size of 1,500 patients will provide 88% power to demonstrate superiority of the capillary refill time-targeted strategy. Conclusions: If hemodynamic phenotype-based, capillary refill time-targeted resuscitation demonstrates to be a superior strategy, care processes in septic shock resuscitation can be optimized with bedside tools.

Does basiliximab induction trigger lifethreatening ARDS and shock in young patients after kidney transplantation?

BACKGROUND: Kidney disease Improving Global Outcomes (KDIGO) guidelines strongly recommend administering an anti-IL-2R mAb (i.e., basiliximab) for induction in all kidney transplant recipients. We describe a life-threatening episode of shock following basiliximab injection and review the literature. METHODS AND RESULTS: A 20-year-old male was given tacrolimus, methylprednisolone, mycophenolate, and basiliximab, 20 mg in the context of living-related kidney transplantation. On post-operative Day 1 (POD 1), he developed acute respiratory distress syndrome (ARDS), shock, multiple organ failure, and had a cardiac arrest. After effective resuscitation, he received rescue therapies (NO inhalation, extra-corporeal membrane oxygenation, and CVVHD) but lost the graft as the result of cortical necrosis. We conducted PubMed searches that yielded 7 similar cases; 6 required invasive ventilation. Three patients developed cardiac arrest, 3 required major inotropic support, and 2 developed MOF and myocardial depression. All but 1 patient recovered rapidly within a few days. There was no evidence for infectious, allergic, or over-hydration concerns. Although the direct causal role of basiliximab cannot be formally proven, the fact that ARDS at the time of induction therapy with other immunosuppressive agents is otherwise extremely rare suggests a direct role for basiliximab. CONCLUSIONS: Basiliximab could be associated with shock and ARDS.

Early management of sepsis.

Increased awareness of the signs and symptoms of sepsis and an emphasis on the importance of early treatment have helped to improve survival rates from this serious and frequent condition in recent years. With no specific, effective anti-sepsis therapies available, management focuses on early source control with adequate and appropriate antibiotics and removal of any source of infection, rapid resuscitation, hemodynamic stabilization and organ support. Use of dedicated teams to care for patients with sepsis can help optimize early management.

Extracorporeal life support associated with hypothermia and normoxemia in refractory cardiac arrest.

AIM: We describe a 1-year experience with extracorporeal cardiopulmonary resuscitation (ECPR) for in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) associated with intra-arrest hypothermia and normoxemia. METHODS: Since January 1st 2012, ECPR has been applied in our hospital to all patients less than 65 years of age and without major co-morbidities who develop refractory cardiac arrest (CA) with bystander CPR. Over a 1-year period of observation, we recorded 28-day survival with intact neurological outcome and the rate of organ donation. RESULTS: During the observational period, 24 patients were treated with ECPR, with a median age of 48 years. Ten patients had IHCA. Acute coronary syndrome and/or major arrhythmias were the main cause of arrest. Intra-arrest cooling was used in 17 patients; temperature on ECMO initiation in these patients was 32.9 °C [32-34]. The time from collapse to ECPR was 58 min [45-70] and was shorter in survivors than in non-survivors (41 min [39-58] vs. 60 min [55-77], p=0.059). Non-survivors were more likely to have coagulopathy and received more blood transfusions. Six patients (25%) survived with good neurological outcome at day 28. Four patients with irreversible brain damage had organ function suitable for donation. CONCLUSION: ECPR provided satisfactory survival rates with good neurologic recovery in refractory CA for both IHCA and OHCA. ECMO may help rapidly stabilise systemic haemodynamic status and restore organ function.

Microcirculatory assessment in daily clinical practice - not yet ready but not too far!

Shock is characterized by an alteration in tissue perfusion that may lead to tissue hypoxia. Recent guidelines recommend aggressive and early resuscitation therapy, but mortality rate is still unacceptably high. Unfortunately, traditional clinical surrogates used to guide resuscitation therapy poorly correlate with microcirculatory blood flow, a key determinant of tissue perfusion. New techniques that directly assess microcirculatory perfusion at the bedside have emerged as a complement to traditional macrohemodynamic parameters. These techniques have been supported by several studies showing microcirculatory alterations in different clinical settings. In addition, these microcirculatory alterations are related with outcome and persist regardless of arterial pressure normalization, being a better predictor of organ dysfunction and mortality than global hemodynamic and laboratory parameters. These findings allowed the concept of "microcirculatory-goal directed therapy", which is now in its preliminary phase, as the impact of many interventions still needs to be assessed. Finally, microcirculation assessment has also been explored in other medical fields such as perioperative, systemic arterial hypertension, heart failure, and hyperviscosity syndromes. In this review, we shortly present the characteristics of microcirculation and the main determinants of capillary blood flow, and we discuss advantages and limitations of some recently available techniques to evaluate microcirculation at the bedside, and how they could be useful for the general clinician in daily practice.