Fluidoterapia reflexiva: desde la fisiología a la práctica clínica / Reflexive fluid therapy: From physiology to clinical practice

Introducción. La fluidoterapia es una intervención ampliamente usada en la práctica clínica. No obstante, su aplicación no está exenta de riesgos y demanda una evaluación cuidadosa de la tolerancia del paciente y su respuesta al volumen. La práctica empírica de la reanimación con líquidos puede ser potencialmente letal. El propósito de esta revisión fue proporcionar una visión general de los principios fisiológicos y terapéuticos para la administración de líquidos intravenosos en pacientes críticamente enfermos, abordando poblaciones especiales, como los pacientes quirúrgicos, sépticos y politraumatizados. Métodos. Se hizo una revisión narrativa a partir de artículos publicados en PUBMED, ScienceDirect y LILACS, entre 2001 y 2023. Para la búsqueda se emplearon los términos MESH fluid therapy, crystalloid solutions y colloids. Resultados. Se encontraron 371 artículos, de los cuales se seleccionaron los estudios clínicos aleatorizados, las revisiones narrativas, las revisiones sistemáticas y los metaanálisis que analizaron el rol de los cristaloides y coloides. Se incluyeron manuscritos publicados en fechas por fuera del rango de búsqueda, que se consideraron relevantes para la descripción de la fisiopatología y los fundamentos del uso de líquidos endovenosos. Conclusión. La reanimación reflexiva se fundamenta en un entendimiento holístico de la fisiología y la individualización de la fluidoterapia. El uso liberal de líquidos endovenosos tiene potenciales efectos nocivos y las estrategias de reanimación deben ser guiadas por medidas dinámicas y estáticas individuales, que proporcionan un panorama seguro para el manejo de los líquidos.

Introduction. Fluid therapy is an intervention widely used in clinical practice. However, its application is not without risks and requires a careful evaluation of patient's tolerance and response to volume. The empirical practice of fluid resuscitation can be potentially lethal. The purpose of this review was to provide an overview of the physiological and therapeutic principles for the administration of intravenous fluids in critically ill patients, addressing special populations, such as surgical, septic, and trauma patients. Methods. A narrative review was carried out based on articles published in PUBMED, ScienceDirect, and LILACS between 2001 and 2023. MESH terms fluid therapy, crystalloid solutions, and colloids were employed. Results. A total of 371 articles were found, of which randomized clinical trials studies, narrative reviews, systematic reviews, and meta-analyses that analyzed the role of crystalloids and colloids were selected. Manuscripts published on dates outside the search range, which were considered relevant for the description of the pathophysiology and the rationale for the use of intravenous fluids, were included. Conclusion. Reflective resuscitation is based on a holistic understanding of physiology and individualization of fluid therapy. The liberal use of intravenous fluids has potential harmful effects and resuscitation strategies should be guided by individual dynamic and static measures, which provide a safe framework for fluid management

Fluids in the treatment of diabetic ketoacidosis in children: A systematic review.

AIM: To determine the comparative effectiveness of fluid schemes for children with diabetic ketoacidosis (DKA). METHODS: We conducted a systematic review with an attempt to conduct network meta-analysis (NMA). We searched MEDLINE, EMBASE, CENTRAL, Epistemonikos, Virtual Health Library, and gray literature from inception to July 31, 2022. We included randomized controlled trials (RCTs) in children with DKA evaluating any intravenous fluid schemes. We planned to conduct NMA to compare all fluid schemes if heterogeneity was deemed acceptable. RESULTS: Twelve RCTs were included. Studies were heterogeneous in the population (patients and DKA episodes), interventions with different fluids (saline, Ringer's lactate (RL), and polyelectrolyte solution-PlasmaLyte®), tonicity, volume, and administration systems. We identified 47 outcomes that measured clinical manifestations and metabolic control, including single and composite outcomes and substantial heterogeneity preventing statistical combination. No evidence was found of differences in neurological deterioration (main outcome), but differences were found among interventions in some comparisons to normalize acid-base status (∼2 h less with low vs. high volume); time to receive subcutaneous insulin (∼1 h less with low vs. high fluid rate); length of stay (∼6 h less with RL vs. saline); and resolution of the DKA (∼3 h less with two-bag vs. one-bag scheme). However, available evidence is scarce and poor. CONCLUSIONS: There is not enough evidence to determine the best fluid therapy in terms of fluid type, tonicity, volume, or administration time for DKA treatment. There is an urgent need for more RCTs, and the development of a core outcome set on DKA in children.

Electrical bioimpedance analysis and comparison in biological tissues through crystalloid solutions implementation.

Electrical bioimpedance is a non-invasive and radiation-free technique that was proposed to be used in different clinical areas, however, its practical use is limited due to its low capacity to discriminate between tissues. In order to overcome this limitation, our research group proposes to incorporate the contrast media into the electrical bioimpedance procedure. The main objective of the present study was to assess the crystalloid solutions as a possible contrast media to discriminate between different tissue types in the bioimpedance technique. Two medical-grade crystalloid solutions (Hartmann and NaCl 0.9%) were injected into three biological ex vivo models: kidney, liver, and brain. BIOPAC system was used to acquire bioimpedance data before and after the injections. The data was adjusted to the Debye electrical model. The analysis of measured values showed substantial bioimpedance disparities in tissues subjected to isotonic solutions. The NaCl solution exhibited more pronounced changes in electrical parameters compared to the Hartmann solution. Similarly, NaCl solution displayed superior discriminatory capabilities among tissues, with variations of 465%, 157%, and 206%. Distinct spectral modifications were identified, with tissues demonstrating unique responses at each frequency of analysis relative to untreated tissue. Variations in bandwidth alterations were discernible among tissues, providing clear distinctions. In conclusion, the research showed that the crystalloid solution exhibited greater sensitivity and superior tissue contrast at specific frequencies. This study's findings underscore the feasibility of implementing crystalloid solutions to enhance tissue discrimination, similar to the effects of contrast agents.

Perioperative care in digestive surgery: the eras and acerto protocols - brazilian college of digestive surgery position paper / Cuidados perioperatórios em cirurgia digestiva: protocolos eras e acerto - posicionamento do colégio brasileiro de cirurgia digestiva

ABSTRACT BACKGROUND: The concept introduced by protocols of enhanced recovery after surgery modifies perioperative traditional care in digestive surgery. The integration of these modern recommendations components during the perioperative period is of great importance to ensure fewer postoperative complications, reduced length of hospital stay, and decreased surgical costs. AIMS: To emphasize the most important points of a multimodal perioperative care protocol. METHODS: Careful analysis of each recommendation of both ERAS and ACERTO protocols, justifying their inclusion in the multimodal care recommended for digestive surgery patients. RESULTS: Enhanced recovery programs (ERPs) such as ERAS and ACERTO protocols are a cornerstone in modern perioperative care. Nutritional therapy is fundamental in digestive surgery, and thus, both preoperative and postoperative nutrition care are key to ensuring fewer postoperative complications and reducing the length of hospital stay. The concept of prehabilitation is another key element in ERPs. The handling of crystalloid fluids in a perfect balance is vital. Fluid overload can delay the recovery of patients and increase postoperative complications. Abbreviation of preoperative fasting for two hours before anesthesia is now accepted by various guidelines of both surgical and anesthesiology societies. Combined with early postoperative refeeding, these prescriptions are not only safe but can also enhance the recovery of patients undergoing digestive procedures. CONCLUSIONS: This position paper from the Brazilian College of Digestive Surgery strongly emphasizes that the implementation of ERPs in digestive surgery represents a paradigm shift in perioperative care, transcending traditional practices and embracing an intelligent approach to patient well-being.

RESUMO RACIONAL: O conceito introduzido pelos protocolos de recuperação após a cirurgia modifica os cuidados perioperatórios tradicionais em cirurgia digestiva. A integração desses componentes modernos de recomendações, durante o período perioperatório, é de grande importância para garantir menos complicações pós-operatórias, redução do tempo de internação hospitalar e diminuição dos custos cirúrgicos. OBJETIVOS: Enfatizar os pontos mais importantes de um protocolo multimodal de cuidados perioperatórios. MÉTODOS: Análise criteriosa de cada recomendação dos protocolos ERAS e ACERTO, justificando sua inclusão no atendimento multimodal recomendado para pacientes de cirurgia digestiva. RESULTADOS: Os programas de recuperação avançada (PRAs), tais como os protocolos ERAS e ACERTO, são a base dos cuidados perioperatórios modernos. A terapia nutricional é de grande importância na cirurgia digestiva e, portanto, tanto os cuidados nutricionais pré-operatórios, quanto pós-operatórios são fundamentais para garantir menos complicações pós-operatórias e reduzir o tempo de internação hospitalar. O conceito de pré-habilitação é outro elemento-chave nos PRAs. O manuseio de fluidos cristalóides em perfeito equilíbrio é vital. A sobrecarga de fluidos pode atrasar a recuperação dos pacientes e aumentar as complicações pós-operatórias. A abreviação do jejum pré-operatório para duas horas antes da anestesia é agora aceita por diversas diretrizes das sociedades cirúrgicas e de anestesiologia. Combinadas com a realimentação pós-operatória precoce, essas prescrições não são apenas seguras, mas também podem melhorar a recuperação de pacientes submetidos a procedimentos digestivos. CONCLUSÕES: Este posicionamento do Colégio Brasileiro de Cirurgia Digestiva enfatiza fortemente que a implementação de PRAs em cirurgia digestive, representa uma mudança de paradigma no cuidado perioperatório, transcendendo as práticas tradicionais e adotando uma abordagem inteligente para o bem-estar do paciente.

Effects of Plasma-Lyte® and 0. 9% saline in renal function after deceased-donor kidney transplant: a randomized controlled trial

Abstract Background The influence of different crystalloid solutions infused during deceased-donor kidney transplant on the incidence of delayed graft function remains unclear. We investigated the influence of Plasma-Lyte® vs. 0.9% saline on the incidence of delayed graft function in deceased-donor kidney transplant recipients. Methods We conducted a single-blind randomized controlled trial of 104 patients aged 18 to 65 years who underwent deceased-donor kidney transplant under general anesthesia. Patients were randomly assigned to receive either Plasma-Lyte® (n = 52) or 0.9% saline (n = 52), at the same infusion volume, for intraoperative fluid replacement. The primary outcome was the occurrence of delayed graft function. Secondary outcomes included metabolic and electrolytic changes at the end of surgery. Results Two patients in the Plasma-Lyte® group and one in the 0.9% saline group died postoperatively and were not included for analysis. The incidence of delayed graft function in Plasma-Lyte® and 0.9% saline groups were 60.0% (95% Confidence Interval [95% CI 46.2-72.4]) and 74.5% (95% CI 61.1-84.4), respectively (p= 0.140). Mean (standard deviation) values of immediate postoperative pH and serum chloride levels in Plasma-Lyte® and 0.9% saline groups were 7.306 (0.071) and 7.273 (0.061) (p= 0.013), and 99.6 (4.2) mEq.L-1 and 103.3 (5.6) mEq.L-1, respectively (p< 0.001). All other postoperative metabolic and electrolyte variables were not statistically different at the immediate postoperative period (p> 0.05). Conclusion In deceased-donor kidney transplant recipients, the incidence of delayed graft function is not influenced by Plasma-Lyte® or 0.9% saline used for intraoperative fluid replacement.

Effects of Plasma-Lyte.½ and 0.9% saline in renal function after deceased-donor kidney transplant: a randomized controlled trial.

BACKGROUND: The influence of different crystalloid solutions infused during deceased-donor kidney transplant on the incidence of delayed graft function remains unclear. We investigated the influence of Plasma-Lyte.½ vs. 0.9% saline on the incidence of delayed graft function in deceased-donor kidney transplant recipients. METHODS: We conducted a single-blind randomized controlled trial of 104 patients aged 18 to 65 years who underwent deceased-donor kidney transplant under general anesthesia. Patients were randomly assigned to receive either Plasma-Lyte.½ (n.ß=.ß52) or 0.9% saline (n.ß=.ß52), at the same infusion volume, for intraoperative fluid replacement. The primary outcome was the occurrence of delayed graft function. Secondary outcomes included metabolic and electrolytic changes at the end of surgery. RESULTS: Two patients in the Plasma-Lyte.½ group and one in the 0.9% saline group died postoperatively and were not included for analysis. The incidence of delayed graft function in Plasma-Lyte.½ and 0.9% saline groups were 60.0% (95% Confidence Interval [95% CI 46.2...72.4]) and 74.5% (95% CI 61.1...84.4), respectively (p.ß=.ß0.140). Mean (standard deviation) values of immediate postoperative pH and serum chloride levels in Plasma-Lyte.½ and 0.9% saline groups were 7.306 (0.071) and 7.273 (0.061) (p.ß=.ß0.013), and 99.6 (4.2) mEq.L-1 and 103.3 (5.6) mEq.L-1, respectively (p.ß<.ß0.001). All other postoperative metabolic and electrolyte variables were not statistically different at the immediate postoperative period (p.ß>.ß0.05). CONCLUSION: In deceased-donor kidney transplant recipients, the incidence of delayed graft function is not influenced by Plasma-Lyte.½ or 0.9% saline used for intraoperative fluid replacement.

Prehospital Damage Control: The Management of Volume, Temperature… and Bleeding! / Control de Daños Prehospitalario: ¡Para Los Cristaloides, Para La Hipotermia Y…! ¡Para El Sangrado!

Abstract Damage control resuscitation should be initiated as soon as possible after a trauma event to avoid metabolic decompensation and high mortality rates. The aim of this article is to assess the position of the Trauma and Emergency Surgery Group (CTE) from Cali, Colombia regarding prehospital care, and to present our experience in the implementation of the "Stop the Bleed" initiative within Latin America. Prehospital care is phase 0 of damage control resuscitation. Prehospital damage control must follow the guidelines proposed by the "Stop the Bleed" initiative. We identified that prehospital personnel have a better perception of hemostatic techniques such as tourniquet use than the hospital providers. The use of tourniquets is recommended as a measure to control bleeding. Fluid management should be initiated using low volume crystalloids, ideally 250 cc boluses, maintaining the principle of permissive hypotension with a systolic blood pressure range between 80- and 90-mm Hg. Hypothermia must be management using warmed blankets or the administration of intravenous fluids warmed prior to infusion. However, these prehospital measures should not delay the transfer time of a patient from the scene to the hospital. To conclude, prehospital damage control measures are the first steps in the control of bleeding and the initiation of hemostatic resuscitation in the traumatically injured patient. Early interventions without increasing the transfer time to a hospital are the keys to increase survival rate of severe trauma patients.

Resumen La resucitación en el control de daños debe iniciarse lo más rápido posible después de presentado el evento traumático para evitar descompensación metabólica y aumento de la mortalidad. El objetivo de este artículo es sustentar nuestro enfoque respecto a la atención prehospitalaria y presentar nuestra experiencia en la implementación de la iniciativa "Stop the Bleed" en Latinoamérica. La atención prehospitalaria es la fase Cero de la resucitación del control de daños. Por medio de la implementación de la iniciativa "Stop the Bleed" se identificó que el personal prehospitalario tiene una mejor percepción sobre el uso de técnicas hemostáticas como el torniquete que el personal hospitalario. Se recomienda el uso de torniquetes como medida de control de sangrado en extremidades. El manejo de líquidos debe realizarse usando cristaloides a bajos volúmenes, con bolos de 250 mL para cumplir el principio de la hipotensión permisiva con un rango entre 80 y 90 mm Hg de presión arterial sistólica. Se deben realizar medidas para evitar la hipotermia como el uso de sábanas térmicas o paso de líquidos calientes. Estas medidas no deben retrasar en ningún momento el tiempo de traslado para recibir la atención hospitalaria. En conclusión, la atención prehospitalaria es el paso inicial para garantizar las primeras medidas de control de sangrado y de resucitación hemostática de los pacientes. Realizar intervenciones tempranas sin acortar el tiempo de traslado a la atención hospitalaria son las claves para aumentar la tasa de supervivencia.

Whole blood for blood loss: hemostatic resuscitation in damage control / Sangre total: la nueva alternativa en la resucitación hemostática

Abstract Hemorrhagic shock and its complications are a major cause of death among trauma patients. The management of hemorrhagic shock using a damage control resuscitation strategy has been shown to decrease mortality and improve patient outcomes. One of the components of damage control resuscitation is hemostatic resuscitation, which involves the replacement of lost blood volume with components such as packed red blood cells, fresh frozen plasma, cryoprecipitate, and platelets in a 1:1:1:1 ratio. However, this is a strategy that is not applicable in many parts of Latin America and other low-and-middle-income countries throughout the world, where there is a lack of well-equipped blood banks and an insufficient availability of blood products. To overcome these barriers, we propose the use of cold fresh whole blood for hemostatic resuscitation in exsanguinating patients. Over 6 years of experience in Ecuador has shown that resuscitation with cold fresh whole blood has similar outcomes and a similar safety profile compared to resuscitation with hemocomponents. Whole blood confers many advantages over component therapy including, but not limited to the transfusion of blood with a physiologic ratio of components, ease of transport and transfusion, less volume of anticoagulants and additives transfused to the patient, and exposure to fewer donors. Whole blood is a tool with reemerging potential that can be implemented in civilian trauma centers with optimal results and less technical demand.

Resumen El choque hemorrágico y sus complicaciones son la principal causa de muerte en los pacientes con trauma. La resucitación en control de daños ha demostrado una disminución en la mortalidad y mejoría en el manejo del paciente. La resucitación hemostática consiste en la recuperación del volumen con hemoderivados como glóbulos rojos, plasma, crioprecipitado y plaquetas, en proporciones de 1:1:1:1. Sin embargo, esta demanda de hemo componentes podría no aplicarse para toda Latinoamérica u otros países de medianos y bajos ingresos. Las principales barreras para la implementación de esta estrategia serían la escasa disponibilidad de bancos de sangre y de hemoderivados insuficientes para contar con un protocolo de transfusión masiva. Una propuesta para superar estas barreras es el uso de sangre total fresca fría para la resucitación hemostática de los pacientes exsanguinados. Ecuador ha sido pionero en la implementación de esta estrategia con una experiencia ya de seis años, en que han demostrado que la sangre total tiene ventajas sobre la terapia de hemo componentes incluyendo, pero no limitando, la trasfusión de sangre con una razón fisiológica de componentes, fácil transporte y transfusión, menor volumen de anticoagulantes y aditivos trasfundidos al paciente, y menor exposición a donantes. La sangre total es una herramienta con un potencial reemergente que puede ser implementado en centros de trauma civil con óptimos resultados y menor demanda técnica.

Prehospital Damage Control: The Management of Volume, Temperature and Bleeding!

Damage control resuscitation should be initiated as soon as possible after a trauma event to avoid metabolic decompensation and high mortality rates. The aim of this article is to assess the position of the Trauma and Emergency Surgery Group (CTE) from Cali, Colombia regarding prehospital care, and to present our experience in the implementation of the "Stop the Bleed" initiative within Latin America. Prehospital care is phase 0 of damage control resuscitation. Prehospital damage control must follow the guidelines proposed by the "Stop the Bleed" initiative. We identified that prehospital personnel have a better perception of hemostatic techniques such as tourniquet use than the hospital providers. The use of tourniquets is recommended as a measure to control bleeding. Fluid management should be initiated using low volume crystalloids, ideally 250 cc boluses, maintaining the principle of permissive hypotension with a systolic blood pressure range between 80- and 90-mm Hg. Hypothermia must be management using warmed blankets or the administration of intravenous fluids warmed prior to infusion. However, these prehospital measures should not delay the transfer time of a patient from the scene to the hospital. To conclude, prehospital damage control measures are the first steps in the control of bleeding and the initiation of hemostatic resuscitation in the traumatically injured patient. Early interventions without increasing the transfer time to a hospital are the keys to increase survival rate of severe trauma patients.

La resucitación en el control de daños debe iniciarse lo más rápido posible después de presentado el evento traumático para evitar descompensación metabólica y aumento de la mortalidad. El objetivo de este artículo es sustentar nuestro enfoque respecto a la atención prehospitalaria y presentar nuestra experiencia en la implementación de la iniciativa "Stop the Bleed" en Latinoamérica. La atención prehospitalaria es la fase Cero de la resucitación del control de daños. Por medio de la implementación de la iniciativa "Stop the Bleed" se identificó que el personal prehospitalario tiene una mejor percepción sobre el uso de técnicas hemostáticas como el torniquete que el personal hospitalario. Se recomienda el uso de torniquetes como medida de control de sangrado en extremidades. El manejo de líquidos debe realizarse usando cristaloides a bajos volúmenes, con bolos de 250 mL para cumplir el principio de la hipotensión permisiva con un rango entre 80 y 90 mm Hg de presión arterial sistólica. Se deben realizar medidas para evitar la hipotermia como el uso de sábanas térmicas o paso de líquidos calientes. Estas medidas no deben retrasar en ningún momento el tiempo de traslado para recibir la atención hospitalaria. En conclusión, la atención prehospitalaria es el paso inicial para garantizar las primeras medidas de control de sangrado y de resucitación hemostática de los pacientes. Realizar intervenciones tempranas sin acortar el tiempo de traslado a la atención hospitalaria son las claves para aumentar la tasa de supervivencia.

Whole blood for blood loss: hemostatic resuscitation in damage control.

Hemorrhagic shock and its complications are a major cause of death among trauma patients. The management of hemorrhagic shock using a damage control resuscitation strategy has been shown to decrease mortality and improve patient outcomes. One of the components of damage control resuscitation is hemostatic resuscitation, which involves the replacement of lost blood volume with components such as packed red blood cells, fresh frozen plasma, cryoprecipitate, and platelets in a 1:1:1:1 ratio. However, this is a strategy that is not applicable in many parts of Latin America and other low-and-middle-income countries throughout the world, where there is a lack of well-equipped blood banks and an insufficient availability of blood products. To overcome these barriers, we propose the use of cold fresh whole blood for hemostatic resuscitation in exsanguinating patients. Over 6 years of experience in Ecuador has shown that resuscitation with cold fresh whole blood has similar outcomes and a similar safety profile compared to resuscitation with hemocomponents. Whole blood confers many advantages over component therapy including, but not limited to the transfusion of blood with a physiologic ratio of components, ease of transport and transfusion, less volume of anticoagulants and additives transfused to the patient, and exposure to fewer donors. Whole blood is a tool with reemerging potential that can be implemented in civilian trauma centers with optimal results and less technical demand.

El choque hemorrágico y sus complicaciones son la principal causa de muerte en los pacientes con trauma. La resucitación en control de daños ha demostrado una disminución en la mortalidad y mejoría en el manejo del paciente. La resucitación hemostática consiste en la recuperación del volumen con hemoderivados como glóbulos rojos, plasma, crioprecipitado y plaquetas, en proporciones de 1:1:1:1. Sin embargo, esta demanda de hemo componentes podría no aplicarse para toda Latinoamérica u otros países de medianos y bajos ingresos. Las principales barreras para la implementación de esta estrategia serían la escasa disponibilidad de bancos de sangre y de hemoderivados insuficientes para contar con un protocolo de transfusión masiva. Una propuesta para superar estas barreras es el uso de sangre total fresca fría para la resucitación hemostática de los pacientes exsanguinados. Ecuador ha sido pionero en la implementación de esta estrategia con una experiencia ya de seis años, en que han demostrado que la sangre total tiene ventajas sobre la terapia de hemo componentes incluyendo, pero no limitando, la trasfusión de sangre con una razón fisiológica de componentes, fácil transporte y transfusión, menor volumen de anticoagulantes y aditivos trasfundidos al paciente, y menor exposición a donantes. La sangre total es una herramienta con un potencial reemergente que puede ser implementado en centros de trauma civil con óptimos resultados y menor demanda técnica.

Comparison of the effects of albumin and crystalloid on mortality among patients with septic shock: systematic review with meta-analysis and trial sequential analysis

ABSTRACT BACKGROUND: This study aimed to compare the effects on mortality of albumin and crystalloid, used for fluid resuscitation among adult patients with septic shock, through conducting a meta-analysis and trial sequential analysis (TSA). DESIGN AND SETTING: Meta-analysis and TSA conducted at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. METHODS: Data were collected from several major databases including MEDLINE, EMBASE, Clinical Trials.gov and Cochrane Central Register of Controlled Trials. Studies that compared the effects of albumin therapy versus crystalloid therapy on mortality among adult septic shock patients were eligible for inclusion in the analyses. The study name, year of publication, country of the trial, albumin concentration, type of crystalloid and all reported mortalities at different follow-up endpoints were extracted. RESULTS: Compared with crystalloid, albumin did not decrease all-cause mortality at the final follow-up. However, in TSA, the required information size was not achieved in all groups, which means that the effect size was not definitive and further RCTs are needed to confirm or deny these findings CONCLUSIONS: Compared with crystalloid solutions, albumin was unable to decrease all-cause mortality. However, TSA indicated that these results could be false-negative. Additional randomized controlled trials are needed to clarify this discrepancy.