Non-catecholaminergic vasopressors in the management of shock: a narrative review and meta-analysis of randomized clinical trials

Martín Díaz: Estudiante de Facultad de Medicina, Universidad de la República. Montevideo, Uruguay.-- Mariana Funes: Estudiante de Facultad de Medicina, Universidad de la República. Montevideo, Uruguay.-- Verónica Hermida: Estudiante de Facultad de Medicina, Universidad de la República. Montevideo, Uruguay.-- Catalina Kavedjian: Estudiante de Facultad de Medicina, Universidad de la República. Montevideo, Uruguay.-- Martín Kavedjian: Estudiante de Facultad de Medicina, Universidad de la República. Montevideo, Uruguay.-- José Gorrasi: Docente supervisor, Prof. Agr. Departamento de Emergencia, Facultad de Medicina, Universidad de la República, Uruguay. Contacto: José Gorrasi - [email protected]; Martín Kavedjian – [email protected] refractariedad a catecolaminas es un final hemodinámico común a los diferentes tipos de shock, que deriva en la administración de altas dosis de estos, situación asociada a resultados clínicos desfavorables. Es de interés el uso de vasopresores no catecolaminérgicos, que actúan en diferentes vías de la contracción muscular lisa vascular, aportando un efecto vasopresor sinérgico. El objetivo es evaluar la respuesta a vasopresores no catecolaminérgicos en shock asociado al postoperatorio de cirugía cardíaca (POCC), sepsis y grandes quemados. Se realizó una búsqueda en las bases PubMed, LILACS, Embase y Cochrane Central Register de estudios clínicos y revisiones en pacientes adultos con shock séptico, POCC o asociado a grandes quemados y administración de al menos uno de los siguientes vasopresores: azul de metileno (AM), angiotensina II (AII), vasopresina (VP), terlipresina (TP). Se realizó una revisión narrativa y un metaanálisis de ensayos clínicos aleatorizados (ECA) para el análisis estadístico de variables hemodinámicas, efecto ahorrador de catecolaminas y mortalidad. Se incluyeron 137 artículos, 31 ECA se utilizaron para el metaanálisis. Del análisis cualitativo se observó un aumento de la presión arterial media (PAM) y resistencias vasculares sistémicas (RVS) con efecto ahorrador de catecolaminas para los 4 fármacos. El metaanálisis evidenció una disminución significativa de la mortalidad con AM (RR: 0,12 IC95%: 0,02;0,95) en pacientes con shock en el POCC. No hubo cambios en la mortalidad en shock séptico. Todos los fármacos aumentan la PAM y tienen efecto ahorrador de catecolaminas preservando la función cardíaca. Sus efectos sobre la mortalidad son menos claros.Refractoriness to catecholamines is a final potential hemodynamic state for all types of circulatory shock leading to the administration of high doses of catecholamines, which is associated with poor clinical outcomes. The pathophysiology of systemic vasodilation is complex, in this sense, there is a rising interest in non-catecholaminergic vasopressors which target different vasoconstriction pathways, potentially resulting in a synergistic vasopressor effect. The purpose is to assess the hemodynamic and clinical response of patients with shock associated with sepsis, post cardiac surgery (POCC) and burns to non-catecholaminergic vasopressors. PubMed, LILACS, Embase and the Cochrane Central Register were searched. Clinical studies and reviews in adult patients with septic, postcardiac surgery and burns shock with the administration of at least one of the following non adrenergic vasopressors: methylene blue (MB), angiotensin II (AII), vasopressin (VP), terlipressin (TP) were included. A literature review and a meta-analysis of randomized clinical trials was done to analyze hemodynamic variables, catecholaminergic sparing effect and mortality 137 articles were included, 31 clinical trials for the metanalysis. The qualitative revision showed an increase in mean arterial pressure (MAP), systemic vascular resistance (SVR) and a catecholamine sparing effect for all vasopressors. Metanalysis results evidenced a significant decrease in mortality in shock postcardiac surgery with MB (RR: 0,12 IC95%: 0,02;0,95). Non-significant effects were shown for mortality in septic shock. All included vasopressors increase MAP resulting in a catecholamine sparing effect with no decrease in cardiac output. Effects on mortality are less precise

Different Contribution of Splanchnic Organs to Hyperlactatemia in Fecal Peritonitis and Cardiac Tamponade

Background. Changes in hepatosplanchnic lactate exchange are likely to contribute to hyperlactatemia in sepsis. We hypothesized that septic and cardiogenic shock have different effects on hepatosplanchnic lactate exchange and its contribution to hyperlactatemia. Materials and Methods. 24 anesthetized pigs were randomized to fecal peritonitis (P), cardiac tamponade (CT), and to controls ( = 8 per group). Oxygen transport and lactate exchange were calculated during 24 hours. Results. While hepatic lactate influx increased in P and in CT, hepatic lactate uptake remained unchanged in P and decreased in CT. Hepatic lactate efflux contributed 20% (P) and 33% (CT), respectively, to whole body venous efflux. Despite maintained hepatic arterial blood flow, hepatic oxygen extraction did not increase in CT. Conclusions. Whole body venous lactate efflux is of similar magnitude in hyperdynamic sepsis and in cardiogenic shock. Although jejunal mucosal pCO 2 gradients are increased, enhanced lactate production from other tissues is more relevant to the increased arterial lactate. Nevertheless, the liver fails to increase hepatic lactate extraction in response to rising hepatic lactate influx, despite maintained hepatic oxygen consumption. In cardiac tamponade, regional, extrasplanchnic lactate production is accompanied by hepatic failure to increase oxygen extraction and net hepatic lactate output, despite maintained hepatic arterial perfusion

Effect of fluid resuscitation on mortality and organ function in experimental sepsis models

Introduction Several recent studies have shown that a positive fluid balance in critical illness is associated with worse outcome. We tested the effects of moderate vs. high-volume resuscitation strategies on mortality, systemic and regional blood flows, mitochondrial respiration, and organ function in two experimental sepsis models. Methods 48 pigs were randomized to continuous endotoxin infusion, fecal peritonitis, and a control group (n = 16 each), and each group further to two different basal rates of volume supply for 24 hours [moderate-volume (10 ml/kg/h, Ringer's lactate, n = 8); high-volume (15 + 5 ml/kg/h, Ringer's lactate and hydroxyethyl starch (HES), n = 8)], both supplemented by additional volume boli, as guided by urinary output, filling pressures, and responses in stroke volume. Systemic and regional hemodynamics were measured and tissue specimens taken for mitochondrial function assessment and histological analysis. Results Mortality in high-volume groups was 87% (peritonitis), 75% (endotoxemia), and 13% (controls). In moderate-volume groups mortality was 50% (peritonitis), 13% (endotoxemia) and 0% (controls). Both septic groups became hyperdynamic. While neither sepsis nor volume resuscitation strategy was associated with altered hepatic or muscle mitochondrial complex I- and II-dependent respiration, non-survivors had lower hepatic complex II-dependent respiratory control ratios (2.6 +/- 0.7, vs. 3.3 +/- 0.9 in survivors; P = 0.01). Histology revealed moderate damage in all organs, colloid plaques in lung tissue of high-volume groups, and severe kidney damage in endotoxin high-volume animals. Conclusions High-volume resuscitation including HES in experimental peritonitis and endotoxemia increased mortality despite better initial hemodynamic stability. This suggests that the strategy of early fluid management influences outcome in sepsis. The high mortality was not associated with reduced mitochondrial complex I- or II-dependent muscle and hepatic respiration

Assessment of Ball Milling as a Compounding Technique to Develop Nanocomposites of Poly(3-Hydroxybutyrate-co-3-Hydroxyvalerate) and Bacterial Cellulose Nanowhiskers

The aim of this study was the assessment of high energy ball milling technique to develop poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanocomposites containing bacterial cellulose nanowhiskers (BCNW). Crystallization behaviour of PHBV/BCNW nanocomposites was studied under non-isothermal and isothermal conditions using differential scanning calorimetry. The changes in PHBV crystalline structure were also studied using X-ray diffraction. The results confirmed that BCNW acted as nucleating agents and, hence, favored the crystallization of the PHBV. The oxygen permeability of the nanocomposites was reduced by ~22 % when compared to that of the neat PHBV. This work provides a new insight into the development of polyhydroxyalkanoate composites by means of the high energy ball milling technique.J. Ambrosio-Martín would like to thank the Spanish Ministry of Economy and Competitiveness for the FPI grant BES-2010-038203. M. J. Fabra is recipient of a “Juan de la Cierva” contract from the Spanish Ministry of Economy and Competitiveness. The authors acknowledge financial support from the MINECO (MAT2012-38947-C02-01 project) and from the FP7 ECOBIOCAP project.Peer reviewe

Kinetic modeling of Shewanella baltica KB30 growth on different substrates through respirometry

Abstract Background Shewanella baltica KB30 was isolated from seawater collected in Kandalaksha Bay, White Sea (Russia). This strain is known for its ability to grow on a pool of different substrates, including carbohydrates, carboxylic and amino acids, and lipids. However, no data are available on its metabolic efficiency in relation to the use of different carbon sources typologies. This work represents the first attempt to characterize S. baltica by its heterotrophic kinetic performance. Results Growth and substrate consumption, during the biodegradation of sodium acetate, glucose, tween 80 and peptone, were analyzed through a respirometric method. To find the model best fitting the experimental data and to obtain the kinetic parameters, the equations of Monod, Moser, Contois and Tessier were applied. The kinetic behavior of S. baltica was fitted to Monod model for sodium acetate and tween 80, while it was adjusted to Contois model for glucose and peptone. In this regard, peptone was consumed faster than the other substrates, as indicated by the highest values of substrate degradation rate, which exceeded 60 mg O2 L−1 h−1. Conclusions Proteolytic metabolism was favored than lipidic and glucidic metabolism, which could contribute much more to mineralization and recycling of proteins than lipids and carbohydrates

Different Contribution of Splanchnic Organs to Hyperlactatemia in Fecal Peritonitis and Cardiac Tamponade

Background. Changes in hepatosplanchnic lactate exchange are likely to contribute to hyperlactatemia in sepsis. We hypothesized that septic and cardiogenic shock have different effects on hepatosplanchnic lactate exchange and its contribution to hyperlactatemia. Materials and Methods. 24 anesthetized pigs were randomized to fecal peritonitis (P), cardiac tamponade (CT), and to controls ( per group). Oxygen transport and lactate exchange were calculated during 24 hours. Results. While hepatic lactate influx increased in P and in CT, hepatic lactate uptake remained unchanged in P and decreased in CT. Hepatic lactate efflux contributed 20% (P) and 33% (CT), respectively, to whole body venous efflux. Despite maintained hepatic arterial blood flow, hepatic oxygen extraction did not increase in CT. Conclusions. Whole body venous lactate efflux is of similar magnitude in hyperdynamic sepsis and in cardiogenic shock. Although jejunal mucosal pCO2 gradients are increased, enhanced lactate production from other tissues is more relevant to the increased arterial lactate. Nevertheless, the liver fails to increase hepatic lactate extraction in response to rising hepatic lactate influx, despite maintained hepatic oxygen consumption. In cardiac tamponade, regional, extrasplanchnic lactate production is accompanied by hepatic failure to increase oxygen extraction and net hepatic lactate output, despite maintained hepatic arterial perfusion

Effects of lung recruitment maneuvers on splanchnic organ perfusion during endotoxin-induced pulmonary arterial hypertension

Lung recruitment maneuvers (RMs), used to reopen atelectatic lung units and to improve oxygenation during mechanical ventilation, may result in hemodynamic impairment. We hypothesize that pulmonary arterial hypertension aggravates the consequences of RMs in the splanchnic circulation. Twelve anesthetized pigs underwent laparotomy and prolonged postoperative ventilation. Systemic, regional, and organ blood flows were monitored. After 6 h (= baseline), a recruitment maneuver was performed with sustained inflation of the lungs. Thereafter, the pigs were randomly assigned to group C (control, n = 6) or group E with endotoxin-induced pulmonary arterial hypertension (n = 6). Endotoxemia resulted in a normotensive and hyperdynamic state and a deterioration of the oxygenation index by 33%. The RM was then repeated in both groups. Pulmonary artery pressure increased during lipopolysaccharide infusion from 17 ± 2 mmHg (mean ± SD) to 31 ± 10 mmHg and remained unchanged in controls (P < 0.05). During endotoxemia, RM decreased aortic pulse pressure from 37 ± 14 mmHg to 27 ± 13 mmHg (mean ± SD, P = 0.024). The blood flows of the renal artery, hepatic artery, celiac trunk, superior mesenteric artery, and portal vein decreased to 71% ± 21%, 69% ± 20%, 76% ± 16%, 79% ± 18%, and 81% ± 12%, respectively, of baseline flows before RM (P < 0.05 all). Organ perfusion of kidney cortex, kidney medulla, liver, and jejunal mucosa in group E decreased to 65% ± 19%, 77% ± 13%, 66% ± 26%, and 71% ± 12%, respectively, of baseline flows (P < 0.05 all). The corresponding recovery to at least 90% of baseline regional blood flow and organ perfusion lasted 1 to 5 min. Importantly, the decreases in regional blood flows and organ perfusion and the time to recovery of these flows did not differ from the controls. In conclusion, lipopolysaccharide-induced pulmonary arterial hypertension does not aggravate the RM-induced significant but short-lasting decreases in systemic, regional, and organ blood flows

Perioperative Fluid Accumulation Impairs Intestinal Contractility to a Smilar Extent as Peritonitis and Endotoxemia

BACKGROUND: Perioperative resuscitation with large amounts of fluid may cause tissue edema, especially in the gut, and thereby impair its functions. This is especially relevant in sepsis where capillaries become leaky and fluid rapidly escapes to the pericapillary tissue. We assessed the effects of endotoxemia and peritonitis, and the use of high and moderate volume fluid resuscitation on jejunal contractility. We hypothesized that both endotoxemia and peritonitis impair jejunum contractility and relaxation, and that this effect is aggravated in peritonitis and with high fluid administration. METHODS: Pigs were randomized to endotoxin (n = 16), peritonitis (n = 16), or sham operation (n = 16), and either high (20 mL/kg/h) or moderate volume (10 mL/kg/h) fluid resuscitation for 24 hours or until death. At the end of the experiment, jejunal contractility and relaxation were measured in vitro using acetylcholine and sodium nitroprusside reactivity, and the effect of nitric oxide synthase inhibition (NOS-I) was assessed. RESULTS: Mortality in the respective groups was 88% (peritonitis high), 75% (endotoxemia high), 50% (peritonitis moderate), 13% (endotoxemia moderate and sham operation high) and 0% (sham operation moderate volume resuscitation). While gut perfusion was preserved in all groups, jejunal contractility was impaired in the two peritonitis and in the two endotoxemia groups, and similarly also in the sham operation group treated with high but not with moderate volume fluid resuscitation [model-fluid-contraction-interaction, p = 0.036; maximal contractility 136 ± 28% (average of both peritonitis, both endotoxemia and sham operation high volume groups) vs. 170 ± 74% of baseline (sham operation moderate volume group)]. NOS-I reduced contractility (contraction-inhibition-interaction, p = 0.011) without significant differences between groups and relaxation was affected neither by peritonitis and endotoxemia nor by the fluid regimen. CONCLUSIONS: Intestinal contractility is similarly impaired during peritonitis and during endotoxemia. Moreover, perioperative high volume fluid resuscitation in sham operated animals also decreases intestinal contractility. This may have consequences for post-operative recovery

Influence of thymol and silver nanoparticles on the degradation of poly(lactic acid) based nanocomposites: thermal and morphological properties

Biopolymers, such as poly(lactic acid) (PLA), have been proposed as environmentally-friendly alternatives in applications such as food packaging. In this work, silver nanoparticles and thymol were used as active additives in PLA matrices, combining the antibacterial activity of silver with the antioxidant performance of thymol. The combined action of both additives influenced PLA thermal degradation in ternary systems. DSC results showed that the addition of thymol resulted in a clear decrease of the glass transition temperature (Tg) of PLA, suggesting its plasticizing effect in PLA matrices. Slight modifications in mechanical properties of dog-bone bars were also observed after the addition of the active components, especially in the elastic modulus. FESEM analyses showed the good distribution of active additives through the PLA matrix, obtaining homogenous surfaces and highlighting the presence of silver nanoparticles successfully embedded into the bulk matrix. Degradation of these PLA-based nanocomposites with thymol and silver nanoparticles in composting conditions indicated that the inherent biodegradable character of this biopolymer was improved after this modification. The obtained nanocomposites showed suitable properties to be used as biodegradable active-food packaging systems with antioxidant and antimicrobial effects.Authors would like to thank Spanish Ministry of Economy and Competitiveness for financial support (MAT-2011-28468-C02-01). Moreover, Marina Ramos would like to thank University of Alicante (Spain) for UAFPU2011-48539721S predoctoral research grant