The endocannabinoid system includes G-protein-coupled cannabinoid receptors, the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and multiple enzymes involved in the biosynthesis and degradation of endocannabinoids, including the anandamide metabolizing enzyme fatty acid amide hydrolase. Endocannabinoids play an important role in the physiologic control of sleep, pain processing, and emesis. The authors therefore investigated the effects of general anesthesia on the endocannabinoid system in humans.The authors measured whole blood levels of anandamide in 12 patients after induction of general anesthesia with etomidate (an agent shown to have no effect on anandamide levels) and maintenance of anesthesia with the volatile agent sevoflurane as well as in 12 patients undergoing total intravenous anesthesia with propofol, a known inhibitor of fatty acid amide hydrolase in the mouse brain. Anandamide levels were measured using high-performance liquid chromatography-tandem mass spectrometry at four time points (before and at 10, 20, 30, and 40 min after induction of anesthesia).Patients of the sevoflurane group showed a significant decline in anandamide levels from induction of anesthesia to 40 min after induction, whereas anandamide levels in patients of the propofol group remained unchanged (type III sum of squares = 1725.66, F = 162.60, P < 0.001, repeated-measures analysis of variance).General anesthesia influences the endocannabinoid system in a drug-dependent way, which may explain side effects of general anesthetics such as psychomimetic and antiemetic properties of propofol and the high incidence of postoperative nausea and vomiting after volatile anesthetics. These findings suggest new targets for anesthetic drug development.
Background Sepsis occurs when an infection is complicated by organ failure. Sepsis may be complicated by impaired corticosteroid metabolism. Thus, providing corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and 2015 prior to this update. Objectives To examine the effects of corticosteroids on death in children and adults with sepsis. Search methods We searched CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, ISRCTN, and the WHO Clinical Trials Search Portal, on 25 July 2019. In addition, we conducted reference checking and citation searching, and contacted study authors, to identify additional studies as needed. Selection criteria We included randomized controlled trials (RCTs) of corticosteroids versus placebo or usual care (antimicrobials, fluid replacement, and vasopressor therapy as needed) in children and adults with sepsis. We also included RCTs of continuous infusion versus intermittent bolus of corticosteroids. Data collection and analysis All review authors screened and selected studies for inclusion. One review author extracted data, which was checked by the others, and by the lead author of the primary study when possible. We obtained unpublished data from the authors of some trials. We assessed the methodological quality of trials and applied GRADE to assess the certainty of evidence. Review authors did not contribute to assessment of eligibility and risk of bias, nor to data extraction, for trials they had participated in. Main results We included 61 trials (12,192 participants), of which six included only children, two included children and adults, and the remaining trials included only adults. Nine studies are ongoing and will be considered in future versions of this review. We judged 19 trials as being at low risk of bias. Corticosteroids versus placebo or usual care Compared to placebo or usual care, corticosteroids probably slightly reduce 28-day mortality (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.84 to 0.99; 11,233 participants; 50 studies; moderate-certainty evidence). Corticosteroids may result in little to no difference in long-term mortality (RR 0.97, 95% CI 0.91 to 1.03; 6236 participants; 7 studies; low-certainty evidence) and probably slightly reduce hospital mortality (RR 0.90, 95% CI 0.82 to 0.99; 8183 participants; 26 trials; moderate-certainty evidence). Corticosteroids reduced length of intensive care unit (ICU) stay for all participants (mean difference (MD) -1.07 days, 95% CI -1.95 to -0.19; 7612 participants; 21 studies; high-certainty evidence) and resulted in a large reduction in length of hospital stay for all participants (MD -1.63 days, 95% CI -2.93 to -0.33; 8795 participants; 22 studies; high-certainty evidence). Corticosteroids increase the risk of muscle weakness (RR 1.21, 95% CI 1.01 to 1.44; 6145 participants; 6 studies; high-certainty evidence). Corticosteroids probably do not increase the risk of superinfection (RR 1.06, 95% CI 0.95 to 1.19; 5356 participants; 25 studies; moderate-certainty evidence). Corticosteroids increase the risk of hypernatraemia (high-certainty evidence) and probably increase the risk of hyperglycaemia (moderate-certainty evidence). Moderate-certainty evidence shows that there is probably little or no difference in gastroduodenal bleeding, stroke, or cardiac events, and low-certainty evidence suggests that corticosteroids may result in little to no difference in neuropsychiatric events. Continuous infusion of corticosteroids versus intermittent bolus We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration. Three studies reported data for this comparison, and the certainty of evidence for all outcomes was very low. Authors' conclusions Moderate-certainty evidence indicates that corticosteroids probably reduce 28-day and hospital mortality among patients with sepsis. Corticosteroids result in large reductions in ICU and hospital length of stay (high-certainty evidence). There may be little or no difference in the risk of major complications; however, corticosteroids increase the risk of muscle weakness and hypernatraemia, and probably increase the risk of hyperglycaemia. The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.
A liquid chromatographic-mass spectrometric method for the determination of cortisol in serum using atmospheric pressure electrospray ionization and tandem mass spectrometry is described. During sample preparation, 150 μl of serum were deproteinized with methanol/zinc sulfate followed by on-line solid phase extraction employing column switching. Tri-deuterated cortisol was used as the internal standard. The following transitions were monitored: cortisol, 363>309 m/z; d3-cortisol, 366>312 m/z. The total run-time was 5 minutes. The method proved linear (0–500 μg/l; r=0.999), precise (total coefficient of variation between 5.0% and 3.2% at a mean cortisol concentration of 15.1 μg/l and 269 μg/l, respectively; n=16) and specific with regard to relevant endogenous and exogenous steroids.
Pregunta de revision: Se revisaron las pruebas del efecto del uso de corticosteroides en ninos y adultos con sepsis sobre la mortalidad.
Fundamento: La sepsis se presenta cuando una infeccion se complica por la falla de un organo. Las personas desarrollan respiracion rapida, hipotension (presion arterial baja) y confusion mental. La sepsis puede interferir con la eficacia de los corticosteroides propios del organismo, que sirven como una defensa clave contra la infeccion. Los corticosteroides se han administrado durante decadas a las personas con infecciones derivadas de diversas causas.
Fecha de busqueda: Las evidencias aportadas en esta revision estan vigentes hasta julio de 2019.
Caracteristicas del estudio: Esta revision incluyo 61 ensayos (12.192 participantes): 58 ensayos compararon corticosteroides frente a no corticosteroides (placebo o atencion habitual en 48 y 9 ensayos, respectivamente); 3 ensayos tambien compararon la administracion continua con bolo de corticosteroides.
Estudio sobre las fuentes de financiacion: Tres ensayos fueron financiados por una empresa farmaceutica, 27 por organizaciones publicas o mediante fondos de beneficencia, y 6 tanto por una empresa farmaceutica como por organizaciones publicas o fondos de beneficencia; 25 no declararon la fuente de financiacion.
Resultados clave: Se han analizado las 2 siguientes comparaciones:
– Corticosteroides versus placebo/cuidado habitual: Los corticosteroides probablemente reducen en un 9% el riesgo de muerte a los 28 dias (50 ensayos; 11.233 participantes), con efectos de tratamiento consistentes en ninos y adultos. Probablemente tambien reducen ligeramente el riesgo de morir en el hospital. Ademas, es posible que tengan poco o ningun efecto sobre el riesgo de morir a largo plazo (mas de 3 meses), pero estos resultados tienen menos certeza. Los corticosteroides dan lugar a una gran reduccion de la duracion de la estancia en la UCI y en el hospital. Ademas, aumentan el riesgo de debilidad muscular e hipernatremia. Probablemente aumentan el riesgo de hiperglucemia y no aumentan el riesgo de sobreinfeccion. Tienen poco o ningun efecto en el riesgo de hemorragia gastroduodenal, eventos neuropsiquiatricos, apoplejia o eventos cardiacos.
– Infusion continua versus bolos intermitentes de corticoesteroides: No existe seguridad respecto a los efectos de la infusion continua de corticosteroides comparada con la administracion de bolos intermitentes. Tres estudios informaron de datos para esta comparacion, y la certeza de las evidencias para todos los resultados fue muy baja.
Certeza de la evidencia: Se considero que la certeza de las evidencias de los estudios que comparaban los efectos de corticosteroides versus placebo/cuidado habitual sobre la mortalidad a los 28 dias era moderada debido a cierta incoherencia relacionada con las diferencias entre las poblaciones de estudio, los tipos de corticoides y como se administraron, y el uso de intervenciones adicionales. Se considero que la certeza de las evidencias de la comparacion de los efectos de la infusion continua versus bolos intermitentes de corticoesteroides sobre la mortalidad a los 28 dias era muy baja debido a la inconsistencia e imprecision.
High-dose intravenous administration of sodium selenite has been proposed to improve outcome in sepsis by attenuating oxidative stress. Procalcitonin-guided antimicrobial therapy may hasten the diagnosis of sepsis, but effect on outcome is unclear.To determine whether high-dose intravenous sodium selenite treatment and procalcitonin-guided anti-infectious therapy in patients with severe sepsis affect mortality.The Placebo-Controlled Trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT), a multicenter, randomized, clinical, 2 × 2 factorial trial performed in 33 intensive care units in Germany, was conducted from November 6, 2009, to June 6, 2013, including a 90-day follow-up period.Patients were randomly assigned to receive an initial intravenous loading dose of sodium selenite, 1000 µg, followed by a continuous intravenous infusion of sodium selenite, 1000 µg, daily until discharge from the intensive care unit, but not longer than 21 days, or placebo. Patients also were randomized to receive anti-infectious therapy guided by a procalcitonin algorithm or without procalcitonin guidance.The primary end point was 28-day mortality. Secondary outcomes included 90-day all-cause mortality, intervention-free days, antimicrobial costs, antimicrobial-free days, and secondary infections.Of 8174 eligible patients, 1089 patients (13.3%) with severe sepsis or septic shock were included in an intention-to-treat analysis comparing sodium selenite (543 patients [49.9%]) with placebo (546 [50.1%]) and procalcitonin guidance (552 [50.7%]) vs no procalcitonin guidance (537 [49.3%]). The 28-day mortality rate was 28.3% (95% CI, 24.5%-32.3%) in the sodium selenite group and 25.5% (95% CI, 21.8%-29.4%) (P = .30) in the placebo group. There was no significant difference in 28-day mortality between patients assigned to procalcitonin guidance (25.6% [95% CI, 22.0%-29.5%]) vs no procalcitonin guidance (28.2% [95% CI, 24.4%-32.2%]) (P = .34). Procalcitonin guidance did not affect frequency of diagnostic or therapeutic procedures but did result in a 4.5% reduction of antimicrobial exposure.Neither high-dose intravenous administration of sodium selenite nor anti-infectious therapy guided by a procalcitonin algorithm was associated with an improved outcome in patients with severe sepsis. These findings do not support administration of high-dose sodium selenite in these patients; the application of a procalcitonin-guided algorithm needs further evaluation.clinicaltrials.gov Identifier: NCT00832039.
Sarcoidosis is a rare indication for lung transplantation. In this article, our experiences with recurring sarcoidosis following lung transplantation are described. Literature concerning recurrence of the disease in kidney, liver, heart, and lung and transmission of sarcoidosis via transplanted organs are discussed.
