Effect of combined sedation using multiple drugs on inflammatory cytokines in patients with acute respiratory distress syndrome

Abstract he innate immune response plays an important role in the pathophysiology of acute respiratory distress syndrome (ARDS); however, no drug has been proven to be beneficial in the management of ARDS. Therefore, the aim of this study was to investigate the effects of using combined sedatives on systemic inflammatory responses in patients with ARDS. A total of 90 patients with ARDS and an intubation time of > 120 h were randomly divided into the propofol group (group P), midazolam group (group M), and combined sedation group (group U). Patients in groups P and M were sedated with propofol and midazolam, respectively, whereas patients in group U were sedated with a combination of propofol, midazolam, and dexmedetomidine. The dosage of sedatives and vasoactive drugs, duration of mechanical ventilation, and incidence of sedative adverse reactions were documented. The dosage of sedatives and vasoactive drugs, as well as the incidence of sedative adverse reactions in group U, was significantly lower than those in groups P and M. Similarly, the duration of mechanical ventilation in group U was significantly shorter than that in groups P and M. Hence, inducing sedation through a combination of multiple drugs can significantly reduce their adverse effects, improve their sedative effect, inhibit systemic inflammatory responses, and improve oxygenation in patients with ARDS

Dexmedetomidine inhibits astrocyte pyroptosis and subsequently protects the brain in in vitro and in vivo models of sepsis.

Sepsis is life-threatening and often leads to acute brain damage. Dexmedetomidine, an α2-adrenoceptor agonist, has been reported to possess neuroprotective effects against various brain injury but underlying mechanisms remain elusive. In this study, in vitro and in vivo models of sepsis were used to explore the effects of dexmedetomidine on the inflammasome activity and its associated glia pyroptosis and neuronal death. In vitro, inflammasome activation and pyroptosis were found in astrocytes following lipopolysaccharide (LPS) exposure. Dexmedetomidine significantly alleviated astrocyte pyroptosis and inhibited histone release induced by LPS. In vivo, LPS treatment in rats promoted caspase-1 immunoreactivity in astrocytes and caused an increase in the release of pro-inflammatory cytokines of IL-1ß and IL-18, resulting in neuronal injury, which was attenuated by dexmedetomidine; this neuroprotective effect was abolished by α2-adrenoceptor antagonist atipamezole. Dexmedetomidine significantly reduced the high mortality rate caused by LPS challenge. Our data demonstrated that dexmedetomidine may protect glia cells via reducing pyroptosis and subsequently protect neurons, all of which may preserve brain function and ultimately improve the outcome in sepsis.

Variation in the α(2A) adrenoceptor gene and the effect of dexmedetomidine on plasma insulin and glucose.

OBJECTIVES: Sympathetic activation inhibits insulin secretion through activation of pancreatic α(2)A adrenoreceptors (α(2A)ARs). A common genetic α(2A)AR variant (rs553668) is associated with impaired insulin secretion. α(2A)R agonists would be expected to decrease insulin secretion, but their effects on glucose homeostasis in humans are poorly characterized. We examined the hypotheses that the selective α(2A)R agonist, dexmedetomidine, decreases plasma insulin levels and increases plasma glucose levels in humans and that these effects are modified by genetic α(2A)AR variants. METHODS: Healthy, fasting, White (n=31) and Black (n=33) participants aged between 18 and 45 years received three sequential infusions of placebo (normal saline) at 30-min intervals, followed by three infusions of dexmedetomidine (0.1, 0.15, and 0.15 mcg/kg). Plasma insulin and glucose concentrations were measured at baseline and after the administration of placebo and dexmedetomidine. We genotyped ADRA2A rs553668 and rs2484516, which characterize haplotypes 4 and 4b, respectively. RESULTS: Dexmedetomidine decreased fasting insulin concentrations by 37%, from a median value after placebo administration of 7.9 µU/ml (interquartile range: 6.0-12.6) to 4.9 µU/ml (interquartile range: 3.5-7.9; P<0.001). Plasma glucose concentrations increased from 76±6 to 79±7 mg/dl (P<0.001). The rs2484516 variant allele was associated with higher baseline insulin concentrations before (P=0.001) and after adjustment for potential confounders (P=0.014) and a greater decrease in insulin concentration after dexmedetomidine administration (P=0.016), which was no longer significant after adjustment for baseline concentrations and other confounders (P=0.58). CONCLUSION: Low-dose dexmedetomidine decreased plasma insulin concentration and mildly increased plasma glucose concentration in healthy fasting individuals. The ADRA2A genetic variation may affect baseline insulin concentrations and thus the insulin decrease after dexmedetomidine administration.

Calcium sensitization involved in dexmedetomidine-induced contraction of isolated rat aorta.

Dexmedetomidine, a full agonist of the α2B-adrenoceptor that is mainly involved in vascular smooth muscle contraction, is primarily used for analgesia and sedation in intensive care units. High-dose dexmedetomidine produces hypertension in children and adults. The goal of this in vitro study was to investigate the role of the calcium (Ca(2+)) sensitization mechanism involving Rho-kinase, protein kinase C (PKC), and phosphoinositide 3-kinase (PI3-K) in mediating contraction of isolated rat aortic smooth muscle in response to dexmedetomidine. The effect of dexmedetomidine on the intracellular Ca(2+) level ([Ca(2+)]i) and tension was measured simultaneously. Dexmedetomidine concentration-response curves were generated in the presence or absence of the following antagonists: rauwolscine, Y 27632, LY 294002, GF 109203X, and verapamil. Dexmedetomidine-induced phosphorylation of PKC and membrane translocation of Rho-kinase were detected with Western blotting. Rauwolscine, Y 27632, GF 109203X, LY 294002, and verapamil attenuated dexmedetomidine-induced contraction. The slope of the [Ca(2+)]i-tension curve for dexmedetomidine was higher than that for KCl. Dexmedetomidine induced phosphorylation of PKC and membrane translocation of Rho-kinase. These results suggest that dexmedetomidine-induced contraction involves a Ca(2+) sensitization mechanism mediated by Rho-kinase, PKC, and PI3-K that is secondary to α2-adrenoceptor stimulation in rat aortic smooth muscle.

Efeitos hemodinâmicos do cloridrato de dexmedetomidina administrado por infusão intravenosa contínua em cães anestesiados com propofol / Hemodynamic effects of dexmedetomidine hydrochloride administered by continuous intravenous infusion in dogs anesthetized with propofol

O emprego de procedimentos de anestesia intravenosa total em cães tem sido mais frequente, devido ao melhor conhecimento do perfil farmacocinético dos fármacos empregados. Como ainda não existe um único fármaco que produza todas as características desejáveis em uma anestesia geral, há a necessidade de se associar ao hipnótico, agentes com propriedades analgésicas. O objetivo desse estudo foi avaliar os efeitos hemodinâmicos causados pela associação do cloridratode dexmedetomidina, nas doses de 1 e 2 micrograma/kg/h, e propofol na dose de 0,3mg/kg/min, administrada em infusão intravenosa contínua em cães, bem como o tempo de recuperação anestésica após duas horas de infusão. Seis cães, clinicamente sadios, sem raça definida, pesando 17,6 mais ou menos 1,8 kg, foram submetidos a três tratamentos com intervalo de uma semana e em sequência aleatória. Todos os animais foram inicialmente anestesiados com isofluorano a 5V% com fluxo de 3 I/min de O2. Após a indução e intubação, os animais foram posicionados em decúbito lateral esquerdo e mantidos com isofluorano na concentração de 1,8V%. As veias cefálicas e a artéria dorsal podal foram cateterizadas e um cateter de Swan Ganz 5F foi introduzido pela veia jugular. Após fixação dos cateteres na pele, a administração do isofluorano foi interrompida. Os cães permaneceram despertos por 1 hora, e após esse período, foi realizada a avaliação das variáveis hemodinâmicas...

Função e histologia renais após hemorragia aguda em ratos sob a ação da dexmedetomidina / Renal function and histology after acute hemorrhage in rats under dexmedetomidine action

Justificativa e objetivos - Aproximadamente metade das indicações de diálise em insuficiência renal aguda deve-se a problemas originados no período pré-operatório. É o caso da exposição de paciente grave a agentes nefrotóxicos e procedimento de alto risco. Outro fator importante são as alterações hemodinâmicas, como as observadas em hemorragia, as quais levam à vasoconstrição renal, deixando os rins dependentes unicamente da ação vasodilatadora das prostaglandinas, podendo ocorrer lesões isquêmicas. Trabalhos descritos na literatura atribuem à dexmedetomidina, agonista adrenérgico 02, aumento da diurese, quando utilizada no período pré- operatório. Contudo, não está definido seu papel como agente protetor renal em situação de hemorragia. O objetivo deste estudo foi avaliar sua atuação na função e histologia renais após hemorragia aguda, em ratos. Método - Este estudo foi encoberto e desenvolvido com 20 ratos Wistars machos, anestesiados com pentobarbital sódico (PS), 50 mg. kg-1, por via peritoneal, e divididos, de forma randomizada, em dois grupos submetidos à sangria de 30 % da volemia. No grupo GD, 10 animais receberam solução de exmedetomidina, 3 micro/g. kg-1, durante 10 minutos, seguida de infusão contínua de 3 micro/g. kg-1. h-1. No grupo controle, GC, os animais permaneceram apenas com PS e infusão de solução fisiológica em volume correspondente ao utilizado em GD para a administração de dexmedetomidina. Para avaliação da função renal, utilizou-se método por meio do qual se estimam clearances renais, utilizando-se infusão de para-aminohipurato de sódio e iotalamato de sódio, com posterior determinação de suas concentrações plasmáticas. Os atributos estudados foram: peso, frequência cardíaca, pressão arterial média, temperatura retal, hematócrito, clearance de iotalamato de sódio, clearance de para-aminohipurato de sódio, fração de filtração, resistência vascular renal, fluxo sanguíneo renal e exame histológico dos rins...