Dexmedetomidina, tendencias y actuales aplicaciones / Dexmedetomidine, trends and current applications

Dexmedetomidine (DXM), is a potent, versatile and highly selective a-2 adrenergic receptor agonist, currently described as an agent with sedative, anxiolytic, sympatholytic, and hypnotic effects that preserve the integrity of respiratory functions. It has highly lipophilic chemical characteristics and conforms to a two-compartment distribution and elimination model. Among its unique pharmacodynamic characteristics, at the cardiac level there is a biphasic hemodynamic effect, with a transient increase in blood pressure and reflex bradycardia determined by its plasma concentration, at the renal level it improves ischemic damage by improving external medullary blood flow through local renal vasodilation and allowing an increase in glomerular filtration. At the respiratory level, it induces a minimal depressant effect, allowing a wide margin of safety in various surgical and sedation scenarios outside the operating room. From its neuroprotective characteristics, it is suggested that the catecholamine pathways at the level of a-2 adrenoceptors modulate the release of neurotransmitters in the central and peripheral sympathetic nervous system. They are diverse clinical applications from a "cooperative sedation", anxiolysis in pediatric patients, during the intubation process in difficult airways, as well as its use in cardiovascular and neurological surgery and management of the critical patient.

La dexmedetomidina (DXM), un agonista de los receptores adrenérgicos a-2 potente, versátil y altamente selectivo, actualmente descrito como un agente con efectos sedantes, ansiolíticos, simpaticolíticos e hipnóticos que permite conservar la integridad de las funciones respiratorias. De características químicas altamente lipofilicas se ajusta a un modelo de distribución y eliminación bicompartimental. Entre sus rasgos farmacodinámicos únicos, a nivel cardíaco se produce un efecto hemodinámico bifásico, con un aumento transitorio de la presión arterial y bradicardia refleja determiando por su concentración plasmática, a nivel renal mejora el daño por isquemia, mejorando el flujo sanguíneo medular externo, a través de la vasodilatación renal local y permitiendo un aumento en la filtración glomerular. A nivel respiratorio, induce un mínimo efecto depresor, permitiendo un amplio margen de seguridad en diversos escenarios quirurgicos y de sedación fuera de quirófano. Su propiedad de neuroprotección, modulan la liberación de neurotransmisores en el sistema nervioso simpático central y periférico. Resalta un amplio expectro de aplicaciones clínicas desde una "sedación cooperativa", ansiolisis en pacientes pediátricos, durante el proceso de intubación en vías áreas difíciles, al igual que su uso en cirugía cardiovascular, neurológica y manejo del paciente crítico.

Effect of bupivacaine versus bupivacaine plus intrathecal dexmedetomidine in postoperative pain

Background: Pain is defined as "unpleasant sensory and sensory experience", associated with actual or potential tissue domage or described in terms of such damage. Objetive: To assess the effect of bupivacaine versus bupivacaine plus intrathecal dexmedetomidine in postoperative pain. Patients and method: An experimental design was made of a controlled clinical trial type, in patients scheduled for lower abdomen surgery or lower extremities. A sample of 60 patients was studied during the period from October 1 to december 15, 2018, who agreed to participate in the study through of signing consent under information. Results: It was observed that the time of the rescue analgesia was prolonged in more than 120 min in the case of dexmedetomidine when compared with bupivacaine (p<0.0001); also VAS scores at the time of analgesia rescue for the group with dexmedetomidine were 3.71 ± 1.27 and in the bupivacaine group of 5.7 ± 1.59, the difference of two pints of the VAS (p= <0.001) was significant, which demonstrates that dexmedetomidine is effective for prolong postoperative analgesia and decrease the analgesia requirements. Conclusions: Dexmedetomidine at a dose of 5 ug associated with bupivacaine administered intrathecally is more Effective in postoperative analgesia compared with this substance alone in abdominal surgery inferior and lower extremities (AU)

Dexmedetomidine attenuates P2X4 and NLRP3 expression in the spine of rats with diabetic neuropathic pain

Purpose: To evaluate the effects of Dexmedetomidine (Dex) on spinal pathology and inflammatory factor in a rat model of Diabetic neuropathic pain (DNP). Methods: The rats were divided into 3 groups (eight in each group): normal group (N group), diabetic neuropathic pain model group (DNP group), and DNP model with dexmedetomidine (Dex group). The rat model of diabetes was established with intraperitoneal streptozotocin (STZ) injections. Nerve cell ultrastructure was evaluated with transmission electron microscopy (TEM). The mechanical withdrawal threshold (MWT) and motor nerve conduction velocity (MNCV) tests documented that DNP rat model was characterized by a decreased pain threshold and nerve conduction velocity. Results: Dex restored the phenotype of neurocytes, reduced the extent of demyelination and improved MWT and MNCV of DNP-treated rats (P=0.01, P=0.038, respectively). The expression of three pain-and inflammation-associated factors (P2X4, NLRP3, and IL-IP) was significantly upregulated at the protein level in DNP rats, and this change was reversed by Dex administration (P=0.0022, P=0.0092, P=0.0028, respectively). Conclusion: The P2X4/NLRP3 signaling pathway is implicated in the development and presence of DNP in vivo, and Dex protects from this disorder.(AU)

Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients.

BACKGROUND: Obesity has been associated with reduced dexmedetomidine clearance, suggesting impaired hepatic function or reduced hepatic blood flow. The aim of this study was to clarify the effect of obesity in dexmedetomidine metabolic clearance. METHODS: Forty patients, ASA I-III, 18-60 yr old, weighing 47-126 kg, scheduled for abdominal laparoscopic surgery, were enrolled. Anaesthetic agents (propofol, remifentanil, and dexmedetomidine) were dosed based on lean body weight measured by dual X-ray absorptiometry. Serial venous samples were drawn during and after dexmedetomidine infusion. A pharmacokinetic analysis was undertaken using non-linear mixed-effect models. In the modelling approach, the total body weight, lean body weight, and adjusted body weight were first tested as size descriptors for volumes and clearances. Hepatic blood flow, liver histopathology, liver enzymes, and gene expression of metabolic enzymes (UGT2B10 and UGT1A4) were tested as covariates of dexmedetomidine metabolic clearance. A decrease in NONMEM objective function value (ΔOFV) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. RESULTS: A total of 637 dexmedetomidine serum samples were obtained. A two-compartmental model scaled to measured lean weight adequately described the dexmedetomidine pharmacokinetics. Liver blood flow was a covariate for dexmedetomidine clearance (ΔOFV=-5.878). Other factors, including fat mass, histopathological damage, and differential expression of enzymes, did not affect the dexmedetomidine clearance in the population studied (ΔOFV<3.84). CONCLUSIONS: We did not find a negative influence of obesity in dexmedetomidine clearance when doses were adjusted to lean body weight. Liver blood flow showed a significant effect on dexmedetomidine clearance. CLINICAL TRIAL REGISTRATION: NCT02557867.

Impact of dexmedetomidine on amino acid contents and the cerebral ultrastructure of rats with cerebral ischemia-reperfusion injury

Purpose: To investigate the effects of dexmedetomidine (DEX) on amino acid contents and the cerebral ultrastructure of rats with cerebral ischemia-reperfusion injury (I/R). Methods: Thirty-six, male, Wistar rats were randomly divided into three groups: the sham operation group (group C), the ischemia-reperfusion group (group I/R), and the DEX group (group D). The middle cerebral artery occlusion model was prepared by the modified Longa method. The time of ischemia was 180 min, and 120 min after reperfusion, the amount of glutamate (Glu), and -aminobutyric acid (GABA) in the brain were measured, and the ultrastructure-level changes in the cerebral cortex were examined using electron microscopy. Results: Compared to group C, Glu contents in group D, and I/R significantly increased. Compared to group I/R, Glu contents in group D significantly decreased. Compared to group C, GABA contents in group D, and I/R significantly increased, and those in group D significantly increased, as compared to group I/R. The cerebral ultrastructure was normal in group C. Vacuolar degeneration in the plastiosome and nervous processes, was more critical than in group D. Vascular endothelial cells (VEC) were damaged. On the contrary, these changes in group D significantly improved. Conclusion: Dexmedetomidine is capable of decreasing glutamergic content, and increasing GABAergic content, in order to decrease the injury of the cerebral ultrastructure, following cerebral ischemia-reperfusion injury.(AU)

Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock.

BACKGROUND: Persistent hyperlactatemia during septic shock is multifactorial. Hypoperfusion-related anaerobic production and adrenergic-driven aerobic generation together with impaired lactate clearance have been implicated. An excessive adrenergic response could contribute to persistent hyperlactatemia and adrenergic modulation might be beneficial. We assessed the effects of dexmedetomidine and esmolol on hemodynamics, lactate generation, and exogenous lactate clearance during endotoxin-induced septic shock. METHODS: Eighteen anesthetized and mechanically ventilated sheep were subjected to a multimodal hemodynamic/perfusion assessment including hepatic and portal vein catheterizations, total hepatic blood flow, and muscle microdialysis. After monitoring, all received a bolus and continuous infusion of endotoxin. After 1 h they were volume resuscitated, and then randomized to endotoxin-control, endotoxin-dexmedetomidine (sequential doses of 0.5 and 1.0 µg/k/h) or endotoxin-esmolol (titrated to decrease basal heart rate by 20 %) groups. Samples were taken at four time points, and exogenous lactate clearance using an intravenous administration of sodium L-lactate (1 mmol/kg) was performed at the end of the experiments. RESULTS: Dexmedetomidine and esmolol were hemodynamically well tolerated. The dexmedetomidine group exhibited lower epinephrine levels, but no difference in muscle lactate. Despite progressive hypotension in all groups, both dexmedetomidine and esmolol were associated with lower arterial and portal vein lactate levels. Exogenous lactate clearance was significantly higher in the dexmedetomidine and esmolol groups. CONCLUSIONS: Dexmedetomidine and esmolol were associated with lower arterial and portal lactate levels, and less impairment of exogenous lactate clearance in a model of septic shock. The use of dexmedetomidine and esmolol appears to be associated with beneficial effects on gut lactate generation and lactate clearance and exhibits no negative impact on systemic hemodynamics.

Dexmedetomidine pharmacokinetics in the obese.

PURPOSE: This study aims to characterize the influence of body weight and composition on the pharmacokinetics of dexmedetomidine. METHODS: Twenty obese patients and 20 non-obese patients scheduled for elective laparoscopic surgery were given dexmedetomidine infusion schemes. Venous blood samples were taken during and after dexmedetomidine administration. Population pharmacokinetic modeling was undertaken to investigate fat free mass (FFM) and normal fat mass (NFM) as size descriptors of volumes and clearances using non-linear mixed effects modeling. NFM partitions total body weight into FFM and fat mass calculated from total body weight (TBW) minus FFM. The relative influence of fat mass compared to FFM is described by the fraction of fat mass that makes fat equivalent to FFM (Ffat). RESULTS: Theory-based allometric scaling using FFM best described weight and body composition differences in clearances and volumes A negative effect of fat mass of with an exponential parameter of -0.00541/kg (95 % CI -0.0118 to -0.00246) was estimated for clearance which indicates increased fat mass is associated with impairment of clearance. CONCLUSIONS: The use of theory-based allometry with predictions of fat free mass has been able to separate the influences of weight and body composition and indicates that size-normalized clearance of dexmedetomidine is impaired in patients who are obese.

A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates.

OBJECTIVE: To investigate the safety, efficacy, and pharmacokinetic profile of dexmedetomidine in preterm and full-term neonates ≥ 28 to ≤ 44 weeks gestational age. STUDY DESIGN: Forty-two intubated, mechanically ventilated patients (n = 42) were grouped by gestational age into group I (n = 18), ≥ 28 to <36 weeks, and group II (n = 24), ≥ 36 to ≤ 44 weeks. Within each age group, there were 3 escalating dose levels, including a loading dose (LD, µg/kg) followed by a maintenance dose (MD, µg · kg(-1) · h(-1)) for 6-24 hours: level 1, 0.05 LD/MD; level 2, 0.1 LD/MD; and level 3, 0.2 LD/MD. The primary endpoint was the number of patients requiring sedation as determined by the Neonatal Pain, Agitation, Sedation Scale. RESULTS: During dexmedetomidine infusion, 5% of Neonatal Pain, Agitation, Sedation Scale scores were >3, indicating agitation/pain, with 4 patients (10%) requiring more sedation and 17 (40%) requiring more analgesia. Though there was significant variability in pharmacokinetic variables, group I appeared to have lower weight-adjusted plasma clearance (0.3 vs 0.9 L · h(-1) · kg(-1)) and increased elimination half-life (7.6 vs 3.2 hours) compared with group II. Fifty-six adverse events (AEs) were reported in 26 patients (62%); only 3 AEs (5%) were related to dexmedetomidine. There were no serious AEs and no AEs or hemodynamic changes requiring dexmedetomidine discontinuation. CONCLUSION: Dexmedetomidine is effective for sedating preterm and full-term neonates and is well-tolerated without significant AEs. Preterm neonates had decreased plasma clearance and longer elimination half-life.

Dexmedetomidina: papel atual em anestesia e cuidados intensivos / Dexmedetomidine: current role in anesthesia and intensive care

JUSTIFICATIVA E OBJETIVOS: Atualizar e rever a aplicação da dexmedetomidina em anestesia e cuidados intensivos. Este trabalho é uma revisão abrangente dos usos clínicos, farmacologia, farmacocinética, mecanismo de ação e efeitos adversos da dexmedetomidina. CONTEÚDO: O uso efetivo de agentes sedativo-hipnóticos e analgésicos é parte integral do conforto e segurança dos pacientes. A dexmedetomidina é um potente e altamente seletivo agonista dos adrenoceptores α-2 com propriedades simpaticolíticas, sedativas, amnésicas e analgésicas, que tem sido descrito como um adjuvante útil e seguro em várias aplicações clínicas. Proporciona uma "sedação consciente" única, analgésica, sem depressão respiratória. Os usos correntes revistos incluem sedação na unidade de tratamento intensivo - UTI (adulta e pediátrica), departamento de emergência, anestesia regional e geral, neurocirurgia, sedação para procedimentos pediátricos, intubação por fibra ótica em doentes acordados, cirurgia cardíaca e cirurgia bariátrica. CONCLUSÕES: A dexmedetomidina oferece a capacidade única de fornecer sedação e analgesia sem depressão respiratória. É um agente novo com uma grande margem de segurança, excelente capacidade sedativa e moderadas propriedades analgésicas. Embora o seu amplo uso seja, atualmente, em pacientes de unidades de cuidados intensivos cirúrgicos e não cirúrgicos, a dexmedetomidina parece ter futuras aplicações promissoras nas áreas de neuroproteção, cardioproteção e renoproteção. São necessários mais estudos detalhados para definir o seu papel como sedativo em doentes críticos, neurocirúrgicos e pediátricos, como adjuvante da anestesia e como sedativo durante procedimentos.

BACKGROUND AND OBJECTIVES: To update and review the application of dexmedetomidine in anesthesia and intensive care. This study is a comprehensive review of clinical uses, pharmacology, pharmacokinetics, mechanism of action and adverse effects of dexmedetomidine. CONTENT: The effective use of sedative-hypnotic agents and analgesics is an integral part of comfort and safety of patients. Dexmedetomidine is a potent and highly selective α-2 adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties, which has been described as a useful and safe adjunct in many clinical applications. It provides a unique "conscious sedation", analgesia, without respiratory depression. The current reviewed uses include sedation at Intensive Care Unit - ICU (both adult and pediatric), emergency department, regional and general anesthesia, neurosurgery, sedation for pediatric procedures, awake fiber-optic intubation, cardiac surgery and bariatric surgery. CONCLUSIONS: Dexmedetomidine offers a unique ability of providing both sedation and analgesia without respiratory depression. It is a new agent with a wide safety margin, excellent sedative capacity and moderate analgesic properties. Although its wide use is currently in patients of surgical and non-surgical intensive care units, dexmedetomidine seems to have promising future applications in neuroprotection, cardioprotection and renoprotection. More detailed studies are required to define its role as sedative in critical, neurosurgical and pediatric patients, as anesthesia adjunct and sedative during procedures.

JUSTIFICATIVA Y OBJETIVOS: Actualizar y analizar nuevamente la aplicación de la dexmedetomidina en la anestesia y en los cuidados intensivos. Este trabajo es una revisión bastante exhaustiva de los usos clínicos, farmacología, farmacocinética, mecanismo de acción, y de los efectos adversos de la dexmedetomidina. CONTENIDO: El uso efectivo de los agentes sedativo-hipnóticos y analgésicos, forma parte integral de la comodidad y de la seguridad de los pacientes. La dexmedetomidina es un potente y altamente selectivo agonista de los adrenoceptores α-2 con propiedades simpaticolíticas, sedativas, amnésicas y analgésicas, que se ha venido describiendo como un adyuvante útil y seguro en varias aplicaciones clínicas. Proporciona una "sedación conciente" única, analgésica, y sin depresión respiratoria. Sus usos más comunes ya analizados, incluyen la sedación en la Unidad de Cuidados Intensivos (UCI) (adulta y pediátrica), en Urgencias, anestesia regional y general, neurocirugía, sedación para procedimientos pediátricos, intubación por fibra óptica en enfermos despiertos, cirugía cardíaca y cirugía bariátrica. CONCLUSIONES: La dexmedetomidina ofrece la capacidad única de suministrar sedación y analgesia sin depresión respiratoria. Es un agente nuevo con un gran margen de seguridad, excelente capacidad sedativa y moderadas propiedades analgésicas. Aunque su amplio uso sea hoy por hoy, para pacientes de unidades de cuidados intensivos quirúrgicos y no quirúrgicos, la dexmedetomidina parece tener aplicaciones futuras promisorias en las áreas de neuroprotección, cardioprotección y renoprotección. Aunque de todas formas, son necesarios más estudios detallados para definir su rol como sedativo en los enfermos criticos, neuroquirúrgicos y pediátricos, como adyuvante en la anestesia y como sedativo durante los procedimientos.

Uso de dexmedetomidina em neurocirurgia / The use of dexmedetomidine in neurosurgery

JUSTIFICATIVA E OBJETIVOS: Os fármacos alfa2-agonistas são a cada dia mais utilizados em Anestesiologia, seja como adjuvantes ou como agentes anestésicos únicos. Atualmente, o emprego da dexmedetomidina vem se popularizando devido à sua maior seletividade aos receptores alfa2 e, também, ao seu perfil farmacocinético. O objetivo desta revisão foi fazer uma análise do emprego da dexmedetomidina em neurocirurgia. CONTEUDO: Além das considerações e revisão da literatura quanto ao emprego da dexmedetomidina especificamente em procedimentos neurocirúrgicos, foi realizada descrição dos efeitos do fármaco nos diversos sistemas do organismo. CONCLUSÕES: A dexmedetomidina tem perfil farmacocinético e farmacodinâmico que favorece seu emprego em diversos procedimentos neurocirúrgicos. A utilização clínica em procedimentos cirúrgicos com craniotomia para pinçamento de aneurisma e remoção de tumores é crescente. Além disso, seu uso em intervenções cirúrgicas funcionais é promissor.

BACKGROUND AND OBJECTIVES: The use of alpha2-adrenergic agonists is increasingly more frequent in Anesthesiology, as adjuvant or the sole anesthetic drug. Currently, dexmedetomidine is gaining popularity due to its greater selectivity for the alpha2-adrenergic receptors and its pharmacokinetic profile. The aim of this review was to analyze the use of dexmedetomidine in neurosurgery. CONTENTS: Besides considerations and review of the literature regarding the use of dexmedetomidine, specifically in neurosurgical procedures, its effects on the different organ systems are described. CONCLUSIONS: The pharmacokinetic and pharmacodynamic profile of dexmedetomidine favors its use in several neurosurgical procedures. Its use in craniotomy for the treatment of aneurysms and tumor removal is recent. Besides, its use in functional surgical interventions is promising.

JUSTIFICATIVA Y OBJETIVOS: Los fármacos alfa2-agonistas son cada día más utilizados en Anestesiología, sea como adyuvantes o como agentes anestésicos únicos. Actualmente, el empleo de la dexmedetomidina se ha venido popularizando debido a su mayor selectividad a los receptores alfa2 y, también, a su perfil farmacocinético. El objetivo de esta revisión fue hacer una análisis del empleo de la dexmedetomidina en Neurocirugía. CONTENIDO: Además de las consideraciones y de la revisión de la literatura en cuanto al empleo de la dexmedetomidina específicamente en procedimientos neuro-quirúrgicos, fue realizada una descripción de los efectos del fármaco en los diversos sistemas del organismo. CONCLUSIONES: La dexmedetomidina tiene un perfil farmacocinético y farmacodinámico que favorece su empleo en diversos procedimientos neuro-quirúrgicos. La utilización clínica en procedimientos quirúrgicos con craneotomia para el pinzamiento de aneurisma y la retirada de tumores va en aumento. Además, su uso en intervenciones quirúrgicas funcionales es promisorio.

Aspectos anestésicos do grande obeso / Anesthetic aspects of the very obese

A população obesa no mundo tem aumentado e o conhecimento das repercussões da obesidade mórbida (OM) sobre o organismo tem se ampliado significativamente. A terapêutica cirúrgica para seu tratamento esta sob franco desenvolvimento e frente a estanova situação os subsídios para a adequada avaliação dos fatoresde risco destes pacientes tem se tornado cada vez mais claros e evidentes. A obesidade mórbida é uma doença sistêmica e como tal afeta os diferentes órgãos e sistemas, e são particularmente do interesse do anestesiologista, o comprometimento dos sistemas cardiovascular e respiratório, aí incluídas as vias aéreas superiores. A farmacocinética das drogas também é afetada e será foco deatenção. Esta revisão busca fundamentalmente trazer informaçõesrelevantes sobre as alterações nos diversos órgãos e sistemas quegeram os fatores de risco e suas possíveis repercussões na anestesia,permitindo ao médico anestesiologista um planejamento anestésico-cirúrgico mais específico e seguro.