Dexmedetomidine, a full agonist of α2B-adrenoceptors, is used for analgesia and sedation in the intensive care units. Dexmedetomidine produces an initial transient hypertension due to the activation of post-junctional α2B-adrenoceptors on vascular smooth muscle cells (SMCs). The aims of this in vitro study were to identify mitogen-activated protein kinase (MAPK) isoforms that are primarily involved in full, α2B-adrenoceptor agonist, dexmedetomidine-induced contraction of isolated rat aortic SMCs.
Materials and Methods
Rat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dexmedetomidine (10-9 to 10-6 M) dose-response curves were generated in the presence or absence of extracellular signal-regulated kinase (ERK) inhibitor PD 98059, p38 MAPK inhibitor SB 203580, c-Jun NH2-terminal kinase (JNK) inhibitor SP 600125, L-type calcium channel blocker (verapamil and nifedipine), and α2-adrenoceptor inhibitor atipamezole. Dexmedetomidine-induced phosphorylation of ERK, JNK, and p38 MAPK in rat aortic SMCs was detected using Western blotting.
SP 600125 (10-6 to 10-5 M) attenuated dexmedetomidine-evoked contraction in a concentration-dependent manner, whereas PD 98059 had no effect on dexmedetomidine-induced contraction. SB 203580 (10-5 M) attenuated dexmedetomidine-induced contraction. Dexmedetomidine-evoked contractions were both abolished by atipamezole and attenuated by verapamil and nifedipine. Dexmedetomidine induced phosphorylation of JNK and p38 MAPK in rat aortic SMCs, but did not induce phosphorylation of ERK.
Dexmedetomidine-induced contraction involves a JNK- and p38 MAPK-mediated pathway downstream of α2-adrenoceptor stimulation in rat aortic SMCs. In addition, dexmedetomidine-induced contractions are primarily dependent on calcium influx via L-type calcium channels.
Dexmedetomidine; mitogen-activated protein kinase; α2B-adrenoceptors; hypertension; rat aorta
The α2-adrenoreceptor agonist dexmedetomidine is known to provide renoprotection against ischemia and reperfusion (I/R) injury. However the underlying molecular mechanisms remain unclear. The purpose of this study was to investigate whether the Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a role in dexmedetomidine’s renoprotection.
I/R model was induced by bilateral renal pedicle clamping for 45 min followed by 48 h of reperfusion in male Wistar rat. Sham laparotomy served as controls. Animals received dexmedetomidine (50 μg/kg, i.p.) in the absence or presence of atipamezole (250 μg/kg, i.p.), or vehicle (DMSO) in the absence or presence of selective JAK2 inhibitor tyrphostin AG490 (10 mg/kg, i.p.) before ischemia. Renal function, histology, apoptosis, expression of cleaved caspase 3 protein, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and phosphorylations of JAK2, STAT1 and STAT3 were assessed.
The animals treated with either dexmedetomidine or AG490 exhibited an improved renal functional recovery, attenuated histological lesions and reduced number of apoptotic tubular epithelial cells. Either dexmedetomidine or AG490 inhibited the phosphorylations of JAK2 and its downstream molecule STAT1 and STAT3, accompanied by down-regulation the expression of cleaved caspase 3, ICAM-1 and MCP-1 proteins, and significantly ameliorated renal I/R injury.
Dexmedetomidine protects kidney against I/R injury, at least in part, through its inhibitory effects on injury-induced activation of JAK/STAT signaling pathway. If our data can be extrapolated to clinical setting, then dexmedetomidine may therefore serve as a clinical strategy to treat/prevent perioperative renal I/R injury.
Dexmedetomidine; Ischemia and Reperfusion Injury; AG490; JAK/STAT; Renoprotection
The aim of this experimental study was to investigate the possible protective effect of dexmedetomidine (DEX) on traumatic spinal cord injury (SCI). Twenty-two New Zealand rabbits were divided into three groups: sham (no drug or operation, n = 6), Control [SCI + single dose of 1 mL saline intraperitoneally (i.p), after trauma; n = 8] and DEX (SCI + 1 μg/kg dexmedetomidine in 1 mL, i.p, after trauma, n = 8). Laminectomy was performed at T10 and balloon angioplasty catheter was applied extradurally. Four and 24 h after surgery, rabbits were evaluated by an independent observer according to the Tarlov scoring system. Blood, cerebrospinal fluid (CSF), tissue samples from spinal cord were taken for biochemical and histopathological evaluations. After 4 h of SCI, all animals in control or DEX treated groups became paraparesic. On the other hand, 24 h after SCI, partial improvements were observed in both control and DEX treated groups. Traumatic SCI leads to increase in the lipid peroxidation and decreases enzymatic or nonenzymatic endogenous antioxidative defense systems. Again, SCI leads to apoptosis in spinal cord. DEX treatment slightly prevented lipid peroxidation and augmented endogenous antioxidative defense systems in CSF or spinal cord tissue, but failed to prevent apoptosis or neurodeficit after traumatic SCI. Therefore, it could be suggested that treatment with dexmedetomidine does not produce beneficial results in SCI.
Spinal cord injury; Dexmedetomidine; Neuroprotection; Oxidative stress; Apoptosis
Surgical brain injury (SBI) is damage to functional brain tissue resulting from neurosurgical manipulations such as sharp dissection, electrocautery, retraction, and direct applied pressure. Brain edema is the major contributor to morbidity with inflammation, necrosis, oxidative stress and apoptosis likely playing smaller roles. Effective therapies for SBI may improve neurological outcomes and postoperative morbidities associated with brain surgery. Previous studies show an adrenergic correlation to blood-brain barrier control. The alpha-2 receptor agonist dexmedetomidine (DEX) has been shown to improve neurological outcomes in stroke models. We hypothesized that DEX may reduce brain edema and improve neurological outcomes in a rat model of SBI.
Male Sprague-Dawley rats (n=63) weighing 280–350g were randomly assigned to one of four intraperitoneal (IP) treatment groups: sham IP, vehicle IP, DEX 10 mg/kg, and DEX 30 mg/kg. Treatments were given 30 minutes before SBI. These treatment groups were repeated to observe the physiologic impact of DEX on mean arterial blood pressure (MAP), heart rate (HR), and blood glucose on SBI naïve animals. Rats were also assigned to four postinjury IV treatment groups: sham IV, vehicle IV, DEX 10/5, and DEX 30/15 (DEX group doses were 10 and 30 mg/kg/hr, with 5 and 15 mg/kg initial loading doses respectively). Initial loading doses began 20 minutes after SBI, followed by 2 hours of infusion. SBI animals were subjected to neurological testing 24 hours after brain injury by a blinded observer, promptly killed, and brain water content measured via the dry/wet weight method.
All treatment groups showed a significant difference in ipsilateral frontal brain water content and neurological scores when compared with sham animals. However, there was no difference between DEX-treated and vehicle animals. Physiologic monitoring showed treatment with low or high doses of DEX significantly decreased MAP and HR, and briefly increased blood glucose compared with naïve or vehicle-treated animals.
DEX administration did not reduce brain edema or improve neurological function after SBI in this study. The statistical difference in brain water content and neurological scores when comparing sham treatment to vehicle and DEX treatments shows consistent reproduction of this model. Significant changes in MAP, HR, and blood glucose after DEX as compared to vehicle and sham treatments suggest appropriate delivery of drug.
Acute kidney injury following surgery incurs significant mortality with no proven preventative therapy. We investigated whether the α2 adrenoceptor agonist dexmedetomidine (Dex) provides protection against ischemia-reperfusion induced kidney injury in vitro and in vivo.
In vitro, a stabilised cell line of human kidney proximal tubular cells (HK2) was exposed to culture medium deprived of oxygen and glucose. Dex decreased HK2 cell death in a dose-dependent manner, an effect attenuated by the α2 adrenoceptor antagonist atipamezole, and likely transduced by phosphatidylinositol 3-kinase (PI3K-Akt) signaling. In vivo C57BL/6J mice received Dex (25 μg/kg, intraperitoneal (i.p.)) 30 minutes before or after either bilateral renal pedicle clamping for 25 minutes or right renal pedicle clamping for 40 minutes and left nephrectomy.
Pre- or post-treatment with Dex provided cytoprotection, improved tubular architecture and function following renal ischemia. Consistent with this cytoprotection, dexmedetomidine reduced plasma high-mobility group protein B1 (HMGB-1) elevation when given prior to or after kidney ischemia-reperfusion; pretreatment also decreased toll-like receptor 4 (TLR4) expression in tubular cells. Dex treatment provided long-term functional renoprotection, and even increased survival following nephrectomy.
Our data suggest that Dex likely activates cell survival signal pAKT via α2 adrenoceptors to reduce cell death and HMGB1 release and subsequently inhibits TLR4 signaling to provide reno-protection.
Dexmedetomidine (DEX) has been used under perioperative settings as an adjuvant to enhance the analgesic property of local anesthetics by some anesthesiologists. However, the analgesic mechanisms and neurotoxicity of DEX were poorly understood. This study examined the effect of DEX alone on inflammatory pain, and it also examined the underlying molecular mechanisms of DEX in the spinal cord. Furthermore, in vivo and in vitro experiments were performed to investigate the neurotoxicity of DEX on the spinal cord and cortical neurons.
This study used adult, male Kunming mice. In the acute inflammatory model, the left hind-paws of mice were intradermally injected with pH 5.0 PBS while chronic constrictive injury (CCI) of the sciatic nerve was used to duplicate the neuropathic pain condition. Thermal paw withdrawal latency and mechanical paw withdrawal threshold were tested with a radiant heat test and the Von Frey method, respectively. Locomotor activity and motor coordination were evaluated using the inverted mesh test. Western blotting examined spinal ERK1/2, p-ERK1/2, caspase-3 and β-actin expressions, while spinal c-Fos protein expression was realized with immunohistochemical staining. Hematoxylin eosin (HE) staining was used to examine the pathological impacts of intrathecal DEX on the spinal cord. DAPI (4′,6-diamidino-2-phenylindole) staining was used to observe cell death under an immunofluorescence microscope.
Intra-plantar pH 5.0 PBS-induced acute pain required spinal ERK1/2 activation. Inhibition of spinal ERK1/2 signaling by intrathecal injection of DEX displayed a robust analgesia, via a α2-receptor dependent manner. The analgesic properties of DEX were validated in CCI mice. In vivo studies showed that intrathecal DEX has no significant pathological impacts on the spinal cord, and in vitro experiments indicated that DEX has potential protective effects of lidocaine-induced neural cell death.
Intrathecal injection of DEX alone or as an adjuvant might be potential for pain relief.
In the present study, the effects of dexmedetomidine on secondary lung and kidney injuries were studied in the rat model of intra-abdominal sepsis by immunohistological and biochemical examinations. We measured serum creatinine, kidney tissue malondialdehide and plasma neutrophil gelatinase-associated lipocalin levels. In order to evaluate tissue injury we determined kidney tissue mononuclear cell infiltration score, alveolar macrophage count, histological kidney and lung injury scores and kidney and lung tissue immunoreactivity scores. We demonstrated that dexmedetomidine attenuates sepsis-induced lung and kidney injuries and apoptosis in the rat model of sepsis. There is still need for comparative studies in order to determine the effects of dexmedetomidine on organ functions in early human sepsis.
Recently, it has been shown in several experimental settings that the noble gases xenon and helium have neuroprotective properties. In this study we tested the hypothesis that the noble gas argon has a neuroprotective potential as well. Since traumatic brain injury and stroke are widespread and generate an enormous economic and social burden, we investigated the possible neuroprotective effect in in vitro models of traumatic brain injury and cerebral ischemia.
Organotypic hippocampal slice cultures from mice pups were subjected to either oxygen-glucose deprivation or to a focal mechanical trauma and subsequently treated with three different concentrations (25, 50 and 74%) of argon immediately after trauma or with a two-or-three-hour delay. After 72 hours of incubation tissue injury assessment was performed using propidium iodide, a staining agent that becomes fluorescent when it diffuses into damaged cells via disintegrated cell membranes.
We could show argon's neuroprotective effects at different concentrations when applied directly after oxygen-glucose deprivation or trauma. Even three hours after application, argon was still neuroprotective.
Argon showed a neuroprotective effect in both in vitro models of oxygen-glucose deprivation and traumatic brain injury. Our promising results justify further in vivo animal research.
We investigated the neuroprotective properties of levosimendan, a novel inodilator, in an in vitro model of traumatic brain injury.
Organotypic hippocampal brain slices from mouse pups were subjected to a focal mechanical trauma. Slices were treated after the injury with three different concentrations of levosimendan (0.001, 0.01 and 0.1 μM) and compared to vehicle-treated slices. After 72 hrs, the trauma was quantified using propidium iodide to mark the injured cells.
A significant dose-dependent reduction of both total and secondary tissue injury was observed in cells treated with either 0.01 or 0.1 μM levosimendan compared to vehicle-treated slices.
Levosimendan represents a promising new pharmacological tool for neuroprotection after brain injury and warrants further investigation in an in vivo model.
The anaesthetic agent propofol (2,6-diisopropylphenol) has been shown to be an effective neuroprotective agent in different in vitro models of brain injury induced by oxygen and glucose deprivation. We examined its neuroprotective properties in an in vitro model of traumatic brain injury.
In this controlled laboratory study organotypic hippocampal brain-slice cultures were gained from six- to eight-day-old mice pups. After 14 days in culture, hippocampal brain slices were subjected to a focal mechanical trauma and subsequently treated with different molar concentrations of propofol under both normo- and hypothermic conditions. After 72 hours of incubation, tissue injury assessment was performed using propidium iodide (PI), a staining agent that becomes fluorescent only when it enters damaged cells via perforated cell membranes. Inside the cell, PI forms a fluorescent complex with nuclear DNA.
A dose-dependent reduction of both total and secondary tissue injury could be observed in the presence of propofol under both normo- and hypothermic conditions. This effect was further amplified when the slices were incubated at 32°C after trauma.
When used in combination, the dose-dependent neuroprotective effect of propofol is additive to the neuroprotective effect of hypothermia in an in vitro model of traumatic brain injury.
While abdominal aortic aneurysms have traditionally been treated with a major open surgical procedure, minimally invasive endovascular techniques are much less traumatic, with significantly less strain on the heart and vital organs. A sedation technique using dexmedetomidine, an alpha 2-adrenoreceptor agonist, was developed for this procedure. We retrospectively reviewed records of 231 patients who underwent endovascular repair of abdominal aortic aneurysms at the Baylor Jack and Jane Hamilton Heart and Vascular Hospital from January 1, 2001, until September 30, 2005. Intraoperative and early postoperative data of 14 patients who had endovascular repairs using the dexmedetomidine sedation technique were compared with those of 22 patients who received general endotracheal tube anesthesia for the procedure during the time period of January 1, 2003, through September 1, 2005. The surgery and anesthesia times were shorter in the dexmedetomidine group, and less opioid medication was required. In addition, the postoperative pain scores were lower, and the need for postoperative pain medication was less in the dexmedetomidine group. This retrospective analysis demonstrates that a dexmedetomidine sedation technique offers a successful alternative to routine general anesthesia for endovascular repair of abdominal aortic aneurysms.
Dexmedetomidine is an α2-adrenoreceptor agonist with sedative, analgesic and anxiolytic effects, and it has more selective α2-adrenergic effect than clonidine. We evaluate the effect of preansethetic dexmedetomidine 1 µg/kg single infusion on sedation, hemodynamics, anesthetic consumption, and recovery profiles during anesthesia.
Forty-two female patients with American Society of Anesthesiologists physical status I or II undergoing gynecologic surgery with anticipated operation time of 2 h, were randomly assigned to receive dexmedetomidine 1 µg/kg (Dex group) or saline (control group) iv over 10 min before anesthetic induction. After tracheal intubation with propofol 2 mg/kg, cisatracurium 0.15 mg/kg iv, anesthesia was maintained with sevoflurane, O2 50%, N2O 50% around a BIS value of 40.
After study drug infusion, BIS of Dex group was lower than that of control group (93.9 ± 3.1 vs 51.5 ± 5.2, P < 0.05). Mean arterial pressure (MAP) and heart rate (HR) after intubation were increased in control group, but did not change in Dex group. During maintenance, there was no difference in MAP between groups, but HR of Dex group was lower compared to that of control group. End-tidal concentration (2.0 ± 0.5 vol% vs 1.4 ± 0.3 vol%, P < 0.05) and total cumulative consumption of sevoflurane (34.6 ± 3.8 ml vs 26.5 ± 5.3 ml, P < 0.05) were lower in Dex group than in control group. Recovery profiles, modified Aldrete score, postoperative nausea vomiting, and visual analogue pain score were not significantly different between groups.
Preanesthetic dexmetomidine 1 µg/kg single infusion is a simple, easy, and economic general anesthetic adjuvant that maintains stable hemodynamics and decrease anesthetic consumption without the change of recovery profiles.
Dexmedetomidine; Economics; Hemodynamics; Recovery of function; Sevoflurane
Laparoscopic cholecystectomy is performed with increasing frequency in aging populations. However, in elderly patients, cognitive dysfunction following surgery may impair the outcome of surgical procedures. Dexmedetomidine (DEX) has been demonstrated to have a neuroprotectve effect in animal experiments. However, it is unclear whether DEX also has a neuroprotective effect in human patients. The present study was a randomized, placebo-controlled double-blind trial of 126 patients who had undergone laparoscopic cholecystectomy, using clinical interviews to determine whether intravenously administrated DEX during general anesthesia ameliorates cognitive function impairment. The cognitive deficit of each patient was assessed using the Mini-Mental State Examination (MMSE). The scores on the MMSE for the DEX and control groups one week after surgery (DEX group, 27.6±1.2; control group, 25.7±1.5) were significantly different (P=0.005). The MMSE scores of patients ≤65 years old were significantly higher than those of patients >65 one week after surgery. The MMSE scores were significantly different between the two age groups in the control patients (≤65 years old, 28.3±1.2; >65 years old, 26.6±2.1; P=0.036), while the difference was not statistically significant in the DEX-treated patients. Eight patients in the DEX group and 15 patients in the control group had mild cognitive impairment (26≥ MMSE score ≥21) although the difference was not statistically significant. The findings of the present study support the hypothesis that DEX administration may be an effective method for ameliorating postoperative cognitive impairment in elderly patients who have undergone laparoscopic cholecystectomy. Further research is required to confirm the findings of the present study.
dexmedetomidine; cognitive function; laparoscopic cholecystectomy
Hepatic ischemia–reperfusion injury is a common clinical problem in hepatic surgery and transplantation. Several cellular and tissue structural and functional alterations are observed in such injury. The aim of this study was to evaluate the effect of dexmedetomidine on lipid peroxidation and erythrocyte deformability during ischemia–reperfusion injury in rats.
Twenty-four Wistar Albino rats were randomly separated into three groups as control (C), ischemia–reperfusion injury (I/R) and dexmedetomidine group (I/R-D). Ischemia was induced with portal clampage for 45 min and reperfusion period was 45 min after declampage. Group I/R-D received dexmedetomidine 100 µg/kg i.p. 30 min before portal clampage. Serum malondialdehyde and superoxide dismutase activities to document lipid peroxidation and erythrocyte deformability index were investigated.
Serum superoxide dismutase and malondialdehyde activity levels were significantly higher and erythrocyte deformability index was decreased in hepatic ischemia–reperfusion group. However, these changes were observed to be prevented with dexmedetomidine treatment when given before portal clampage.
These findings clearly indicate that erythrocyte deformability index is decreased in hepatic ischemia reperfusion injury and has a potential role to prevent these alterations. The protective effect of dexmedetomidine on hepatic I/R injury is also decreased lipid peroxidation. Further experimental and clinical investigations may clarify the molecular mechanisms and clinical significance of these findings.
hepatic ischemia–reperfusion injury; lipid peroxidation; malondialdehyde; superoxide dismutase; erythrocyte deformability; dexmedetomidine
The aim of this study was to evaluate the effect of dexmedetomidine on shivering during spinal anesthesia.
Sixty patients (American Society of Anesthesiologists physical status I or II, aged 18-50 years), scheduled for elective minor surgical operations under spinal anesthesia with hyperbaric bupivacaine, were enrolled. They were administered saline (group C, n = 30) or dexmedetomidine (group D, n = 30). Motor block was assessed using a Modified Bromage Scale. The presence of shivering was assessed by a blinded observer after the completion of subarachnoid drug injection.
Hypothermia was observed in 21 patients (70%) in group D and in 20 patients (66.7%) in group C (p = 0.781). Three patients (10%) in group D and 17 patients (56.7%) in group C experienced shivering (p = 0.001). The intensity of shivering was lower in group D than in group C (p = 0.001). Time from baseline to onset of shivering was 10 (5-15) min in group D and 15 (5-45) min in group C (p = 0.207).
Dexmedetomidine infusion in the perioperative period significantly reduced shivering associated with spinal anesthesia during minor surgical procedures without any major adverse effect during the perioperative period. Therefore, we conclude that dexmedetomidine infusion is an effective drug for preventing shivering and providing sedation in patients during spinal anesthesia.
Dexmedetomidine; Shivering; Spinal anesthesia
Dexmedetomidine is a highly specific, potent and selective α2-adrenoceptor agonist. Although intrathecal and epidural administration of dexmedetomidine has been found to produce analgesia, whether this analgesia results from an effect on spinal cord substantia gelatinosa (SG) neurons remains unclear. Here, we investigated the effects of dexmedetomidine on postsynaptic transmission in SG neurons of rat spinal cord slices using the whole-cell patch-clamp technique. In 92% of the SG neurons examined (n= 84), bath-applied dexmedetomidine induced outward currents at −70 mV in a concentration-dependent manner, with the value of effective concentration producing a half-maximal response (0.62 μm). The outward currents induced by dexmedetomidine were suppressed by the α2-adrenoceptor antagonist yohimbine, but not by prazosin, an α1-, α2B- and α2C-adrenoceptor antagonist. Moreover, the dexmedetomidine-induced currents were partially suppressed by the α2C-adrenoceptor antagonist JP-1302, while simultaneous application of JP-1302 and the α2A-adrenoceptor antagonist BRL44408 abolished the current completely. The action of dexmedetomidine was mimicked by the α2A-adrenoceptor agonist oxymetazoline. Plots of the current–voltage relationship revealed a reversal potential at around −86 mV. Dexmedetomidine-induced currents were blocked by the addition of GDP-β-S [guanosine-5′-O-(2-thiodiphosphate)] or Cs+ to the pipette solution. These findings suggest that dexmedetomidine hyperpolarizes the membrane potentials of SG neurons by G-protein-mediated activation of K+ channels through α2A- and α2C-adrenoceptors. This action of dexmedetomidine might contribute, at least in part, to its antinociceptive action in the spinal cord.
α2-adrenoceptor; analgesia; dexmedetomidine; dorsal horn; substantia gelatinosa; whole-cell patch-clamp
Dexmedetomidine (DEX) has a minimal respiratory depressive effect, which is beneficial for dentistry; however, it has the disadvantage of permitting an intraoperative arousal response such that the patient appears to be suddenly no longer sedated, and it has a variable amnestic effect. Since midazolam (MDZ) in an appropriate dose has a profound amnesic effect, we investigated whether additional MDZ compensates for the disadvantage of DEX and enables a better quality of sedation. Forty-three subjects were randomly divided into 4 groups. In group 1, MDZ (0.02 mg/kg) was administered intravenously, followed by a dose of 0.01 mg/kg every 45 minutes. After the first dose of MDZ, preloading with DEX (2 µg/kg/h for 10 minutes) was started and maintained with a dosage of 0.5 µg/kg/h. In group 2, MDZ was infused in the same manner as in group 1, followed by preloading with DEX (1 µg/kg/h for 10 minutes) and maintenance (0.3 µg/kg/h). In group 3, MDZ was infused 0.03 mg/kg, and a dose of 0.01 mg/kg was given every 30 minutes; DEX was administered at the same as in group 2. In group 4, DEX was infused using the same method as in group 1 without MDZ. The sedation levels, amnesia, and patient satisfaction were also investigated. Group 2 had a lower sedation level and a poor evaluation during the first half of the operation. Group 4 did not exhibit an amnesic effect at the beginning of the operation. An evaluation of the degree of patient satisfaction did not reveal any differences among the groups. Optimal sedation was achieved through the combined use of MDZ (0.02 mg/kg with the addition of 0.01 mg/kg every 45 minutes) and DEX (2 µg/kg/h for 10 minutes followed by 0.5 µg/kg/h).
Dexmedetomidine; Midazolam; Sedation; Dental treatment; Implant; Amnesia
Dexmedetomidine (DEX) is an α2-adrenergic agonist. It decreases the levels of norepinephrine release, resulting in a reduction of postsynaptic adrenergic activity. In the present study, the effects of DEX on postpartum bleeding-induced multiple organ dysfunction syndrome (BMODS) were studied in rats in which BMODS was induced by the combination of hypotension and clamping of the superior mesenteric artery. We evaluated the role of dexmedetomidine (DEX) in cytokine release during postpartum BMODS in rats. In summary, the present study demonstrated that DEX administration reduced IFN-r and IL-4 release and decreased lung injury during postpartum BMODS. It is possible that DEX administration decreased inflammatory cytokine production in BMODS by inhibiting inflammation and free radical release by leukocytes independent of the DEX dose.
Dexmedetomidine is a highly selective α2-adrenoceptor agonist that is widely used for sedation and analgesia during the perioperative period. Intravenous administration of dexmedetomidine induces transient hypertension due to vasoconstriction via the activation of the α2-adrenoceptor on vascular smooth muscle. The goal of this in vitro study is to investigate the calcium-dependent mechanism underlying dexmedetomidine-induced contraction of isolated endothelium-denuded rat aorta.
Isolated endothelium-denuded rat thoracic aortic rings were suspended for isometric tension recording. Cumulative dexmedetomidine concentration-response curves were generated in the presence or absence of the following inhibitors: α2-adrenoceptor inhibitor rauwolscine; voltage-operated calcium channel blocker verapamil (5 × 10-7, 10-6 and 5 × 10-5 M); purported inositol 1,4,5-trisphosphate receptor blocker 2-aminoethoxydiphenylborate (5 × 10-6, 10-5 and 5 × 10-5 M); phospholipase C inhibitor U-73122 (10-6 and 3 × 10-6 M); and store-operated calcium channel inhibitor gadolinium chloride hexahydrate (Gd3+; 5 × 10-6 M). Dexmedetomidine concentration-response curves were also generated in low calcium concentrations (1 mM) and calcium-free Krebs solution.
Rauwolscine, verapamil, and 2-aminoethoxydiphenylborate attenuated dexmedetomidine-induced contraction in a concentration-dependent manner. Low calcium concentrations attenuated dexmedetomidine-induced contraction, and calcium-free Krebs solution nearly abolished dexmedetomidine-induced contraction. However, U-73122 and Gd3+ had no effect on dexmedetomidine-induced contraction.
Taken together, these results suggest that dexmedetomidine-induced contraction is primarily dependent on extracellular calcium concentrations that contribute to calcium influx via voltage-operated calcium channels of isolated rat aortic smooth muscle. Dexmedetomidine-induced contraction is mediated by α2-adrenoceptor stimulation. Dexmedetomidine-induced contraction appears to be partially mediated by calcium release from the sarcoplasmic reticulum.
Aorta; Calcium; Contraction; Dexmedetomidine; Voltage-operated calcium channel
It has been postulated that Multiple sclerosis (MS) stems from a narrowing in the veins that drain blood from the brain, known medically as chronic cerebrospinal venous insufficiency, or CCSVI. It has been proposed that balloon angioplasty should alleviate the symptoms of MS. This procedure is also known as The “Liberation Procedure”. Accordingly, a clinical study was undertaken to determine the effects of dexmedetomidine in patients undergoing the liberation procedure.
To assess the effectiveness of dexmedetomidine in providing adequate sedation and pain relief for patients undergoing the liberation procedure.
Settings and design:
A prospective, nonrandomized observational study of 60 consecutive adult patients undergoing the liberation procedure under monitored anesthesia care (MAC) who will receive dexmedetomidine as an anesthetic agent.
A total of 60 adult patients were enrolled in the study. Dexmedetomidine was administered to all patients in a loading dose of 1 mcg/kg, which was followed by a maintenance dose of 0.2–0.5 mcg/kg/h. The evaluation of quality of sedation was based on Ramsay Sedation and the quality of analgesia was assessed using the visual analog scale. The following parameters were measured continuously: heart rate, mean arterial pressure and hemoglobin oxygen saturation. Patients were asked to answer the question, “How would you rate your experience with the sedation you have received during surgery?” using a seven-point Likert-like verbal rating scale.
Repeated measurements were analyzed by repeated measures ANOVA for HR and BP.
Most of our patients were satisfied with their sedation. In most of the patients, MAP and HR dropped after the bolus dose of dexmedetomidine, and the drop was statistically significant.
Dexmedetomidine can be used as a sole sedative agent in patients undergoing the liberation procedure.
Dexmedetomidine; monitored anesthesia care; multiple sclerosis liberation procedure
Patients undergoing alcohol withdrawal in the intensive care unit (ICU) often require escalating doses of benzodiazepines and not uncommonly require intubation and mechanical ventilation for airway protection. This may lead to complications and prolonged ICU stays. Experimental studies and single case reports suggest the α2-agonist dexmedetomidine is effective in managing the autonomic symptoms seen with alcohol withdrawal. We report a retrospective analysis of 20 ICU patients treated with dexmedetomidine for benzodiazepine-refractory alcohol withdrawal.
Records from a 23-bed mixed medical-surgical ICU were abstracted from November 2008 to November 2010 for patients who received dexmedetomidine for alcohol withdrawal. The main analysis compared alcohol withdrawal severity scores and medication doses for 24 h before dexmedetomidine therapy with values during the first 24 h of dexmedetomidine therapy.
There was a 61.5% reduction in benzodiazepine dosing after initiation of dexmedetomidine (n = 17; p < 0.001) and a 21.1% reduction in alcohol withdrawal severity score (n = 11; p = .015). Patients experienced less tachycardia and systolic hypertension following dexmedetomidine initiation. One patient out of 20 required intubation. A serious adverse effect occurred in one patient, in whom dexmedetomidine was discontinued for two 9-second asystolic pauses noted on telemetry.
This observational study suggests that dexmedetomidine therapy for severe alcohol withdrawal is associated with substantially reduced benzodiazepine dosing, a decrease in alcohol withdrawal scoring and blunted hyperadrenergic cardiovascular response to ethanol abstinence. In this series, there was a low rate of mechanical ventilation associated with the above strategy. One of 20 patients suffered two 9-second asystolic pauses, which did not recur after dexmedetomidine discontinuation. Prospective trials are warranted to compare adjunct treatment with dexmedetomidine versus standard benzodiazepine therapy.
Alcohol withdrawal delirium; Alcohol withdrawal syndrome; Dexmedetomidine; Intensive care; Critical care; Benzodiazepines
Background and Objectives
Although the pharmacokinetics of dexmedetomidine in healthy volunteers have been studied, there are limited data about the pharmacokinetics of long-term administration of dexmedetomidine in critically ill patients.
This population pharmacokinetic analysis was performed to quantify the pharmacokinetics of dexmedetomidine in critically ill patients following infusions up to 14 days in duration. The data consisted of three phase III studies (527 patients with sparse blood sampling, for a total of 2,144 samples). Covariates were included in a full random-effects covariate model and the most important covariate relationships were tested separately. The linearity of dexmedetomidine clearance was evaluated by observing steady-state plasma concentrations acquired at various infusion rates.
The data were adequately described with a one-compartment model. The clearance of dexmedetomidine was 39 (95 % CI 37–41) L/h and volume of distribution 104 (95 % CI 93–115) L. Both clearance and volume of distribution were highly variable between patients (coefficients of variation of 62 and 57 %, respectively), which highlights the importance of dose titration by response. Covariate analysis showed a strong correlation between body weight and clearance of dexmedetomidine. The clearance of dexmedetomidine was constant in the dose range 0.2–1.4 μg/kg/h.
The pharmacokinetics of dexmedetomidine are dose-proportional in prolonged infusions when dosing rates of 0.2–1.4 μg/kg/h, recommended by the Dexdor® summary of product characteristics, are used.
Benzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an α2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients.
In this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis.
Of the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11).
In this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results.
Dexmedetomidine is an α2-adrenergic receptor agonist with sedative and analgesic effects in mechanically ventilated adults and children. Safety and efficacy data are limited in children. The purpose of this study is to retrospectively identify the incidence and types of adverse events noted in children receiving continuous infusions of dexmedetomidine and evaluate potential risk factors for adverse events.
Between July 1, 2006, and July 31, 2007, data were collected on all children (< 18 years) who received continuous infusions of dexmedetomidine. Data collection included demographics, dexmedetomidine regimen, and type/number of adverse events. The primary endpoint was the total number of adverse events noted, including: transient hypertension, hypotension, neurological manifestations, apnea, and bradycardia. Secondary endpoints included categorization of each type of adverse event and an assessment of risk factors. A logistic regression model was used to assess the relationship of adverse events with independent variables including length of ICU stay, cumulative dose, peak infusion rate, duration of therapy, PRISM III score, and bolus dose.
Thirty-six patients received dexmedetomidine representing 41 infusions. The median age was 16 months (range, 0.1–204 months) and median PRISM III score was 2 (range, 0–18). Eighteen (43.9%) patients received a bolus dose of dexmedetomidine. The median cumulative dose (mcg/kg) and peak dose (mcg/kg/hr) were 8.5 (range, 2.2–193.7) and 0.5 (range, 0.2–0.7), respectively. Dexmedetomidine was continued for a median of 20 (range, 3–263) hours. Six (14.6%) patients were slowly tapered off the continuous infusions. Twenty-one adverse events were noted in 17 patients, including 4 neurologic manifestations. Fourteen patients required interventions for adverse events. ICU length of stay was the only independent risk factor (p=0.036) for development of adverse events.
Several potential adverse events were noted with dexmedetomidine continuous infusions including possible neurological manifestations. Further studies are needed looking at adverse events associated with dexmedetomidine use in the pediatric population.
adverse events; children; dexmedetomidine; intensive care unit; sedation
Dexmedetomidine, which is a selective α2-adrenoceptor agonist, was recently introduced into clinical practice for its analgesic properties. The purpose of this study was to evaluate the effects of dexmedetomidine in a vincristine-evoked neuropathic rat models. Sprague-Dawley rats were injected intraperitoneally with vincristine or saline (0.1 mg/kg/day) using a 5-day-on, 2-day-off schedule for 2 weeks. Saline and dexmedetomidine (12.5, 25, 50, and 100 µg/kg) were injected to rats developed allodynia 14 days after vincristine injection, respectively. We evaluated allodynia at before, 15, 30, 60, 90, 120, 180, and 240 min, and 24 hr after intraperitoneal drug (normal saline or dexmedetomidine) injection. Saline treatment did not show any differences for all the allodynia. Maximal paw withdrawal thresholds to mechanical stimuli were 3.0 ± 0.4, 9.1 ± 1.9, 13.0 ± 3.6, 16.6 ± 2.4, and 24.4 ± 1.6 g at saline, 12.5, 25, 50, and 100 µg/kg dexmedetomidine injection, respectively. Minimal withdrawal frequency to cold stimuli were 73.3 ± 4.2, 57.1 ± 6.8, 34.3 ± 5.7, 20.0 ± 6.2, and 14.3 ± 9.5 g at saline, 12.5, 25, 50, and 100 µg/kg dexmedetomidine injection, respectively. Dexmedetomidine shows a dose-dependent antiallodynic effect on mechanical and cold stimuli in vincristine-evoked neuropathic rat models (P < 0.05).
Dexmedetomidine; Neuropathy; Pain; Vincristine