Alpha-adrenergic Agonist Research Articles

Pharmacogenetics in Child and Adolescent Psychiatry: Background and Evidence-Based Clinical Applications.

The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic factors. Pharmacogenetics (PGx) in child and adolescent psychiatry can potentially improve treatment outcomes and minimize adverse drug reactions. This article reviews key pharmacokinetic and pharmacodynamic genes and principles of pharmacogenetic testing and discusses the evidence base for clinical decision-making concerning PGx testing. This article reviews current guidelines from the United States Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Dutch Pharmacogenetics Working Group (DPWG) and explores potential future directions. This review discusses key clinical considerations for clinicians prescribing psychotropic medications in children and adolescents, focusing on antidepressants, antipsychotics, stimulants, norepinephrine reuptake inhibitors, and alpha-2 agonists. Finally, this review synthesizes the practical use of pharmacogenetic testing and clinical decision support systems.

Enteral Pentobarbital in the Difficult to Sedate Critically Ill Children

OBJECTIVE Difficult analgosedation is common and challenging in the pediatric intensive care unit (PICU). It is important to study alternative and supplemental sedatives for when the first-line agents become ­insufficient. METHODS In this retrospective chart-review study, we report our center’s experience in using intermittent doses of enteral pentobarbital as an adjunct sedative in 13 difficult to sedate critically ill and mechanically ventilated children. We compare the average sedation score and cumulative doses of other ­sedatives (opioids, benzodiazepines and alpha-2 agonists) in the 24 hours before and 24 hours after enteral ­pentobarbital initiation. RESULTS The addition of enteral pentobarbital was associated with lower State Behavioral State (SBS) scores in 8 out of the 13 patients and on average smaller doses of opioids (decreased by 11%), ­benzodiazepines (BZD) (decreased by 5%) and alpha-agonists (decreased by 20%). No adverse effects were noted attributable to pentobarbital administration. CONCLUSION Enteral pentobarbital seems to be safe and effective agent in the difficult to sedate critically ill child.

Combination of a propofol emulsion with alpha-2 adrenergic receptor agonists used for multimodal analgesia or sedation in intensive care units: a physicochemical stability study

ObjectivesTo assess the physicochemical stability of the combination of a propofol emulsion with an alpha-2 (α2) adrenergic receptor agonist (α2A; clonidine or dexmedetomidine) under conditions mimicking routine practice in an...

The use of dexmedetomidine in suppressing cardiovascular response due to intubation in general anesthesia

Endotracheal intubation is commonly used to maintain a safe airway during general anesthesia. This intubation action can trigger a dangerous response for the patient, one of which is the cardiovascular system. Increases in arterial blood pressure, plasma catecholamine levels, and heart rate are responses that can occur during intubation. Therefore, various methods and treatments have been used to control this cardiovascular response, including dexmedetomidine. Dexmedetomidine is a highly selective α2-adrenergic receptor agonist that has analgesic, sympatholytic, and sedative effects with minimal depression of ventilation. Much research has been done on how well dexmedetomidine works to stop the cardiovascular response to intubation. Dexmedetomidine was significantly associated with reductions in heart rate, systolic blood pressure, and MAP.

Alpha-2 Agonists in Children and Adolescents With Post-traumatic Stress Disorder: A Systematic Review.

Exposure to traumatic stress is common among children.Post-traumatic stress disorder (PTSD) is a debilitating chronic mental disorder that can develop following exposure to a traumatic event. Psychopharmacological research in pediatric PTSD is limited. There is some evidence supporting the use of alpha-2 (α2)agonists for symptoms associated with PTSD. This systematic review identified published studies evaluating the effectiveness of α2 agonists in treating PTSD symptoms in children and adolescents. We conducted an extensive literature search on PubMed, MEDLINE, EMBASE, Cochrane Collaboration, and PsycINFO databases for published articles that evaluated the use of α2agonists (clonidine and guanfacine) for treating symptoms of PTSD in children and adolescents. The study protocol was registered in Prospero (ID: CRD42021273692) and followed the PRISMA guidelines. A total of 10 published articles about clonidine or guanfacine use in PTSD in children and adolescents were identified. Studies found clonidine effective in reducing PTSD symptoms; however, the effects were variable. Clonidine and guanfacine showed effectiveness in treating nightmares, hyperarousal, aggression, and sleep disturbances and reducing re-experiencing, avoidant, and hyperarousal symptom clusters. No randomized, double-blind, placebo-controlled trials were found during the literature search. α2 agonists' effectiveness in treating symptoms associated with PTSD in children and adolescents is preliminary. Future placebo-controlled trials are needed to assess the efficacy and safety of α2 agonists.

The Dual Cardiovascular Effect of Centrally Administered Clonidine: A Comparative Study between Pentobarbital- and Ketamine/Xylazine-Anesthetized Rats

The administration of the α2-adrenergic receptor agonist clonidine via intracerebroventricular route produces hypotension in pentobarbital-anesthetized rats and pressor responses in conscious normotensive rats. We explored the impact of different anesthetics on the central nervous system-dependent cardiovascular effects of clonidine. Normotensive male Wistar rats with guide cannulas previously implanted in the cerebroventricular system were anesthetized with pentobarbital or ketamine/xylazine and prepared for blood pressure measurement. The animals received intracerebroventricular injections of 10 μg clonidine or 0.6 μg dexmedetomidine, and the effects on the systolic, diastolic, mean arterial pressure, and heart rate were evaluated. The influence of 5 μg yohimbine, a selective α2-adrenergic receptor antagonist, was also assessed. The i.c.v. microinjection of clonidine decreased all three components of systemic arterial pressure and the heart rate of pentobarbital-anesthetized rats. On the other hand, clonidine increased the blood pressure and generated a less intense reduction in the heart rate of ketamine/xylazine-anesthetized rats. The pressor and bradycardic effects of clonidine in ketamine/xylazine-anesthetized animals were reproduced by dexmedetomidine, a more selective α2-adrenergic receptor agonist. Notably, the previous intracerebroventricular injection of yohimbine significantly inhibited the hypertensive effect of clonidine and dexmedetomidine. This study discloses that while normotensive rats anesthetized with pentobarbital show hypotensive responses, the stimulation of α2-adrenergic receptors increases the blood pressure in rats under ketamine/xylazine-induced anesthesia, reproducing the effects seen in conscious normotensive animals. Recognizing the mechanisms involved in these differences may allow us to understand better the final effects of clonidine and other α2-adrenergic receptor agonists in the central nervous system, contributing to the repurposing of these drugs.

Xylazine-Associated Wounds and Related Health Concerns Among People Who Use Drugs: Reports From Front-Line Health Workers in 7 US States.

Xylazine, an adrenergic alpha-2 agonist increasingly present in the US drug supply, is associated with severe skin ulcers and other harms. Expert knowledge from front-line harm reduction and healthcare professionals is an essential component of evidence-based practice. The purpose of this study is to describe the progression and treatment of xylazine-associated wounds, other xylazine-related health concerns, and the most urgent research priorities as reported by front-line harm reduction and healthcare professionals serving people who use drugs. A convenience sample of 17 healthcare and harm reduction professionals who serve people who use drugs in the US states of Maryland, Massachusetts, Michigan, Minnesota, North Carolina, Pennsylvania, and Texas participated in semi-structured interviews. Participants were asked about the appearance and progression of xylazine-associated wounds; preferred treatment strategies; other xylazine-related harms experienced by people who use drugs; and the most urgent priorities for xylazine-related research. Xylazine-associated wounds were broadly described as small lesions appearing mostly on extremities both at and away from injection sites, often within hours or days of exposure, that quickly developed into large, complex, chronic wounds. Reported risk of secondary infection was generally low but appeared more common among unhoused populations. Most participants preferred conservative treatment strategies that included regular wound care, enzymatic debridement, and hygiene. Xylazine-associated wounds and xylazine withdrawal reportedly act as significant barriers to care, including addiction treatment. Participants reported urgent need for scientific research and evidence-based guidance on the management of xylazine-associated wounds and withdrawal. High-quality scientific evidence on risk factors for xylazine-associated wounds and on their biologic mechanisms is needed. Such studies could inform new strategies for the prevention and treatment of these wounds. Efforts to improve the management of xylazine withdrawal and to reduce stigma by incorporating harm reduction professionals into healthcare settings may improve access to and retention in care.

Current Management Approaches and Future Directions for Kratom Use Disorder: A Comprehensive Review

This comprehensive literature review examines the current state of knowledge regarding the management of kratom use disorder (KUD). Kratom, a tropical plant containing psychoactive alkaloids, has seen rising popularity and concerns about dependence and public health impacts. The review covers the pharmacology of kratom, diagnostic criteria and assessment of KUD, and various treatment approaches. Psychosocial interventions like cognitive-behavioral therapy, motivational interviewing, contingency management, and peer support groups are discussed. Pharmacological treatments explored include opioid agonist therapy, alpha-2 agonists, antidepressants, and emerging potential therapies. Integrative and alternative approaches like acupuncture, mindfulness, and supplements are also examined. Challenges highlighted include limited research, societal stigma, and barriers to treatment access. Future directions emphasize developing novel pharmacotherapies, improving treatment availability through specialized programs and telehealth, longitudinal studies on comorbidities and harm reduction, and evidence-based policies balancing public health and therapeutic considerations. The review underscores the need for a multidisciplinary approach combining psychosocial, pharmacological, and alternative modalities supported by robust research to effectively address the growing public health challenge of KUD.

Comparison of Postoperative Analgesic Effect of Dexmedetomidine and Morphine as an Adjuvant to Intrathecal Bupivacaine in Infraumbilical Surgeries: A Randomised Clinical Trial

Introduction: Regional anaesthesia is the standard technique for lower limb infraumbilical procedures. To provide a better analgesic profile, adjuvants are added to local anaesthetics to enhance their action. Opioids have been used as an adjuvant for a long-time. With evolving pharmacology, various drugs satisfy the criteria of being an adjuvant. One such drug is Dexmedetomidine, a novel alpha-2 agonist. Aim: To compare the duration of analgesia of intrathecal Morphine and Dexmedetomidine as an adjuvant to bupivacaine in a subarachnoid block for lower limb infraumbilical surgeries. Materials and Methods: In this randomised clinical, doubleblinded study conducted in a multispecialty hospital over the period of June 2020 to February 2021, 70 patients were randomly divided into two groups: Group M received Morphine 125 µg, and Group D received dexmedetomidine 5 µg as an adjuvant to 15 mg of 0.5% hyperbaric bupivacaine. The primary outcome was to compare the duration of postoperative analgesia. The secondary results assessed the block characteristics, haemodynamic parameters, rescue analgesic consumption, sedation score, and side-effects like bradycardia, hypotension, nausea, vomiting, pruritus, and respiratory depression. Data was spread in an Excel sheet and descriptive analysis done. Normally distributed continuous variables were compared using a Student’s t-test, and discrete variables were compared using a Chi-square test. A p-value of <0.05 was considered significant. Results: Both groups were similar with respect to age, sex, body mass index, American Society of Anaesthesiologists grading, and duration of surgery. The duration of analgesia was 956.97±120.043 minutes in group M and 392.83±50.354 minutes in group D (p-value <0.001). The total consumption of paracetamol was 1984.71±499.111 mg in group M and 3543.86±406.17 mg in group D. The onset and regression were significantly faster in group D. There was significant hypotension and bradycardia up to the 40th minute and an increase in heart rate, respiratory rate, and mean arterial pressure between 5-7 hours in group D. The sedation score was more in group D for the initial two hours. Postoperatively, the incidence of nausea, vomiting, and pruritus was more in group M. Conclusion: It can be concluded that 125 µg of intrathecal morphine is a better adjuvant to spinal bupivacaine, providing excellent postoperative analgesia compared to 5 µg of intrathecal dexmedetomidine. However, dexmedetomidine had more incidence of hypotension, bradycardia, and sedation when compared to morphine intrathecally.

Semen collection and characterization of normative reproductive traits in free-ranging ocelots (Leopardus pardalis) and bobcats (Lynx rufus) in southern Texas

Decreased genetic diversity and possible inbreeding depression have recently been documented in the last wild ocelot (Leopardus pardalis) population in the United States. One consequence of inbreeding depression in felids may be reduced semen quality which can adversely affect reproductive potential. Detailed assessments of reproductive parameters in wild individuals and populations can be conducted using assisted reproductive technologies, such as semen collection and analysis. For most felid species, semen has traditionally been collected via electroejaculation (EEJ22Electroejaculation); however, an alternative method has been developed using alpha-2 agonist drugs to induce direct sperm release into the urethra, allowing collection by catheterization without requiring specialized equipment. The goal of this study was to characterize normative reproductive traits in free-ranging ocelots and co-occurring bobcats (Lynx rufus) in southern Texas and assess the effectiveness of urethral catheterization (UC33Urethral Catheterization) for semen recovery in both species. For semen collection, free-ranging cats were live-captured and anesthetized using intramuscular ketamine and medetomidine/dexmedetomidine (alpha-2 agonist) with UC conducted 20–40 minutes post-induction. In ocelots only, EEJ was subsequently performed if UC failed to recover a viable sample. Semen collection was attempted in 31 felids (n=9 ocelots; n=22 bobcats), with sperm recovery by UC in seven of nine ocelots (78 %) and 14 of 22 bobcats (66 %), and by EEJ in four of five ocelots (80 %). For ocelots, the percentage of primary morphologic abnormalities was higher (p<0.001) for UC (47.75 ± 6.7; mean ± SEM) compared to EEJ (9 ± 2.7) but percent normal morphology (MORPH) did not differ between UC and EEJ (p=0.218). In wild ocelots, seminal parameters appeared lower relative to historical values reported for zoo-managed ocelots, possibly related to reduced heterozygosity. In wild bobcats, seminal traits were inferior to those of ocelots but similar to reports for other zoo-managed Lynx species. In conclusion, detailed male reproductive traits have been characterized for the first time in wild, free-ranging ocelots and bobcats in southern Texas. Although UC allowed semen recovery for assessment of seminal traits in both species, EEJ produced higher quality samples in ocelots when applied after UC while also mitigating the adverse impact of urine contamination observed frequently with both collection methods.

Effect of antiglaucomatous eye drops on corneal endothelium

First choice therapy for reducing the intraocular pressure in context of glaucoma remains the applications of eye drops. Longterm exposure to topical therapy can clearly have an impact on the ocular surface, but as the medications penetrate through the cornea and are present in humour aqueous, also on all other layers of cornea, including corneal endothelium. In general, none of the medications from the standard pharmacological groups influences significantly an otherwise healthy corneal endothelium in an eye with glaucoma or ocular hypertension – be it in terms of central corneal thickness, be it in terms of endothelial cell density and morphology, be it for beta blockers, carbonic anhydrase inhibitors, pilocarpine, alpha2 agonists or prostaglandin analogues. The situation changes in diseased corneas, such as in Fuchs endothelial dystrophy, where topically applied carbonic anhydrase inhibitors can lead to increase in corneal thickness. Benzalkonium chloride has been proven toxic for corneal endothelial cells in vitro. However, in the daily practice and under real life circumstances, it is from the specific point of view on the corneal endothelium still not clear whether using non‐preserved topical glaucoma medications is an absolute imperative. One separate topic here is also a group of Rho‐kinase inhibiting topical medications. Apart from new mechanisms of action for reducing the intraocular pressure, this group of medications has also a direct influence on the corneal structures – from cornea verticillata on the epithelium corneal level, to mobilizing peripheral endothelial corneal cells as a possible therapeutic path for Fuchs endothelial dystrophy. One part of the lecture will address also these issues.

Oral Clonidine versus Ivabradine for Attenuating Stress Response in Functional Endoscopic Sinus Surgery: A Randomised Placebo-controlled Study

Introduction: Peri-anaesthetic haemodynamic alterations, such as hypertension and tachycardia, can cause increased bleeding during Functional Endoscopic Sinus Surgery (FESS), impairing the visibility of the surgical field and resulting in scarring, adhesions, and prolonged surgery time. Various strategies involving pharmacological techniques have been used to mitigate these unfavourable reflexes. Alpha-2 agonists, such as Clonidine, are currently being employed to attenuate sympathoadrenal stimulation caused by tracheal intubation and surgery. Ivabradine is a new drug that selectively lowers Heart Rate (HR) by inhibiting cardiac funny current channels. Aim: To compare the effects of premedication with oral Clonidine versus oral Ivabradine on attenuating haemodynamic stress response and improving the quality of the surgical field in FESS. Materials and Methods: The present randomised, placebocontrolled, double-blind study was conducted in the Department of Anaesthesiology and Intensive care at Rajendra Hospital, Government Medical College, Patiala, Punjab, India from April 2021 to December 2022 on 90 American Soceity of Anaesthelogists ( ASA) Physical status I and II adult patients (aged 18-60 years) undergoing FESS. Group A (n=30) received oral Ivabradine 5 mg, Group B (n=30) received oral Clonidine 0.2 mg, and Group C (n=30) received oral placebo tablets 2 hours before surgery. Haemodynamic parameters, including HR and Mean Arterial Pressure (MAP), quality of the intraoperative surgical field, postoperative sedation score, Visual Analogue Scale (VAS) score, time to analgesia request, blood loss, and adverse effects, were recorded. Descriptive statistics were used to calculate mean±Standard Deviation (SD) and percentage. Analysis of Variance (ANOVA), Tukey post-hoc test, Kruskal-wallis H test, and Pearson’s Chi-square were applied as appropriate. Results: The mean ages were 33.87±12.84, 35.03±12.93, and 40.9±14.46 years for Groups A, B, and C, respectively. The mean weights were 60.5±8.91, 57.83±5.66, and 57.9±5.42 kg, and the mean duration of surgery was 88.67±4.29, 88.8±4.29, and 88.03±3.93 minutes for Groups A, B, and C, respectively. There were no significant differences in terms of gender, ASA score, and type of surgery between the groups. Baseline HR and MAP were comparable among the groups. HR was significantly lower in both Groups A and B compared to Group C at all time intervals (p-value &lt;0.001). Both drugs significantly attenuated tachycardia and hypertension in response to cardiovascular stress induced by laryngoscopy, endotracheal intubation, and extubation. However, Group B showed significantly better control of MAP throughout the intraoperative period and at extubation. The average category scale score, estimated blood loss, and postoperative VAS Score were all significantly lower in Group B than in Group A. Postoperative sedation scores were significantly higher in Group B, and the time to first rescue analgesic was longest in Group B (p&lt;0.05). No significant side effects were observed. Conclusion: Both Clonidine and Ivabradine effectively attenuated the haemodynamic stress response. Clonidine provided better control of MAP, resulting in reduced bleeding, improved operative field visibility, and lower postoperative analgesic requirements compared to Ivabradine.

Interaction between Nuclear Receptor and Alpha-Adrenergic Agonist Subtypes in Metabolism and Systemic Hemodynamics of Spontaneously Hypertensive Rats.

Partial and full PPAR-γ agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study is aimed at examining the role of PPAR-γ, alpha-adrenoceptors, and adiponectin receptors in the modulation of vasopressor responses to angiotensin II (Ang II) and adrenergic agonists, after a subset treatment of partial and full PPAR-γ agonists, each individually, and also when coupled with adiponectin in SHRs. The antioxidant potential and metabolic indices for these animals were also determined. Group I (WKY) and group II (SHR) were designated as normotensive control and hypertensive control, respectively. Groups III (SHR) and IV (SHR) received irbesartan (30 mg/kg) and pioglitazone (10 mg/kg) orally for 28 days, and groups V (SHR), VI (SHR), and VII (SHR) were treated with adiponectin (2.5 μg/kg) intraperitoneally alone, in combination with irbesartan, and in combination with pioglitazone, respectively, from days 21 to 28 only. On day 29, sodium pentobarbitone (60 mg/kg) was used to anesthetize all test animals, and systemic hemodynamic and plasma adiponectin concentrations and in vitro and in vivo antioxidant potential were measured. As compared to the WKY control, the SHR control group's noninvasive blood pressure and basal mean arterial pressure were significantly greater, along with increased arterial stiffness, lower plasma nitric oxide, adiponectin concentration, and antioxidant enzyme levels (all P < 0.05). However, they were gradually normalized by single drug treatments in all groups, and to a greater extent in the SHR + Irb + Adp group (P < 0.05). In the acute study, the dose dependant mean arterial pressure responses to intravenously administered adrenergic agonists and angiotensin-II were significantly larger in SHRs as compared to WKY by 20-25%. Adiponectin alone and in combination significantly blunted vasopressor responses to these alpha-adrenergic agonists in the SHR + Pio + Adp group by 63%, whereas attenuated responses to ANG-II administration to 70% in SHR + Irb + Adp. In conclusion, the combined treatment of adiponectin with PPAR-agonists reduced the systemic vascular responses to adrenergic agonists and improved arterial stiffness. This an evidence of the interaction of adiponectin receptors, PPAR-γ, alpha-adrenoceptors, and ANG-II in the systemic vasculature of SHRs. A significant level of synergism has also been proved among full PPAR-γ agonists and adiponectin receptors.

Advancements in antiglaucoma medications: A comprehensive review

Abstract Glaucoma is a common ocular condition that has permanent effects and is a serious threat to everyone’s vision health. The course of the disease is still significantly influenced by increased intraocular pressure (IOP), also known as eye pressure. This emphasizes the significance of effective use of medications to treat this illness. Significant progress has been made in the development of glaucoma medications over time. There are several different ways to lower IOP using these drugs. This in-depth analysis examines the evolving field of pharmacological glaucoma treatments, covering a range of drug classes including beta-blockers, prostaglandin analogs, alpha agonists, carbonic anhydrase inhibitors, and rho kinase inhibitors. The mode of action, clinical effectiveness, and safety issues of each drug category are studied.

Change in Intraocular Pressure after Selective Laser Trabeculoplasty in North Indian Primary Open Angle Glaucoma Patients: A Prospective Analytical Study

Introduction: Glaucoma is the second leading cause of blindness in the world. The only known modifiable risk factor for the onset and progression of glaucoma is Intraocular Pressure (IOP). There are a limited number of studies documenting the IOP-lowering effect of Selective Laser Trabeculoplasty (SLT) in Primary Open Angle Glaucoma (POAG) patients, especially within the North Indian population. Understanding the effect of SLT on IOP reduction in this population is crucial for the proper management of glaucoma patients. Aim: To study the IOP-lowering effect of SLT in North Indian POAG patients (who had not achieved target IOP on two or more antiglaucoma drugs) after a period of six months. Materials and Methods: A hospital-based, single-arm, prepost type of prospective analytical study was conducted at Lady Hardinge Medical College and associated hospitals in New Delhi, India, from January 2021 to June 2022. POAG patients aged 18 years or older, who had not achieved the target IOP while on two or more Antiglaucoma Medications (AGM), were given the option of treatment with SLT. A total of 33 eyes were considered for the study as per sample size calculations. PreSLT, IOP was recorded along with other baseline parameters. The SLT procedure was carried out according to the standard protocol. IOP was recorded during follow-ups at one week, one month, three months, and six months. The Friedman test was used to compare IOP values, with a significance level set at 0.05. Spearman correlation was employed to explore the correlation between baseline IOP and the change in IOP at six months. Results: A total of 33 eyes were included in the study. Of these, 28 (84.8%) eyes had advanced glaucoma, while 5 (15.2%) eyes had moderate glaucoma according to International Classification of Diseases, Tenth Revision (ICD-10) staging. Patients were on two or more commonly used AGMs, including prostaglandin analogues, beta blockers, alpha agonists, topical carbonic anhydrase inhibitors, and rho kinase inhibitors. The mean number of topical AGMs that patients were using was 3.03. The number and type of AGMs for each patient remained consistent pre and post-SLT throughout the study period. The mean IOP (baseline) was 16.39±2.73 mmHg, and after six months, the mean IOP was 13.86±1.99 mmHg. The mean IOP reduced by 2.53 mm Hg (15.44%). There was a strong negative correlation between baseline IOP and the change in IOP at six months, which was statistically significant (rho=-0.78, p-value&lt;0.001). Conclusion: The present study indicates that SLT can be considered an adjunctive treatment for lowering IOP in North Indian POAG patients. A strong negative correlation was found between baseline IOP and IOP at six months post-SLT, suggesting that a higher reduction can be expected in patients with elevated baseline IOP.

Dexmedetomidine protects against sepsis-induced lung injury through autophagy and Smad2/3 signaling pathway.

Dexmedetomidine (Dex) is a potent α2-adrenergic receptor(α2-AR) agonist that has been shown to protect against sepsis-induced lung injury, however, the underlying mechanisms of this protection are not fully understood. Autophagy and the Smad2/3 signaling pathway play important roles in sepsis-induced lung injury, but the relationship between Dex and Smad2/3 is not clear. This study aimed to investigate the role of autophagy and the Smad2/3 signaling pathway in Dex-mediated treatment of sepsis-induced lung injury. Sepsis was performed using cecal ligation and puncture (CLP) in C57BL/6J mice. Mice were randomly assigned to four groups (n=6 per group): sham, CLP, CLP-Dex, and CLP-Dex-YOH, Yohimbine hydrochloride (YOH) is an α2-AR blocker. The cecum was carefully separated to avoid blood vessel damage and was identified and punctured twice with an 18-gauge needle. The pathological changes, inflammatory factor levels, oxidative stress, autophagy, Smad2/3 signaling pathway-related protein levels in lung tissues, and the activity of superoxide dismutase (SOD) and malonaldehyde (MDA) in the serum were measured. CLP-induced lung injury was reflected by increased levels of inflammatory cytokines, apoptosis, and oxidative stress, along with an increase in the expression of autophagy and Smad2/3 signaling pathway-related proteins. Dex could reverse these changes and confer a protective effect on the lung during sepsis. However, the administration of YOH significantly reduced the positive effects of Dex in mice with sepsis. Dex exerts its beneficial effects against sepsis-induced lung injury through the regulation of autophagy and the Smad2/3 signaling pathway.

Management of severe delirium with dexmedetomidine in a palliative care patient—a case report

Dexmedetomidine is used as an adjunct to anaesthesia or as a stand-alone agent for conscious sedation. It is a potent α2-adrenergic receptor agonist, with a fast onset of action and peak effects in 30 minutes to 1 hour after application, depending on the route of administration. It is metabolized in the liver and excreted in urine as a glucuronide. It potentiates analgesia and is effective in opioid sparing. Clinical trials show its efficacy in the treatment of Intensive Care Unit (ICU) delirium with an effect comparable to antipsychotics and benzodiazepines. It has also been used at the Eye Clinic of the University Medical Centre Ljubljana to sedate patients undergoing intraocular surgery. It proved to be an excellent alternative to other sedatives and analgesics, such as midazolam and remifentanil. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine and to investigate its potential use in the palliative care population, particularly in the management of delirium. This area of application is still largely unexplored and opens up a new field of application. At the Institute of Oncology (IO) Ljubljana, we have used it with success in several palliative patients with delirium, when all other modalities were failing. At the IO Ljubljana, anaesthesiologists are involved in the palliative management of patients, especially in pain management, but also in sedation and delirium treatment. Given its favourable pharmacokinetic and pharmacodynamic effects, dexmedetomidine could be used more frequently and perhaps alternative and less complex routes of administration, such as intranasal administration, could be explored. In this paper, we present a case of a palliative care patient in whom dexmedetomidine was used successfully.

Comparison of nebulized ropivacaine (0.75%) with nebulized dexmedetomidine on the hemodynamic response on intubation in patients undergoing surgery under general anesthesia: A comparative randomized double-blind placebo-controlled study.

Laryngoscopy and tracheal intubation lead to sympathetic stimulation resulting in hemodynamic fluctuations. We compared local anesthetic ropivacaine 0.75% with alpha agonist dexmedetomidine through ultrasonic nebulization for direct local action of the drug in the airway. In our randomized study, 180 patients were prospectively assigned to three groups of 60 each: group R (0.75%), group D (1 microgram/kg), and group C (control). The primary objective was to determine whether nebulized ropivacaine or nebulized dexmedetomidine can cause a reduction in stress response to laryngoscopy and intubation. The secondary objectives were to compare the hemodynamic parameters at extubation, cough response at extubation, and postoperative sore throat. A total of 165 patients were analyzed. Demographically, all the groups were similar. Group R and group D were found to significantly attenuate the heart rate (HR) at intubation and extubation when compared to group C (P < 0.05). A significant reduction in mean arterial pressure (MAP) was seen (P < 0.05; group D: 90 ± 18.4 mmHg, group C: 99.5 ± 15.9 mmHg, group R: 92.4 ± 16.1 mmHg). There was a significant reduction in cough response in both groups in comparison with group C at 0 minutes (P value; group C vs group D: <.0001; group C vs group R:.01) and 5 minutes (P value; group C vs group D: <.0001; group C vs group R: <.0001). Preinduction topical use of ropivacaine or dexmedetomidine, through the nebulization route, effectively attenuated the pressor responses when compared to placebo.

Physicians' beliefs and perceived importance of traumatic brain injury-associated agitation in critically ill patients: a survey of Canadian intensivists.

Agitation is a common behavioural problem following traumatic brain injury (TBI). Intensive care unit (ICU) physicians' perspectives regarding TBI-associated agitation are unknown. Our objective was to describe physicians' beliefs and perceived importance of TBI-associated agitation in critically ill patients. Following current standard guidance, we built an electronic, self-administrated, 42-item survey, pretested it for reliability and validity, and distributed it to 219 physicians working in 18 ICU level-1 trauma centres in Canada. We report the results using descriptive statistics. The overall response rate was 93/219 (42%), and 76/93 (82%) respondents completed the full survey. Most respondents were men with ten or more years of experience. Respondents believed that pre-existing dementia (90%) and regular recreational drug use (86%) are risk factors for agitation. Concerning management, 91% believed that the use of physical restraints could worsen agitation, 90% believed that having family at the bedside reduces agitation, and 72% believed that alpha-2 adrenergic agonists are efficacious for managing TBI agitation. Variability was observed in beliefs on epidemiology, sex, gender, age, socioeconomic status, and other pharmacologic options. Respondents considered TBI agitation frequent enough to justify the implementation of management protocols (87%), perceived the current level of clinical evidence on TBI agitation management to be insufficient (84%), and expressed concerns about acute and long-term detrimental outcomes and burden to patients, health care professionals, and relatives (85%). Traumatic brain injury-associated agitation in critically ill patients was perceived as an important issue for most ICU physicians. Physicians agreed on multiple approaches to manage TBI-associated agitation although agreement on epidemiology and risk factors was variable.

Cold nociception as a measure of hyperalgesia during spontaneous heroin withdrawal in mice

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests—thermal gradient ring (5–30 °C, 5–50 °C, 15–40 °C, and 25–50 °C), dynamic cold plate (4 °C to −1 °C at −1 °C/min, −1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)—to measure hyperalgesia in a mouse protocol of heroin dependence. On the thermal gradient ring, mice in the heroin withdrawal group preferred warmer temperatures, and the results depended on the ring's temperature range. On the dynamic cold plate, heroin withdrawal increased the number of nociceptive responses, with a temperature ramp from 4 °C to −1 °C yielding the largest response. On the stable cold plate, heroin withdrawal increased the number of nociceptive responses, and a plate temperature of 2 °C yielded the most significant increase in responses. Among the three tests, the stable cold plate elicited the most robust change in behavior between heroin-dependent and nondependent mice and had the highest throughput. To pharmacologically characterize the stable cold plate test, we used μ-opioid and non-opioid receptor-targeting drugs that have been previously shown to reverse OWIH in mechanical and heat nociception assays. The full μ-opioid receptor agonist methadone and μ-opioid receptor partial agonist buprenorphine decreased OWIH, whereas the preferential μ-opioid receptor antagonist naltrexone increased OWIH. Two N-methyl-d-aspartate receptor antagonists (ketamine, MK-801), a corticotropin-releasing factor 1 receptor antagonist (R121919), a β2-adrenergic receptor antagonist (butoxamine), an α2-adrenergic receptor agonist (lofexidine), and a 5-hydroxytryptamine-3 receptor antagonist (ondansetron) had no effect on OWIH. These data demonstrate that the stable cold plate at 2 °C yields a robust, reliable, and concise measure of OWIH that is sensitive to opioid agonists.