Alpha-adrenergic Agonist Research Articles

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.

Intranasal alpha-adrenergic receptor agonists and corticosteroids as medical treatments for nasal congestion

Nasal congestion has been a longstanding issue which exerts burdens on both individual patients and society as a whole. It arises from various underlying illnesses like nasal polyposis, rhinosinusitis, allergic rhinitis and rhinitis medicamentosa, but the fundamental mechanism of induced nasal congestion is nasal mucosas swelling as a result of inflammation in all of these cases. Among all the therapies currently available, intranasal sprays of alpha-adrenergic receptor agonists or corticosteroids appeared to be prominent options. After reviewing research on treatments extensively, limited studies focused on the comparison of -adrenergic agonists and corticosteroids. This research explores the mechanisms, efficacy, and safety of these two medical approaches. Intranasal alpha-adrenergic receptor agonist sprays target the smooth muscles for vasoconstriction, acting rapidly to give way to airflow. They are effective as a treatment for short-term nasal congestion, otherwise, continued use may lead to rhinitis medicamentosa. Corticosteroid sprays, on the other hand, aim to reduce the severity of nasal inflammation via suppression of pro-inflammatory molecules. They are a promising treatment barely with concerns about the occurrence of side effects, authenticated by their excellent pharmaceutical performance over years.

Analgesia and sedation strategies in neonates undergoing whole-body therapeutic hypothermia: A scoping review

Background Therapeutic hypothermia (TH) is a widely practiced neuroprotective strategy for neonates with hypoxic-ischemic encephalopathy. Induced hypothermia is associated with shivering, cold pain, agitation, and distress. Objective This scoping review determines the breadth of research undertaken for pain and stress management in neonates undergoing hypothermia therapy, the pharmacokinetics of analgesic and sedative medications during hypothermia and the effect of such medication on short- and long-term neurological outcomes. Methods We searched the following online databases namely, (i) MEDLINE, (ii) Web of Science, (iii) Cochrane Library, (iv) Scopus, (v) CINAHL, and (vi) EMBASE to identify published original articles between January 2005 and December 2022. We included only English full-text articles on neonates treated with TH and reported the sedation/analgesia strategy used. We excluded articles that reported TH on transport or extracorporeal membrane oxygenation, did not report the intervention strategies for sedation/analgesia, and reported hypoxic-ischemic encephalopathy in which hypothermia was not applied. Results The eligible publications (n = 97) included cohort studies (n = 72), non-randomized experimental studies (n = 2), pharmacokinetic studies (n = 4), dose escalation feasibility trial (n = 1), cross-sectional surveys (n = 5), and randomized control trials (n = 13). Neonatal Pain, Agitation, and Sedation Scale (NPASS) is the most frequently used pain assessment tool in this cohort. The most frequently used pharmacological agents are opioids (Morphine, Fentanyl), benzodiazepine (Midazolam) and Alpha2 agonists (Dexmedetomidine). The proportion of neonates receiving routine sedation-analgesia during TH is center-specific and varies from 40–100% worldwide. TH alters most drugs’ metabolic rate and clearance, except for Midazolam. Dexmedetomidine has additional benefits of thermal tolerance, neuroprotection, faster recovery, and less likelihood of seizures. There is a wide inter-individual variability in serum drug levels due to the impact of temperature, end-organ dysfunction, postnatal age, and body weight on drug metabolism. Conclusions No multidimensional pain scale has been tested for reliability and construct validity in hypothermic encephalopathic neonates. There is an increasing trend towards using routine sedation/analgesia during TH worldwide. Wide variability in the type of medication used, administration (bolus versus infusion), and dose ranges used emphasizes the urgent need for standardized practice recommendations and guidelines. There is insufficient data on the long-term neurological outcomes of exposure to these medications, adjusted for underlying brain injury and severity of encephalopathy. Future studies will need to develop framework tools to enable precise control of sedation/analgesia drug exposure customized to individual patient needs.

Dexmedetomidine Versus Midazolam for End-of-Life Sedation and Agitation: Protocol for a Randomized Controlled Trial (The DREAMS Trial).

Sedation at the end of life is used to relieve distressing symptoms including agitation and delirium. Standard care may include infused benzodiazepines or antipsychotics. These agents often result in deep sedation with loss of interaction with loved ones, which may be distressing. The DREAMS (Dexmedetomidine for the Reduction of End-of-life Agitation and for optiMised Sedation) trial aimed to compare the sedative and antidelirium effects of the alpha-2 agonist dexmedetomidine, a novel palliative care sedative, compared with midazolam, a benzodiazepine when administered by subcutaneous infusion at the end of life, with doses of both agents targeting lighter, or potentially interactive sedation. Participants were recruited from adult inpatients admitted for end-of-life care under a palliative care team in regional New South Wales, Australia. Inclusion criteria included patients older than 18 years, with a preference for lighter sedation at the end of life. Exclusion criteria included severe cardiac dysfunction (contraindication to dexmedetomidine). Participants consented and were placed on a treatment-pending list. Upon experiencing terminal deterioration, patients were randomized to either arm 1 (dexmedetomidine) or arm 2 (midazolam) as their treatment arm. These treatments were administered by continuous subcutaneous infusion. The level of consciousness and agitation of the patients were measured by the Richmond Agitation-Sedation Scale-Palliative version and the Memorial Delirium Assessment Score. Richmond Agitation-Sedation Scale-Palliative version assessments were performed by both nursing and medical staff, while Memorial Delirium Assessment Score assessments were carried out by medical staff only. Families and patients were asked to complete, as able, a patient comfort assessment form, to gauge perceptions of distress. Data were collected and matched with the breakthrough medication doses administered, along with qualitative comments in the medical record. In addition, the study tracked symptoms and patient functional status that were recorded as part of the Palliative Care Outcomes Collaborative, a national tracking project for monitoring symptom outcomes in palliative care. The DREAMS trial was funded in May 2020, approved by the ethics committee in November 2020, and started recruiting participants in May 2021. Data collection commenced in May 2021 and is anticipated to continue until December 2024. Publication of results is anticipated from 2024 to 2026. The evidence base for sedative dosing in palliative care for distress and agitation is not robust, with standard care based primarily on clinical experience and not robust scientific evidence. This study is important because it will compare a standard and a novel sedative used in end-of-life treatment. By assessing the potential efficacy and benefits of both, it seeks to optimize the quality of dying by providing targeted sedation that can improve the communication between dying patients and their loved ones. Australia New Zealand Clinical Trials Register ACTRN12621000052831; https://uat.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380889. DERR1-10.2196/55129.

A Comparative Clinical Study to Evaluate the Antinociceptive Efficacy of Intravenous versus Intraperitoneal Dexmedetomidine with Ropivacaine in Patients Undergoing Laparoscopic Cholecystectomy

Background and Aims: Intraperitoneal (IP) local anesthetic administration has become a routine in laparoscopic surgeries. An additive to local anesthetic like alpha-2 agonist such as dexmedetomidine may enhance the efficacy of local anesthetic. Our primary objective was to compare the duration of analgesia and our secondary objectives were to compare the total amount of rescue analgesics in 24 h, hemodynamic changes, and adverse effects after the use of dexmedetomidine intraperitoneally versus intravenously in addition to 0.25% ropivacaine instillation intraperitoneally. Materials and Methods: Eighty patients aged 18–60 years of American Society of Anesthesiologists physical status I and II, undergoing laparoscopic cholecystectomy, were randomly allocated into two groups – Group V (n = 40) received 100 ml normal saline (NS) with 0.7 µg/kg dexmedetomidine over 15 min followed by 30 ml 0.25% ropivacaine intraperitoneally and Group P (n = 40) received 100 ml NS over 15 min followed by 30 ml 0.25% ropivacaine with 0.7 µg/kg dexmedetomidine intraperitoneally soon after removal of gallbladder at the end of surgery. Results: The duration of analgesia was significantly longer in Group V (246.45 ± 27.00 min) as compared to Group P (112.83 ± 11.61 min) (P &lt; 0.0001). The total amount of rescue analgesic consumption in 24 h was significantly reduced in Group V (185.00 ± 73.55 mg) as compared to Group P (225.00 ± 77.63 mg) (P &lt; 0.05). As compared to Group P, patients in Group V had a statistically significant Ramsay Sedation Score. The hemodynamic parameters and side effect profile were comparable in both the groups. Conclusion: IV dexmedetomidine 0.7μg/kg is more efficacious as compared to IP dexmedetomidine along with IP ropivacaine 0.25% in laparoscopic cholecystectomy in terms of prolonged duration of analgesia and decreased requirement of rescue analgesia in 24 h.

Features of α2-Adrenergic Regulation of Isolated Rat Heart after Hypokinesia.

We studied the effect of the α2-adrenergic receptor agonist clonidine hydrochloride (10-9-10-6 M) on the isolated heart of adult rats after 30-day restriction of motor activity. In hypokinetic rats, in comparison with control animals, clonidine caused a positive inotropic effect; the dynamics of coronary flow was changed after stimulation of α2-adrenergic receptors by clonidine in the minimum and maximum concentrations. Moreover, clonidine in concentrations of 10-8 and 10-7 M reduced coronary flow both in the control group and against the background of hypokinesia. Clonidine (10-8-10-6 M) had a negative chronotropic effect in control and hypokinetic animals, while the dynamics of HR was multidirectional, i.e. either an increase or decrease in the effects was observed depending of the agonist concentration. Overall, the data obtained indicate the participation of α2-adrenergic receptors in adaptive processes after motor activity limitation.

Dexmedetomidine at Home for Intractable Dystonia and Insomnia in Children With Special Needs: A Case Series.

We know that syndromic conditions and severe chronic diseases can be associated with symptoms that may interfere with sleep, significantly impacting the life quality of children and caregivers. Drugs commonly used in treating insomnia, such as melatonin, benzodiazepines, niaprazine, and antihistamines, are often either ineffective or associated with adverse effects, requiring new therapeutic perspectives. Dexmedetomidine is a selective alpha-2 agonist with hypnotic and anxiolytic effects, which, by stimulating alpha-2 adrenergic receptors in the locus coeruleus, induces sleep comparable to stages 2-3 of the non-REM phase without substantially affecting the respiratory drive during sedation. Its use has already been extensively described in pediatric intensive care or procedural sedation literature. In 2018, the Italian Medicines Agency (Agenzia Italiana Del Farmaco AIFA) authorized the off-label use of dexmedetomidine outside of intensive care in Children undergoing palliative treatment to control distressing symptoms related to pathology and refractory sleep disorders, and the literature reported cases of children who received dexmedetomidine at home. Our study aims to describe the home use of dexmedetomidine in children with insomnia or intractable dystonic states. We conducted a retrospective analysis through a questionnaire addressed to 12 Italian pediatric palliative care centers regarding the home use of dexmedetomidine in sleep disorders and intractable dystonic states. We collected a case series of 9 children treated with dexmedetomidine at home, 8 via intranasal and 1 via intravenous route. All children received the first drug administration in the hospital or hospice during a dedicated admission, under close monitoring of vital signs parameters for 72 hours (3 days, range 2-7 days). After discharge, the potential side effects of the drug were explained to the patient's families, and, once informed consent was obtained, the home administration of dexmedetomidine continued, with follow-up by the palliative care team. At home, dexmedetomidine was administered for 3000 days (minimum 1 month, maximum 36 months). The first patient was treated for 1095 days, from 2019 to 2021 (discontinued due to underlying condition-related death). All patients observed a persistent benefit from the treatment on symptoms, and none of them discontinued dexmedetomidine administration due to drug-related adverse effects or perceived lack of therapeutic efficacy. Therefore, its use at home may represent a promising therapeutic approach for intractable sleep disorders or dystonic states in pediatric palliative care children. Further studies are needed to confirm our results.

Unveiling the Therapeutic Potential of Myocardium Targeted Asiatic Acid: A PPAR Alpha Agonist for Pathological Cardiac Hypertrophy.

Unveiling the Therapeutic Potential of Myocardium Targeted Asiatic Acid: A PPAR Alpha Agonist for Pathological Cardiac Hypertrophy.

Sıçanlarda sirkadiyen ritim bozuklukları ile ilgili çeşitli koşulların plazma ve eritrosit lipidleri üzerindeki etkileri: peroksizomal bir bakış açısı

Purpose: Lipidomics studies of sleep restriction, which is known to be associated with circadian perturbations, revealed alterations in some plasma phospholipid levels including plasmalogens which are partly synthesized in liver peroxisomes. To this end it was aimed to investigate effects of various conditions known to cause circadian rhythm disturbances on various peroxisomal parameters and to compare those effects with that of fenofibrate, a peroxisome proliferator-activated receptor alpha agonist.&#x0D; Materials and Methods: Plasmalogens and some fatty acids in erythrocyte lysates were analyzed by GC. Peroxisomal metabolites including very long chain fatty acids as well as phytanic and pristanic acids in plasma were measured by GC-MS. Immunohistological analyses by catalase antibodies were conducted on liver sections. &#x0D; Results: All the conditions tested exhibited increased catalase immunoreactivity in liver sections compared to that of controls. Both calorie restriction, time-restricted feeding, as well as fenofibrate treatment exhibited lower C18:0 plasmalogen contents of erythrocyte lysates. As plasmalogens are known to be synthesized by peroxisomes, the present results suggest that the peroxisomal lipid content in membranes might be affected by conditions co-occuring with circadian perturbations.&#x0D; Conclusion: Shared effects of conditions associated with circadian rhythm disturbances and peroxisomal induction by fenofibrate on erythrocyte membrane lipids might indicate a link between them.