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BACKGROUND: A subset of patients with postural tachycardia syndrome (POTS) are thought to have a primary hyperadrenergic cause. We assessed clinical biomarkers to identify those that would benefit from sympatholytic therapy. METHODS: We measured sympathetic function (supine muscle sympathetic nerve activity, upright plasma norepinephrine, and blood pressure responses to the Valsalva maneuver) in 28 patients with POTS (phenotyping cohort) to identify clinical biomarkers that are associated with responsiveness to the central sympatholytic guanfacine in a separate uncontrolled treatment cohort of 38 patients that had received guanfacine clinically for suspected hyperadrenergic POTS (HyperPOTS). RESULTS: In the phenotyping cohort, an increase in diastolic blood pressure (DBP) >17 mm Hg during late phase 2 of the Valsalva maneuver identified patients with the highest quartile of resting muscle sympathetic nerve activity (HyperPOTS) with 71% sensitivity and 85% specificity. In the treatment cohort, patients with HyperPOTS, identified by this clinical biomarker, more often reported clinical improvement (85% versus 44% in nonhyperadrenergic; P=0.016), had better orthostatic tolerance (∆Orthostatic Hypotension Daily Activities Scale: -1.9±0.9 versus 0.1±0.5; P=0.032), and reported less chronic fatigue (∆PROMIS Fatigue Short Form 7a: -12.9±2.7 versus -2.2±2.2; P=0.005) in response to guanfacine. CONCLUSIONS: These results are consistent with the concept that POTS is caused by a central sympathetic activation in a subset of patients, which can be identified clinically by an exaggerated DBP increase during phase 2 of the Valsalva maneuver and improved by central sympatholytic therapy. These results support further clinical trials to determine the safety and efficacy of guanfacine in patients with POTS enriched for the presence of this clinical biomarker.

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Stellate ganglion block (SGB) is a procedure involving the injection of a local anesthetic surrounding the stellate ganglion to inhibit sympathetic outflow. The objective of this review was to summarize existing evidence on the use of SGB in adults with psychiatric disorders. A systematic search identified 17 published studies and 4 registered clinical trials. Eighty-eight percent of published studies, including 2 randomized controlled trials (RCTs), used SGB for posttraumatic stress disorder (PTSD), although its use for schizophrenia spectrum disorders was also explored. Administration of 1 to 2 SGBs using right-sided laterality with 0.5% ropivacaine was most common. Preliminary evidence from clinical trials and case studies supports the feasibility of SGB for treating psychiatric disorders involving dysregulation of the sympathetic nervous system, although effectiveness evidence from RCTs is mixed. One RCT concluded that improvement in PTSD symptoms was significant, while the other concluded that it was nonsignificant. Improvements were noted within 5 minutes of SGB and lasted 1 month or longer. Registered clinical trials are exploring the use of SGB in new psychiatric disorders, including major depressive disorder and borderline personality disorder. More studies with larger sample sizes and alternate protocols are needed to further explore therapeutic potential of SGB for psychiatric disorders.

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Moxonidine is an oral antihypertensive drug from the group of 2nd generation sympatholytics. In patients with mild to moderate hypertension, moxonidine lowers blood pressure (BP) as effectively as most first-line antihypertensives when used as monotherapy - if appropriate, and is also an effective adjunctive therapy in combination with other antihypertensives. It improves metabolic profile in patients with hypertension and diabetes mellitus or impaired glucose tolerance, is very well tolerated, has a low potential for drug interactions and is administered in a single daily dose. Thus, moxonidine is a good choice especially in the treatment of patients with more severe forms of hypertension, especially as adjunctive therapy in patients with metabolic syndrome or with mental stress.

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BACKGROUND: Sympathetic activity and insulin resistance have recently been linked with chronic tendon and musculoskeletal pain. Polycystic ovarian syndrome is linked with insulin resistance and increased sympathetic drive and was therefore an appropriate condition to study the effects of modulating sympathetic activity on Achilles tendon and musculoskeletal symptoms. METHODS: A secondary analysis of a double-blinded, randomised controlled trial on women with polycystic ovarian syndrome was conducted. Participants received 12 weeks of moxonidine (n = 14) or placebo (n = 18). Musculoskeletal symptom and Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaires were distributed, and ultrasound tissue characterisation quantified tendon structure at 0 and 12 weeks. 2-way ANOVA was used for multiple comparisons. RESULTS: There was no difference in mean change in musculoskeletal symptoms (- 0.6 ± 1.7 vs - 0.4 ± 1.8, p = 0.69) or VISA-A (moxonidine - 0.2 ± 8.8 vs placebo + 4.2 ± 14.6, p = 0.24) attributable to the intervention. There was no difference in any measures of Achilles structure. Moxonidine did not reduce sympathetic drive when compared to placebo. CONCLUSIONS: This was the first study to investigate the effects of blocking sympathetic drive on musculoskeletal and Achilles tendon symptoms in a metabolically diverse population. While the study was limited by small sample size and lack of sympathetic modulation, moxonidine did not change tendon pain/structure or musculoskeletal symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01504321 . Registered 5 January 2012.

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PURPOSE: To review the efficacy and safety of transitioning from dexmedetomidine to clonidine to facilitate weaning of patients from sedation with dexmedetomidine. There is a paucity of data describing dexmedetomidine withdrawal syndrome (DWS) as well as clonidine's place in therapy for DWS. This review will describe and analyze current literature to provide clinical recommendations. SUMMARY: A MEDLINE literature search was performed to identify original research articles describing DWS and/or transitioning from dexmedetomidine to clonidine for the purpose of weaning patients from sedation with dexmedetomidine. Four case reports describing DWS, 3 case reports describing the use of clonidine to treat DWS, and 3 observational studies describing the use of clonidine to facilitate dexmedetomidine weaning were identified. The incidence of and risk factors for DWS are unknown; factors including patient age and dexmedetomidine infusion rate, loading dose, and discontinuation strategy have inconsistent associations with DWS. All cases of DWS have been associated with infusion durations greater than 72 hours. While there are limited data describing clonidine use for the treatment of dexmedetomidine withdrawal, clonidine appears to be beneficial for dexmedetomidine weaning and its use for that purpose has been well described. Clonidine dosages that have been assessed for discontinuing dexmedetomidine vary from 0.1 to 0.3 mg orally or enterally every 6 to 8 hours; one study assessed use of transdermal clonidine (100 µg/24 h patch). Patients with extensive cardiac comorbidities may be more susceptible to adverse effects of clonidine, which may limit the drug's use for DWS intervention. CONCLUSION: Despite limited supportive data, clonidine provides a promising option for sedation management in adult ICU patients, with successful transitions from dexmedetomidine reported within 24 hours after clonidine initiation.

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Acute kidney injury (AKI) is frequently accompanied by activation of the sympathetic nervous system (SNS). This may result from pre-exisiting chronic diseases associated with sympathetic activation prior to AKI or it may be induced by stressors that ultimately lead to AKI such as endotoxins and arterial hypotension in circulatory shock. Conversely, sympathetic activation may also result from acute renal injury. Focusing on studies in experimental renal ischaemia and reperfusion (IR), this review summarizes the current knowledge on how the SNS is activated in IR-induced AKI and on the consequences of sympathetic activation for the development of acute renal damage. Experimental studies show beneficial effects of sympathoinhibitory interventions on renal structure and function in response to IR. However, few clinical trials obtained in scenarios that correspond to experimental IR, namely major elective surgery, showed that peri-operative treatment with centrally acting sympatholytics reduced the incidence of AKI. Apparently, discrepant findings on how sympathetic activation influences renal responses to acute IR-induced injury are discussed and future areas of research in this field are identified.

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Dexmedetomidine is a potent, highly selective α-2 adrenoceptor agonist, with sedative, analgesic, anxiolytic, sympatholytic, and opioid-sparing properties. Dexmedetomidine induces a unique sedative response, which shows an easy transition from sleep to wakefulness, thus allowing a patient to be cooperative and communicative when stimulated. Dexmedetomidine may produce less delirium than other sedatives or even prevent delirium. The analgesic effect of dexmedetomidine is not strong; however, it can be administered as a useful analgesic adjuvant. As an anesthetic adjuvant, dexmedetomidine decreases the need for opioids, inhalational anesthetics, and intravenous anesthetics. The sympatholytic effect of dexmedetomidine may provide stable hemodynamics during the perioperative period. Dexmedetomidine-induced cooperative sedation with minimal respiratory depression provides safe and acceptable conditions during neurosurgical procedures in awake patients and awake fiberoptic intubation. Despite the lack of pediatric labelling, dexmedetomidine has been widely studied for pediatric use in various applications. Most adverse events associated with dexmedetomidine occur during or shortly after a loading infusion. There are some case reports of dexmedetomidine-related cardiac arrest following severe bradycardia. Some extended applications of dexmedetomidine discussed in this review are promising, but still limited, and further research is required. The pharmacological properties and possible adverse effects of dexmedetomidine should be well understood by the anesthesiologist prior to use. Moreover, it is necessary to select patients carefully and to determine the appropriate dosage of dexmedetomidine to ensure patient safety.

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Dexmedetomidine is a potent, highly selective α-2 adrenoceptor agonist, with sedative, analgesic, anxiolytic, sympatholytic, and opioid-sparing properties. Dexmedetomidine induces a unique sedative response, which shows an easy transition from sleep to wakefulness, thus allowing a patient to be cooperative and communicative when stimulated. Dexmedetomidine may produce less delirium than other sedatives or even prevent delirium. The analgesic effect of dexmedetomidine is not strong; however, it can be administered as a useful analgesic adjuvant. As an anesthetic adjuvant, dexmedetomidine decreases the need for opioids, inhalational anesthetics, and intravenous anesthetics. The sympatholytic effect of dexmedetomidine may provide stable hemodynamics during the perioperative period. Dexmedetomidine-induced cooperative sedation with minimal respiratory depression provides safe and acceptable conditions during neurosurgical procedures in awake patients and awake fiberoptic intubation. Despite the lack of pediatric labelling, dexmedetomidine has been widely studied for pediatric use in various applications. Most adverse events associated with dexmedetomidine occur during or shortly after a loading infusion. There are some case reports of dexmedetomidine-related cardiac arrest following severe bradycardia. Some extended applications of dexmedetomidine discussed in this review are promising, but still limited, and further research is required. The pharmacological properties and possible adverse effects of dexmedetomidine should be well understood by the anesthesiologist prior to use. Moreover, it is necessary to select patients carefully and to determine the appropriate dosage of dexmedetomidine to ensure patient safety.

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INTRODUCTION: Effective control of sympathetic response to pneumoperitoneum is vital to avoid morbidity in patients undergoing laparoscopic surgeries. This control must be achieved without any side effects of the drugs being used as well as ensuring a raid recovery from anaesthesia in order to maximise operation theatre utility. AIM: To study the effectiveness of dexmedetomidine in attenuating the haemodynamic response to pneumoperitoneum during laparoscopic cholecystectomy (using only the maintenance dose) with that of propofol and compare time to extubation, haemodynamics on extubation, sedation score after extubation and any incidence of side effects between the two study drug. MATERIALS AND METHODS: Sixty American Society of Anaesthesiologist (ASA) I and II patients undergoing laparoscopic cholecystectomy between age of 20-60 years were randomly divided into two groups of 30 patients each: Group D to receive dexmedetomidine in dose of 0.2-0.7 µg/kg/hr titrated as per clinical response and Group P to receive propofol in dose of 25-75 µg/kg/min (1.5-4.5 mg/kg/hr) titrated as per clinical response after standard anaesthetic induction. Data recording was done for changes in haemodynamic parameters, time to extubation and post extubation sedation score. Statistical analysis was done using student's-test and Chi-square test with p-value of< 0.05 was considered significant. RESULTS: Attenuation of haemodynamic parameters by dexmedetomidine during the intraoperative period even without the loading dose was comparable to that by propofol (p-value >0.05). Time to extubation was similar in both the groups (p-value >0.05). Haemodynamics on extubation was better controlled in dexmedetomidine group (p-value <0.05) while the sedation score was better in propofol group (p-value <0.05). Mean dose of dexmedetomidine and propofol used were 0.504±0.09 µg/kg/hr and 3.19±0.7 mg/kg/hr respectively. CONCLUSION: Dexmedetomidine in a dose of 0.2-0.7 µg/kg/hr provides a stable haemodynamics without any side effects in patients undergoing laparoscopic cholecystectomy.

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OBJECTIVE: To provide a systematic review of the current role of clonidine in neonatal abstinence syndrome (NAS). DATA SOURCES: A MEDLINE literature search inclusive of the dates 1946 to November 2015 was performed using the search terms clonidine and abstinence syndromes, neonatal. Excerpta Medica was searched from 1980 to November 2015 using the search terms clonidine and newborn. Additionally, Web of Science was searched using the terms clonidine and neon* inclusive of 1945 to November 2015. STUDY SELECTION AND DATA EXTRACTION: We utilized the PRISMA guidelines to select English language, human primary literature, review articles, and supporting data assessing the efficacy of clonidine in the treatment of NAS. DATA SYNTHESIS: Three clinical trials and 5 observational studies demonstrated evidence of clonidine's effectiveness in NAS. Clonidine's therapeutic use as monotherapy and in combination with other agents was shown to reduce the time needed for pharmacotherapy treatment. Adverse reactions associated with clonidine in neonates, when reported, are mild. CONCLUSION: The American Academy of Pediatrics recommends opioids as first-line agents in the treatment of NAS when pharmacological treatment is indicated. Limited data suggest that clonidine, in combination with other agents or as monotherapy, may be as effective, with minimal adverse effects and reduced treatment time. Prospective clinical trials are necessary to clarify the ultimate role of clonidine in NAS and establish long-term safety.

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Direct vasodilators and sympatholytic agents were some of the first antihypertensive medications discovered and utilized in the past century. However, side effect profiles and the advent of newer antihypertensive drug classes have reduced the use of these agents in recent decades. Outcome data and large randomized trials supporting the efficacy of these medications are limited; however, in general the blood pressure-lowering effect of these agents has repeatedly been shown to be comparable to other more contemporary drug classes. Nevertheless, a landmark hypertension trial found a negative outcome with a doxazosin-based regimen compared to a chlorthalidone-based regimen, leading to the removal of α-1 adrenergic receptor blockers as first-line monotherapy from the hypertension guidelines. In contemporary practice, direct vasodilators and sympatholytic agents, particularly hydralazine and clonidine, are often utilized in refractory hypertension. Hydralazine and minoxidil may also be useful alternatives for patients with renal dysfunction, and both hydralazine and methyldopa are considered first line for the treatment of hypertension in pregnancy. Hydralazine has also found widespread use for the treatment of systolic heart failure in combination with isosorbide dinitrate (ISDN). The data to support use of this combination in African Americans with heart failure are particularly robust. Hydralazine with ISDN may also serve as an alternative for patients with an intolerance to angiotensin antagonists. Given these niche indications, vasodilators and sympatholytics are still useful in clinical practice; therefore, it is prudent to understand the existing data regarding efficacy and the safe use of these medications.

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OBJECTIVE: To review available evidence evaluating dexmedetomidine in alcohol withdrawal syndrome (AWS) while identifying gaps in evidence for its use in this setting. DATA SOURCES: A MEDLINE search (1966-August 2015) to identify English-language articles evaluating the efficacy and safety of dexmedetomidine in alcohol withdrawal. Key words included alcohol, withdrawal, delirium tremens, and dexmedetomidine. Additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: All English-language observational studies, retrospective reviews, and clinical trials were included. Case reports and case series describing the use of dexmedetomidine in 10 or fewer patients were excluded. DATA SYNTHESIS: One randomized, controlled trial, 1 prospective observational study, and 6 retrospective reviews were identified. The only randomized, controlled trial identified showed that the addition of dexmedetomidine decreases benzodiazepine requirements more than placebo in the first 24 hours after initiation compared with the 24 hours prior to initiation (-56.8 mg vs -8 mg; P = 0.037). Overall, dexmedetomidine appears to lower benzodiazepine requirements in patients with AWS and decreases the sympathomimetic response seen in these patients. There was no convincing evidence that dexmedetomidine improves clinical endpoints in patients with AWS, such as need for mechanical ventilation or intensive care unit or hospital length of stay. CONCLUSIONS: Dexmedetomidine reduces hypertension and tachycardia in AWS and also reduces benzodiazepine requirements; however, the impact of these findings on important clinical endpoints is yet to be determined. Dexmedetomidine may be useful as adjunctive therapy; however, it cannot be recommended as a single agent in the management of AWS.

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BACKGROUND: A wide range of doses has been suggested for intrathecal clonidine, but no dose-ranging study has examined analgesic effects below 100 µg. The primary aim of this volunteer study was to assess the dose vs analgesic effect relationship for doses of intrathecal clonidine below 100 µg. METHODS: After IRB approval and signed informed consent, 11 healthy female volunteers participated in this randomized, double-blinded, cross-over study using a dose-ranging sparse-sampling technique. Participants received intrathecal clonidine (doses 0-100 µg; n=10) and intrathecal bupivacaine (doses 0-8.8 mg; n=9) on separate study days. At baseline, 30, and 60 min from drug administration, experimental heat pain tolerance was assessed at both a lumbar and a cranial dermatome. Heat and cold perception thresholds were assessed at the same time intervals. Heart rate (HR), arterial pressure, and forearm-finger and toe-leg cutaneous temperature gradients (Tfinger-arm and Ttoe-leg) were used as measures of sympatholysis. RESULTS: Both intrathecal clonidine and bupivacaine caused significant, dose-dependent analgesic effects at the leg but not the head. Significant analgesia to experimental heat pain was detected above 25 µg clonidine and 3 mg bupivacaine. Administration of bupivacaine but not clonidine resulted in a significant dose-related decrease in HR and Ttoe-leg; neither drug caused dose-related sympatholytic effects in the doses used. CONCLUSIONS: After 50 µg clonidine or 5 mg bupivacaine, the heat pain tolerance increased by ∼1°C, similar to the analgesic effect of 5 mg epidural morphine or 30 µg epidural fentanyl in previous studies using this experimental heat pain model. Our results provide additional data for rational dose selection of intrathecal clonidine.

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