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Critical Care (London, England) Jun 2023To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI).
BACKGROUND
Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit.
METHODS
This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16-64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study.
RESULTS
Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (- 5.4, 5.8), p = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p = 0.012), there were no between-group differences in the secondary outcomes.
CONCLUSION
Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.
Topics: Humans; Propranolol; Clonidine; Pilot Projects; Treatment Outcome; Brain Injuries, Traumatic; Adrenergic Agents
PubMed: 37296432
DOI: 10.1186/s13054-023-04479-6 -
American Journal of Hypertension May 2022There are limited and nonconcordant data on the rapidity and safety of blood pressure response to clonidine in the setting of asymptomatic severe hypertension. We... (Review)
Review
BACKGROUND
There are limited and nonconcordant data on the rapidity and safety of blood pressure response to clonidine in the setting of asymptomatic severe hypertension. We evaluated the blood pressure response to clonidine in hospitalized patients with asymptomatic severe hypertension.
METHODS
We performed a review of hospitalized, noncritically ill patients receiving clonidine within 6 hours of developing asymptomatic severe hypertension (systolic blood pressure [SBP] >180 or diastolic blood pressure [DBP] >110 mm Hg in the absence of acute hypertension-mediated target organ damage). The incidence of mean arterial pressure (MAP) reduction by ≥30% at 4 hours after clonidine was the primary endpoint.
RESULTS
We identified 200 relevant patient encounters (median age 63 years, 48.5% women). Median time to clonidine following asymptomatic severe hypertension was 2.8 hours. A total of 20 (10%) patients had ≥30% MAP reduction within 4 hours after clonidine, and 32 (16%) patients had ≥30% reduction in either SBP, DBP, or MAP. Older age, female sex, and preexisting vascular disease were associated with ≥30% MAP reductions (P < 0.05). Only patient sex and clonidine dose of 0.3 mg were significant in multivariable models. There were 14 adverse events observed within 24 hours of administration of clonidine; most (9) were acute kidney injury. There were no ischemic (myocardial, cerebrovascular) events.
CONCLUSIONS
A substantial minority of hospitalized patients with asymptomatic severe hypertension experience precipitous blood pressure decline with clonidine, and though blood pressure declines more precipitously in women and those receiving higher doses (0.3 mg specifically), the response to clonidine is generally not predictable on clinical grounds.
Topics: Blood Pressure; Clonidine; Female; Humans; Hypertension; Incidence; Male; Middle Aged
PubMed: 35038322
DOI: 10.1093/ajh/hpac004 -
The Cochrane Database of Systematic... May 2017Although routine administration of pharmacologic sedation or analgesia during mechanical ventilation in preterm neonates is not recommended, its use in clinical practice... (Review)
Review
BACKGROUND
Although routine administration of pharmacologic sedation or analgesia during mechanical ventilation in preterm neonates is not recommended, its use in clinical practice remains common. Alpha-2 agonists, mainly clonidine and dexmedetomidine, are used as adjunctive (or alternative) sedative agents alongside opioids and benzodiazepines. Clonidine has not been systematically assessed for use in neonatal sedation during ventilation.
OBJECTIVES
To assess whether clonidine administered to term and preterm newborn infants receiving mechanical ventilation reduces morbidity and mortality rates. To compare the intervention versus placebo, no treatment, and dexmedetomidine; and to assess the safety of clonidine infusion for potential harms.To perform subgroup analyses according to gestational age; birth weight; administration method (infusion or bolus therapy); dose, duration, and route of clonidine administration; and pharmacologic sedation as a co-intervention.
SEARCH METHODS
We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12) in the Cochrane Library, MEDLINE via PubMed (1966 to January 10, 2017), Embase (1980 to January 10, 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to January 10, 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials.
SELECTION CRITERIA
We searched for randomized controlled trials, quasi-randomized controlled trials, and cluster trials comparing clonidine versus placebo, no treatment, or dexmedetomidine administered to term and preterm newborns receiving mechanical ventilation via an endotracheal tube.
DATA COLLECTION AND ANALYSIS
For the included trial, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, all-cause death during initial hospitalization, duration of respiratory support, sedation scale, duration of hospital stay) and assessed risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). This review considered primary outcomes of all-cause neonatal death, all-cause death during initial hospitalization, and duration of mechanical ventilation in days.
MAIN RESULTS
One trial, which included 112 infants, met the inclusion criteria for this review. Term newborn infants on mechanical ventilation with the need for continuous analgesia and sedation with fentanyl and midazolam were eligible for enrollment during the first 96 hours of ventilation. Study authors administered clonidine 1 μg/kg/h or placebo on day 4 after intubation.We found no differences between the two groups in all-cause death during hospitalization (risk ratio [RR] 0.69, 95% confidence interval [CI] 0.12 to 3.98). The quality of the evidence supporting these findings is low owing to imprecision of the estimates (one study; few events). The median (interquartile range) duration of mechanical ventilation was 7.1 days (5.7 to 9.1 days) in the clonidine group and 5.8 days (4.9 to 7.9 days) in the placebo group, respectively (P = 0.070). Among secondary outcomes, we found no differences in terms of duration of stay in the intensive care unit. Sedation scale values (COMFORT) and analgesia scores (Hartwig) during the first 72 hours of infusion of study medication were lower in the clonidine group than in the placebo group.
AUTHORS' CONCLUSIONS
At present, evidence is insufficient to show the efficacy and safety of clonidine for sedation and analgesia in term and preterm newborn infants receiving mechanical ventilation.
Topics: Cause of Death; Clonidine; Dexmedetomidine; Hospital Mortality; Humans; Hypnotics and Sedatives; Infant, Newborn; Intensive Care Units, Neonatal; Length of Stay; Randomized Controlled Trials as Topic; Respiration, Artificial
PubMed: 28488361
DOI: 10.1002/14651858.CD012468.pub2 -
Critical Care (London, England) Feb 2017This systematic review and meta-analysis investigates the efficacy and safety of clonidine as a sedative in critically ill patients requiring invasive mechanical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This systematic review and meta-analysis investigates the efficacy and safety of clonidine as a sedative in critically ill patients requiring invasive mechanical ventilation.
METHODS
We performed a comprehensive search of MEDLINE, EMBASE, CINAHL and the Cochrane trial registry. We identified RCTs that compared clonidine to any non-clonidine regimen in critically ill patients, excluding neonates, requiring mechanical ventilation. The GRADE method was used to assess certainty of evidence.
RESULTS
We included eight RCTs (n = 642 patients). In seven of the trials clonidine was used for adjunctive rather than stand-alone sedation. There was no difference in the duration of mechanical ventilation (mean difference (MD) 0.05 days, 95% confidence interval (CI) = -0.65 to 0.75, I = 86%, moderate certainty), ICU mortality (relative risk (RR) 0.98, 95% CI = 0.51 to 1.90, I = 0%, low certainty), or ICU length of stay (MD 0.04 days, 95% CI = -0.46 to 0.53, I = 16%, moderate certainty), with clonidine. There was a significant reduction in the total dose of narcotics (standard mean difference (SMD) -0.26, 95% CI = -0.50 to -0.02, I = 0%, moderate certainty) with clonidine use. Clonidine was associated with increased incidence of clinically significant hypotension (RR 3.11, 95% CI = 1.64 to 5.87, I = 0%, moderate certainty).
CONCLUSIONS
Until further RCTs are performed, data remains insufficient to support the routine use of clonidine as a sedative in the mechanically ventilated population. Clonidine may act as a narcotic-sparing agent, albeit with an increased risk of clinically significant hypotension.
Topics: Clonidine; Critical Illness; Humans; Hypnotics and Sedatives; Hypotension; Intensive Care Units; Length of Stay; Respiration, Artificial
PubMed: 28330506
DOI: 10.1186/s13054-017-1610-8 -
Pharmacology 2016Clonidine, an alpha agonist, formally prescribed in clinical medicine as antihypertensive medication, is currently being used more frequently to address a multitude of... (Review)
Review
Clonidine, an alpha agonist, formally prescribed in clinical medicine as antihypertensive medication, is currently being used more frequently to address a multitude of psychiatric entities. The long-acting formulation is approved by the Food and Drug Administration for use in treating the attention-deficit/hyperactivity disorder. In addition to this only legitimate indication, it has long been used successfully for opiate detoxification, post-traumatic stress disorder and de la Tourette syndrome. Moreover, clonidine helps in the treatment of neuroleptic-induced akathisia, stimulant-induced insomnia and clozapine-induced sialorrhea. It has been tried in treating menopausal syndrome and psychogenic polydipsia. Although the strength of evidence supporting the use of clonidine in such clinical scenarios is highly variable and oscillating, from strong to only flimsy, this overview is intended to shed some light on the clonidine portfolio as a potential and attractive addition to the psychopharmacologic armamentarium.
Topics: Animals; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Clonidine; Humans; Menopause; Opioid-Related Disorders; Psychomotor Agitation; Sialorrhea; Stress Disorders, Post-Traumatic; Tics
PubMed: 27161101
DOI: 10.1159/000446441 -
BMC Research Notes May 2021The naked mole rat (NMR) (Heterocephalus glaber) is increasingly considered an important biomedical research model for various conditions like hypoxic brain injury,...
OBJECTIVE
The naked mole rat (NMR) (Heterocephalus glaber) is increasingly considered an important biomedical research model for various conditions like hypoxic brain injury, cancer and nociception. This study was designed to investigate the effects of clonidine and yohimbine, an alpha-2 (α) adrenoceptor agonist and antagonist respectively in the tail flick and hot plate tests.
RESULTS
A significant difference in tail flick latency was noted between saline control and 30 µg/kg clonidine, which was reduced after administration of 30 µg/kg yohimbine. A significant difference in hot plate latency was also noted between saline control and 30 µg/kg clodinine during the periods 30, 45, 60, 75 and 90 min after administration, and between saline control and 10 µg/kg clonidine during 30 min after administration. The hot plate latency by 30 µg/kg clonidine was also reduced by 30 µg/kg yohimbine during 30 min after administration. Since the tail-flick and hot plate tests mediate the effects at spinal and supraspinal levels respectively, the present study indicates the presence and involvement of noradrenergic receptors in thermal antinociception at spinal and supraspinal levels of the NMR, similar to what has been found in other mammals.
Topics: Analgesics; Animals; Clonidine; Mole Rats; Yohimbine
PubMed: 34001271
DOI: 10.1186/s13104-021-05607-7 -
The Cochrane Database of Systematic... May 2016Withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment.
OBJECTIVES
To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists compared with placebo, reducing doses of methadone, symptomatic medications, or an alpha2-adrenergic agonist regimen different to the experimental intervention, for the management of the acute phase of opioid withdrawal. Outcomes included the withdrawal syndrome experienced, duration of treatment, occurrence of adverse effects, and completion of treatment.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to November week 2, 2015), EMBASE (January 1985 to November week 2, 2015), PsycINFO (1806 to November week 2, 2015), Web of Science, and reference lists of articles.
SELECTION CRITERIA
Randomised controlled trials comparing alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS
We included 26 randomised controlled trials involving 1728 participants. Six studies compared an alpha2-adrenergic agonist with placebo, 12 with reducing doses of methadone, four with symptomatic medications, and five compared different alpha2-adrenergic agonists. We assessed 10 studies as having a high risk of bias in at least one of the methodological domains that were considered.We found moderate-quality evidence that alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.18 to 0.57; 3 studies; 148 participants). We found moderate-quality evidence that completion of treatment was significantly more likely with alpha2-adrenergic agonists compared with placebo (RR 1.95, 95% CI 1.34 to 2.84; 3 studies; 148 participants).Peak withdrawal severity may be greater with alpha2-adrenergic agonists than with reducing doses of methadone, as measured by the likelihood of severe withdrawal (RR 1.18, 95% CI 0.81 to 1.73; 5 studies; 340 participants; low quality), and peak withdrawal score (standardised mean difference (SMD) 0.22, 95% CI -0.02 to 0.46; 2 studies; 263 participants; moderate quality), but these differences were not significant and there is no significant difference in severity when considered over the entire duration of the withdrawal episode (SMD 0.13, 95% CI -0.24 to 0.49; 3 studies; 119 participants; moderate quality). The signs and symptoms of withdrawal occurred and resolved earlier with alpha2-adrenergic agonists. The duration of treatment was significantly longer with reducing doses of methadone (SMD -1.07, 95% CI -1.31 to -0.83; 3 studies; 310 participants; low quality). Hypotensive or other adverse effects were significantly more likely with alpha2-adrenergic agonists (RR 1.92, 95% CI 1.19 to 3.10; 6 studies; 464 participants; low quality), but there was no significant difference in rates of completion of withdrawal treatment (RR 0.85, 95% CI 0.69 to 1.05; 9 studies; 659 participants; low quality).There were insufficient data for quantitative comparison of different alpha2-adrenergic agonists. Available data suggest that lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine.
AUTHORS' CONCLUSIONS
Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. We detected no significant difference in efficacy between treatment regimens based on clonidine or lofexidine and those based on reducing doses of methadone over a period of around 10 days, but methadone was associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.
Topics: Acute Disease; Adrenergic alpha-2 Receptor Agonists; Clonidine; Controlled Clinical Trials as Topic; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome
PubMed: 27140827
DOI: 10.1002/14651858.CD002024.pub5 -
The New England Journal of Medicine Apr 2014Marked activation of the sympathetic nervous system occurs during and after noncardiac surgery. Low-dose clonidine, which blunts central sympathetic outflow, may prevent... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Marked activation of the sympathetic nervous system occurs during and after noncardiac surgery. Low-dose clonidine, which blunts central sympathetic outflow, may prevent perioperative myocardial infarction and death without inducing hemodynamic instability.
METHODS
We performed a blinded, randomized trial with a 2-by-2 factorial design to allow separate evaluation of low-dose clonidine versus placebo and low-dose aspirin versus placebo in patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery. A total of 10,010 patients at 135 centers in 23 countries were enrolled. For the comparison of clonidine with placebo, patients were randomly assigned to receive clonidine (0.2 mg per day) or placebo just before surgery, with the study drug continued until 72 hours after surgery. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days.
RESULTS
Clonidine, as compared with placebo, did not reduce the number of primary-outcome events (367 and 339, respectively; hazard ratio with clonidine, 1.08; 95% confidence interval [CI], 0.93 to 1.26; P=0.29). Myocardial infarction occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (hazard ratio, 1.11; 95% CI, 0.95 to 1.30; P=0.18). Significantly more patients in the clonidine group than in the placebo group had clinically important hypotension (2385 patients [47.6%] vs. 1854 patients [37.1%]; hazard ratio 1.32; 95% CI, 1.24 to 1.40; P<0.001). Clonidine, as compared with placebo, was associated with an increased rate of nonfatal cardiac arrest (0.3% [16 patients] vs. 0.1% [5 patients]; hazard ratio, 3.20; 95% CI, 1.17 to 8.73; P=0.02).
CONCLUSIONS
Administration of low-dose clonidine in patients undergoing noncardiac surgery did not reduce the rate of the composite outcome of death or nonfatal myocardial infarction; it did, however, increase the risk of clinically important hypotension and nonfatal cardiac arrest. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.).
Topics: Adrenergic alpha-2 Receptor Agonists; Aged; Clonidine; Female; Humans; Hypotension; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Perioperative Care; Postoperative Complications; Surgical Procedures, Operative; Treatment Failure
PubMed: 24679061
DOI: 10.1056/NEJMoa1401106 -
Medical Gas Research 2020Dexmedetomidine (DEX) can prolong duration of anesthesia and shorten onset of sensory and motor block relative to clonidine. This study attempted to compare the efficacy... (Comparative Study)
Comparative Study Randomized Controlled Trial
Comparing intravenous dexmedetomidine and clonidine in hemodynamic changes and block following spinal anesthesia with ropivacaine in lower limb orthopedic surgery: a randomized clinical trial.
Dexmedetomidine (DEX) can prolong duration of anesthesia and shorten onset of sensory and motor block relative to clonidine. This study attempted to compare the efficacy of intravenous DEX and clonidine for hemodynamic changes and block after spinal anesthesia with ropivacaine in lower limb orthopedic surgery. In a double-blind randomized clinical trial, 120 patients undergoing spinal anesthesia in lower limb orthopedic surgery were recruited and divided into three groups using balanced block randomization: DEX group (n = 40; intravenous DEX 0.2 µg/kg), clonidine group (n = 40; intravenous clonidine 0.4 µg/kg), and placebo group (n = 40; intravenous normal saline 10 mL) in which pain scores were assessed using visual analogue scales (at recovery, and 2, 4, 6, and 12 hours after surgery) and time to achieve and onset of sensory and motor block. Statistically significant differences were found in mean arterial pressure among the groups at all times except baseline (P = 0.001), with a less mean arterial pressure and a prolonged duration of sensory and motor block (P = 0.001) in the DEX group where pain relieved in patients immediately after surgery and at above mentioned time points (P = 0.001). Simultaneous administration of intravenous DEX with ropivacaine for spinal anesthesia prolongs the duration of sensory and motor block and relieves postoperative pain, and however, can decrease blood pressure. Although intravenous DEX as an adjuvant can be helpful during spinal anesthesia with ropivacaine, it should be taken with caution owing to a lowering of mean arterial pressure in patients especially in the older adults. This study was approved by Ethical Committee of Arak University of Medical Sciences (No. IR.Arakmu.Rec.1395.450) in March, 2017, and the trial was registered and approved by the Iranian Registry of Clinical Trials (IRCT No. IRCT2017092020258N60) in 2017.
Topics: Administration, Intravenous; Adult; Anesthesia, Spinal; Clonidine; Dexmedetomidine; Double-Blind Method; Drug Interactions; Female; Hemodynamics; Humans; Lower Extremity; Male; Orthopedic Procedures; Ropivacaine
PubMed: 32189663
DOI: 10.4103/2045-9912.279977 -
Revista Da Associacao Medica Brasileira... Jul 2022This study aimed to assess the clonidine infusion rate in the first 6 h, as maintenance dose (first 24 h), and in the pre-extubation period (last 24 h), as well as the...
OBJECTIVE
This study aimed to assess the clonidine infusion rate in the first 6 h, as maintenance dose (first 24 h), and in the pre-extubation period (last 24 h), as well as the cumulative dose of other sedatives and the hemodynamic response.
METHODS
This is a retrospective cohort study.
RESULTS
Children up to the age of 2 years who were admitted to the pediatric intensive care unit of a tertiary referral hospital in the south region of Brazil, between January 2017 and December 2018, were submitted to mechanical ventilation, and received continuous clonidine infusions were included in the study. The initial, maintenance, and pre-extubation doses of clonidine; the vasoactive-inotropic score; heart rate; and systolic and diastolic blood pressure of the study participants were assessed. A total of 66 patients with a median age of 4 months who were receiving clonidine infusions were included. The main indications for mechanical ventilation were acute viral bronchiolitis (56%) and pneumonia associated with acute respiratory distress syndrome (15%). The median of clonidine infusion in the first 6 h (66 patients) was 0.53 μg/kg/h (IQR 0.49-0.88), followed by 0.85 μg/kg/h (IQR 0.53-1.03) during maintenance (57 patients) and 0.63 μg/kg/h (IQR 0.54-1.01) during extubation period (42 patients) (p=0.03). No differences were observed in the doses regarding the indication for mechanical ventilation. Clonidine infusion was not associated with hemodynamic changes and showed no differences when associated with adjuvants.
CONCLUSION
Clonidine demonstrated to be a well-tolerated sedation option in pediatric patients submitted to mechanical ventilation, without relevant influence in hemodynamic variables.
Topics: Child; Child, Preschool; Clonidine; Humans; Hypnotics and Sedatives; Infant; Intensive Care Units, Pediatric; Respiration, Artificial; Retrospective Studies
PubMed: 35830018
DOI: 10.1590/1806-9282.20220166