Clonidine use during dexmedetomidine weaning:A systematic review

BACKGROUND Dexmedetomidine is a centrally acting alpha-2A adrenergic agonist that is commonly used as a sedative and anxiolytic in the intensive care unit(ICU),with prolonged use increasing risk of withdrawal symptoms upon sudden discontinuation.As clonidine is an enterally available alpha-2A adrenergic agonist,it may be a suitable agent to taper off dexmedetomidine and reduce withdrawal syndromes.The appropriate dosing and conversion strategies for using enteral clonidine in this context are not known.The objective of this systematic review is to summarize the evidence of enteral clonidine application during dexmedetomidine weaning for prevention of withdrawal symptoms.AIM To systematically review the practice,dosing schema,and outcomes of enteral clonidine use during dexmedetomidine weaning in critically ill adults.METHODS This was a systematic review of enteral clonidine used during dexmedetomidine weaning in critically ill adults(≥18 years).Randomized controlled trials,prospective cohorts,and retrospective cohorts evaluating the use of clonidine to wean patients from dexmedetomidine in the critically ill were included.The primary outcomes of interest were dosing and titration schema of enteral clonidine and dexmedetomidine and risk factors for dexmedetomidine withdrawal.Other secondary outcomes included prevalence of adverse events associated with enteral clonidine use,re-initiation of dexmedetomidine,duration of mechanical ventilation,and ICU length of stay.RESULTS A total of 3427 studies were screened for inclusion with three meeting inclusion criteria with a total of 88 patients.All three studies were observational,two being prospective and one retrospective.In all included studies,the choice to start enteral clonidine to wean off dexmedetomidine was made at the discretion of the physician.Weaning time ranged from 13 to 167 h on average.Enteral clonidine was started in the prospective studies in a similar protocolized method,with 0.3 mg every 6 h.After starting clonidine,patients remained on dexmedetomidine for a median of 1-28 h.Following the termination of dexmedetomidine,two trials tapered enteral clonidine by increasing the interval every 24 h from 6 h to 8h,12h,and 24 h,followed by clonidine discontinuation.For indicators of enteral clonidine withdrawal,the previously tolerable dosage was reinstated for several days before resuming the taper on the same protocol.The adverse events associated with enteral clonidine use were higher than patients on dexmedetomidine taper alone with increased agitation.The re-initiation of dexmedetomidine was not documented in any study.Only 17(37%)patients were mechanically ventilated with median duration of 3.5 d for 13 patients in one of the 2 studies.ICU lengths of stay were similar.CONCLUSION Enteral clonidine is a strategy to wean critically ill patients from dexmedetomidine.There is an association of increased withdrawal symptoms and agitation with the use of a clonidine taper.

农药杀虫脒基对大鼠前脑细胞_(α2)—肾上腺受体与~3H-clonidine结合抑制效应研究

杀虫脒基(Chlordimeform,简称CDM)系甲脒类农药。结构式为在美已广泛地用于果树防病中,是有效的杀螨剂和杀虫剂。现我国也已生产和应用。

Effect of clonidine on the cutaneous silent period during spinal anesthesia

AIM To investigate the effect of clonidine on the cutaneous silent period(CSP) during spinal anesthesia. METHODS A total of 67 adult patients were included in this randomized, prospective, single-center, double-blind trial. They did not have neurological disorders and were scheduled for inguinal hernia repair surgery. This trial was registered on ClinicalTrials.gov(NTC03121261). The patients were randomized into two groups with regards to the intrathecally administered solution:(1) 15 mg of 0.5% levobupivacaine with 50 μg of 0.015% clonidine, or(2) 15 mg of 0.5% levobupivacaine alone. There were 34 patients in the levobupivacaine-clonidine(LC) group and 33 patients in the levobupivacaine(L) group. CSP and its latency were measured four times: prior to the subarachnoid block(SAB), after motor block regression to the 0 level of the Bromage scale, with ongoing sensory blockade, and both 6 and 24 h after SAB.RESULTS Only data from 30 patients in each group were analyzed. There were no significant differences between the groups investigated preoperatively and after 24 h. The CSP of the L group at the time point when the Bromage scale was 0 was 44.8 ± 8.1 ms, while in the LC group it measured 40.2 ± 3.8 ms(P = 0.007). The latency in the L group at the time point when the Bromage scale was 0 was 130.3 ± 10.2 ms, and in the LC group it was 144.7 ± 8.3 ms(P < 0.001). The CSP of the L group after 6 h was 59.6 ± 9.8 ms, while in the LC group it was 44.5 ± 5.0 ms(P < 0.001). The latency in the L group after 6 h was 110.4 ± 10.6 ms, while in LC group it was 132.3 ± 9.7 ms(P < 0.001).CONCLUSION Intrathecal addition of clonidine to levobupivacaine for SAB in comparison with levobupivacaine alone resultsin a diminished inhibitory tonus and shortened CSP.

Effects of Dexamethasone, Clonidine, Tramadol and Nalbuphine on Fentanyl-Induced Hyperalgesia in Rats

Opioids are drugs used to alleviate pain. However, studies have demonstrated that these drugs can cause an increase in pain sensitivity, which is called opioid-induced hyperalgesia. The objective of this study was to describe the effects of dexamethasone, clonidine, tramadol and nalbuphine on fentanyl-induced hyperalgesia in rats. After obtaining approval from the Committee for the Ethical Use of Animals (CEUA), 36 male Wistar rats were divided into 6 groups: Group 1 (GCSSL) wherein the rats received 1 ml 0.9% saline solution in two injections;Group 2 (GFTSL), received fentanyl at a dose of 100 ug·kg-1 followed by 1 ml 0.9% saline solution via intraperitoneal;the remaining groups (3, 4, 5, 6) received fentanyl at a dose of 100 ug·kg-1 following doses via intraperitoneal: Group 3 (GFTDX), dexamethasone at a dose of 1.0 mg·kg-1;Group 4 (GFTCL), clonidine at a dose of 20 mg·kg-1;Group 5 (GFTTR), tramadol at a dose of 50 mg·kg-1, and Group 6 (GFTNB), nalbuphine at a dose of 5 mg·kg-1. Under general anestesia using isoflurane, the animals were submitted to a surgical incision. Hyperalgesia was evaluated by applying Von Frey filaments at 2 hours after the incision and on the 1st, 3rd and 5th days afterward. At 2 hours after the surgical procedure, there was lower intensity of pain in the fentanyl group (GFTSL) compared to the other groups, and on the fifth day there were no significant differences for pain intensity between groups. The results suggest the presence of fentanyl-induced hyperalgesia and efficacy in its reduction by dexamethasone, clonidine, tramadol and nalbuphine.

Effects of clonidine on anxiety-like behaviors of rats subjected to chronic hypoperfusional cerebral ischemia

Aim To investigate the effect of clonidine on anxiety-like behaviors of rats subjected to chronic hy- popeffusional cerebral ischemia. Methods Chronic hypopeffusional cerebral ischemia was established by perma- nent bilateral common carotid arteries occlusion （two-vessel occlusion, 2VO）. Three weeks after 2VO, rats were given clonidine （0.05 mg·kg^-1, i. p. ） for 14 days. Behavioural experiments including elevated plus maze （EPM） and open field test （OFT） were applied to evaluate anxiey-like behaviour after four-week ischemia. Re- suits 2VO rats significantly spent less time in open arm of EPM and more time in peripheral region of OFT com- pared with sham rats. Clonidine notably increased open arm time in EPM and prolonged time spent in center region in OFT of 2VO rats. Conlusion Chronic hypopeffusional cerebral ischemia caused anxiety-like behaviors of rats and clonidine showed an important role in improving anxiety-like behaviors in 2VO rats.

Clinical Study of Epidural Analgesia with Clonidine andSumatriptan in Posthysterectomy

A clinical study was conducted to compare the analgestic effect of clonidine with those of sumatriptan and their mixture and their effects on hemodynamics. 40 patients undergoing elective total hysterectomy were randomly divided into 4 groups in terms of the epidurally administered drugs with 10 patients in each group (group C1: clonidine 150 μg, group C2: clonidine 75 μg, group S: sumatriptan 6 mg and group S+C:clonidine 75 μg + sumatriptan 3 mg). MAP, HR,SpO2, VT VAS, VRS and ePDT were measured in the initial 4 h. The demographic data and the doses of intraoperative local anesthetics among the 4 groups were not staistically different. It was found that no significant difference in the pre- and postadministration values of HR, SpO2 and VT. A obvious reduction of MAP appeared in the groups of C1 and C2, but in the other groups the hemodynamical parameters were stable. The groups of C1, C2 and S+C showed significant increase in VAS and VRS, along with increase of ePDT when comapred with the pre-drug level. There was no obvious alteration in group S after the drug administration. It was concluded that (1) single use of sumatriptan is ineffective in the dose given in this study; (2) small dose (150 μg and 75μg) of clonidine has epidurally analgesic effects; (3) combined use of sumatriptan and clonidine is an acceptable way in epidural analgesia, in terms of its analgesic effect and hemodynamic changes.

Differences in the Receptor Binding Profile of Lofexidine Compared to Clonidine

Lucemyra? (lofexidine hydrochloride) has recently been approved by the US FDA for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Lofexidine is an alpha-2 adrenoceptor agonist. However, the clinical attributes of lofexidine differ in advantageous ways from the classical alpha-2 adrenoceptor agonist clonidine. In the present study, we measured the receptor binding profile of lofexidine and clonidine in an effort to gain an insight into the clinical difference(s).

A Comparative Study of Intrathecal Injection of Bupivacaine Alone or with Fentanyl, Clonidine, and Neostigmine in Lower Abdominal Surgeries

Background: Anesthesiologists are responsible for the development of pain services in the current era. Hence ideal adjuvants that can be used with bupivacaine for stable intraoperative conditions and prolonging the postoperative analgesia with fewer side effects are being investigated. Opioids, despite useful as adjuvants, are associated with undesirable side effects. Aim of the work: The study was done to compare analgesic efficacy and hemodynamic of intrathecal injection of bupivacaine alone or with fentanyl, clonidine, and neostigmine in lower abdominal surgeries, over the first 24 postoperative hours, in a randomized, double-blind, and clinical trial. Methods: 100 Patients were randomized into four equal groups, 25 patients in each group;Group B patients received 2.5 ml of 0.5% hyperbaric bupivacaine and 0.5 ml of normal saline. Group BF patients received 2.5 ml of 0.5% hyperbaric bupivacaine with (25 mics) of fentanyl. Group BC patients received 2.5 ml of 0.5% hyperbaric bupivacaine with 0.5 ml (75 mics) of clonidine. Group BN patients received 2.5 ml of 0.5% hyperbaric bupivacaine with 0.1 ml of neostigmine (50 mics) and 0.4 ml of normal saline. Intrathecal anesthesia was done with a recording of parameters intraoperative and the post-operative period. Each patient was assessed for hemodynamic parameters and effective analgesia in operation, and presence of complications (nausea, vomiting, sedation and pruritus) visual analogue pain score (VAS) postoperatively by a blinded investigator in the post-anesthesia care unit (PACU) and at 1, 2, 3, 4, 8 12, 18 and 24 h postoperatively. Results: The postoperative analgesia is more effective with group BC (the gold standard) than group B, group BF, and group BN. As regard complications during the study in all groups, complications as nausea, and vomiting were mainly with group BN;hypotension was primarily in group BC. Conclusion: Bupivacaine clonidine, bupivacaine neostigmine, and bupivacaine fentanyl intrathecal anesthesia produced a longer duration of postoperative analgesia after lower abdominal surgery in patients than bupivacaine alone. Bupivacaine clonidine mixture had the most extended period of analgesia, but with hypotension. So bupivacaine fentanyl mixture with moderate duration of analgesia and minimal side effects is most safe for a patient.

Comparison of Clonidine and Metoprolol Effectiveness on the Control of Post-Operative Blood Pressure in Otorhinolaryngology-Head and Neck Surgeries: A Clinical Trial

Objectives: Adequate control of hemodynamic parameters in patients undergoing otolaryngology-head and neck (OLHN) surgeries is one of the objectives of peri-operative anesthesia management. In this context, we seek to evaluate the effectiveness of metoprolol compared to clonidine in the post-operative control of systolic (SBP) and diastolic (DBP) blood pressures, and heart rate (HR), when these medications are used in the immediate pre-operative period. Method: this is a randomized double-blind clinical trial. Patients over 18 years old, according to the American Society of Anesthesiologists Physical Status Classification (ASA) I or II, who would undergo OLHN surgery, presenting with greater than 140 mmHg (SBP) or 90 mmHg (DBP), upon arrival at the surgical ward, were included in the study. 46 patients were randomized into two groups (C or M) who received clonidine (75 or 150 mcg) or metoprolol (5 or 10 mg), respectively. The averages of SBP, DBP and HR were compared between groups upon arrival at the post anesthesia care unit (PACU) and four hours post-surgery. Results: In group C, SBP (127.7 ± 18.8 vs 137.3 ± 14.1 mmHg, p = 0.03) and DBP (73.1 ± 15.46 vs 82.6 ± 7.9 mmHg, p < 0.01) were lower, when compared with group M. No difference was observed in HR immediately upon PACU arrival. In addition, for four hours post-surgery, no change was noted in the SBP, DBP or HR. Conclusion: metoprolol was less effective than clonidine in reducing systolic and diastolic blood pressures in the immediate post-operative period of OLHN surgeries.

Prophylactic Effect of Oral Clonidine and Tramadol in Postoperative Shivering in Lower Abdominal Surgery

Background and Objectives: Several drugs and methods are used to reduce postoperative shivering, the most common complications occurring after surgery. This study aimed to evaluate the effects of the oral Clonidine and Tramadol premedication in reducing postoperative shivering after spinal anesthesia. Materials and Methods: In this study, patients aged 20 - 60 years, based on the American Society of Anesthesia functional class I (Anesthesiologists grade-1), were included in controlled double-blind clinical trials. Each was a candidate of a hydrocele, varicocele, and inguinal hernia under spinal anesthesia. The patients were assigned to three groups and 1 h prior to surgery, group A received 0.2 mg of Clonidine, group B received 50 mg of a Tramadol tablet, and group C received a placebo. We collected information on the severity of shivering, pain intensity levels (VAS score), duration of analgesia, and the patients’ hemodynamic condition at base time of 5, 15, and 30 min and 1, 2, 4, and 6 h postoperatively. Results: The incidence of shivering was significantly lower in the Clonidine group than that in the other groups. Analgesia duration was significantly longer in the Clonidine group than that in the control group. In this study, side effects in different groups were not significantly different from each other. Conclusion: Results of this study showed that the oral administration of Clonidine can be effective in preventing the side effects and shivering after spinal anesthesia.

Safety threshold of intravitreal clonidine in rabbit's eyes

AIM： To determine the safe dose of intravitreal clonidine（IVC）, a potential drug for neuroprotection and angiogenesis inhibition in rabbits. METHODS： A total of 28 rabbits were divided into four groups. Three groups received IVC with concentrations of 15（Group A）, 25（Group B）, and 50（Group C） g/0.1 m L and the control group（Group D） received 0.1 m L balanced salt solution（BSS）. To investigate IVC safety, electroretinography（ERG） was performed at baseline, then at 1, 4 and 8 wk after injection. After last ERG, all rabbits were euthanized, their eyes were enucleated and subjected to routine histopathological evaluation, immunohistochemistry for glial fibrillary acidic protein（GFAP） and terminal deoxynucleotidyl transferase d UTP nick end labeling（TUNEL） test.RESULTS： Based on ERG, histopathology, GFAP and TUNEL assay findings, 15 g IVC was determined as the safe dose in rabbit eyes. While, the results of routine histopathology and TUNEL assay were unremarkable in all groups, toxic effects attributed to 25 and 50 g IVC were demonstrated by ERG and GFAP tests. CONCLUSION： Totally 15 g clonidine is determined as the safe dose for intravitreal injection in rabbits. Contribution of IVC in neuroprotection and inhibition of angiogenesis deserve more studies.

Clonidine Inhibits Phenylephrine-Induced Contraction of Rat Thoracic Aortae by Competitive Antagonism of α₁-Adrenoceptors Independent of α₂-Adrenoceptor Stimulation

Clonidine is a classically categorized α2-adrenoceptor (α2-AR) agonist that produces vascular contractions by stimulating arterial smooth muscle α2-ARs. However, clonidine inhibits α1-AR-mediated arterial contractions. Recently, it was suggested that repeated stimulation with clonidine induces desensitization of α2-ARs, thus inhibiting noradrenaline-induced smooth muscle contractions. In the present study, we examined whether clonidine-mediated inhibition of α1-AR contractions involves interactions with α2-ARs in rat thoracic aortae. 1) Clonidine and guanfacine inhibited electrical field stimulation-induced contractions in a concentration-dependent, yohimbine-sensitive manner in isolated rat vas deferens preparations. 2) Clonidine almost completely suppressed phenylephrine-induced sustained contractions of rat thoracic aortae. 3) Clonidine competitively inhibited phenylephrine-induced contractions with a pA2 value of 6.77 at concentrations between 10-7 and 10-6 M. At 10-5 M, clonidine inhibited phenylephrine-induced contractions and dramatically reduced maximum contractions. 4) In contrast, clonidine did not inhibit contractions produced by high KCl or prostaglandin F2α. 5) Inhibition of phenylephrine-induced sustained contractions by clonidine was also produced in the presence of yohimbine. However, guanfacine did not inhibit phenylephrine-induced sustained contractions. These findings suggest that clonidine inhibits phenylephrine-induced contraction of rat thoracic aortae by competitive antagonism of α1-ARs, which is mediated through a mechanism independent of α2-AR stimulation.

Treatment of prolonged clonidine-induced autonomic instability with midodrine:a case report about a new approach or a cautionary tale?

Background:Clonidine is a centrally acting a2 adrenergic and imidazoline-1 receptor agonist that can cause somnolence,bradycardia,and hypotension within several hours of ingestion.Less well-described but observed by us locally is the observation that patients presenting after large overdoses including clonidine can have prolonged autonomic instability.As a result,they may require many days in hospital before recovery.We have previously used midodrine as an indirect antagonist with good effect;however,there are no previous reports of its use for this indication.Case presentation:We present the case of a young female patient who developed prolonged autonomic instability following a large overdose of clonidine(coingested with smaller doses of escitalopram+lisdexamfetamine)that was treated with midodrine but complicated by a type 2 non-ST segment elevated myocardial infarction.Conclusion:Midodrine seems to ameliorate this protracted instability and may provide a means to decrease hospital length of stay in appropriate individuals.

THE ANTAGONISM OF ANGIOTENSIN Ⅱ ON THE DEPRESSOR EFFECT OF CLONIDINE IN RAT SPINAL CORD

There is a large body of evidence to suggest existence of endogenous anti-opioid substances (AOS) in central nervous system to antagonize the actions of endogenous opioid peptides. Angiotensin Ⅱ has been considered as one of the AOS because it was found to antagonize opioid activity in various physiological and pharmacological systems. In present work, we studied the antagonistic effect of angiotensin Ⅱ on the cardiovascular activities of endogenous opioids.

Alpha2-adrenergic receptor activation reinstates motor deficits in rats recovering from cortical injury

Norepinephrine plays an important role in motor functional recovery after a brain injury caused by ferrous chloride.Inhibition of norepinephrine release by clonidine is correlated with motor deficits after motor cortex injury.The aim of this study was to analyze the role ofα-adrenergic receptors in the restoration of motor deficits in recovering rats after brain damage.The rats were randomly assigned to the sham and injury groups and then treated with the following pharmacological agents at 3 hours before and 8 hours,3 days,and 20 days after ferrous chloride-induced cortical injury:saline,clonidine,efaroxan(a selective antagonist ofα-adrenergic receptors)and clonidine+efaroxan.The sensorimotor score,the immunohistochemical staining forα-adrenergic receptors,and norepinephrine levels were evaluated.Eight hours post-injury,the sensorimotor score and norepinephrine levels in the locus coeruleus of the injured rats decreased,and these effects were maintained 3 days post-injury.However,20 days later,clonidine administration diminished norepinephrine levels in the pons compared with the sham group.This effect was accompanied by sensorimotor deficits.These effects were blocked by efaroxan.In conclusion,an increase inα-adrenergic receptor levels was observed after injury.Clonidine restores motor deficits in rats recovering from cortical injury,an effect that was prevented by efaroxan.The underlying mechanisms involve the stimulation of hypersensitiveα-adrenergic receptors and inhibition of norepinephrine activity in the locus coeruleus.The results of this study suggest thatαreceptor agonists might restore deficits or impede rehabilitation in patients with brain injury,and therefore pharmacological therapies need to be prescribed cautiously to these patients.

PLATELET FREE CALCIUM AND SERUM FREE CALCIUM IN ESSENTIAL HYPERTENSION

Intracellular free calcium of platelets and serum free calcium were studied in human essential hypertension. Intracellular free calcium of platelets was significantly higher in hypertensive patients than that in normotensive subjects, and this was correlated with blood pressure. There was no difference of serum free calcium between hypertensives and normotensive controls. Antihypertensive treatment with nifedipine resulted in a reduction of platelet free calcium, and this was correlated with the fall of blood pressure. In patients treated with clonidine, although there was no difference of platelet free calcium between hypertensives and normotensive controls, serum free clacium was significantly reduced. These results indicated that intracellular free calcium may be regulated by same hormonal or pharmacological factors which determined the height of blood pressure, calcium channel blockers may be more effective in prevention of cardiovascular and cerebrovascular complications caused by platelet hyperfunction in essential hypertension.

Relationship between Growth Hormone and Cytokines in Short Children Undergoing Growth Hormone Stimulation Testing

Background: The relationship between growth hormone (GH) and cytokines remains unclear. Several studies have suggested that GH increases tumor necrosis factor (TNF)-α production in both children and adults. However, a number of studies have demonstrated a negative correlation between GH and TNF α. The aim of this study is to explore the relationship between endogenous GH secretion and certain pro and anti-inflammatory cytokines in short children undergoing GH stimulation testing for evaluation for GH deficiency. Methods: Plasma growth hormone, TNF α, CRP, IL-6, IL1-β, IL-4 and IL-10 levels are obtained at baseline and every 30 minutes for 150 minutes following two provocative agents (clonidine, and either arginine or glucagon). Results: Among the 23 children, 7 are found to be GH deficient. No significant differences in baseline TNF α levels are found between GH deficient and GH sufficient children. No correlation is identified between TNF α levels and GH levels during stimulation testing. Furthermore, no relationship is found between GH and pro-inflammatory cytokines or GH and anti-inflammatory cytokines. Conclusion: Our results do not demonstrate an acute relationship between endogenous GH secretion and the cytokines examined.

围术期α_2肾上腺素受体激动剂应用进展

The α2-adrenoceptor agonists are widely applied in perioperative period because they have antinociceptive, sedative, anxiolytic, sympatholytic effects. With the development of investigation, the α2-adrenoceptor agonists’ indications are expanded and have not been investigated as a kind of adjuvant. They will not only reduce anesthetic requirements during operation, cause sedation in ICU postoperatively, offer benefits in the prophylaxis of perioperative myocardial ischaemia but probably become some kind of anesthetic by themselves in perioperative application.

Mast Cell Stabilizing,Antianaphylactic and Antihistaminic Activity of Coccinia grandis Fruits in Asthma

Coccinia grandis Linn(Curcubitaceae) is a climber herb cultivated throughout India.In traditional medicine fruits have been used to treat leprosy,fever,asthma,bronchitis and jaundice.In present study,ethanol extract of C.grandis fruit(ECGF) at 100,125 and 150 mg·kg-1,i.p.,was evaluated for mast cell stabilizing,antianaphylactic and antihistaminic activity using egg albumin induced mast cell degranulation in mice;passive cutaneous anaphylaxis in rats and clonidine induced catalepsy in mice respectively.ECGF at(100-150 mg·kg-1,i.p.) significantly protected egg albumin induced degranulations of mast cells and caused reduction of blue dye leakage in passive cutaneous anaphylaxis in dose dependently.The treatment ECGF also inhibited clonidine induced catalepsy in dose dependent manner.Phytochemical studies observed presence of saponin,steroids,alkaloids,flavonoids and glycosides.In conclusion ECGF possesses mast cell stabilizing;anti anaphylactic and antihistaminic potential which might be used in treatment of asthma.