High-dose Clonidine Research Articles

High Dose Clonidine as a Novel Therapy for Symptomatic Status Dystonicus in a Pediatric Patient (P5-9.009)

<h3>Objective:</h3> To highlight the role of high dose clonidine in the treatment of refractory status dystonicus in children. <h3>Background:</h3> Status dystonicus (SD) is a movement disorder emergency characterized by involuntary sustained dystonia that can result from infections, traumatic brain injuries, hypoxia, or toxins. If under-treated, it can result in respiratory failure and end organ dysfunction. Therefore, it is crucial for SD to be identified and treated early with both supportive care and pharmacologic agents. Common pharmacologic agents include dopamine receptor blockers, baclofen, anticholinergics, and benzodiazepines. However, some patients remain refractory to standard treatments. <h3>Design/Methods:</h3> Case report and literature review. <h3>Results:</h3> A 16-month-old female presented to an outside facility in febrile status epilepticus of &gt;90 minutes duration. She suffered a brief cardiorespiratory arrest, was quickly resuscitated, and then subsequently suffered a second cardiorespiratory arrest and was transferred to our facility. Due to concern for status dystonicus, she was treated with a combination of Baclofen, Diazepam, Clonazepam, Amantadine and Trihexyphenidyl with minimal improvement. MRI showed acute bilateral globus pallidus injury. Extensive infectious, autoimmune, and genetic testing was overall unremarkable. After several days of continued refractory SD with maximized medication therapy, high-dose enteral clonidine was started, increasing dosing over the course of the week from 6 mcg/kg/day to 33 mcg/kg/day, which correlated with significant improvement in symptoms after reaching maximal dose. As she continued to improve with high dose clonidine, she was able to be weaned off of several medications and discharged to acute inpatient rehab. <h3>Conclusions:</h3> Status dystonicus can be a difficult condition to treat, as there are limited pharmaceutical treatment options in pediatric patients. Studies in adult populations have shown effectiveness of high dose clonidine, yet this has not been well described in children. This case suggests that high dose oral clonidine may be a safe and effective treatment option for refractory SD in children. <b>Disclosure:</b> Mr. Woods has nothing to disclose. Dr. Chandler has nothing to disclose. Dr. Barton has nothing to disclose.

A Dose Response Study Of Oral clonidine as premedication in patients undergoing abdominal gynaecological surgery

Background: The current study was designed to investigate the safe and effective dose of oral clonidine onpost-operative analgesia in patients undergoing gynaecological laparotomy. The objective of the study was to see theeffectiveness of oral Clonidine as a preanesthetic medication and to determine which dose of oral Clonidine givesbetter analgesic effect. Method: In this prospective, randomized, double-blind, controlled study sixty adult female patients of ASA physicalstatus I &amp; II aged 18-40 yrs, undergoing gynaecological laparotomy received low dose clonidine 2-2.5mcg/kg (n=30)and high dose clonidine 4-4.5mcg/kg (n=30).These drugs were administered 105 min before the estimated time ofinduction of anesthesia. Heart rate &amp; arterial pressure were recorded prior to induction, 5 min intervally upto 20 minin peroperative time and 2 hour intervally upto 6 hours in postoperative period. In the Group-A (clonidine2-2.5mcg/kg) mean heart rate ranged from73.80 ±8.69 to 71.45±5.80, in Group-B mean heart rate decreased morefrom 70.85±7.64 to 67.85±6.47. Systolic blood pressure in Group-A (low dose clonidine) was 113.00±7.32, inGroup-B (high dose clonidine) was 120.00±10.38 and where p=0.024. Diastolic blood pressure of Group-A (low doseclonidine) was 76.15±5.29, in Group-B(high dose clonidine) was 80.10±5.3. Postoperative pain was assessed by ablinded observer using a VAS scale. This study was done in the department of anesthesiology of Apollo HospitalsDhaka over a period of six months. Results: Patients in group A (low dose) and group B (high dose) showed no significant hemodynamic changesbetween groups. Five patients in group B showed marked hypotension and bradycardia and treatedaccordingly.Group B patients (high dose clonidine) showed more post operative analgesia compared to group A. Conclusion: These data suggest that low dose clonidine (100mcg/kg) premedication is safe and effective to facilitatepost-operative analgesia with stable haemodynamics &amp; without any side effects. On the other hand,.high doseclonidine showed more post op analgesia &amp;.marked hypotension and bradycardia. JBSA 2022; 35 (2) : 12-16

Quantitative assessment of the central versus peripheral effect of intravenous clonidine using baroreflex equilibrium diagrams

Clonidine is a first-generation central antihypertensive that reduces sympathetic nerve activity (SNA). Although clonidine also exerts peripheral vasoconstriction, the extent to which this vasoconstriction offsets the centrally mediated arterial pressure (AP)-lowering effect remains unknown. In anesthetized rats (n = 8), we examined SNA and AP responses to stepwise changes in carotid sinus pressure under control conditions and after intravenous low-dose (2 μg/kg) and high-dose clonidine (5 μg/kg). In the baroreflex equilibrium diagram analysis, the operating-point AP under the control condition was 115.2 (108.5–127.7) mmHg [median (25th–75th percentile range)]. While the operating-point AP after low-dose clonidine was not significantly different with or without the peripheral effect, the operating-point AP after high-dose clonidine was higher with the peripheral effect than without [81.3 (76.2–98.2) mmHg vs. 70.7 (57.7–96.9), P < 0.05]. The vasoconstrictive effect of clonidine partly offset the centrally mediated AP-lowering effect after high-dose administration.

Efficacy of buprenorphine and clonidine in opioid detoxification: A hospital- based study.

Background:The need for effective and accepted method for opioid detoxification is ever increasing. Sublingual buprenorphine and oral clonidine have been effective in opioid detoxification. As often, there is a great variation in the dosage of buprenorphine and clonidine prescribed by the clinicians; hence, there is a felt need to find an effective dosage for a favorable outcome of opioid detoxification.Objective:The objective of this study was to compare the effectiveness of different doses of sublingual buprenorphine and clonidine in opioid detoxification.Materials and Methods:A total of 100 patients with the diagnosis of opioid dependence as per the international classification of diseases-10 criteria were recruited for this study. Participants were assigned randomly into four groups – low-dose clonidine, high-dose clonidine, low-dose sublingual buprenorphine, and high sublingual dose buprenorphine using a computer-generated random number table, resulting in 25, 26, 23, and 26 patients in each group, respectively.Results:The four groups had comparable scores on all the items of “stages of change readiness and treatment eagerness scale” for the assessment of motivation at baseline. Progressive decrease in withdrawal score was seen in all the groups on “clinical opiate withdrawal scale” and “subjective opiate withdrawal scale.”Conclusion:From the current study, we can infer that both low and high doses of buprenorphine and clonidine are comparable regarding controlling withdrawal.

Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier.

The impermeability of the adult blood-brain barrier (BBB) to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases.Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse) of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy.

Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination.

Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced anti-nociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore- or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.

Partial neuroprotection with low-dose infusion of the α 2-adrenergic receptor agonist clonidine after severe hypoxia in preterm fetal sheep

We have previously shown that brief α 2-adrenergic receptor blockade increased neuronal injury after severe hypoxia in preterm fetal sheep. We now examine whether infusion of an α 2-adrenergic receptor agonist, clonidine, is neuroprotective. Preterm fetal sheep (70% gestation) received either saline-vehicle or clonidine at either 10 μg/kg/h (low-dose) or 100 μg/kg/h (high-dose) from 15 min until 4 h after 25 min of umbilical cord occlusion. Both low- and high-dose clonidine infusions after sham-occlusion were associated with transient EEG suppression but no neuronal loss. Low-dose but not high-dose clonidine infusions after umbilical cord occlusion were associated with a significant overall increase in numbers of surviving neurons after three days' recovery. High-dose clonidine was associated with transient hyperglycemia and increased numbers of delayed electrographic seizures. These results provide further evidence that α 2-adrenergic receptor activation shortly after perinatal hypoxia–ischemia can promote neural recovery, but highlight the complex dose–response of exogenous therapy.

Growth parameters, growth hormone (GH) response to clonidine and circulating insulin-like growth factor-I (IGF-I), free thyroxine (FT4) and cortisol concentrations in relation to glycaemic control in children with insulin-dependent diabetes mellitus.

The objective of this paper was to determine the effect of glycaemic control and endocrine functions on linear growth in children with IDDM. We studied 45 prepubertal children with IDDM (30 males, 15 females) over 1 year period. The mean +/- SD for age of onset and duration of IDDM were 6.2 +/- 2.3 years and 3.5 +/- 1.3 years, respectively. At each clinic visit (every 3 months), glycaemic control was assessed by measuring glycosylated haemoglobin (HbA1C). Growth hormone and cortisol responses to high dose clonidine (0.15 mg/m2) and ACTH, respectively, were evaluated and circulating concentrations of free thyroxine (FT4) and TSH estimated. The average insulin dose (unit/kg/day) during this period was calculated for each patient. Growth was assessed by determining both height standard deviation score (HtSDS) and growth velocity standard deviation scores (GVSDS) and bone age determined according to the atlas of Greulich and Pyle. Two-hundred-and-fifty age- and sex-matched normal children served as controls for growth data, and 20 normal age-matched children and 20 normal children with short stature (NVSS) served as controls for the hormonal studies. Growth velocity (GV) (cm/year) and GVSDS were significantly lower in children with IDDM compared to normal children, and significantly lower in children with poorly controlled diabetes compared to those with good glycaemic control. GV and GVSDS were inversely correlated to HbA1C (r = -0.356, P < 0.01 and r = 0.335, P < 0.01 respectively). GVSDS was correlated with serum IGF-I (r = 0.22, P < 0.01), FT4 (r = 0.321, P < 0.01) and inversely with basal GH (r = -0.362, P < 0.01) concentrations, but was not correlated with cortisol levels or peak GH concentrations in response to clonidine. GVSDS was correlated with HtSDS (r = 0.222, P < 0.01) and inversely with age (r = -0.43, P < 0.05). There was no significant correlation between GVSDS on the one hand and weight gain or body mass index (BMI) on the other hand. Peak GH response to clonidine was correlated with BMI (r = 0.68, P < 0.001) and insulin dose/kg/day (r = 0.602, P < 0.01). This study confirms that in children with IDDM linear growth velocity is dependent on the age of the child and the degree of glycaemic control, as well as on growth promoting hormones such as IGF-I and FT4. High BMI is associated with more GH secretion in response to clonidine, this might explain the higher requirements of insulin/kg in children with IDDM and high BMI.

Nocturnal growth hormone (GH) secretion and GH response to clonidine provocation in children before and after long-term prednisone therapy.

Glucocorticoids reduce growth hormone (GH) response to the majority of exogenously administered stimuli and can variably inhibit growth in man and animals. Recently, however, glucocorticoids have been shown to have varying effects on GH secretion depending on the time of administration and, furthermore, to be potent secretagogues. We evaluated growth parameters, GH response to high-dose clonidine and integrated (12-h) nocturnal and mean (12-h) nocturnal GH secretion in 10 prepubertal children before and after long-term alternate-day prednisone therapy (LTPT). Height standard deviation scores (HtSDS) and growth velocity standard deviation scores (GVSDS) decreased significantly after LTPT. GH response to clonidine as well as integrated and mean nocturnal GH secretion were significantly after LTPT. GH response to clonidine as well as integrated and mean nocturnal GH secretion were significantly depressed after LTPT v. before treatment. We compared growth parameters and GH data of two groups of children before and after LTPT. Group 1 had low GH peak response to clonidine after LTPT, and group 2 had normal GH response to clonidine. Group 1 children had significantly more impairment of their statural growth and nocturnal GH secretion. Growth parameters (HtSDS and GVSDS) during LTPT correlated significantly with the peak GH response to clonidine (r=0.69 and 0.78, respectively) as well as to the growth parameters before therapy (r > 0.9). It appears that LTPT impairs both physiologic and pharmacologically provoked GH secretion and consequently retards growth in children. However, this effect is variable and is affected by the attained statural growth before therapy.

Analgesie und Hämodynamik unter 8 μg/kg Clonidin epidural zur Schmerztherapie nach großen abdominellen Eingriffen

To characterise the haemodynamic profile after epidural injection of high-dose clonidine for postoperative pain management and to establish recommendations for the therapy of haemodynamic instabilities. 20 patients with major surgery on pancreas, stomach or infrarenal aorta took part in the study. Anaesthesia was a combined epidural/inhalational regimen with bupivacaine 0.25%, enflurane, oxygen/nitrous oxide, fentanyl 0.1 mg and pancuronium. Postoperative analgesia consisted of morphine 50 micrograms/kg in 10 ml NaCl 0.9% for the first 12 postoperative hours; if pain > = 5 points on the VAS occurred after > 12 h postoperatively clonidine 8 micrograms/kg in 10 ml NaCl 0.9% was injected epidurally and the pain intensity (self-assessment by the patient using the visual analog scale) and circulation (invasive pressure monitoring, pulmonary artery catheter) was monitored for 60 minutes in ten minutes intervals. The reduction of the initial VAS score of 6 was 50% after 20 minutes and 100% after 60 minutes. We observed a significant decline in heart rate (87 +/- 11 (t0), 74 +/- 10 min-1 (t60)), mean arterial pressure (97 +/- 17 (t0), 72 +/- 15 mmHg (t60)) and cardiac output (8.7 +/- 1.3 (t0), 7.0 +/- 1.3 l.min-1 (t60)) (all p < 0.001) and no change of systemic vascular resistance. Filling pressures (CVP and PCWP) remained stable. In 9 patients the mean arterial pressure fell below 60 mmHg (always within the first 40 min); 6 of these patients responded to infusion of a colloid (500 ml of hydroxyethyl starch at > = 2 ml/kg.min) whereas the other 3 patients needed a bolus injection of a betamimetic catecholamine (theodrenaline/cafedrine, Akrinor). Epidural clonidine 8 micrograms/kg causes rapid and intense analgesia. Haemodynamic instability is a consequence of a drop in heart rate and has to be treated accordingly. The application of a pure vasopressor does not seem to be indicated taking in account the fact that the total peripheral resistance remains unchanged and in the normal range.

Clinical Efficacy of Oral—Transdermal Clonidine Combinations during the Perioperative Period

In an attempt to maintain stable levels of an alpha 2-adrenergic agonist throughout the perioperative period, two different oral-transdermal clonidine dosage regimens were administered according to a randomized, double-blind, placebo-controlled study in patients undergoing abdominal surgery. We determined the clinical efficacy of a high- and a low-dose clonidine regimen on sedation, hemodynamic parameters, anesthesia, and analgesia. The low-dose clonidine group of patients (n = 14) received a 7-cm2 clonidine transdermal patch (Catapres-TTS #2), which was supplemented with oral doses of clonidine approximately 3 micrograms.kg-1 on the evening prior to surgery and on the morning of surgery. The high-dose clonidine group (n = 14) received a 10.5-cm2 clonidine transdermal patch (Catapres-TTS #3) with oral clonidine approximately 4.5 micrograms.kg-1 at bedtime and 6.0 micrograms.kg-1 on the morning of surgery. Placebo-treated (control) patients received the same occlusive patch without active ingredient and oral placebo tablets at bedtime and on the morning of surgery. Preanesthetic medication included midazolam 50 micrograms.kg-1 intramuscularly (im). Anesthesia was induced with alfentanil 30 micrograms.kg-1 intravenously (iv), thiopental 3 mg.kg-1 iv, and vecuronium 0.1 mg.kg-1 iv, and was maintained with 70% nitrous oxide in oxygen and a continuous infusion of alfentanil 0.5 microgram.kg-1.min-1. Isoflurane was added when the blood pressure exceeded 110% of the patient's prestudy value. For pain relief postoperatively, the patients received morphine, 1-2-mg iv boluses, via a patient-controlled analgesia pump. The low-dose clonidine patient group had mean plasma clonidine concentrations that varied from 1.47 ng.ml-1 (preoperative) to 1.32 ng.ml-1 (postoperative day 2).(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose clonidine motor syndrome: relationship to serotonin syndrome.

Reciprocal forepaw treading, hindlimb abduction, and Straub tail are some of the abnormal motor behaviors of the classical 'serotonin syndrome,' which results from activation of serotonin (5-HT) receptors. However, we also observed them in the syndrome evoked by the alpha-adrenergic agonist clonidine, at high doses (5-40 mg/kg). Other features of the clonidine syndrome (scored from videotapes) were body and head tremor, forelimb hyperextension, ataxia, vertical jumping, tactile hyperreactivity, and autonomic signs (piloerection, pupillary dilatation, salivation, proptosis). The clonidine syndrome persisted for several hours and was not lethal. Clonidine suppressed locomotor activity (photocell recording) and induced episodes of catalepsy and 5-HT-independent impairment of motor habituation. Single high doses of drugs active at several different neurotransmitter receptors significantly reduced total behavioral score through effects primarily on tremor and autonomic signs, but none prevented the clonidine syndrome. Lesions of monoaminergic neurons [intracisternal 5,7-dihydroxytryptamine (DHT) or 6-hydroxydopamine] or monoamine depletion by intraperitoneal reserpine all failed to prevent this motor syndrome. Co-administration of 5-HTP and clonidine did not exacerbate the clonidine syndrome in naive rats and did not prevent the onset of the serotonergic syndrome in rats with DHT lesions. These data suggest that neither catecholamines nor 5-HT have a major role in the serotonin-like behavioral responses to high doses of clonidine.

Alpha-2-adrenergic control of prolactin release.

The role of the alpha 2-adrenergic system in regulating prolactin release has been studied in vivo in male rats. Yohimbine administration alone, at doses ranging from 0.2 to 5.0 mg/kg, resulted in a dose-related elevation of plasma prolactin levels from a basal level of 8 +/- 2 to 65 +/- 6 ng/ml at the highest dose. In the same experiment clonidine, 0.2 mg/kg, suppressed basal prolactin levels to 4 +/- 1 ng/ml and returned prolactin levels of all animals receiving 0.2-5.0 mg/kg yohimbine to basal levels. Rats were treated with increasing doses of clonidine (0.05-1.0 mg/kg) in the presence or absence of a constant dose (1.0 mg/kg) of yohimbine. Clonidine alone at doses of 0.05 and 0.2 mg/kg again significantly suppressed prolactin levels, while a dose of 1.0 mg/kg did not (failure of high dose clonidine to suppress prolactin levels suggests an additional effect of clonidine on prolactin secretion unrelated to alpha 2-adrenergic agonist action). All three doses of clonidine completely reversed yohimbine-induced prolactin release. Basal prolactin levels were also significantly reduced by the selective alpha 2-adrenergic agonist UK-14,304 at a dose of 0.2 mg/kg. Yohimbine-induced prolactin release was reversed by UK-14,304 at doses of 0.2 and 1.0 mg/kg, but not at the lowest dose studied, 0.05 mg/kg. The lower potency of UK-14,304 than clonidine in this assay is consistent with the lower potency of UK-14,304 as an alpha 2-adrenergic-agonist antihypertensive agent. Several alpha 2-antagonists in addition to yohimbine were studied.(ABSTRACT TRUNCATED AT 250 WORDS)