Topical Clonidine Accelerates Cutaneous Wound Healing in Diabetic Rats by Regulating the Expression of Related Cytokine Signaling.

Based on the analgesic and anti-inflammatory effects of clonidine in previous studies, we hypothesized that clonidine could accelerate wound healing in rats by regulating the expression of related cytokines. In this study, the wound healing effect of clonidine was evaluated using an excision wound model in diabetic rats and a HaCaT cell model. The wounds were treated daily with topical clonidine. The results analyzed by ImageJ2 software show that the wounds of the rats that were treated with 15 ng/mL clonidine recovered faster, and the wound size was also significantly reduced compared to the control group. Western blot assays determined that clonidine induced an increase in the expression of vascular growth factors, namely, Ang-1, Ang-2, and VEGF. Moreover, clonidine demonstrated a rescuing effect on JAK2 within the JAK/STAT pathway by inhibiting SOCS3 expression, leading to decreased SOCS3 levels and increased expression of JAK2 and phospho-STAT3. Histopathological analysis revealed that clonidine promoted complete epithelial repair and minimized inflammation in skin tissue. Additionally, clonidine stimulated HaCaT cell proliferation in vitro and enhanced cellular energy levels in the presence of AGEs. In conclusion, clonidine promoted vascular growth and wound healing by stimulating the expression of cytokines that are beneficial for wound healing.

Partial chemogenetic inhibition of the locus coeruleus due to heterogeneous transduction of noradrenergic neurons preserved auditory salience processing in wild-type rats.

The acoustic startle reflex (ASR) and prepulse inhibition of the ASR (PPI) assess the efficiency of salience processing, a fundamental brain function that is impaired in many psychiatric conditions. Both ASR and PPI depend on noradrenergic transmission, yet the modulatory role of the locus coeruleus (LC) remains controversial. Clonidine (0.05 mg/kg, i.p.), an alpha2-adrenoreceptor agonist, strongly reduced the ASR amplitude. In contrast, chemogenetic LC inhibition only mildly suppressed the ASR and did affect the PPI in virus-transduced rats. The canine adenovirus type 2 (CAV2)-based vector carrying a gene cassette for the expression of inhibitory receptors (hM4Di) and noradrenergic cell-specific promoter (PRSx8) had high cell-type specificity (94.4 ± 3.1%) but resulted in heterogeneous virus transduction of DbH-positive LC neurons (range: 9.2-94.4%). Clozapine-N-oxide (CNO; 1 mg/kg, i.p.), a hM4Di actuator, caused the firing cessation of hM4Di-expressing LC neurons, yet complete inhibition of the entire population of LC neurons was not achieved. Case-based immunohistochemistry revealed that virus injections distal (> 150 µm) to the LC core resulted in partial LC transduction, while proximal (< 50 µm) injections caused neuronal loss due to virus neurotoxicity. Neither the ASR nor PPI differed between the intact and virus-transduced rats. Our results suggest that a residual activity of virus-non-transduced LC neurons might have been sufficient for mediating an unaltered ASR and PPI. Our study highlights the importance of a case-based assessment of the virus efficiency, specificity, and neurotoxicity for targeted cell populations and of considering these factors when interpreting behavioral effects in experiments employing chemogenetic modulation.

Attention-deficit/hyperactivity disorder in pregnancy and the postpartum period.

Attention-deficit/hyperactivity disorder is a childhood-onset neurodevelopmental disorder that frequently persists into adulthood with 3% of adult women having a diagnosis of attention-deficit/hyperactivity disorder. Many women are diagnosed and treated during their reproductive years, which leads to management implications during pregnancy and the postpartum period. We know from clinical practice that attention-deficit/hyperactivity disorder symptoms frequently become challenging to manage during the perinatal period and require additional support and attention. There is often uncertainty among healthcare providers about the management of attention-deficit/hyperactivity disorder in the perinatal period, particularly the safety of pharmacotherapy for the developing fetus. This guideline is focused on best practices in managing attention-deficit/hyperactivity disorder in the perinatal period. We recommend (1) mitigating the risks associated with attention-deficit/hyperactivity disorder that worsen during the perinatal period via individualized treatment planning; (2) providing psychoeducation, self-management strategies or coaching, and psychotherapies; and, for those with moderate or severe attention-deficit/hyperactivity disorder, (3) considering pharmacotherapy for attention-deficit/hyperactivity disorder, which largely has reassuring safety data. Specifically, providers should work collaboratively with patients and their support networks to balance the risks of perinatal attention-deficit/hyperactivity disorder medication with the risks of inadequately treated attention-deficit/hyperactivity disorder during pregnancy. The risks and impacts of attention-deficit/hyperactivity disorder in pregnancy can be successfully managed through preconception counselling and appropriate perinatal planning, management, and support.

Intraoperative clonidine in endometriosis and spine surgery: A protocol for two randomised, blinded, placebo-controlled trials.

BACKGROUND: A high proportion of patients who undergo surgery continue to suffer from moderate to severe pain in the early postoperative period despite advances in pain management strategies. Previous studies suggest that clonidine, an alpha2 adrenergic agonist, administered during the perioperative period could reduce acute postoperative pain intensity and opioid consumption. However, these studies have several limitations related to study design and sample size and hence, further studies are needed. AIM: To investigate the effect of a single intravenous (IV) dose of intraoperative clonidine on postoperative opioid consumption, pain intensity, nausea, vomiting and sedation after endometriosis and spine surgery. METHODS: Two separate randomised, blinded, placebo-controlled trials are planned. Patients scheduled for endometriosis (CLONIPAIN) will be randomised to receive either 150 µg intraoperative IV clonidine or placebo (isotonic saline). Patients undergoing spine surgery (CLONISPINE) will receive 3 µg/kg intraoperative IV clonidine or placebo. We aim to include 120 patients in each trial to achieve power of 90% at an alpha level of 0.05. OUTCOMES: The primary outcome is opioid consumption within the first three postoperative hours. Secondary outcomes include pain intensity at rest and during coughing, nausea, vomiting and sedation within the first two postoperative hours and opioid consumption within the first six postoperative hours. Time to discharge from the PACU will be registered. CONCLUSION: This study is expected to provide valuable information on the efficacy of intraoperative clonidine in acute postoperative pain management in patients undergoing endometriosis and spine surgery.

Presynaptic Adrenoceptors.

Presynaptic α2-adrenoceptors are localized on axon terminals of many noradrenergic and non-noradrenergic neurons in the peripheral and central nervous systems. Their activation by exogenous agonists leads to inhibition of the exocytotic release of noradrenaline and other transmitters from the neurons. Most often, the α2A-receptor subtype is involved in this inhibition. The chain of molecular events between receptor occupation and inhibition of the exocytotic release of transmitters has been determined. Physiologically released endogenous noradrenaline elicits retrograde autoinhibition of its own release. Some clonidine-like α2-receptor agonists have been used to treat hypertension. Dexmedetomidine is used for prolonged sedation in the intensive care; It also has a strong analgesic effect. The α2-receptor antagonist mirtazapine increases the noradrenaline concentration in the synaptic cleft by interrupting physiological autoinhibion of release. It belongs to the most effective antidepressive drugs. ß2-Adrenoceptors are also localized on axon terminals in the peripheral and central nervous systems. Their activation leads to enhanced transmitter release, however, they are not activated by endogenous adrenaline.

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats.

Apoptosis is the crucial pathological mechanism following cerebral ischemic injury. Our previous studies demonstrated that clonidine, one agonist of alpha2-adrenergic receptor (α2-AR), could attenuate cerebral ischemic injury in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). However, it's unclear whether clonidine exerts neuroprotective effects by regulating neuronal apoptosis. In this study, we elucidated whether clonidine can exert anti-apoptotic effects in cerebral ischemic injury, and further explored the possible mechanisms. Neurological deficit score was measured to evaluate the neurological function. TTC staining was used for the measurement of brain infarct size. Hematoxylin-Eosin (HE) staining was applied to examine the cell morphology. TUNEL and DAPI fluorescent staining methods were used to analyze the cell apoptosis in brain tissue. Fluorescence quantitative real-time PCR was performed to assess the gene expression of Caspase-3 and P53. Western blotting assay was applied to detect the protein expression of Caspase-3 and P53. The results showed that clonidine improved neurological function, reduced brain infarct size, alleviated neuronal damage, and reduced the ratio of cell apoptosis in the brain with MCAO/R injury. moreover, clonidine down-regulated the gene and protein expression of Caspase-3 and P53 which were over-expressed after MCAO/R injury. Whereas, yohimbine (one selective α2-AR antagonist) mitigated the anti-apoptosis effects of clonidine, accompanied by reversed gene and protein expression changes. The results indicated that clonidine attenuated cerebral MCAO/R injury via suppressing neuronal apoptosis, which may be mediated, at least in part, by activating α2-AR.

Blood pressure response to clonidine in children with short stature is correlated with postural characteristics: a retrospective cross-sectional study.

BACKGROUND: Clonidine stimulation test has been widely used in the diagnosis of growth hormone deficiency in children with short stature with a high level of reliability. However, it may cause hypotension, which usually appears as headache, dizziness, bradycardia, and even syncope. It is well known that elevating the beds to make patients' feet above their cardiac level might relieve this discomfort. However, the real efficiency of this method remains to be proved while the best angle for the elevated bed is still unclear. METHODS: A total of 1200 children with short stature were enrolled in this retrospective cross-sectional study. Age, gender, weight, and basic systolic and diastolic blood pressure were collected. Blood pressure at 1, 2, 3, and 4 h after stimulation tests were recorded. The participants were divided into 3 groups based on the angles of the elevated foot of their beds named 0°, 20°, and 40° groups. RESULTS: At one hour after the commencement of the tests, participants lying on the elevated beds showed a higher mean increase on the change of pulse pressure. The difference in the angles of the elevated beds did not show statistical significance compared with those who did not elevate their beds (0.13 vs. 2.83, P = 0.001; 0.13 vs. 2.18, P = 0.005; 2.83 vs. 2.18, P = 0.369). When it came to 4 h after the tests began, participants whose beds were elevated at an angle around 20° had a significantly higher mean increase in the change of pulse pressure values compared with those whose beds were elevated at an angle around 40° (1.46 vs. -0.05, P = 0.042). CONCLUSION: Elevating the foot of the beds of the patients who are undergoing clonidine stimulation tests at an angle of 20°might be a good choice to alleviate the hypotension caused by the tests.

The Impact of Sedative Choice in the Management of Aneurysmal Subarachnoid Hemorrhage: A Scoping Review.

Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high mortality and morbidity. This scoping review assesses the current evidence regarding the use of sedatives and analgesics in the acute intensive care unit management of aSAH. We conducted a systematic search of Ovid MEDLINE, Ovid Embase, Ovid EmCare, APA PsycInfo, CINAHL, and the Cochrane Database of Systematic Reviews from inception to June 2023. Studies were included if they enrolled intensive care unit patients aged 18 or older with a significant proportion (> 20%) who had aSAH and evaluated the impact of one or more commonly used analgosedatives on physiological parameters in the management of aSAH. The methodological quality of the studies was assessed using the Methodological Index for Nonrandomized Studies score. Of 2,583 articles, 11 met the inclusion criteria. The median sample size was 47 (interquartile range 10-127), and the median Methodological Index for Nonrandomized Studies score was 9.5 (interquartile range 8-11). The studies' publication years ranged from 1980 to 2023. Dexmedetomidine and ketamine showed potential benefits in reducing the incidence of cortical spreading depolarization and delayed cerebral ischemia. Propofol and opioids appeared safe but lacked robust evidence for efficacy. Benzodiazepines were associated with increased delayed cerebral ischemia-related cerebral infarctions and cortical spreading depolarization events. The evidence available to guide the use of analgosedative medications in aSAH is critically inadequate. Dexmedetomidine and ketamine warrant further exploration in large-scale prospective studies because of their potential benefits. Improved study designs with consistent definitions and a focus on patient-centered outcomes are necessary to inform clinical practice.

A Comparative Study of the Antiemetic Effects of α2-Adrenergic Receptor Agonists Clonidine and Dexmedetomidine against Diverse Emetogens in the Least Shrew (Cryptotis parva) Model of Emesis.

In contrast to cats and dogs, here we report that the α2-adrenergic receptor antagonist yohimbine is emetic and corresponding agonists clonidine and dexmedetomidine behave as antiemetics in the least shrew model of vomiting. Yohimbine (0, 0.5, 0.75, 1, 1.5, 2, and 3 mg/kg, i.p.) caused vomiting in shrews in a bell-shaped and dose-dependent manner, with a maximum frequency (0.85 ± 0.22) at 1 mg/kg, which was accompanied by a key central contribution as indicated by increased expression of c-fos, serotonin and substance P release in the shrew brainstem emetic nuclei. Our comparative study in shrews demonstrates that clonidine (0, 0.1, 1, 5, and 10 mg/kg, i.p.) and dexmedetomidine (0, 0.01, 0.05, and 0.1 mg/kg, i.p.) not only suppress yohimbine (1 mg/kg, i.p.)-evoked vomiting in a dose-dependent manner, but also display broad-spectrum antiemetic effects against diverse well-known emetogens, including 2-Methyl-5-HT, GR73632, McN-A-343, quinpirole, FPL64176, SR141716A, thapsigargin, rolipram, and ZD7288. The antiemetic inhibitory ID50 values of dexmedetomidine against the evoked emetogens are much lower than those of clonidine. At its antiemetic doses, clonidine decreased shrews' locomotor activity parameters (distance moved and rearing), whereas dexmedetomidine did not do so. The results suggest that dexmedetomidine represents a better candidate for antiemetic potential with advantages over clonidine.

Neuraxial clonidine is not associated with lower post-cesarean opioid consumption or pain scores in parturients on chronic buprenorphine therapy: a retrospective cohort study.

PURPOSE: Adequate post-cesarean delivery analgesia can be difficult to achieve for women diagnosed with opioid use disorder receiving buprenorphine. We sought to determine if neuraxial clonidine administration is associated with decreased opioid consumption and pain scores following cesarean delivery in women receiving chronic buprenorphine therapy. METHODS: This was a retrospective cohort study at a tertiary care teaching hospital of women undergoing cesarean delivery with or without neuraxial clonidine administration while receiving chronic buprenorphine. The primary outcome was opioid consumption (in morphine milligram equivalents) 0-6 h following cesarean delivery. Secondary outcomes included opioid consumption 0-24 h post-cesarean, median postoperative pain scores 0-24 h, and rates of intraoperative anesthetic supplementation. Multivariable analysis evaluating the adjusted effects of neuraxial clonidine on outcomes was conducted using linear regression, proportional odds model, and logistic regression separately. RESULTS: 196 women met inclusion criteria, of which 145 (74%) received neuraxial clonidine while 51 (26%) did not. In univariate analysis, there was no significant difference in opioid consumption 0-6 h post-cesarean delivery between the clonidine (8 [IQR 0, 15]) and control (1 [IQR 0, 8]) groups (P = 0.14). After adjusting for potential confounders, there remained no significant association with neuraxial clonidine administration 0-6 h (Difference in means 2.77, 95% CI [- 0.89 to 6.44], P = 0.14) or 0-24 h (Difference in means 8.56, 95% CI [- 16.99 to 34.11], P = 0.51). CONCLUSION: In parturients receiving chronic buprenorphine therapy at the time of cesarean delivery, neuraxial clonidine administration was not associated with decreased postoperative opioid consumption, median pain scores, or the need for intraoperative supplementation.

The Effect of Clonidine Premedication on Hemodynamic Changes Following Tracheal Intubation and Co2 Gas Insufflation and Postoperative Shivering In Patients Undergoing Laparoscopic Cholecystectomy; a Randomized Clinical Trial.

BACKGROUND: Laparoscopic cholecystectomy is a proper treatment for cholecystitis but the Carbon dioxide gas which is used in surgery stimulates the sympathetic system and causes hemodynamic changes and postoperative shivering in patients undergoing operations. This study was conducted to evaluate the effects of clonidine on reducing hemodynamic changes during tracheal intubation and Carbon dioxide gas insufflation and postoperative shivering in patients undergoing laparoscopic cholecystectomy. MATERIAL AND METHODS: This prospective, randomized, triple-blind clinical trial was conducted on 60 patients between the 18-70 years-old age group, who were candidates of laparoscopic cholecystectomy surgery. The patients randomized into two groups (30 patients received 150 µg oral clonidine) and 30 patients received 100 mg oral Vitamin C). Heart rate and mean arterial pressure of patients were recorded before anesthesia, before and after laryngoscopy, before and after Carbon dioxide gas insufflation. Data were analyzed using Chi-2, student t-test, and analysis of variance by repeated measure considering at a significant level less than 0.05. RESULTS: The findings of this study showed that both heart rate and mean arterial pressure in clonidine group after tracheal intubation and Carbon dioxide gas insufflation were lower than patients in the placebo group, but there was not any statistically significant difference between the two groups (p>0.05) and also postoperative shivering was not different in groups. There was no significant statistical difference in postoperative shivering between the two groups (p>0.05). CONCLUSION: Using 150 µg oral clonidine as a cheap and affordable premedication in patients undergoing laparoscopic cholecystectomy improves hemodynamic stability during operation.

A double-blinded randomized control trial to compare the duration of analgesia using morphine, clonidine, or dexmedetomidine as adjuvants to ropivacaine in caudal anesthesia in children undergoing infraumbilical surgeries.

Background and Aims: Adjuvants added to the caudal block prolong the duration of analgesia. In a developing country with economic constraints, the choice of an adjuvant will be the medication with a longer duration of analgesia, a favorable side-effect profile, and the least expensive option. We wished to study the duration of postoperative analgesia afforded by three adjuvants: morphine, clonidine, and dexmedetomidine, at doses wherein minimal or nil adverse effects would be attributed to the adjuvant. The primary objective of the current study is to compare the duration of postoperative analgesia with morphine, clonidine, or dexmedetomidine as adjuvants to 0.2% ropivacaine in a for caudal block, in children undergoing elective abdominal, urogenital, and lower limb surgeries. The secondary objectives are (a) to study the total analgesic requirement during the first 24 hours after surgery and (b) to compare the incidence of complications among the three groups. Material and Methods: Sixty-three children aged 1-6 years, belonging to American Society of Anesthesia (ASA) physical status I, II, and scheduled to undergo elective infraumbilical surgeries, were enrolled in the study. The children were randomly assigned to one of three groups: Group D received a caudal block with dexmedetomidine 1 µg/kg, Group M received morphine 30 µg/kg, and Group C received clonidine 1.5 µg/kg. All groups also received 0.2% ropivacaine (1-1.25 ml/kg) as part of the caudal block. The duration of analgesia, total analgesic requirements during the first 24 hours after the surgery, and the incidence of complications in the three groups were monitored by a pain nurse who was blinded to the study allocation. Results: The three groups were comparable with respect to age, sex, weight, and duration of surgery. The median time taken for the first rescue analgesic in the dexmedetomidine group was 380 minutes, in the clonidine group was 360 minutes, and in the morphine group was 405 minutes. Though the morphine group had a longer duration of analgesia, it was not statistically significant (P = 0.843). The total perioperative opioids used and side effects were similar among the three groups. There were no episodes of intraoperative bradycardia noted in Groups D, M, and C. However, one patient in Group D required treatment for bradycardia in the postanesthesia care unit. In terms of intraoperative hypotension, 10 patients (43.5%) in Group D, 5 patients (27.8%) in Group C, and 5 patients (22.7%) in Group M required treatment, but this difference was not statistically significant (P = 0.299). There was no significant difference observed in the time to awakening after the anesthesia among the three groups. Postoperative nausea and vomiting were noted in five patients (21.7%) in Group D, one patient (5.6%) in Group C, and four patients (18.2%) in Group M (P = 0.382). One patient in Group M had a sedation score of 5 and required 4 hours of supplemental oxygen via face mask in the ward. Additionally, one patient in Group D reported numbness in both feet lasting 12 hours with spontaneous resolution. While a significant number of patients in all three study groups experienced urinary retention, no patient reported pruritus in the ward. Conclusion: Caudal administration of morphine, dexmedetomidine, and clonidine in children undergoing infraumbilical surgery resulted in an equivalent duration of analgesia.

Effect of oral clonidine on pain reduction in patients with opioid use disorder in the emergency department: A randomized clinical trial.

AIMS: Pain can create physical and psychosocial discomfort. Pain management of patients with opioid misuse history can be challenging, in part due to their tolerance to opioids. Clonidine is an alpha-2 agonist that has been used for the reduction of anxiety and pain. The aim of this study was to investigate the effect of oral clonidine on pain outcomes in patients with a history of opioid use disorder presenting with orthopaedic fractures in the emergency room. METHODS: In this blinded clinical trial in the emergency department, 70 opioid-dependent patients with orthopaedic fractures were divided into a control group of 35 and an intervention group of 35 subjects. Initially, 0.2 mg of oral clonidine was given to the intervention group and the control group received placebo tablets. Pain levels were recorded based on the Numerical Rating Scale rating before intervention, at 30 min, 1 h after intervention and at disposition from the emergency room (3-6 h after intervention). The total morphine requirement was also recorded. RESULTS: The pain score of the clonidine group was significantly lower than that of the control group at 1 h and at disposition time. The amount of morphine required was significantly reduced in the clonidine group (P < 0.05). Oral clonidine had no significant effect on pulse rate. Oral clonidine was more effective for pain reduction in lower limb injuries. CONCLUSION: Oral clonidine significantly reduced pain and the need for morphine in opioid-dependent patients with orthopaedic fractures.

Effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients in southwestern Iran: a randomized clinical trial.

BACKGROUND: Peripheral neuropathy is not only the most prevalent consequence of diabetes but also the main reason for foot ulceration, disability, and amputation. Therefore, the current study aims to determine the effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients. METHODS: This 12-week, randomized, and parallel-group trial was conducted to compare the efficacy of oral clonidine and gabapentin with gabapentin alone in diabetic patients in southwest Iran during the first half of 2021. Thirty patients with type 2 diabetes with peripheral neuropathy as assessed by a visual analog scale (VAS) and divided into two groups of 15 patients, treated for up to three months. The data were analyzed using SPSS-21 software. In order to report the results, descriptive indices, independent t-test, one-way analysis of covariance (ANCOVA) and analysis of variance with repeated measures were used. RESULTS: The mean and standard deviation of the age of the participants in the clonidine + gabapentin group was equal to 50.20 ± 7.44, and in the gabapentin group was equal to 50.47 ± 7.57 (t = 0.10, P-value = 0.923). This research showed a significant difference between the clonidine + gabapentin group and with gabapentin group in terms of neuropathic pain and the severity of neuropathic pain (P < 0.001). CONCLUSIONS: According to this research results, clonidine + gabapentin can reduce neuropathic pain and the severity of neuropathic pain in diabetic patients. Therefore, it is recommended that healthcare professionals with diabetes expertise prescribe these medications to reduce neuropathic pain and its severity. TRIAL REGISTRATION: This study was registered in the Iranian Clinical Trials System with the ID (IRCT20211106052983N1) on 14/01/2022.

Extinction and reinstatement of methamphetamine-induced conditioned place preference in zebrafish.

Conditioned place preference (CPP) paradigm in zebrafish has been used to measure drug reward, but there is limited research on CPP reinstatement to determine relapse vulnerability. The present study aimed to investigate extinction and reinstatement of methamphetamine (MA)-induced CPP in zebrafish and evaluate the model's predictive validity. Zebrafish received different doses of MA (0-60 mg/kg) during CPP training. The preferred dose of MA at 40 mg/kg was used for extinction via either confined or nonconfined procedures. The extinguished CPP was reinstated by administering a priming dose of MA (20 mg/kg) or various stressors. To assess persistent susceptibility to reinstatement, MA CPP and reinstatement were retested following 14 days of abstinence. In addition, the effects of SCH23390, naltrexone, and clonidine on MA CPP during acquisition, expression, or reinstatement phases were monitored. MA induced CPP in a dose-dependent manner. Both nonconfined and confined extinction procedures time-dependently reduced the time spent on the MA-paired side. A priming dose of MA, chasing stress, or yohimbine reinstated the extinguished CPP. After 14 days of abstinence, the MA CPP remained extinguished and was significantly reinstated by MA priming or chasing stress. Similar to the observations in rodents, SCH23390 suppressed the acquisition of MA CPP, naltrexone reduced the expression and MA priming-induced reinstatement, while clonidine prevented stress-induced reinstatement of MA CPP. This work expanded the zebrafish CPP paradigm to include extinction and reinstatement phases, demonstrating predictive validity and highlighting its potential as a valuable tool for exploring drug relapse.

Clonidine for preventing emergence agitation in infants (PREVENT AGITATION II): Protocol and statistical analysis plan.

BACKGROUND: Emergence agitation is a common clinical condition in children. Symptoms pertaining to the spectrum of early postoperative negative behavior typically occur upon emergence from anesthesia. Clonidine is an effective adjunctive agent for the prevention of emergence agitation in children, but evidence in the smallest age groups is sparse We aim to investigate the efficacy and safety of an intraoperative bolus of intravenous clonidine for preventing emergence agitation in children 3-12 months of age. METHODS: This is a randomized, placebo-controlled, double-blind trial. We will enroll 320 patients aged 3-12 months who have been scheduled for general anesthesia maintained with sevoflurane and opioid. The randomization is parallel and stratified by age group, sex, and site. The investigational medicinal product will be administered intravenously ~20 min before the anticipated end of the surgical procedure. The intervention is clonidine 3 µg/kg and placebo is isotonic saline in a corresponding volume. RESULTS: The primary outcome is the incidence of emergence agitation as assessed on the Watcha scale, that is, any Watcha score >2 during participants' stay in the postanesthetic care unit. Secondary outcomes are the proportion of participants with postoperative pain, with postoperative nausea and vomiting, and a composite safety outcome. Statistical analysis will be conducted according to the Statistical Analysis Plan with the intention-to-treat population for our primary analyses. CONCLUSION: The PREVENT AGITATION II trial will contribute valuable knowledge on efficacy for the prevention of emergence agitation and safety in infants.

Pediatric Takotsubo cardiomyopathy resulting from clonidine overdose.

Takotsubo cardiomyopathy is a syndrome characterized by localized apical dysfunction of the left ventricle. It is rarely seen in pediatric patients, but can carry significant morbidity and mortality. While most commonly associated with psychosocial stressors or physical exertion, a growing number of cases are being attributed to medications. We describe a case of a six-month-old male diagnosed with Takotsubo cardiomyopathy in the setting of an accidental clonidine overdose. The patient presented with altered mental status and hypertension. In the course of his broad workup, cardiac dysfunction was indicated by bedside ultrasound in the Emergency Department. The classic apical dyskinesis was seen on a follow-up, cardiology-based echocardiogram. The patient responded to high-dose naloxone and only briefly required an epinephrine infusion. His symptoms resolved in a few days and serial echocardiograms showed a return to normal LV function. Rates of pediatric clonidine overdoses are increasing in the setting of changing prescribing practices. Our case illustrates some key features of the clinical presentation, as well as demonstrates a rare sequelae to this common toxic exposure. To our knowledge, this is the first reported pediatric case of Takotsubo cardiomyopathy secondary to a clonidine overdose.

Postoperative recovery in preschool-aged children: A secondary analysis of a randomized controlled trial comparing premedication with midazolam, clonidine, and dexmedetomidine.

BACKGROUND: Preoperative anxiety in pediatric patients can worsen postoperative outcomes and delay discharge. Drugs aimed at reducing preoperative anxiety and facilitating postoperative recovery are available; however, their effects on postoperative recovery from propofol-remifentanil anesthesia have not been studied in preschool-aged children. Thus, we aimed to investigate the effects of three sedative premedications on postoperative recovery from total intravenous anesthesia in children aged 2-6 years. METHODS: In this prespecified secondary analysis of a double-blinded randomized trial, 90 children scheduled for ear, nose, and throat surgery were randomized (1:1:1) to receive sedative premedication: oral midazolam 0.5 mg/kg, oral clonidine 4 µg/kg, or intranasal dexmedetomidine 2 µg/kg. Using validated instruments, outcome measures including time for readiness to discharge from the postoperative care unit, postoperative sedation, emergence delirium, anxiety, pain, and nausea/vomiting were measured. RESULTS: After excluding eight children due to drug refusal or deviation from the protocol, 82 children were included in this study. No differences were found between the groups in terms of median time [interquartile range] to readiness for discharge (midazolam, 90 min [48]; clonidine, 80 min [46]; dexmedetomidine 100.5 min [42]). Compared to the midazolam group, logistic regression with a mixed model and repeated measures approach found no differences in sedation, less emergence delirium, and less pain in the dexmedetomidine group, and less anxiety in both clonidine and dexmedetomidine groups. CONCLUSIONS: No statistical difference was observed in the postoperative recovery times between the premedication regimens. Compared with midazolam, dexmedetomidine was favorable in reducing both emergence delirium and pain in the postoperative care unit, and both clonidine and dexmedetomidine reduced anxiety in the postoperative care unit. Our results indicated that premedication with α2 -agonists had a better recovery profile than short-acting benzodiazepines; although the overall recovery time in the postoperative care unit was not affected.

Stability of Morphine Sulfate-Clonidine and Sufentanil-Clonidine Mixtures.

BACKGROUND: Spinal analgesia is recommended for intractable cancer pain. Morphine-clonidine and sufentanil-clonidine are often used in association in intrathecal drug delivery systems, injected by intraabdominal pumps. To refill these pumps and to limit patient transport, it may be necessary to ship the mixtures in polypropylene syringes to peripheral establishments located near patient homes. The purpose of this study is to determine the stability of morphine-clonidine and sufentanil-clonidine mixtures in polypropylene syringes to ensure the best and safest transport conditions and in implantable pumps for intrathecal use. MATERIALS AND METHODS: The stability study method was conceived according to the International Council for Harmonization guidelines. For polypropylene syringes, four different mixtures of morphine-clonidine and sufentanil-clonidine were assessed over seven days. Two storage temperatures were tested (5 ± 3 °C and 25 ± 2 °C). For implantable pumps, two different mixtures of morphine-clonidine and sufentanil-clonidine were assessed over 28 days and stored at 37 °C. RESULTS: For the morphine-clonidine mixtures in polypropylene syringes, all mixtures remained stable for five days in both storage conditions (5 ± 3 °C and 25 ± 2 °C) because of relative concentrations systematically positioned between 90% and 110% (95% CIs of the mean of three samples). The two mixtures in implantable pumps remained stable for 28 days. For the sufentanil-clonidine mixtures in polypropylene syringes, cold conservation kept all the preparations stable for seven days, whereas a quick degradation was observed after only two days for ambient storage conditions. This result is similar to that with an implantable pump, in which the concentration is <90% on day 7 for low concentration mixtures. No visual modification, no significant pH modification, and no changes in turbidity assays were observed in either study. CONCLUSION: This study shows the stability of the morphine-clonidine mixtures in syringes stored at 5 °C for five days and in implantable pumps stored at 37 °C for 28 days. For the sufentanil-clonidine mixtures, the results show stability in syringes for seven days at 5 °C. Pump results show stability of seven days for low concentrations and 28 days for high concentrations.

Cardiorespiratory Response to Sedative Premedication in Preschool Children: A Randomized Controlled Trial Comparing Midazolam, Clonidine, and Dexmedetomidine.

PURPOSE: Sedative premedication in children may negatively impact their cardiorespiratory status during the perioperative course, and no clear consensus exists on the optimal premedication treatment for pediatric patients. The objective was to compare the perioperative cardiorespiratory responses to sedation using three different sedative premedication regimens in preschool children scheduled for surgery with total intravenous anesthesia. DESIGN: A single-center randomized controlled trial. METHODS: This is a planned secondary analysis of a study conducted at a 200-bed tertiary referral hospital. Ninety children participated in the study. They were aged 2-6 years and scheduled for ear, nose, and throat surgery with propofol/remifentanil anesthesia. Participants were randomly assigned to receive oral midazolam 0.5 mg/kg-1 (MID), oral clonidine 4 mcg/kg-1 (CLO), or intranasal dexmedetomidine 2 mcg/kg-1 (DEX). The main outcome measures were the sedation level, based on the Ramsay Sedation Scale (RSS), and cardiorespiratory status, monitored during the perioperative period. FINDINGS: The final cohort had 83 children (MID, n=27; CLO, n=26; DEX, n=30), with similar intergroup patient characteristics. RSS scores were lower in the MID group than in the CLO and DEX groups before induction and within 30 min postsurgery (P<0.001 and P=0.006, respectively). A negative correlation existed between the RSS and heart rate (HR) (r=-0.570, P<0.001). Before anesthesia induction, the respiratory rate was lowest in the DEX group (MID 21.5±1.7 min-1, CLO 20.6±2.6 min-1, DEX 20.2±1.7 min-1; P=0.042). The HR was lower in the CLO and DEX groups than in the MID group (MID, 102.8±10.0 min-1; CLO, 87.4±9.6 min-1; DEX, 87.6±7.9 min-1; P<0.001). The HR was lower immediately after induction (P=0.009) and intraoperatively (P=0.025) in the CLO and DEX groups than in the MID group. CONCLUSIONS: When used as premedication before propofol/remifentanil anesthesia, clonidine and dexmedetomidine provided deeper preoperative sedation compared to midazolam. From a clinical perspective, all three study drugs provided essentially stable cardiovascular and respiratory conditions during the entire perioperative period.