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.

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.

Review of clinical pharmacokinetics and pharmacodynamics of clonidine as an adjunct to opioids in palliative care.

Clonidine is an α-adrenoceptor agonist acting on receptors in the brain and peripheral tissues, leading to a reduction in sympathetic outflow and release of certain neurotransmitters. Clonidine has multiple uses across various medical conditions. One of its uses is as adjuvant to anaesthetic and analgesic agents specially opioids, mostly administered through intravenous and epidural routes. The opioids, effective in cancer pain management, are associated with various side effects such as sedation, pruritus, constipation, nausea, respiratory depression, tolerance and dependence. Combination of clonidine with opioids seems to help to achieve better pain management and less need of opioids. Use of clonidine in palliative care has been less common, but it is gradually gaining recognition for its potential benefits in managing symptoms like cancer pain and agitation. This combination approach has been explored in palliative care settings, including cancer pain and agitation, where patients experience complex and refractory symptoms. It seems to be well tolerated and gives better symptom relief. The available literature on clonidine's use in cancer pain and agitation management, especially in subcutaneous form, is limited and outdated. Therefore, the optimal dosing, safety profile and overall effectiveness of subcutaneous clonidine requires further exploration through prospective research studies.

Low dose lofexidine for medically directed outpatient opioid tapering in adults with chronic pain: a prospective case series.

BACKGROUND: In adults with chronic pain, mild-to-moderate withdrawal symptoms during medically directed opioid tapering in the outpatient setting may not be accompanied by hypertension or tachycardia. This clinical scenario could limit the use of lofexidine at dosages reported in clinical trials of opioid withdrawal precipitated by abrupt opioid discontinuation. Thus, the primary aim of this prospective case series is to describe the use of low dose lofexidine for opioid withdrawal in patients with chronic pain undergoing medically directed opioid tapering in an outpatient setting. METHODS: Six patients (white 5, Latino 1) admitted to an outpatient interdisciplinary pain rehabilitation program met inclusion and exclusion criteria. Patients self-selected to undergo medically directed opioid tapering, and the medication the patients were prescribed upon admission was used in the taper schedule. Upon initiation of the opioid taper, patients received 0.18 mg of lofexidine every 6 hours. RESULTS: Five of the six patients were women, and the median morphine milligram equivalents at baseline were 36.9. The median taper duration was 15 days, and the median duration of lofexidine administration was 14 days. Withdrawal scores were mild throughout the taper in four patients, and two patients with fibromyalgia experienced single episodes of moderately severe withdrawal symptoms at the median morphine milligram equivalent midpoint of the taper. No hypotension or sustained bradycardia were observed, and no adverse effects related to lofexidine were reported. CONCLUSION: The observations from this prospective case series suggest that low-dose lofexidine may be a feasible adjunct medication to attenuate withdrawal symptoms in adults with chronic pain undergoing outpatient opioid tapering.

Eliminating the benzos: A benzodiazepine-sparing approach to preventing and treating alcohol withdrawal syndrome.

BACKGROUND: Alcohol withdrawal syndrome (AWS) represents significant cost to the hospitalized trauma population from a clinical and financial perspective. Historically, AWS has been managed with benzodiazepines. Despite their efficacy, benzodiazepines carry a heavy adverse effect profile. Recently, benzodiazepine-sparing protocols for the prophylaxis and treatment of AWS have been used in medical patient populations. Most existing benzodiazepine-sparing protocols use phenobarbital, while ours primarily uses gabapentin and clonidine, and no such protocol has been developed and examined for safety and efficacy specifically within a trauma population. METHODS: In December of 2019, we implemented our benzodiazepine-sparing protocol for trauma patients identified at risk for alcohol withdrawal on admission. Trauma patients at risk for AWS admitted to an academic Level 1 trauma center before (conventional) and after (benzodiazepine-sparing [BS]) protocol implementation were compared. Outcomes examined include morphine milligram equivalent dosing rates and lorazepam equivalent dosing rates as well as the Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) scores, hospital length of stay, intensive care unit length of stay, and ventilator days. RESULTS: A total of 387 conventional and 134 benzodiazepine sparing patients were compared. Injury Severity Score (13 vs. 16, p = 0.10) and admission alcohol levels (99 vs. 149, p = 0.06) were similar. Patients in the BS pathway had a lower maximum daily CIWA-Ar (2.7 vs. 1.5, p = 0.04). While mean morphine milligram equivalent per day was not different between groups (31.5 vs. 33.6, p = 0.49), mean lorazepam equivalents per day was significantly lower in the BS group (1.1 vs. 0.2, p < 0.01). Length of stay and vent days were not different between the groups. CONCLUSION: Implementation of a benzodiazepine-sparing pathway that uses primarily clonidine and gabapentin to prevent and treat alcohol withdrawal syndrome in trauma patients is safe, reduces the daily maximum CIWA-Ar, and significantly decreases the need for benzodiazepines. Future studies will focus on outcomes affected by avoiding AWS and benzodiazepines in the trauma population. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Characterization of infant spinal anesthesia using surface electromyography: An observational study.

BACKGROUND: As the risks of general anesthesia in infants become clearer, pediatric anesthesiologists are seeking alternatives. Though infant spinal anesthesia is one such alternative, its use is limited by its perceived short duration. Prior studies investigating infant spinal anesthesia are open to interpretation and may not have accurately characterized block onset or density. Surface electromyography is a passive, noninvasive modality that can measure the effects of neural blockade. AIMS: To quantitatively describe the onset, density, and duration of infant spinal anesthesia using surface electromyography. METHODS: In this observational study, 13 infants undergoing lower abdominal surgery received spinal anesthesia (0.5% bupivacaine with clonidine). Surface electromyography collected continuous data at T2, right T8, left T8, and L2. Data were processed in MATLAB. Onset, density, and duration were defined as the mean derivative within the first 30 s after block administration, the maximum difference in signal compared with preblock baseline, and the time elapsed between block administration and the return of a persistent signal to 50% above the maximum difference, respectively. RESULTS: Mean patient age and weight were 7.5 ± 2.6 months and 8.0 ± 2.2 kg, respectively. All patients were male. There was a statistically significant difference in the average rate of spinal anesthesia onset (mean percent decrease per second [95% confidence interval]) between myotomes (F (3, 35) = 7.42, p < .001): T2 = 15.93 (9.23, 22.62), right T8 = 20.98 (14.52, 27.44), left T8 = 17.92 (11.46, 24.38), L2 = 32.92 (26.46, 39.38). There was a statistically significant difference in mean surface electromyography signal (mean decibels, 95% confidence interval) across both pre- and postspinal anesthesia Timepoints between myotomes (F (3, 36) = 32.63, p < .0001): T2 = 45.05 (38.92, 51.18), Right T8 = 41.26 (35.12, 47.39), Left T8 = 43.07 (36.93, 49.20), L2 = 22.79 (16.65, 28.92). Within each myotome, there was statistically significant, near complete attenuation of sEMG signal due to spinal anesthesia: T2 mean (pre-post) difference: mean decibels (95% confidence interval) = 39.53 (28.87, 50.20), p < .0001, right T8 = 51.97 (41.30, 62.64), p < .0001, left T8 = 46.09 (35.42, 56.76), p < .0001, L2 = 44.75 (34.08, 55.42), p < .0001. There was no statistically significant difference in mean (pre-post) differences between myotomes. The mean duration of spinal anesthesia lasted greater than 90 min and there was no statistical difference between myotomes. There were also no statistically significant associations between age and weight and onset or duration. CONCLUSIONS: Surface electromyography can be used to characterize neural blockade in children. Importantly, these results suggest that awake infant spinal anesthesia motor block lasts, conservatively, 90 min. This exploratory study has highlighted the potential for expanding awake infant spinal anesthesia to a broader range of procedures and the utility of surface electromyography in studying regional anesthesia techniques.

The interest of intranasal clonidine in the prevention of perioperative children's anxiety: a prospective randomized trial.

Introduction: perioperative anxiety in children may lead to psychological and physiological side effects. Clonidine is in increasing use in the pediatric population as an anxiolytic, sedative, and analgesic because of its central alpha2-adrenergic agonist effect. Our study aimed to evaluate the effect of clonidine in the prevention of perioperative children´s anxiety. Methods: we conducted a prospective controlled randomized double-blinded clinical trial including children aged between 2 and 15 years undergoing tonsillectomy surgery. The patients were randomly allocated to receive either an intranasal dose of clonidine (4 µg/kg) (clonidine group) or an equal volume dose of saline solution (control group) 30 minutes before entering the operating room. The level of anxiety assessed using the m-YPAS score was recorded before premedication, at the time of parent-child separation, and at the time of installation in the operating room. Acceptance of premedication, degree of sedation on entering the operating room as well as agitation on awakening, and sedation on arrival post-anesthesia care unit were noted. Adverse effects were recorded during the surgical procedure and in the postoperative recovery room. Results: the number of patients analyzed was 78 with 39 patients in each group. There were no signification differences in demographic data and premedication acceptance between the two groups. Levels of anxiety before any premedication were similar in the two groups. However, the anxiety level 30 minutes after premedication and in the operating room was significantly lower in the clonidine group (p<0.001). Children who received clonidine showed better sedation on entering the operating room (p=0.002) as well as postoperatively on entering the post-anesthesia unit care (p=0.006). The hemodynamic and respiratory parameters recorded were statistically comparable. Conclusion: intranasal clonidine is an interesting premedication to prevent perioperative children´s anxiety with few side effects.

Comparison of the effect of scalp block analgesia bupivacaine 0.25% and clonidine 2 µg/kg with bupivacaine 0.25% and dexamethasone 8 mg on cortisol levels and Numeric Rating Scale in craniotomy tumour.

INTRODUCTION: Craniotomy tumour is brain surgery that can induce a stress response. The stress response can be measured using haemodynamic parameters and plasma cortisol concentration. The stress response that occurs can affect an increase in sympathetic response, such as blood pressure and heart rate, which can lead to an increase in intracranial pressure. Scalp block can reduce the stress response to surgery and post-operative craniotomy tumour pain. The local anaesthetic drug bupivacaine 0.25% is effective in reducing post-operative pain and stress in the form of reducing plasma cortisol levels. The adjuvant addition of clonidine 2 µg/kg or dexamethasone may be beneficial. MATERIALS AND METHODS: A randomised control clinical trial was conducted at the Central Surgery Installation and Hasan Sadikin General Hospital Bandung and Dr. Mohammad Husein Hospital Palembang from December 2022 to June 2023. A total of 40 participants were divided into two groups using block randomisation. Group I receives bupivacaine 0.25% and clonidine 2 µg/kg, and group II receives bupivacaine 0.25% and dexamethasone 8 mg. The plasma cortisol levels of the patient will be assessed at (T0, T1 and T2). All the patient were intubated under general anesthaesia and received the drug for scalp block based on the group being randomised. Haemodynamic monitoring was carried out. RESULTS: There was a significant difference in administering bupivacaine 0.25% and clonidine 2µg/kg compared to administering bupivacaine 0.25% and dexamethasone 8 mg/kg as analgesia for scalp block in tumour craniotomy patients on cortisol levels at 12 hours post-operatively (T1) (p=0.048) and 24 hours post-surgery (T2) (p=0.027), while post-intubation cortisol levels (T0) found no significant difference (p=0.756). There is a significant difference in Numeric Rating Scale (NRS) at post-intubation (T0) (p=0.003), 12 hours post-operatively (T1) (p=0.002) and 24 hours post-surgery (T2) (p=0.004), There were no postprocedure scalp block side effects in both groups. CONCLUSION: The study found that scalp block with 0.25% bupivacaine and 2µg/kg clonidine is more effective in reducing NRS scores and cortisol levels compared bupivacaine 0.25% and dexamethasone 8mg in tumour craniotomy patients.

α 2 -ADRENORECEPTOR ANTAGONIST AMELIORATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY SUPPRESSING NOREPINEPHRINE-MEDIATED FIBROBLAST DIFFERENTIATION VIA INHIBITING PKC ACTIVATION.

ABSTRACT: Pulmonary fibrosis is an important factor affecting the prognosis of severe septic patients with acute lung injury. The objective of this study was to explore the effect of norepinephrine (NE) and α 2 -adrenoreceptor (AR) on sepsis-associated pulmonary fibrosis and the mechanism underlying these effects. We found pulmonary fibrotic changes, and increased NE production and α 2A -AR expression in the pulmonary tissue of mice subjected to cecal ligation and puncture surgery. Reserpine and yohimbine alleviated pulmonary fibrosis in mice with sepsis by exhausting NE derived from the lung's adrenergic nerve and blocking α 2 -AR, respectively. There was no significant difference in the expression of the three α 1 -AR subtypes. The effect of NE on promoting pulmonary fibroblast differentiation in vitro was suppressed by yohimbine. Both the protein and mRNA expression levels of α 2A -AR were increased in pulmonary fibroblasts treated with LPS. Clonidine, a selective α 2 -AR agonist, enhanced LPS-induced differentiation in pulmonary fibroblasts, as indicated by the increase in α-smooth muscle actin and collagen I/III, which was mitigated by inhibiting PKC and p38. Further in vivo results indicated that yohimbine alleviated pulmonary fibrosis and inhibited the phosphorylation of PKC, p38, and Smad2/3 in lung tissue of mice exposed to LPS for 4 weeks. Clonidine showed the opposite effect to yohimbine, which aggravated LPS-induced pulmonary fibrosis. These findings demonstrated that the sepsis-induced increase in NE promoted fibroblast differentiation via activating α 2 -AR. Blockage of α 2 -AR effectively ameliorated sepsis-associated pulmonary fibrosis by abolishing NE-induced lung fibroblast differentiation and inhibiting the PKC-p38-Smad2/3 pathway.

Multimodal intrathecal analgesia (MITA) with morphine for reducing postoperative opioid use and acute pain following hepato-pancreato-biliary surgery: A multicenter retrospective study.

INTRODUCTION: The optimal analgesic modality for patients undergoing hepato-pancreato-biliary (HPB) surgery remains unknown. The analgesic effects of a multimodal intrathecal analgesia (MITA) technique of intrathecal morphine (ITM) in combination with clonidine and bupivacaine compared to ITM alone have not been investigated in these patients. METHODS: We performed a multicenter retrospective study of patients undergoing complex HPB surgery who received ITM, bupivacaine, and clonidine (MITA group) or ITM-only (ITM group) as part of their perioperative analgesia strategy. The primary outcome was the unadjusted oral morphine equivalent daily dose (oMEDD) in milligrams on postoperative day 1. After adjusting for age, body mass index, hospital allocation, type of surgery, operation length, and intraoperative opioid use, postoperative oMEDD use was investigated using a bootstrapped quantile regression model. Other prespecified outcomes included postoperative pain scores, opioid-related adverse events, major complications, and length of hospital stay. RESULTS: In total, 118 patients received MITA and 155 patients received ITM-only. The median (IQR) cumulative oMEDD use on postoperative day 1 was 20.5 mg (8.6:31.0) in the MITA group and 52.1 mg (18.0:107.0) in the ITM group (P < 0.001). There was a variation in the magnitude of the difference in oMEDD use between the groups for different quartiles. For the MITA group, on postoperative day 1, patients in the 25th percentile required 14.0 mg less oMEDD (95% CI: -25.9 to -2.2; P = 0.025), patients in the 50th percentile required 27.8 mg less oMEDD (95% CI: -49.7 to -6.0; P = 0.005), and patients in the 75th percentile required 38.7 mg less oMEDD (95% CI: -72.2 to -5.1; P = 0.041) compared to patients in the same percentile of the ITM group. Patients in the MITA group had significantly lower pain scores in the postoperative recovery unit and on postoperative days 1 to 3. The incidence of postoperative respiratory depression was low (<1.5%) and similar between groups. Patients in the MITA group had a significantly higher incidence of postoperative hypotension requiring vasopressor support. However, no significant differences were observed in major postoperative complications, or the length of hospital stay. CONCLUSION: In patients undergoing complex HPB surgery, the use of MITA, consisting of ITM in combination with intrathecal clonidine and bupivacaine, was associated with reduced postoperative opioid use and resulted in superior postoperative analgesia without risk of respiratory depression when compared to patients who received ITM alone. A randomized prospective clinical trial investigating these two intrathecal analgesic techniques is justified.

Multimodal Analgesia Bundle and Postoperative Opioid Use Among Patients Undergoing Colorectal Surgery.

Importance: A key objective in contemporary surgery is to reduce or eliminate the usage of opioids to minimize gastrointestinal adverse effects, fatigue, and long-term opioid dependency. Objectives: To evaluate the association of the implementation of a care bundle of 3 opioid-sparing interventions with the amount of opioids consumed postoperatively among patients undergoing major abdominal surgery and to examine the respective associations of the 3 components. Design, Setting, and Participants: This retrospective cohort study was performed at Ersta Hospital, an elective teaching hospital in Stockholm, Sweden. All patients undergoing major colorectal surgery between January 1, 2016, through December 31, 2019, were included. Data analysis was conducted from February 1, 2020, to May 30, 2022. Exposures: A care bundle consisting of an individualized opioid regimen, regular gabapentinoids, and clonidine as a rescue analgesic was gradually introduced early in the study period. Main Outcomes and Measures: Amount of in-hospital administered intravenous and oral opioids on the day of surgery and the first 5 postoperative days (morphine milligram equivalents [MME]). The association between exposure and outcome was examined using multivariable linear regression. Results: Overall, 842 patients had major colorectal surgery in the study period (mean [SD] age, 64.6 [15.5] years; 421 [50%] men). Median (range) opioid usage decreased from 75 (0-796) MME in 2016 to 22 (0-362) MME in 2019 (P < .001), and the proportion of patients receiving 45 MME or less increased from 35% to 66% (P < .001). On multivariable analysis (F5, 836 = 57.5; P < .001), an individualized opioid strategy (ß = -11.6; SE = 3.8; P = .003), the use of gabapentin (ß = -39.1; SE = 4.5; P < .001), and increasing age (ß = -1.0; SE = 0.11; P < .001) were associated with less opioid consumption, while the use of clonidine was associated with more opioid intake (ß = 11.6; SE = 3.6; P = .001). Conclusions and Relevance: In this cohort study of 842 patients undergoing colorectal surgery, a care bundle consisting of an individualized opioid regimen, regular gabapentin, and clonidine as a rescue analgesic was found to be associated with a significant decrease in opioids consumed postoperatively. Regular gabapentin and an individualized opioid regimen were particularly strongly associated with this decrease and should be further evaluated as components of multimodal, opioid-free postoperative analgesia.

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.

Pharmacologic interventions for the therapy of postanesthetic shivering in adults: a systematic review and network meta-analysis.

INTRODUCTION: Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare but can occur due to increased oxygen consumption. Previous systematic reviews are outdated and have summarized the evidence on the topic using only pairwise comparisons. The objective of this manuscript was a quantitative synthesis of evidence on pharmacological interventions to treat postanesthetic shivering. EVIDENCE ACQUSITION: Systematic review and frequentist network meta-analysis using the R package netmeta. Endpoints were the risk ratio (RR) of persistent shivering at one, five and 10 minutes after treatment with saline/placebo as the comparator. Data were retrieved from Medline, Embase, Central and Web of Science up to January 2022. Eligibility criteria were: randomized, controlled, and blinded trials comparing pharmacological interventions to treat shivering after general anesthesia. Studies on shivering during or after any type of regional anesthesia were excluded as well as sedated patients after cardiac surgery. EVIDENCE SYNTHESIS: Thirty-two trials were eligible for data synthesis, including 28 pharmacological interventions. The largest network included 1431 patients. The network geometry was two-centered with most comparisons linked to saline/placebo or pethidine. The best interventions were after one minute: doxapram 2 mg/kg, tramadol 2 mg/kg and nefopam 10 mg, after 5 minutes: tramadol 2 mg/kg, nefopam 10 mg and clonidine 150 µg and after 10 minutes: nefopam 10 mg, methylphenidate 20 mg and tramadol 1 mg/kg, all reaching statistical significance. Pethidine 25 mg and clonidine 75 µg also performed well and with statistical significance in all networks. CONCLUSIONS: Nefopam, tramadol, pethidine and clonidine are the most effective treatments to stop postanesthetic shivering. The efficacy of doxapram is uncertain since different doses showed contradictory effects and the evidence for methylphenidate is based on a single comparison in only one network. Furthermore, both lack data on side effects. Further studies are needed to clarify the efficacy of dexmedetomidine to treat postanesthetic shivering.

Efficacy of apraclonidine eye drops in treating ptosis secondary to myasthenia gravis: A pilot clinical trial.

INTRODUCTION/AIMS: Most patients with myasthenia gravis (MG) develop ocular manifestations during their illness and up to 22% may have isolated ocular myasthenia gravis (OMG). Apraclonidine elevates the eyelid by activating alpha-2 receptors on Muller's muscle, an accessory eyelid elevator muscle. In this study we evaluate the effect of apraclonidine in alleviating ptosis secondary to MG. METHODS: This clinical trial (NCT05045248) was done at the American University of Beirut Medical Center. Patients with ptosis secondary to MG were administered two drops of apraclonidine 0.5% solution to the most affected eye. We measured palpebral fissure height (PF), marginal reflex distance-1 (MRD1), marginal reflex distance-2 (MRD2), and levator function (LF) before drug administration and at 1, 5, 30, and 60 minutes after administration. RESULTS: Ten participants were enrolled in the study. Improvement in all eyelid measurements was noted in all participants as early as 1 minute after apraclonidine administration. From baseline to 60 minutes after administration, average PF increased from 8.8 ± 1.9 mm to 14.2 ± 2.6 mm, MRD-1 from 1.7 ± 1.4 mm to 5.4 ± 2.9 mm, MRD-2 from 7.1 ± 1.3 mm to 8.8 ± 1.7 mm, and LF from 13.4 ± 2.9 mm to 17.5 ± 2.4 mm. All increases were statistically significant. DISCUSSION: Apraclonidine may alleviate ptosis secondary to MG and may be an effective alternative treatment for this group of patients.

Ropivacaine-Epinephrine-Clonidine-Ketorolac Cocktail as a Local Anesthetic for Lumbar Decompression Surgery: A Single Institutional Experience.

OBJECTIVE: The goal of this study is to discuss our initial experience with a multimodal opioid-sparing cocktail containing ropivacaine, epinephrine, clonidine, and ketorolac (RECK) in the postoperative management of lumbar decompression surgeries. METHODS: Patients were either administered no local anesthetic at the incision site or were administered a weight-based amount of RECK into the paraspinal musculature and subdermal space surrounding the operative site once the fascia was closed. We performed a retrospective chart review of all patients 18 years of age or older undergoing lumbar laminectomy and lumbar diskectomy surgeries between December 2019 and April 2021. Outcomes including total opioid use, measured as morphine milligram equivalent, length of stay, and postoperative visual analog scores for pain, were collected. Relationships between variables were analyzed with Student's t-test, chi-square tests, and Fisher exact tests. RESULTS: A total of 121 patients undergoing 52 lumbar laminectomy and 69 lumbar diskectomy surgeries were identified. For lumbar laminectomy, patients who were administered RECK had decreased opioid use in the postoperative period (11.47 ± 12.32 vs. 78.51 ± 106.10 morphine milligram equivalents, P = 0.019). For patients undergoing lumbar diskectomies, RECK administration led to a shorter length of stay (0.17 ± 0.51 vs. 0.79 ± 1.45 days, P = 0.019) and a lower 2-hour postoperative pain score (3.69 ± 2.56 vs. 5.41 ± 2.28, P = 0.006). CONCLUSIONS: The RECK cocktail has potential to be an effective therapeutic option for the postoperative management of lumbar decompression surgeries.

Comparative Efficacy of Adjuvant Nonopioid Analgesia in Adult Cardiac Surgical Patients: A Network Meta-Analysis.

OBJECTIVES: To compare the relative efficacy of adjuvant nonopioid analgesic regimens in adult cardiac surgical patients. DESIGN: This frequentist, random-effects network meta-analysis (NMA) was prospectively registered on PROSPERO (CRD42021282913) and conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA). The risk of bias (RoB) and confidence of evidence were assessed by RoB 2 and Confidence in Network Meta-Analysis, respectively. Relevant databases were searched from inception to October 9, 2021. SETTING: A total of 124 (N = 26,257) randomized controlled trials were included, of which 110 were analyzed. PARTICIPANTS: Trials enrolling adults (≥18 years of age) undergoing cardiac surgery that compared nonopioid analgesics against other nonopioid analgesics, placebo, or no additional treatment, as adjuvants to standard analgesic management, and reported at least 1 of the outcomes of interest. MEASUREMENT AND MAIN RESULTS: Outcomes of interest included resting postoperative pain scores at 24 hours. Compared with standard care and/or placebo, pain scores were reduced significantly by 10 different regimens, including acetaminophen (N = 176; mean difference [MD] -0.66 points, 95% CI -1.16 to -0.15 points; high confidence), magnesium (N = 323; -0.05 points, 95% CI -0.07 to -0.02 points; high confidence), gabapentin (N = 96; MD -0.40 points, 95% CI -0.71 to -0.09; moderate confidence), and clonidine (N = 64; MD v0.38 points, 95% CI -0.73 to v0.04 points; moderate confidence). Indomethacin, diclofenac, magnesium, and gabapentin significantly reduced 24-hour opioid consumption. Four regimens significantly decreased the intensive care unit length of stay. Hydrocortisone, dexmedetomidine, and clonidine significantly decreased the duration of mechanical ventilation. Magnesium decreased, while methylprednisolone significantly increased, the risk of myocardial infarction. CONCLUSIONS: Given the increasing emphasis on enhanced recovery after surgery(ERAS) protocols and the eventual goal of limiting opiate prescriptions postoperatively, the authors' data suggested far greater use of nonopioid adjuncts to minimize pain and enhance recovery following cardiac surgery.

Preoperative anxiety level is not associated with postoperative negative behavioral changes in premedicated children.

BACKGROUND: Anesthesia preinduction anxiety in children can according to some studies lead to long-term anxiety and negative behavioral changes (NBC), while other studies have not found this effect. This secondary analysis from a recent premedication trial comparing clonidine and midazolam aimed to test the relation between preoperative anxiety assessed with modified Yale Preoperative Anxiety Scale (mYPAS) and postoperative NBCs assessed with Post Hospital Behavior Questionnaire (PHBQ), regardless of premedication type. METHODS: This is a planned secondary analysis from a published premedication comparison trial in an outpatient surgery cohort, children aged 2-7 years. Participant and preoperative factors, particularly preoperative anxiety as mYPAS scores, were assessed for association with development of postoperative NBCs. RESULTS: Fifty-four of the 115 participants had high preinduction anxiety (mYPAS >30), and 19 of 115 developed >3 postoperative NBCs 1 week after surgery. There was no association between preinduction anxiety level as mYPAS scores and the development of postoperative NBCs at 1 week after surgery (10 of 19 had both, p = .62) nor after 4- or 26-weeks post-surgery. Only lower age was associated with development of NBCs postoperatively. CONCLUSIONS: Based on the findings from this cohort, high preinduction anxiety does not appear to be associated with NBCs postoperatively in children premedicated with clonidine or midazolam.

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.

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.