Does Dexmedetomidine Improve or Worsen Restless Leg Syndrome under Sedation: A Case Report and Extensive Review.

Background: Restless leg syndrome (RLS) is a common neurological condition that manifests as creeping, nonpainful urges to move lower extremities and is relieved with movements of the legs. RLS is associated with comorbidities such as gastric surgery, diabetes mellitus, uremia, and iron deficiency anemia, and it is misdiagnosed in many cases. Drugs like levodopa, ropinirole, pramipexole, cabergoline, and pergolide that target the dopaminergic system have been traditionally used to treat symptoms of RLS. α2-adrenoceptor (α2-AR) agonists, like clonidine and dexmedetomidine, have also been reported to show improvement of RLS symptoms during sedation. Specific Aim. This case report suggests that dexmedetomidine may have worsened RLS during sedation in a 71-year-old male with no prior diagnosis of RLS or reported symptoms. The patient had a procedure for right first metatarsophalangeal joint (MTPJ) fusion, with second digit proximal interphalangeal joint (PIPJ) arthrodesis, and flexor tendon transfer due to pain on walking and failing conservative therapy. He underwent intravenous sedation/monitored anesthesia care (MAC) with propofol, dexmedetomidine, and a peripheral regional block for intraoperative anesthesia and postoperative analgesia. During the surgery, the patient experienced continuous bilateral leg movement, unpredictable, and unrelated to surgical stimulation or level of consciousness within 5 minutes of administration of dexmedetomidine. The patient tolerated the procedure, and the unpredicted leg movement was managed by the surgeons intraoperatively. Conclusion: Although no previous literature exists and mechanisms are unclear, this case report hypothesizes that dexmedetomidine may contribute to worsening RLS symptoms.

Budget Impact and Cost-Effectiveness of Intravenous Meloxicam to Treat Moderate-Severe Postoperative Pain.

INTRODUCTION: This study assesses the budget impact and cost-effectiveness of intravenous meloxicam (MIV) to treat moderate-severe acute postoperative pain in adults. METHODS: A two-part Markov cohort model captured the pharmacoeconomic impact of MIV versus non-opioid intravenous analgesics (acetaminophen, ibuprofen, ketorolac) among a hypothetical adult cohort undergoing selected inpatient procedures and experiencing moderate-severe acute postoperative pain: Part 1 (postoperative hour 0 to discharge, cycled hourly), health states were defined by pain level. Pain transition rates, adverse event probabilities, and concomitant opioid utilization were derived from a network meta-analysis. Part 2 (discharge to week 52, cycled weekly), health states were defined by the presence/absence of pain-related readmission and opioid use disorder as determined by literature-based inputs relating to pain control outcomes. Healthcare utilization and direct medical costs were derived from an administrative claims database analysis. Primary outcomes were the incremental cost per member per month (PMPM) and cost per quality-adjusted life year (QALY) gained. Scenario, univariate, and probabilistic sensitivity analyses were conducted. The model assumed a private payer perspective in the USA (no discounting, 2019 US$). RESULTS: Modeled outcomes indicated MIV was associated with lower accumulated postoperative pain, fewer adverse events, and less opioid utilization for most procedures and comparators, with longer-term outcomes also generally favoring MIV. The budget impact of MIV was - $0.028 PMPM. From a cost-effectiveness perspective, MIV had lower costs and better outcomes for all comparisons except against ketorolac in orthopedic procedures where the former was cost-effective but not cost saving ($95,925/QALY). Scenario and sensitivity analyses indicated that modeled outcomes were robust to alternative inputs and underlying input uncertainty. Differences in direct medical costs were driven by reduced costs attributable to length of stay and opioid-related adverse drug events. CONCLUSION: MIV was associated with modeled clinical and economic benefits compared to commonly used non-opioid intravenous analgesics.

Pruritus, neuraxial morphine and recrudescence of oral herpes simplex and treatment: an educational review in obstetric patients.

Neuraxial opioids are well known to cause itching, which may be challenging to treat. Neuraxial morphine has been demonstrated to cause recrudescent herpes simplex viruses (HSV-1), especially in women during labor and childbirth with neuraxial analgesia, and may be an occult etiology of refractory itching. This educational review summaries the clinical and epidemiological characteristics associated with recrudescent HSV-1 in patients treated with neuraxial opioids, especially morphine.

Blood Component Requirements and Erythrocyte Transfusion and Mortality Related to Hemoglobin Deficit in Phase III Trial of Hemoglobin-Based Oxygen Carrier: HBOC-201.

BACKGROUND: Hemoglobin-based oxygen carriers (HBOCs) may cause coagulopathy, changes in total hemoglobin (THb), and affect mortality. Low total hemoglobin concentrations [THb] during hemorrhage may worsen outcomes. STUDY QUESTION: The database of the Hemopure HEM-0115 phase III trial was queried to determine the use of platelets, plasma, or cryoprecipitate and compare transfusion requirements and coagulation studies between patients randomized to erythrocyte transfusion or HBOC-201 infusion. Modeling of hemoglobin (Hb) changes produced by HBOC-201, erythrocyte, and blood product administration were related to [THb], coagulopathy, and mortality. DATA SOURCES: Hemopure HEM-0115 phase III trial database. STUDY DESIGN: Retrospective and Novel Hemoglobin Deficit Formulas Tested Against Existing Database. RESULTS: The HBOC-201 database (n = 688) demonstrated less than 6% of subjects in both groups were administered non-Hb containing blood products (fresh frozen plasma, platelets, or cryoprecipitate) and low rates of coagulopathies in both erythrocyte and HBOC-201 arms. There were no differences in mortality in elective orthopedic patients administered up to 10 bags HBOC-201 (equivalent to 3 units erythrocytes). Low total [Hb] and lack of adequate oxygen carrying capacity was found to be an independent predictor of morbidity/mortality. CONCLUSIONS: The elective use of HBOC-201 for orthopedics versus erythrocytes demonstrated low incidence of blood product requirements in both cohorts and no differences in mortality up to the HBOC-201 equivalent of 3 units erythrocytes. High total Hb may be important to maintain in acute hemorrhage and [Hb] deficit, whereas later in recovery might not be as crucial. Future trauma trials may benefit from the use of HBOC-201 containing 13 g/dL in prehospital management, when erythrocytes are commonly not available.

Blood Substitutes and Oxygen Therapeutics: A Review.

Despite the exhaustive search for an acceptable substitute to erythrocyte transfusion, neither chemical-based products such as perfluorocarbons nor hemoglobin-based oxygen carriers have succeeded in providing a reasonable alternative to allogeneic blood transfusion. However, there remain scenarios in which blood transfusion is not an option, due to patient's religious beliefs, inability to find adequately cross-matched erythrocytes, or in remote locations. In these situations, artificial oxygen carriers may provide a mortality benefit for patients with severe, life-threatening anemia. This article provides an up-to-date review of the history and development, clinical trials, new technology, and current standing of artificial oxygen carriers as an alternative to transfusion when blood is not an option.

Local and Intra-articular Administration of Nonsteroidal Anti-inflammatory Drugs for Pain Management in Orthopedic Surgery.

BACKGROUND: Although growing evidence demonstrates the benefits of locally administered nonsteroidal anti-inflammatory drugs (NSAIDs) for postoperative pain management, there is ongoing debate regarding NSAID use in orthopedic surgery. AREAS OF UNCERTAINTY: Current data largely support a local site of NSAID action and suggest that effective pain control can be achieved with delivery of NSAIDs intra-articularly (IA) and/or locally at the site of injury, where they can block peripheral production of inflammatory mediators and may desensitize nociceptors. Improvements in postoperative pain control with locally administered NSAIDs have been widely reported in the total joint arthroplasty literature and may offer benefits in patient's undergoing arthroscopic procedures and those with osteoarthritis as well. The purpose of this review is to examine the available evidence in the literature regarding the efficacy and safety profile of the use of local and IA NSAIDs in orthopedic surgery. DATA SOURCES: Narrative literature review using keywords, expert opinion, either during or from live conference. THERAPEUTIC ADVANCES: Local and IA administration of NSAIDs for pain management in orthopedic surgery. CONCLUSION: There is convincing evidence that NSAIDs administered locally in and around the joint reduce postoperative pain scores and opioid consumption in patients undergoing total joint arthroplasty, yet further research is required regarding the risks of potential chondrotoxicity and the inhibition of bone and soft-tissue healing with locally administered NSAIDs.

Efficacy of non-opioid analgesics to control postoperative pain: a network meta-analysis.

BACKGROUND: The aim of this network meta-analysis (NMA) was to evaluate the safety and efficacy of intravenous (IV) Meloxicam 30 mg (MIV), an investigational non-steroidal anti-inflammatory drug (NSAID), and certain other IV non-opioid analgesics for moderate-severe acute postoperative pain. METHODS: We searched PubMed and CENTRAL for Randomized Controlled Trials (RCT) (years 2000-2019, adult human subjects) of IV non-opioid analgesics (IV NSAIDs or IV Acetaminophen) used to treat acute pain after abdominal, hysterectomy, bunionectomy or orthopedic procedures. A Bayesian NMA was conducted in R to rank treatments based on the standardized mean differences in sum of pain intensity difference from baseline up to 24 h postoperatively (sum of pain intensity difference: SPID 24). The probability and the cumulative probability of rank for each treatment were calculated, and the surface under the cumulative ranking curve (SUCRA) was applied to distinguish treatments on the basis of their outcomes such that higher SUCRA values indicate better outcomes. The study protocol was prospectively registered with by PROSPERO (CRD42019117360). RESULTS: Out of 2313 screened studies, 27 studies with 36 comparative observations were included, producing a treatment network that included the four non-opioid IV pain medications of interest (MIV, ketorolac, acetaminophen, and ibuprofen). MIV was associated with the largest SPID 24 for all procedure categories and comparators. The SUCRA ranking table indicated that MIV had the highest probability for the most effective treatment for abdominal (89.5%), bunionectomy (100%), and hysterectomy (99.8%). MIV was associated with significantly less MME utilization versus all comparators for abdominal procedures, hysterectomy, and versus acetaminophen in orthopedic procedures. Elsewhere MME utilization outcomes for MIV were largely equivalent or nominally better than other comparators. Odds of ORADEs were significantly higher for all comparators vs MIV for orthopedic (gastrointestinal) and hysterectomy (respiratory). CONCLUSIONS: MIV 30 mg may provide better pain reduction with similar or better safety compared to other approved IV non-opioid analgesics. Caution is warranted in interpreting these results as all comparisons involving MIV were indirect.

Perioperative bleeding and non-steroidal anti-inflammatory drugs: An evidence-based literature review, and current clinical appraisal.

Patient satisfaction measures and the opioid epidemic have highlighted the need for effective perioperative pain management. Multimodal analgesia, including non-steroidal anti-inflammatory drugs (NSAIDs), have been shown to maximize pain relief and reduce opioid consumption, but are also associated with potential perioperative bleeding risks.A multidisciplinary panel conducted a clinical appraisal of bleeding risks associated with perioperative NSAID use. The appraisal consisted of review and assessment of the current published evidence related to the statement "In procedures with high bleeding risk, NSAIDs should always be avoided perioperatively." We report the presented literature and proceedings of the subsequent panel discussion and national pilot survey results. The authors' assessment of the statement based on current evidence was compared to the attempted national survey data, which revealed a wide range of opinions reflecting the ongoing debate around this issue in a small number of respondents.The appraisal concluded that caution is warranted with respect to perioperative use of NSAIDs. However, summarily excluding NSAIDs from perioperative use based on potential bleeding risks would be imprudent. It is recommended that NSAID use be guided by known patient- and procedure-specific factors to minimize bleeding risks while providing effective pain relief.

Platelet Function: Meloxicam Intravenous in Whole Blood Samples From Healthy Volunteers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective treatments for pain but may induce bleeding events due to platelet dysfunction associated with inhibition of cyclooxygenase (COX)-1 impairing thromboxane production. An intravenous nanocrystal formulation of meloxicam, a COX-2 preferential nonsteroidal anti-inflammatory drug, is under development for the treatment of moderate to severe pain. This single-center ex vivo study evaluated the effect of meloxicam intravenous and ketorolac on platelet function in whole blood samples from healthy volunteers. Each whole blood sample was aliquoted to allow analysis using a platelet function analyzer under negative control (untreated), positive control (2 therapeutic ketorolac concentrations), and meloxicam intravenous (1 therapeutic, 3 supratherapeutic concentrations) using both collagen with epinephrine and collagen with adenosine diphosphate reagent cartridges. The platelet function analyzer determines closure time by simulating platelet adhesion and aggregation following vascular injury. The final analysis set included data from 8 subjects. The collagen with adenosine diphosphate analysis (sensitive to thrombocytopathies) showed no significant differences in closure time for meloxicam- or ketorolac-treated samples and untreated control. The collagen with epinephrine analysis (sensitive to aspirin-induced platelet abnormalities) produced no significant difference in closure time between any meloxicam concentration and untreated control. Ketorolac was associated with significantly longer closure times vs untreated control at both the 2.5- and 5-µg/mL concentrations (P = .003 and .0257, respectively) and vs meloxicam at several concentrations. Similar results were observed when all analyzed samples were included. Meloxicam intravenous had no significant effect on closure times at therapeutic or supratherapeutic concentrations in this ex vivo study.

Current Perspective on the Use of Opioids in Perioperative Medicine: An Evidence-Based Literature Review, National Survey of 70,000 Physicians, and Multidisciplinary Clinical Appraisal.

Objective: Opioids represent an important analgesic option for physicians managing acute pain in surgical patients. Opioid management is not without its drawbacks, however, and current trends suggest that opioids might be overused in the United States. An expert panel was convened to conduct a clinical appraisal regarding the use of opioids in the perioperative setting. Methods: The clinical appraisal consisted of the review, presentation, and assessment of current published evidence as it relates to the statement "Opioids are not overused in the United States, even though opioid adjunct therapy achieves greater pain control with less risk." The authors' evaluation of this statement was also compared with the results of a national survey of surgeons and anesthesiologists in the United States. Results: We report the presented literature and proceedings of the panel discussion. The national survey revealed a wide range of opinions regarding opioid overuse in the United States. Current published evidence provides support for the efficacy of opioid therapy in surgical patients; however, it is not sufficient to conclude unequivocally that opioids are-or are not-overused in the management of acute surgical pain in the United States. Conclusions: Opioids remain a key component of multimodal perioperative analgesia, and strategic opioid use based on clinical considerations and patient-specific needs represents an opportunity to support improved postoperative outcomes and satisfaction. Future studies should focus on identifying optimal procedure-specific and patient-centered approaches to multimodal perioperative analgesia.

Pharmacology of Octreotide: Clinical Implications for Anesthesiologists and Associated Risks.

Many patients presenting with a history of foregut, midgut neuroendocrine tumors (NETs) or carcinoid syndrome can experience life-threatening carcinoid crises during anesthesia or surgery. Clinicians should understand the pharmacology of octreotide and appreciate the use of continuous infusions of high-dose octreotide, which can minimize intraoperative carcinoid crises. We administer a prophylactic 500-µg bolus of octreotide intravenously (IV) and begin a continuous infusion of 500 µg/h for all NET patients. Advantages include low cost and excellent safety profile. High-dose octreotide for midgut and foregut NETs requires an appreciation of the pathophysiology involved in the disease, pharmacology, drug-drug interactions, and side effects.

Hemoglobin glutamer-250 (bovine) in South Africa: consensus usage guidelines from clinician experts who have treated patients.

Hemopure (hemoglobin glutamer-250 [bovine]; HBOC-201) is a hemoglobin (Hb)-based oxygen carrier registered with the Medicines Control Council of South Africa. It is indicated for the treatment of adult patients who are acutely anemic, for the purpose of maintaining tissue oxygen delivery thus eliminating, delaying, or reducing the need for allogeneic red blood cells (RBCs). Hemopure is a volume expander, and circulatory volume must be carefully monitored for signs of fluid overload. Hemopure is not as effective as RBCs for restoring Hb content and concentration, but in cases of severe anemia where allogeneic blood is not an option or is unavailable, it may offer an immediate alternative for improving oxygen transport. This document provides clinical recommendations on the safe and effective use of Hemopure based on the postmarketing experience in South Africa as well as a better understanding of Hemopure properties reflected in recent publications.

Safety and Efficacy of Rocuronium With Sugammadex Reversal Versus Succinylcholine in Outpatient Surgery-A Multicenter, Randomized, Safety Assessor-Blinded Trial.

Complex surgical procedures are increasingly performed in an outpatient setting, with emphasis on rapid recovery and case turnover. In this study, the combination of rocuronium for neuromuscular blockade (NMB) reversed by single-dose sugammadex was compared with succinylcholine followed by spontaneous recovery in outpatient surgery. This multicenter, randomized, safety assessor-blinded study enrolled adults undergoing a short elective outpatient surgical procedure requiring NMB and tracheal intubation. Patients were randomized to NMB with either rocuronium 0.6 mg/kg for tracheal intubation with incremental doses of rocuronium 0.15 mg/kg and subsequent reversal with sugammadex 4.0 mg/kg at 1-2 posttetanic counts or succinylcholine 1.0 mg/kg for intubation with spontaneous recovery. The primary efficacy end point was the time from sugammadex administration to recovery of the train-of-four ratio to 0.9; for succinylcholine, time from administration to recovery of the first twitch (T1) to 90% was assessed. From 167 patients enrolled, 150 received treatment. The all-subjects-treated population comprised 70 patients in the rocuronium-sugammadex group and 80 in the succinylcholine group. Geometric mean (95% confidence interval) time from the start of sugammadex administration to recovery of the train-of-four ratio to 0.9 was 1.8 (1.6-2.0) minutes. Geometric mean (95% confidence interval) time from succinylcholine administration to recovery of T1 to 90% was 10.8 (10.1-11.5) minutes. Health outcome variables were similar between the groups. Adverse events were reported in 87.1% and 93.8% of patients for rocuronium-sugammadex and succinylcholine, respectively. In conclusion, rocuronium for intubation followed by sugammadex for reversal of NMB offers a viable treatment option in outpatient surgery without prolonging recovery duration or jeopardizing safety.

Intravenous non-opioid analgesia for peri- and postoperative pain management: a scientific review of intravenous acetaminophen and ibuprofen.

Pain is a predictable consequence following operations, but the management of postoperative pain is another challenge for anesthesiologists and inappropriately controlled pain may lead to unwanted outcomes in the postoperative period. Opioids are indeed still at the mainstream of postoperative pain control, but solely using only opioids for postoperative pain management may be connected with risks of complications and adverse effects. As a consequence, the concept of multimodal analgesia has been proposed and is recommended whenever possible. Acetaminophen is one of the most commonly used analgesic and antipyretic drug for its good tolerance and high safety profiles. The introduction of intravenous form of acetaminophen has led to a wider flexibility of its use during peri- and postoperative periods, allowing the early initiation of multimodal analgesia. Many studies have revealed the efficacy, safety and opioid sparing effects of intravenous acetaminophen. Intravenous ibuprofen has also shown to be well tolerated and demonstrated to have significant opioid sparing effects during the postoperative period. However, the number of randomized controlled trials confirming the efficacy and safety is small and should be used in caution in certain group of patients. Intravenous acetaminophen and ibuprofen are important options for multimodal postoperative analgesia, improving pain and patient satisfaction.

Sugammadex: A Scientific Review Including Safety and Efficacy, Update on Regulatory Issues, and Clinical Use in Europe.

Muscle relaxants are used in the perioperative period to aid in endotracheal intubation, facilitate surgical exposure, and in the critical care setting for prolonged relaxation. Until now, the only mechanism to reverse their effect is acetylcholinesterase inhibitors that result in excess parasympathetic activity and require the second drug to prevent this side effect. Additionally, the onset and degree of neuromuscular antagonism are often unpredictable and unreliable. Sugammadex is the first of the cyclodextrins to be used as a therapeutic agent. It quickly, effectively, and safely reverses steroidal neuromuscular blockers by encapsulating the muscle relaxant and rendering it inactive. Sugammadex may be considered the ideal reversal agent and the first drug in its class, which will likely change the practice of anesthesia and clinical neuromuscular pharmacology.

Sugammadex: A Comprehensive Review of the Published Human Science, Including Renal Studies.

Although neuromuscular block (NMB) allows immobility for airway management and surgical exposure, termination of its effect is limited by and associated with side effects of acetylcholinesterase inhibitors. Sugammadex is a selective relaxant binding agent that has been shown to reverse deep NMB, even when administered 3 minutes following a 1.2 mg/kg dose of rocuronium. This novel drug is a modified gamma cyclodextrin, that through encapsulation process terminates the effects of rocuronium and vecuronium (aminosteroid muscle relaxants), and enables the anesthesiologists rapidly to reverse profound NMB induced by rocuronium or vecuronium, in a "can't ventilate, can't intubate" crisis. In this review, data from published phase 1, 2, and 3 clinical trials are reviewed and presented. In addition, clinical trials on special patient populations (patients with pulmonary disease and renal insufficiency) are evaluated. Each article reviewed will conclude with a discussion of relevance, focus on adverse event profile, and clinical usefulness.