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.

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.

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.

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.

Intravenous acetaminophen: a review of pharmacoeconomic science for perioperative use.

Hospitals are subject to more economic pressures than ever before. On the one hand, cost containment or cost reduction is paramount, particularly in relation to costly branded pharmaceuticals. On the other hand, quality measures and value-based reimbursement penalizes poor patient care. Multimodal analgesia sits squarely in this quandary, since its very nature requires use of multiple drugs with their associated costs, though this approach has the potential to improve quality of care. We undertook a comprehensive review of the pharmacoeconomics of IV acetaminophen, a new drug useful as part of a multimodal analgesic approach. While this new branded drug adds to direct drug costs, there is clear potential for IV acetaminophen to reduce the incidence of opioid-related adverse events and, in so doing, result in net hospital savings. This review describes many clinical studies showing significant improvements in postoperative nausea and vomiting, excessive sedation and pruritus. In addition, we describe studies demonstrating faster recovery times in the post-anesthesia care unit, intensive care unit and total hospital length of stay. Lastly, we summarize many studies demonstrating the robust effect of IV acetaminophen on patient satisfaction. A holistic view of total hospital performance should be adopted when reviewing drugs rather than a silo mentality within the pharmacy. While IV acetaminophen adds to drug costs, the body of evidence indicates this drug has the potential to improve outcomes and hospital efficiency.

Safety and efficacy of intravenous acetaminophen in the elderly after major orthopedic surgery: subset data analysis from 3, randomized, placebo-controlled trials.

As the number of patients aged 65 years and older increases, joint replacement has become a frequent procedure after progressive osteoarthritis or fractures. Although hip and knee arthroplasty has become a relatively commonplace procedure in this age-group, the advanced age in patients undergoing these procedures often is associated with comorbidities and potential complications that can present challenges and limit analgesic choices. This subset analysis is designed to determine the efficacy and safety of intravenous (IV) acetaminophen in the elderly subpopulation from 3 placebo-controlled studies conducted to document the safety and efficacy of IV acetaminophen. A total of 231 patients were enrolled in the 3 trials, and of these, a total of 107 patients (46%) were aged 65 years or older. Across the studies, safety and efficacy were well documented in the elderly subpopulation and were comparable with the subpopulation younger than 65 years. A review of the literature similarly demonstrates the efficacy and safety of IV acetaminophen used for postoperative analgesia after joint replacement.

Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis.

BACKGROUND AND METHODS: From the time that Sinatra et al. (Anesthesiology. 2005;102:822) was published to FDA apaproval of intravenous (IV) acetaminophen, an expanded analysis of the original raw study data became necessary for the regulatory submission. The following analyses were conducted: (1) sum of pain intensity differences over 24 hours (SPID24) using currently accepted imputation methods to account for both missing data and the effects of rescue; (2) efficacy results after the first 6 hours; (3) effects of gender, race/ethnicity, age, weight, surgical site, ASA Class, and serotonin antagonists; and (4) a stepwise regression analysis of why adverse events of nausea and vomiting were numerically (although not statistically) higher in the IV acetaminophen group compared with placebo. RESULTS: Sum of pain intensity differences over 24 hours using a 0- to 100-mm visual analog scale was statistically significantly (P < 0.001) in favor of IV acetaminophen (n = 49) compared with placebo (n = 52). Time to rescue was found to be 3.9 and 2.1 hours, respectively, for total hip and knee arthroplasty compared with 0.8 hours for the placebo group. Rescue medication consumption, requests, and actual administration were all significantly lower in the IV acetaminophen group compared with placebo for each dosing interval, except in the 6- to 12-hours interval where a numerical trend was observed. Analysis of various subset variables demonstrated similar efficacy for each variable. A stepwise regression analysis demonstrated that AE reports of nausea and vomiting were most likely due to prerandomization events, particularly opioid consumption and presence of nausea prior to randomization. CONCLUSION: Repeated-dose 24-hours end points were found to be as robust as previously published results. IV acetaminophen efficacy and safety appeared to be unaffected by specific subset variables.▪

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.

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.

Does HBOC-201 (Hemopure) affect platelet function in orthopedic surgery: a single-site analysis from a multicenter study.

HBOC-201, Hemoglobin glutamer-250 (bovine), (Biopure Corp., Cambridge, MA) has been studied in an international, multicenter, pivotal Phase III trial. A subset analysis of use of blood products indicated that the HBOC-201 group required no more than the packed red blood cell (PRBC) group and was limited to less than 6% in both treatment groups. In a subset analysis from one site, platelet function using PFA-100 was assessed before and after transfusion, and compared those receiving HBOC-201 versus PRBC. After initial IRB approval, patient consent for the Phase III trial and blood draws for PFA-100, an additional IRB exemption for retrospective chart review was obtained. cEPI and cADP means were compared at seven time periods: true baseline(before starting surgery and anesthesia), before transfusion, after transfusion, 1 day, 2 days, 3 to 9 days and 21 or more days after transfusion. Twenty-seven (HBOC: n = 12, PRBC: n = 15) subjects were studied. Comparing data from before transfusion and baseline did not show statistically significant differences in any of cEPI or cADP measurements. cEPI means for the HBOC-201 group increased after transfusion compared to the true baseline (P = 0.01), before transfusion (P = 0.0004) and day 1 after transfusion (P = 0.002). cADP means for the HBOC-201 group were greater after transfusion compared to the true baseline (P = 0.05) and before transfusion (P = 0.005). In the PRBC group there were no significant difference in cEPI and cADP means between all of the time periods. Our study shows that HBOC-201 causes mild platelet dysfunction. Although there were significant changes after HBOC infusion and cEPI and cADP mean values were above the upper normal limit, they did not reach the non-closure time. Further controlled studies are needed to establish definitively the effects that HBOC-201 has on platelet function in patients.