Intravenous versus oral acetaminophen for pain and quality of recovery after ambulatory spine surgery: a randomized controlled trial.

INTRODUCTION: As ambulatory spine surgery increases, efficient recovery and discharge become essential. Multimodal analgesia is superior to opioids alone. Acetaminophen is a central component of multimodal protocols and both intravenous and oral forms are used. While some advantages for intravenous acetaminophen have been touted, prospective studies with patient-centered outcomes are lacking in ambulatory spine surgery. A substantial cost difference exists. We hypothesized that intravenous acetaminophen would be associated with fewer opioids and better recovery. METHODS: Patients undergoing ambulatory spine surgery were randomized to preoperative oral placebo and intraoperative intravenous acetaminophen or preoperative oral acetaminophen. All patients received general anesthesia and multimodal analgesia. The primary outcome was 24-hour opioid use in intravenous morphine milligram equivalents (MMEs), beginning with arrival to the postanesthesia care unit (PACU). Secondary outcomes included pain, Quality of Recovery (QoR)-15 scores, postoperative nausea and vomiting, recovery time, and correlations between pain catastrophizing, QoR-15, and pain. RESULTS: A total of 82 patients were included in final analyses. Demographics were similar between groups. For the primary outcome, the median 24-hour MMEs did not differ between groups (12.6 (4.0, 27.1) vs 12.0 (4.0, 29.5) mg, p=0.893). Postoperative pain ratings, PACU MMEs, QoR-15 scores, and recovery time showed no differences. Spearman's correlation showed a moderate negative correlation between postoperative opioid use and QoR-15. CONCLUSION: Intravenous acetaminophen was not superior to the oral form in ambulatory spine surgery patients. This does not support routine use of the more expensive intravenous form to improve recovery and accelerate discharge. TRIAL REGISTRATION NUMBER: NCT04574778.

Observational study of the effect of ketamine infusions on sedation depth, inflammation, and clinical outcomes in mechanically ventilated patients with SARS-CoV-2.

Severely ill patients with COVID-19 are challenging to sedate and often require high-dose sedation and analgesic regimens. Ketamine can be an effective adjunct to facilitate sedation of critically ill patients but its effects on sedation level and inflammation in COVID-19 patients have not been studied. This retrospective, observational cohort study evaluated the effect of ketamine infusions on inflammatory biomarkers and clinical outcomes in mechanically ventilated patients with SARS-CoV-2 infection. A total of 186 patients were identified (47 received ketamine, 139 did not). Patients who received ketamine were significantly younger than those who did not (mean (standard deviation) 59.2 (14.2) years versus 66.3 (14.4) years; P = 0.004), but there was no statistically significant difference in body mass index (P = 0.25) or sex distribution (P = 0.91) between groups. Mechanically ventilated patients who received ketamine infusions had a statistically significant reduction in Richmond Agitation-Sedation Scale score (-3.0 versus -2.0, P < 0.001). Regarding inflammatory biomarkers, ketamine was associated with a reduction in ferritin (P = 0.02) and lactate (P = 0.01), but no such association was observed for C-reactive protein (P = 0.27), lactate dehydrogenase (P = 0.64) or interleukin-6 (P = 0.87). No significant association was observed between ketamine administration and mortality (odds ratio 0.971; 95% confidence interval 0.501 to 1.882; P = 0.93). Ketamine infusion was associated with improved sedation depth in mechanically ventilated COVID-19 patients and provided a modest anti-inflammatory benefit but did not confer benefit with respect to mortality or intensive care unit length of stay.

In Vivo Study of the Inflammatory Tissue Response Surrounding a Novel Extended-Wear Kink-Resistant Insulin Infusion Set Prototype Compared With a Commercial Control Over Two Weeks of Wear Time.

BACKGROUND: Infusion set function remains the limiting factor of insulin pump therapy due to nonmetabolic complications. Here, we tested an investigational extended-wear infusion set prototype with a soft, angled, wire-reinforced cannula with three additional side holes, and compared failure mechanisms and tissue response with a commercial Teflon control. METHODS: A total of 48 Teflon and 48 prototype infusion sets were inserted subcutaneously every other day for 14 days in 12 swine and infused with dilute insulin. After two weeks, tissue around cannulas was excised, and occlusions, leaks, and kinks were determined. Tissue was processed and stained to assess the total area of inflammation (TAI) and the inflammatory layer thickness (ILT) around the cannulas. Data were analyzed using Fisher's exact, analysis of variance-general linear model, Kruskal-Wallis, and post hoc tests. RESULTS: On average, the TAI surrounding the investigational cannula was 52.6% smaller than around the commercial control. The ILT was 66.3% smaller around investigational cannulas. Kinks occurred in 2.1% (investigational) vs 32.4% (commercial) cannulas (P < .001). There was no difference in occlusion alarms and leaks onto skin. CONCLUSIONS: The data suggest that the infusion set prototype elicits less inflammation over an extended wear time and is resistant to kinking, compared with a commercial Teflon device. This is consistent with previously published data on the impact of cannula material/angle on the inflammatory tissue response. We highlight the following important aspects of infusion set design: (1) secure skin adhesion, (2) reliable cannula insertion, (3) automatic removal of the stylet, (4) cannula material/design that resists kinking, and (5) minimization of local tissue inflammation.

Lidocaine infusions for refractory chronic migraine: a retrospective analysis.

INTRODUCTION: Patients with refractory chronic migraine have poor quality of life. Intravenous infusions are indicated to rapidly 'break the cycle' of pain. Lidocaine infusions may be effective but evidence is limited. METHODS: The records of 832 hospital admissions involving continuous multiday lidocaine infusions for migraine were reviewed. All patients met criteria for refractory chronic migraine. During hospitalization, patients received additional migraine medications including ketorolac, magnesium, dihydroergotamine, methylprednisolone, and neuroleptics. The primary outcome was change in headache pain from baseline to hospital discharge. Secondary outcomes measured at the post-discharge office visit (25-65 days after treatment) included headache pain and the number of headache days, and percentage of sustained responders. Percentage of acute responders, plasma lidocaine levels, and adverse drug effects were also determined. RESULTS: In total, 609 patient admissions met criteria. The mean age was 46±14 years; 81.1% were female. Median pain rating decreased from baseline of 7.0 (5.0-8.0) to 1.0 (0.0-3.0) at end of hospitalization (p<0.001); 87.8% of patients were acute responders. Average pain (N=261) remained below baseline at office visit 1 (5.5 (4.0-7.0); p<0.001). Forty-three percent of patients were sustained responders at 1 month. Headache days (N=266) decreased from 26.8±3.9 at baseline to 22.5±8.3 at the post-discharge office visit (p<0.001). Nausea and vomiting were the most common adverse drug effects and all were mild. CONCLUSION: Lidocaine infusions may be associated with short-term and medium-term pain relief in refractory chronic migraine. Prospective studies should confirm these results.

Ketamine in the Past, Present, and Future: Mechanisms, Metabolites, and Toxicity.

PURPOSE OF REVIEW: While ketamine's analgesia has mostly been attributed to antagonism of N-methyl-D-aspartate receptors, evidence suggests multiple other pathways are involved in its antidepressant and possibly analgesic activity. These mechanisms and ketamine's role in the nociplastic pain paradigm are discussed. Animal studies demonstrating ketamine's neurotoxicity have unclear human translatability and findings from key rodent and human studies are presented. RECENT FINDINGS: Ketamine's metabolites, and (2R,6R)-hydroxynorketamine in particular, may play a greater role in its clinical activity than previously believed. The activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the mammalian target of rapamycin by ketamine are mechanisms that are still being elucidated. Ketamine might work best in nociplastic pain, which involves altered pain processing. While much is known about ketamine, new studies will continue to define its role in clinical medicine. Evidence supporting ketamine's neurotoxicity in humans is lacking and should not impede future ketamine clinical trials.

Ketamine for Refractory Chronic Migraine: An Observational Pilot Study and Metabolite Analysis.

Patients with refractory chronic migraine have substantial disability and have failed many acute and preventive medications. When aggressive intravenous therapy is indicated, both lidocaine and (R,S)-ketamine infusions have been used successfully to provide relief. Retrospective studies have shown that both agents may be associated with short-term analgesia. In this prospective, observational pilot study of 6 patients, we compared the effects of lidocaine and (R,S)-ketamine infusions and performed metabolite analyses of (R,S)-ketamine to determine its metabolic profile in this population. One of (R,S)-ketamine's metabolites, (2R,6R)-hydroxynorketamine, has been shown in animal studies to reduce pain, but human studies in patients undergoing continuous (R,S)-ketamine infusions for migraine are lacking. All 6 patients tolerated both infusions well with mild adverse effects. The baseline mean pain rating (0-10 numeric rating scale) decreased from 7.5 ± 2.2 to 4.7 ± 2.8 by end of lidocaine treatment ( P≤.05 ) but increased to 7.0 ± 1.4 by the postdischarge visit at 4 weeks (P > .05 vs baseline). The baseline mean pain rating prior to ketamine treatment was 7.4 ± 1.4, which decreased to 3.7 ± 2.3 by the end of the hospitalization ( P≤.05 ) but increased to 7.2 ± 1.7 by the postdischarge visit at 6 weeks (P > .05 vs baseline). For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 vs -2.8; P≤.05 ), but this has minimal clinical significance. Ketamine metabolite analysis revealed that (2R,6R)-hydroxynorketamine was the predominant metabolite during most of the infusion, consistent with previous studies.

Effect of difelikefalin, a selective kappa opioid receptor agonist, on respiratory depression: A randomized, double-blind, placebo-controlled trial.

Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, small-peptidic structure limits CNS entry, minimizing potential CNS-mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single-center, randomized, double-blind, placebo-controlled, three-way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg/kg i.v.) or placebo on sequential days with an intervening 24 (±2) h washout period. The primary end points included incidence of increased end-tidal carbon dioxide (ETCO2 ) greater than or equal to 10 mm Hg versus baseline or a level greater than 50 mm Hg sustained greater than or equal to 30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO2 ) to less than 92% sustained greater than or equal to 30 seconds. Secondary end points included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO2 or reduced SpO2 primary end point criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4-h postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO2 , SpO2 , or respiratory rate. The most commonly reported treatment-emergent AEs (TEAEs; ≥20% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg/kg i.v. did not produce respiratory depression.

Risk of Gastrointestinal Bleeding With Extended Use of Nonsteroidal Anti-Inflammatory Drug Analgesia After Joint Arthroplasty.

BACKGROUND: Chronic nonsteroidal anti-inflammatory drug (NSAID) use is associated with gastrointestinal bleeding via inhibition of endogenous mucosal protection and platelet aggregation. This study aimed to determine whether extended NSAIDs after joint arthroplasty is associated with increased risk of gastrointestinal bleeding. METHODS: This was a retrospective study examining 28,794 adults who underwent joint arthroplasty by one of 50 surgeons from 2016 to 2018. Episodes of gastrointestinal bleeding within 90 days postoperatively were identified prospectively. Postoperative medications were reported directly by patients with electronic questionnaires. The primary analysis was performed using binary logistic regression. RESULTS: A total of 74 (0.26%) episodes of gastrointestinal bleeding occurred within 90 days (median 8 days) postoperatively. Of 5086 patients with complete data included in the primary analysis, 59.6% had used NSAIDs with median duration of 2 weeks (interquartile range, 0-6 weeks). Patients with gastrointestinal bleeding were significantly older (71.3 vs 67.0 years), required longer hospitalizations (2.1 vs 1.5 days), and more commonly had a history of peptic ulcers (10.8% vs 0.9%). However, there was no positive association between NSAID use and gastrointestinal bleeding. In fact, the odds of gastrointestinal bleeding were lower in patients taking NSAIDs. Gastrointestinal bleeding was associated with anticoagulants, antiplatelet agents, and, to a lesser extent, aspirin. CONCLUSION: NSAIDs were not associated with gastrointestinal bleeding and may be prescribed safely for a majority of patients after joint arthroplasty. The greatest odds of gastrointestinal bleeding occurred in patients with peptic ulcer disease and those who received antiplatelet and anticoagulation agents. Increasing age and bilateral surgery were also associated with gastrointestinal bleeding. LEVEL OF EVIDENCE: Level III.

An anesthesiologist-led inpatient buprenorphine initiative.

Hospitalized patients with opioid use disorder who present with acute pain are challenging to manage. Without any treatment, their mortality in the first 28 days after discharge is substantially increased. Unlike extended-release naltrexone, which requires a period of withdrawal, or methadone, which can cause prolonged corrected QT (QTc) and carries a higher risk of respiratory depression, buprenorphine provides potent analgesia with low respiratory risk. Hospitalization provides a unique opportunity for clinicians to perform buprenorphine induction, which could potentially reduce mortality without affecting analgesia. Our acute pain management service uses multimodal analgesia to maintain adequate analgesia and minimize withdrawal during buprenorphine induction in the hospital. With the assistance of narcotics addiction rehabilitation program specialists, we help link patients to outpatient buprenorphine providers and maximize the chance of successful recovery. The primary outcome of this study was to determine the percentage of patients who filled an outpatient buprenorphine prescription after undergoing inpatient induction.

A Randomized Trial of Manual Phone Calls Versus Automated Text Messages for Peripheral Nerve Block Follow-Ups.

Mobile phone applications (apps) have been used for patient follow-up in the postoperative period, specifically to assess for complications and patient satisfaction. Few studies have evaluated their use in regional anesthesia. The objective of this study was to compare follow-up response rates using manual phone calls versus an automated patient outreach (APO) app for peripheral nerve block patients. We hypothesized that the response rate would be higher in the APO group. A mobile app, "JeffAnesthesia," was developed, which sends notifications to patients to answer survey questions in the app. We randomly assigned patients who received peripheral nerve blocks for postoperative pain to either a manual phone call or an APO app group, with follow-up in each category occurring between postoperative days (POD) 14-21 and 90-100. In total, 60 patients were assigned to the phone call group and 60 patients to the APO app group. Between POD 14-21, 9 (15%) patients were reached in the manual phone call arm, and 16 (26.7%) patients were reached in the APO arm (p = 0.117). At POD 90-100, follow-up was successful with 5 (8.2%) in the manual phone call group vs. 3 (5.0%) patients in the APO app group (p = 0.300). Overall response rate was poor, with comparable response rates between groups. The APO method may reduce time spent by anesthesia staff on follow-up calls, but our data do not suggest this method improves response rates significantly. Further studies are needed to better understand the reasons for the poor response rate and strategies for improvement.

Acute Amiodarone Pulmonary Toxicity.

Amiodarone is an effective antiarrhythmic that frequently is used during the perioperative period. Amiodarone possesses a significant adverse reaction profile. Amiodarone-induced pulmonary toxicity (AIPT) is among the most serious adverse effects and is a leading cause of death associated with its use. Despite significant advances in the understanding of AIPT, its etiology and pathogenesis remain incompletely understood. The diagnosis of AIPT is one of exclusion. The clinical manifestations of AIPT are categorized broadly as acute, subacute, and chronic. Acute AIPT is a rarer and more aggressive form of the disease, most often encountered in cardiothoracic surgery. Acute respiratory distress syndrome (ARDS) is the predominating pattern of amiodarone's acute pulmonary toxicity. The incidence, risk factors, pathogenesis, and diagnosis of acute AIPT are speculative. Early cardiothoracic literature investigating AIPT often attributed amiodarone to the development of postoperative ARDS. Subsequent studies have found no association between amiodarone and acute AIPT and ARDS development. As a drug that is frequently prescribed to a patient population deemed most at risk for this fatal disease, the conflicting evidence on acute AIPT needs further investigation and clarification.

Mepivacaine versus Bupivacaine Spinal Anesthesia for Early Postoperative Ambulation.

BACKGROUND: Early ambulation after total hip arthroplasty predicts early discharge. Spinal anesthesia is preferred by many practices but can delay ambulation, especially with bupivacaine. Mepivacaine, an intermediate-acting local anesthetic, could enable earlier ambulation than bupivacaine. This study was designed to test the hypothesis that patients who received mepivacaine would ambulate earlier than those who received hyperbaric or isobaric bupivacaine for primary total hip arthroplasty. METHODS: This randomized controlled trial included American Society of Anesthesiologists Physical Status I to III patients undergoing primary total hip arthroplasty. The patients were randomized 1:1:1 to 52.5 mg of mepivacaine, 11.25 mg of hyperbaric bupivacaine, or 12.5 mg of isobaric bupivacaine for spinal anesthesia. The primary outcome was ambulation between 3 and 3.5 h. Secondary outcomes included return of motor and sensory function, postoperative pain, opioid consumption, transient neurologic symptoms, urinary retention, intraoperative hypotension, intraoperative muscle tension, same-day discharge, length of stay, and 30-day readmissions. RESULTS: Of 154 patients, 50 received mepivacaine, 53 received hyperbaric bupivacaine, and 51 received isobaric bupivacaine. Patient characteristics were similar among groups. For ambulation at 3 to 3.5 h, 35 of 50 (70.0%) of patients met this endpoint in the mepivacaine group, followed by 20 of 53 (37.7%) in the hyperbaric bupivacaine group, and 9 of 51 (17.6%) in the isobaric bupivacaine group (P < 0.001). Return of motor function occurred earlier with mepivacaine. Pain and opioid consumption were higher for mepivacaine patients in the early postoperative period only. For ambulatory status, 23 of 50 (46.0%) of mepivacaine, 13 of 53 (24.5%) of hyperbaric bupivacaine, and 11 of 51 (21.5%) of isobaric bupivacaine patients had same-day discharge (P = 0.014). Length of stay was shortest in mepivacaine patients. There were no differences in transient neurologic symptoms, urinary retention, hypotension, muscle tension, or dizziness. CONCLUSIONS: Mepivacaine patients ambulated earlier and were more likely to be discharged the same day than both hyperbaric bupivacaine and isobaric bupivacaine patients. Mepivacaine could be beneficial for outpatient total hip arthroplasty candidates if spinal is the preferred anesthesia type.

High Incidence of Burst Suppression during Propofol Sedation for Outpatient Colonoscopy: Lessons Learned from Neuromonitoring.

BACKGROUND: Although anesthesia providers may plan for moderate sedation, the depth of sedation is rarely quantified. Using processed electroencephalography (EEG) to assess the depth of sedation, this study investigates the incidence of general anesthesia with variable burst suppression in patients receiving propofol for outpatient colonoscopy. The lessons learned from neuromonitoring can then be used to guide institutional best sedation practice. METHODS: This was a prospective observational study of 119 outpatients undergoing colonoscopy at Thomas Jefferson University Hospital (TJUH). Propofol was administered by CRNAs under anesthesiologists' supervision. The Patient State Index (PSi™) generated by the Masimo SedLine® Brain Root Function monitor (Masimo Corp., Irvine, CA) was used to assess the depth of sedation. PSi data correlating to general anesthesia with variable burst suppression were confirmed by neuroelectrophysiologists' interpretation of unprocessed EEG. RESULTS: PSi values of <50 consistent with general anesthesia were attained in 118/119 (99.1%) patients. Of these patients, 33 (27.7%) attained PSi values <25 consistent with variable burst suppression. The 118 patients that reached PSi <50 spent a significantly greater percentage (53.1% vs. 42%) of their case at PSi levels <50 compared to PSi levels >50 (p=0.001). Mean total propofol dose was significantly correlated to patient PSi during periods of PSi <25 (R=0.406, p=0.021). CONCLUSION: Although providers planned for moderate to deep sedation, processed EEG showed patients were under general anesthesia, often with burst suppression. Anesthesiologists and endoscopists may utilize processed EEG to recognize their institutional practice patterns of procedural sedation with propofol and improve upon it.

In vivo investigation of the tissue response to commercial Teflon insulin infusion sets in large swine for 14 days: the effect of angle of insertion on tissue histology and insulin spread within the subcutaneous tissue.

Objective: This study investigated the effects of the inflammatory tissue response (ITR) to an insulin infusion set (IIS) on insulin bolus spread over wear time, as well as the effect of cannula insertion angle on the ITR, bolus shape, and pump tubing pressure. Research design and methods: Angled or straight IISs were inserted every other day for 14 days into the subcutaneous tissue of 11 swine and insulin was delivered continuously. Prior to euthanasia, a 70 µL bolus of insulin/X-ray contrast agent was infused while recording a pressure profile (peak tubing pressure, pmax; area under the pressure curve, AUC), followed by the excision of the tissue-catheter specimen. Bolus surface area (SA) and volume (V) were assessed via micro-CT. Tissue was stained to analyze total area of inflammation (TAI) and inflammatory layer thickness (ILT) surrounding the cannula. Results: A bolus delivered through an angled IIS had a larger mean SA than a bolus delivered through a straight cannula (314.0±84.2 mm2 vs 229.0±99.7 mm2, p<0.001) and a larger volume (198.7±66.9 mm3 vs 145.0±65.9 mm3, p=0.001). Both decreased significantly over wear time, independent of angle. There was a significant difference in TAI (angled, 9.1±4.0 mm2 vs straight, 14.3±8.6 mm2, p<0.001) and ILT (angled, 0.7±0.4 vs straight, 1.2±0.7 mm, p<0.001). pmax (p=0.005) and AUC (p=0.014) were lower using angled IIS. As ILT increased, pmax increased, while SA and V decreased. Conclusions: The progression of the ITR directly affected bolus shape and tubing pressure. Although straight insertion is clinically preferred, our data suggest that an angled IIS elicits lower grades of ITR and delivers a bolus with lower tubing pressure and greater SA and V. The subcutaneous environment plays a crucial role in IIS longevity, and the insertion angle needs to be considered in future IIS designs and clinical trials.

Ketamine for Refractory Headache: A Retrospective Analysis.

BACKGROUND AND OBJECTIVES: The burden of chronic headache disorders in the United States is substantial. Some patients are treatment refractory. Ketamine, an N-methyl-D-aspartate antagonist, provides potent analgesia in subanesthetic doses in chronic pain, and limited data suggest it may alleviate headache in some patients. METHODS: We performed a retrospective study of 61 patients admitted over 3 years for 5 days of intravenous therapy that included continuous ketamine to determine responder rate and patient and ketamine infusion characteristics. Pain ratings at 2 follow-up visits were recorded. An immediate responder was a patient with decrease of 2 points or greater in the numerical rating scale (0-10) from start to final pain in the hospital. Sustained response at office visits 1 and 2 was determined based on maintaining the 2-point improvement at those visits. Patients were assessed daily for pain and adverse events (AEs). RESULTS: Forty-eight (77%) of the 61 patients were immediate responders. There were no differences regarding demographics, opioid use, or fibromyalgia between immediate responders and nonresponders. Maximum improvement occurred 4.56 days (mean) into treatment. Sustained response occurred in 40% of patients at visit 1 (mean, 38.1 days) and 39% of patients at visit 2 (mean, 101.3 days). The mean maximum ketamine rate was 65.2 ± 2.8 mg/h (0.76 mg/kg per hour). Ketamine rates did not differ between groups. Adverse events occurred equally in responders and nonresponders and were mild. CONCLUSIONS: Ketamine was associated with short-term analgesia in many refractory headache patients with tolerable adverse events. A prospective study is warranted to confirm this and elucidate responder characteristics.