A Pharmacological Evaluation of the Analgesic Effect and Hippocampal Protein Modulation of the Ketamine Metabolite (2R,6R)-Hydroxynorketamine in Murine Pain Models.

BACKGROUND: The ketamine metabolite (2R,6R)-hydroxynorketamine ([2R,6R]-HNK) has analgesic efficacy in murine models of acute, neuropathic, and chronic pain. The purpose of this study was to evaluate the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) dependence of (2R,6R)-HNK analgesia and protein changes in the hippocampus in murine pain models administered (2R,6R)-HNK or saline. METHODS: All mice were CD-1 IGS outbred mice. Male and female mice underwent plantar incision (PI) (n = 60), spared nerve injury (SNI) (n = 64), or tibial fracture (TF) (n = 40) surgery on the left hind limb. Mechanical allodynia was assessed using calibrated von Frey filaments. Mice were randomized to receive saline, naloxone, or the brain-penetrating AMPA blocker (1,2,3,4-Tetrahydro-6-nitro-2,3-dioxobenzo [f]quinoxaline-7-sulfonamide [NBQX]) before (2R,6R)-HNK 10 mg/kg, and this was repeated for 3 consecutive days. The area under the paw withdrawal threshold by time curve for days 0 to 3 (AUC 0-3d ) was calculated using trapezoidal integration. The AUC 0-3d was converted to percent antiallodynic effect using the baseline and pretreatment values as 0% and 100%. In separate experiments, a single dose of (2R,6R)-HNK 10 mg/kg or saline was administered to naive mice (n = 20) and 2 doses to PI (n = 40), SNI injury (n = 40), or TF (n = 40) mice. Naive mice were tested for ambulation, rearing, and motor strength. Immunoblot studies of the right hippocampal tissue were performed to evaluate the ratios of glutamate ionotropic receptor (AMPA) type subunit 1 (GluA1), glutamate ionotropic receptor (AMPA) type subunit 2 (GluA2), phosphorylated voltage-gated potassium channel 2.1 (p-Kv2.1), phosphorylated-calcium/calmodulin-dependent protein kinase II (p-CaMKII), brain-derived neurotrophic factor (BDNF), phosphorylated protein kinase B (p-AKT), phosphorylated extracellular signal-regulated kinase (p-ERK), CXC chemokine receptor 4 (CXCR4), phosphorylated eukaryotic translation initiation factor 2 subunit 1 (p-EIF2SI), and phosphorylated eukaryotic translation initiation factor 4E (p-EIF4E) to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). RESULTS: No model-specific gender difference in antiallodynic responses before (2R,6R)-HNK administration was observed. The antiallodynic AUC 0-3d of (2R,6R)-HNK was decreased by NBQX but not with pretreatment with naloxone or saline. The adjusted mean (95% confidence interval [CI]) antiallodynic effect of (2R,6R)-HNK in the PI, SNI, and TF models was 40.7% (34.1%-47.3%), 55.1% (48.7%-61.5%), and 54.7% (46.5%-63.0%), greater in the SNI, difference 14.3% (95% CI, 3.1-25.6; P = .007) and TF, difference 13.9% (95% CI, 1.9-26.0; P = .019) compared to the PI model. No effect of (2R,6R)-HNK on ambulation, rearing, or motor coordination was observed. Administration of (2R,6R)-HNK was associated with increased GluA1, GluA2, p-Kv2.1, and p-CaMKII and decreased BDNF ratios in the hippocampus, with model-specific variations in proteins involved in other pain pathways. CONCLUSIONS: (2R,6R)-HNK analgesia is AMPA-dependent, and (2R,6R)-HNK affected glutamate, potassium, calcium, and BDNF pathways in the hippocampus. At 10 mg/kg, (2R,6R)-HNK demonstrated a greater antiallodynic effect in models of chronic compared with acute pain. Protein analysis in the hippocampus suggests that AMPA-dependent alterations in BDNF-TrkB and Kv2.1 pathways may be involved in the antiallodynic effect of (2R,6R)-HNK.

Efficacy and Safety of Cervical and High-Thoracic Dorsal Root Ganglion Stimulation Therapy for Complex Regional Pain Syndrome of the Upper Extremities.

OBJECTIVES: The purpose of this study was to evaluate analgesic and safety considerations for high thoracic and cervical dorsal root ganglion (DRG) neuromodulation for complex regional pain syndrome (CRPS). We hypothesized that DRG neuromodulation would provide sustained analgesia with complications like that of low thoracic or lumbar electrode implantation. MATERIALS AND METHODS: A single-center, retrospective study was conducted of patients with CRPS I or II of the upper extremities, refractory to previous therapies, who were treated with DRG neuromodulation in the upper thoracic and cervical spine. The primary outcome was successful DRG therapy, defined as ≥ 50% pain relief on a Numeric Rating Scale (NRS) 0 to 10 pain scale at six months after implantation. A secondary outcome was a reduction in daily opioid use after DRG therapy. RESULTS: After a DRG stimulation trial, 17 of 20 patients (85%) had ≥ 50% improvement in NRS pain and underwent a permanent pulse generator implant, with 100% endorsing ≥ 50% pain relief at six months. Mean NRS pain scores before DRG neuromodulation were 9.3 ± 1.1, with a mean reduction of 5.5 (95% CI, 4.5-6.6; p < 0.001) at six months. Ten patients were taking opioids at baseline; the median (interquartile range) dose was 45 mg (23 to 120) morphine equivalents (MME), which was reduced to 20 MME (15 to 40) at six months. The median reduction in daily MME use was -25 (95% CI, -100 to 20; p = 0.099). Six of 20 patients (30%) experienced a complication: three had lead migration; two experienced paresthesias; and one had a reduction in shoulder mobility. One patient had symptoms of a reversible spinal cord compression immediately after implant, requiring emergent electrode removal. CONCLUSIONS: DRG neuromodulation for patients with CRPS of the upper extremities produced clinically important analgesia and reduced opioid use for ≥ six months but was associated with one serious complication.

Analgesic Effectiveness and Dorsal Root Ganglia Protein Modulation of a Peripheral Adenosine Monophosphate Kinase Alpha Activator (O304) Following Lumbar Disk Puncture in the Mouse.

BACKGROUND: Disk herniation is a primary cause of radicular back pain. The purpose of this study was to evaluate the antiallodynic effective dose in 50% of the sample (ED 50 ) and dorsal root ganglion (DRG) protein modulation of a peripheral direct adenosine monophosphate kinase alpha (AMPKα) activator (O304) in a murine model of lumbar disk puncture. METHODS: Male (n = 28) and female (n = 28) mice (C57BL6/J) were assessed for hind paw withdrawal threshold (PWT) and burrowing. Abdominal surgery was performed on all mice, and 48 received a lumbar disk puncture (27-G needle), with 8 serving as nondisk puncture controls. Assessments were repeated at day 7, and mice were then randomized into 5 groups of equal numbers of males and females: O304 at 100 mg/kg (n = 10), 150 mg/kg (n = 10), 200 mg/kg (n = 10), and 250 mg/kg (n = 10) or drug vehicle (n = 8). Starting on day 7, mice received daily gavages of O304 or vehicle for 7 days. On days 14 and 21 PWT and on day 14 burrowing were assessed. The area under the PWT by time curve (AUC) from day 7 to 21 was determined by trapezoidal integration. DRG protein modulation was evaluated in male (n = 10) and female (n = 10) mice (C57BL6/J). Following disk puncture, mice were randomized to receive O304 200 mg/kg or vehicle for 7 days starting on day 7. On day 14, mice were euthanized; the DRG harvested and immunoblot performed for mammalian target of rapamycin (mTOR), transient receptor potential ankyrin 1 (TRPA1), phosphorylated adenosine monophosphate kinase (p-AMPK), phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated eukaryotic translation initiation factor 2 subunit 1 (p-EIF2S1), phosphorylated eukaryotic translation initiation factor 4e (p-EIF4E), and glyceraldehyde 3-phosphate dehydrogenase (GADPH). RESULTS: Disk puncture decreased PWT greater in female mice compared with male mice and decreased burrowing at 7 days. PWTs were increased with increasing doses of O304 from 150 to 250 mg/g on day 14 and sustained through day 21. The ED 50 (95% confidence interval [CI]) for reducing mechanical allodynia was 140 (118-164) mg/kg. Burrowing was not increased at day 14 compared to day 7 by O304 administration. Compared to vehicle-treated animals, O304 increased (95% CI) the p-AMPK/GADPH ratio, difference 0.27 (0.08-0.45; P = . 004) and decreased (95% CI) the ratios of p-TRPA1, p-ERK1/2, pEIF4E, and p-EIF2S1 to GADPH by -0.49 (-0.61 to -0.37; P < . 001), -0.53 (-0.76 to -0.29; P < . 001), -0.27 (-0.42 to 0.11; P = . 001), and -0.21 (-0.32 to -0.08; P = . 003) in the DRG, respectively. CONCLUSIONS: The direct peripheral AMPK activator O304 reduced allodynia in a dose-dependent manner, and immunoblot studies of the DRG showed that O304 increased p-AMPK and decreased TRPA1, p-ERK1/2, as well as translation factors involved in neuroplasticity. Our findings confirm the role of peripheral AMPKα activation in modulating nociceptive pain.

Patient and operative factors associated with unanticipated intensive care admission and outcomes following posterior fossa decompressions in children: A retrospective study.

INTRODUCTION: Posterior fossa decompression for Chiari I Malformation is a common pediatric neurosurgical procedure. We sought to identify the impact of anesthesia-related intraoperative complications on unanticipated admission to the intensive care unit and outcomes following posterior fossa decompression. METHODS: Medical records of all patients <18 years who underwent surgery for Chiari I malformation between 1/1/09 and 1/31/21 at the Ann & Robert H. Lurie Children's Hospital of Chicago were included. Records were reviewed for patient characteristics, anesthesia-related intraoperative complications, postoperative complications, and surgical outcomes. The primary outcome was the incidence of unanticipated admission to the intensive care unit, and the primary variable of interest was an anesthesia-related intraoperative complication. Patient, surgical characteristics, and year of surgery were also compared between patients with and without an unanticipated admission to the intensive care unit, and a multi-variable adjusted estimate of odds of unanticipated admission to the intensive care unit admission following an anesthesia-related intraoperative complication was performed. Secondary outcomes included anesthesia factors associated with an anesthesia-related intraoperative event, and postoperative complications and surgical outcomes between patients admitted to the intensive care unit and those who were not. RESULTS: Two hundred ninety-six patients with Chiari I Malformation were identified. Clinical characteristics associated with an unanticipated admission to the intensive care unit were younger age, American Society of Anesthesiologist (ASA) physical status >2 and an anesthesia-related intraoperative complication. 29 anesthesia-related intraoperative complications were observed in 25 patients (8.4%). Two of 25 patients (8%) with an anesthesia-related intraoperative complication compared with 3 of 271 (1%) patients without anesthesia-related intraoperative complication had an unanticipated admission to the intensive care unit, odds ratio 7.8 (95% CI 1.2-48.8, p = .010). When adjusted for age, sex, ASA physical status, presenting symptoms, concomitant syringomyelia, previous decompression surgery and year of surgery, the odds ratio for an unanticipated admission to the intensive care unit following an anesthesia-related intraoperative complication was 5.9 (95% CI 0.51-59.6, p = .149). There were no differences in surgical outcomes between patients with or without an unanticipated admission to the intensive care unit. CONCLUSION: Our study demonstrates that although anesthesia-related intraoperative complications during posterior fossa decompression are infrequent, they are associated with an increased risk of an unanticipated admission to the intensive care unit.

Prophylactic Intrathecal Morphine and Prevention of Post-Dural Puncture Headache: A Randomized Double-blind Trial.

BACKGROUND: Prophylactic epidural morphine administration after unintentional dural puncture with a large-bore needle has been shown to decrease the incidence of post-dural puncture headache. The authors hypothesized that prophylactic administration of intrathecal morphine would decrease the incidence of post-dural puncture headache and/or need for epidural blood patch after unintentional dural puncture. METHODS: Parturients with an intrathecal catheter in situ after unintentional dural puncture with a 17-g Tuohy needle during intended epidural catheter placement for labor analgesia were enrolled in this randomized, double-blind trial. After delivery, subjects were randomized to receive intrathecal morphine 150 µg or normal saline. The primary outcome was the incidence of post-dural puncture headache. Secondary outcomes included onset, duration, and severity of post-dural puncture headache, the presence of cranial nerve symptoms and the type of treatment the patient received. RESULTS: Sixty-one women were included in the study. The incidence of post-dural puncture headache was 21 of 27 (78%) in the intrathecal morphine group and 27 of 34 (79%) in the intrathecal saline group (difference, -1%; 95% CI, -25% to 24%). There were no differences between groups in the onset, duration, or severity of headache, or presence of cranial nerve symptoms. Epidural blood patch was administered to 10 of 27 (37%) of subjects in the intrathecal morphine and 11 of 21 (52%) of the intrathecal saline group (difference 15%; 95% CI, -18% to 48%). CONCLUSIONS: The present findings suggest that a single prophylactic intrathecal morphine dose of 150 µg administered shortly after delivery does not decrease the incidence or severity of post-dural puncture headache after unintentional dural puncture. This study does not support the clinical usefulness of prophylactic intrathecal morphine after an unintentional dural puncture.

Opioid Stewardship Program and Postoperative Adverse Events: A Difference-in-differences Cohort Study.

BACKGROUND: A 6-month opioid use educational program consisting of webinars on pain assessment, postoperative and multimodal pain opioid management, safer opioid use, and preventing addiction coupled with on-site coaching and monthly assessments reports was implemented in 31 hospitals. The authors hypothesized the intervention would measurably reduce and/or prevent opioid-related harm among adult hospitalized patients compared to 33 nonintervention hospitals. METHODS: Outcomes were extracted from medical records for 12 months before and after the intervention start date. Opioid adverse events, evaluated by opioid overdose, wrong substance given or taken in error, naloxone administration, and acute postoperative respiratory failure causing prolonged ventilation were the primary outcomes. Opioid use in adult patients undergoing elective hip or knee arthroplasty or colorectal procedures was also assessed. Differences-in-differences were compared between intervention and nonintervention hospitals. RESULTS: Before the intervention, the incidence ± SD of opioid overdose, wrong substance given, or substance taken in error was 1 ± 0.5 per 10,000 discharges, and naloxone use was 117 ± 13 per 10,000 patients receiving opioids. The incidence of respiratory failure was 42 ± 10 per 10,000 surgical discharges. A difference-in-differences of -0.2 (99% CI, -1.1 to 0.6, P = 0.499) per 10,000 in opioid overdose, wrong substance given, or substance taken in error and -13.6 (99% CI, -29.0 to 0.0, P = 0.028) per 10,000 in respiratory failure was observed postintervention in the intervention hospitals; however, naloxone administration increased by 15.2 (99% CI, 3.8 to 30.0, P = 0.011) per 10,000. Average total daily opioid use, as well as the fraction of patients receiving daily opioid greater than 90 mg morphine equivalents was not different between the intervention and nonintervention hospitals. CONCLUSIONS: A 6-month opioid educational intervention did not reduce opioid adverse events or alter opioid use in hospitalized patients. The authors' findings suggest that despite opioid and multimodal analgesia awareness, limited-duration educational interventions do not substantially change the hospital use of opioid analgesics.

Early Treatment With Metformin in a Mice Model of Complex Regional Pain Syndrome Reduces Pain and Edema.

BACKGROUND: Metformin, an adenosine monophosphate (AMP)-activated protein kinase activator, as well as a common drug for type 2 diabetes, has previously been shown to decrease mechanical allodynia in mice with neuropathic pain. The objective of this study is to determine if treatment with metformin during the first 3 weeks after fracture would produce a long-term decrease in mechanical allodynia and improve a complex behavioral task (burrowing) in a mouse tibia fracture model with signs of complex regional pain syndrome. METHODS: Mice were allocated into distal tibia fracture or nonfracture groups (n = 12 per group). The fracture was stabilized with intramedullary pinning and external casting for 21 days. Animals were then randomized into 4 groups (n = 6 per group): (1) fracture, metformin treated, (2) fracture, saline treated, (3) nonfracture, metformin treated, and (4) nonfracture, saline treated. Mice received daily intraperitoneal injections of metformin 200 mg/kg or saline between days 14 and 21. After cast removal, von Frey force withdrawal (every 3 days) and burrowing (every 7 days) were tested between 25 and 56 days. Paw width was measured for 14 days after cast removal. AMP-activated protein kinase downregulation at 4 weeks after tibia fracture in the dorsal root ganglia was examined by immunohistochemistry for changes in the AMP-activated protein kinase pathway. RESULTS: Metformin injections elevated von Frey thresholds (reduced mechanical allodynia) in complex regional pain syndrome mice versus saline-treated fracture mice between days 25 and 56 (difference of mean area under the curve, 42.5 g·d; 95% CI of the difference, 21.0-63.9; P < .001). Metformin also reversed burrowing deficits compared to saline-treated tibial fracture mice (difference of mean area under the curve, 546 g·d; 95% CI of the difference, 68-1024; P < .022). Paw width (edema) was reduced in metformin-treated fracture mice. After tibia fracture, AMP-activated protein kinase was downregulated in dorsal root ganglia neurons, and mechanistic target of rapamycin, ribosomal S6 protein, and eukaryotic initiation factor 2α were upregulated. CONCLUSIONS: The important finding of this study was that early treatment with metformin reduces mechanical allodynia in a complex regional pain syndrome model in mice. Our findings suggest that AMP-activated protein kinase activators may be a viable therapeutic target for the treatment of pain associated with complex regional pain syndrome.

Anesthetic management of pediatric patients with Niemann-Pick disease type C for intrathecal 2-hydroxypropyl-ß-cyclodextrin injection.

BACKGROUND: Niemann-Pick disease type C is an autosomal-recessive, lysosomal storage disorder with variable age of onset and a heterogeneous clinical presentation that includes neurological, psychiatric, and visceral findings. Serial intrathecal injections of 2-hydroxypropyl-beta-cyclodextrin are being evaluated as a treatment modality for Niemann-Pick disease type C with a subset of patients requiring anesthesia for this procedure. AIMS: The aim of this study was to evaluate the safety of anesthesia provided for patients undergoing intrathecal injection of 2-hydroxypropyl-beta-cyclodextrin. METHODS: A retrospective review of pediatric patients who received serial intrathecal injections of 2-hydroxypropyl-beta-cyclodextrin with anesthesia at two tertiary care centers was conducted from December 2015 through April 2019. Data were extracted for analysis included preoperative comorbidities, demographics, vital signs, intraoperative anesthesia course, airway management technique, venous access, postoperative course, and perioperative complications. In total, 19 patients were identified and a total of 394 anesthetic encounters were included in this study. RESULTS: All 394 2-hydroxypropyl-beta-cyclodextrin administration procedures were successfully performed, and there were no changes made in the anesthetic plan during the anesthesia encounters. Three hundred forty-nine anesthetics were performed utilizing inhalation induction and mask maintenance, and 45 anesthetics were performed with placement of a supraglottic airway device due to patient body habitus and provider preference. The incidence of a major adverse event (aspirations, arterial desaturation) was 5/394 (1.3%, 95% CI 0.05%-3.1%). Minor adverse events (emesis, delirium, hypotension, seizure, and airway obstruction) were observed in 19/394 encounters (4.8%, 95% CI 3.0%-7.5%). CONCLUSIONS: Our findings suggest that general anesthesia induced via inhalation induction and maintained with volatile anesthetic via mask or supraglottic airway is a safe and effective option for pediatric patients with Niemann-Pick disease type C undergoing serial intrathecal injections of 2-hydroxypropyl-beta-cyclodextrin, supporting this technique as a viable option for anesthetic care in these patients.

A Comparison of Refill Procedures and Patient Outcomes Following Ultrasound-Guided and Template-Guided Intrathecal Drug Delivery Systems With Recessed Ports.

OBJECTIVE: Intrathecal drug delivery systems (IDDS) are refilled using templates and palpation. The 2017 Polyanalgesic Consensus Conference recommends ultrasound only when reservoir ports are difficult to identify. The purpose of this study was to compare procedural outcomes and patient's preference for refill method of IDDS. MATERIALS AND METHODS: The study was approved by the Rush University IRB. Participants were randomized to have their IDDS with ultrasound or template using a 2:1 allocation. The time to reservoir port access, number of needle maneuvers/punctures, pain (NRS 0-10), complications, patient satisfaction, and patient refill modality preference, were recorded. RESULTS: A total of 107 patients underwent 192 refills. There were 67 template-guided refills and 125 ultrasound-guided refills. No procedural pain (NRS = 0) was reported in 84% of the ultrasound-guided refills compared with 67% of the template-guided procedures, difference - 17% (95% difference - 3% to -31%, p = 0.01). When adjusted for age, gender, procedure duration, needle sticks, needle maneuvers and refills in the same patient, the odds ratio for a pain-free procedure with ultrasound-guidance was 3.1 (95% CI 1.3 to 7.2, p = 0.01). There was no difference between the groups in needle punctures (p = 0.87) or redirections (p = 0.34). Following 35/67 (52%) template-guided procedures, patients stated they preferred the ultrasound-guided but following only 12/125 (10%) of ultrasound-guided procedures, patients stated they preferred template-guidance (p < 0.001). CONCLUSIONS: Patients preferred ultrasound even though it lengthened the duration of refills compared to template-guided procedures. Fewer patients experienced procedural pain with ultrasound compared with template-guided refills. No safety issues were observed in either group.

Mixing Studies in Patients With Prolonged Activated Partial Thromboplastin Time or Prothrombin Time.

BACKGROUND: Patients presenting for surgery may have isolated or combined prolonged activated partial thromboplastin time (aPTT) and/or prothrombin time (PT). In patients not receiving anticoagulants or with no identifiable cause for abnormal clot formation, a mixing study is performed. The index of circulating anticoagulant (ICA) has been used to predict the presence of an inhibitor, usually a lupus anticoagulant. METHODS: We retrospectively reviewed the results of mixing studies performed at Northwestern Memorial Hospital, between January 1, 2010 and February 29, 2012. We determined the number of samples that normalized or remained prolonged, the clotting factors associated with prolonged test results, and the presence of coagulation inhibitors. We calculated the ICA in the samples with prolonged aPTT and PT to determine its ability to predict a lupus anticoagulant. The primary comparison of interest was the diagnostic utility of the ICA at cutoff values of 11% for predicting the presence of lupus anticoagulant. RESULTS: There were 269 mixing studies performed: 131 samples with prolonged aPTT; 95 with prolonged PT; and 43 with both prolonged aPTT and prolonged PT. Of the samples with a prolonged aPTT, 55 of 131 (42%) normalized, 36 of 131 (27%) partially corrected, and 40 of 131 (31%) remained prolonged. Thirty-three of 95 samples (35%) with prolonged PT normalized, while 62 of 95 (65%) remained prolonged. Eight of 43 (19%) mixing studies of patients with prolonged PT and aPTT normalized; the aPTT normalized, but the PT remained prolonged in 17 of 43 (39%); the PT normalized, but the aPTT remained prolonged in 7 of 43 (16%); and both tests remained prolonged in 11 of 43 (26%) samples. Prolongations in the aPTT were primarily associated with low activities of CF XII, while the majority of the prolongations in PT were secondary to low activities in CF VII. Combined prolongations were secondary to deficiencies in both the intrinsic and extrinsic as well as the common pathways. An ICA >11% had 100% (95% CI, 59%-100%) sensitivity, 53% (95% CI, 35%-70%) specificity, and 77% (95% CI, 62%-92%) accuracy in predicting the presence of lupus anticoagulant in patients with prolonged aPTT. CONCLUSIONS: Normalization of the aPTT and PT in a mixing study was associated with low clotting factor activity. The ICA may be helpful in predicting the presence of a lupus anticoagulant. As anesthesiologists take ownership of the perioperative surgical home, we need to understand the clinical implications of the results of mixing studies.

Status of Women in Academic Anesthesiology: A 10-Year Update.

BACKGROUND: Gender inequity is still prevalent in today's medical workforce. Previous studies have investigated the status of women in academic anesthesiology. The objective of this study is to provide a current update on the status of women in academic anesthesiology. We hypothesized that while the number of women in academic anesthesiology has increased in the past 10 years, major gender disparities continue to persist, most notably in leadership roles. METHODS: Medical student, resident, and faculty data were obtained from the Association of American Medical Colleges. The number of women in anesthesiology at the resident and faculty level, the distribution of faculty academic rank, and the number of women chairpersons were compared across the period from 2006 to 2016. The gender distribution of major anesthesiology journal editorial boards and data on anesthesiology research grant awards, among other leadership roles, were collected from websites and compared to data from 2005 and 2006. RESULTS: The number (%) of women anesthesiology residents/faculty has increased from 1570 (32%)/1783 (29%) in 2006 to 2145 (35%)/2945 (36%) in 2016 (P = .004 and P < .001, respectively). Since 2006, the odds that an anesthesiology faculty member was a woman increased approximately 2% per year, with an estimated odds ratio of 1.02 (95% confidence interval, 1.014-1.025; P < .001). In 2015, the percentage of women anesthesiology full professors (7.4%) was less than men full professors (17.3%) (difference, -9.9%; 95% confidence interval of the difference, -8.5% to -11.3%; P < .001). The percentage of women anesthesiology department chairs remained unchanged from 2006 to 2016 (12.7% vs 14.0%) (P = .75). To date, neither Anesthesia & Analgesia nor Anesthesiology has had a woman Editor-in-Chief. The percentage of major research grant awards to women has increased significantly from 21.1% in 1997-2007 to 31.5% in 2007-2016 (P = .02). CONCLUSIONS: Gender disparities continue to exist at the upper levels of leadership in academic anesthesiology, most importantly in the roles of full professor, department chair, and journal editors. However, there are some indications that women may be on the path to leadership parity, most notably, the growth of women in anesthesiology residencies and faculty positions and increases in major research grants awarded to women.

Effect of Epidural Infusion Bolus Delivery Rate on the Duration of Labor Analgesia: A Randomized Clinical Trial.

BACKGROUND: Programmed intermittent boluses of local anesthetic have been shown to be superior to continuous infusions for maintenance of labor analgesia. High-rate epidural boluses increase delivery pressure at the catheter orifice and may improve drug distribution in the epidural space. We hypothesized that high-rate drug delivery would improve labor analgesia and reduce the requirement for provider-administered supplemental boluses for breakthrough pain. METHODS: Nulliparous women with a singleton pregnancy at a cervical dilation of less than or equal to 5 cm at request for neuraxial analgesia were eligible for this superiority-design, double-blind, randomized controlled trial. Neuraxial analgesia was initiated with intrathecal fentanyl 25 µg. The maintenance epidural solution was bupivacaine 0.625 mg/ml with fentanyl 1.95 µg/ml. Programmed (every 60 min) intermittent boluses (10 ml) and patient controlled bolus (5 ml bolus, lockout interval: 10 min) were administered at a rate of 100 ml/h (low-rate) or 300 ml/h (high-rate). The primary outcome was percentage of patients requiring provider-administered supplemental bolus analgesia. RESULTS: One hundred eight women were randomized to the low- and 102 to the high-rate group. Provider-administered supplemental bolus doses were requested by 44 of 108 (40.7%) in the low- and 37 of 102 (36.3%) in the high-rate group (difference -4.4%; 95% CI of the difference, -18.5 to 9.1%; P = 0.67). Patient requested/delivered epidural bolus ratio and the hourly bupivacaine consumption were not different between groups. No subject had an adverse event. CONCLUSIONS: Labor analgesia quality, assessed by need for provider- and patient-administered supplemental analgesia and hourly bupivacaine consumption was not improved by high-rate epidural bolus administration.

Differentiation of Papillary Renal Cell Carcinoma Subtypes on MRI: Qualitative and Texture Analysis.

OBJECTIVE: The objective of this study was to determine whether quantitative texture analysis of MR images would improve the ability to distinguish papillary renal cell carcinoma (RCC) subtypes, compared with analysis of qualitative MRI features alone. MATERIALS AND METHODS: A total of 47 pathologically proven papillary RCC tumors were retrospectively evaluated, with 31 (66%) classified as type 1 tumors and 16 (34%) classified as type 2 tumors. MR images were reviewed by two readers to determine tumor size, signal intensity, heterogeneity, enhancement pattern, margins, perilesional stranding, vein thrombosis, and metastasis. Quantitative texture analysis of gray-scale images was performed. A logistic regression was derived from qualitative and quantitative features. Model performance was compared with and without texture features. RESULTS: The significant qualitative MR features noted were necrosis, enhancement appearance, perilesional stranding, and metastasis. A multivariable model based on qualitative features did not identify any factor as an independent predictor of a type 2 tumor. The logistic regression model for predicting papillary RCCs on the basis of qualitative and quantitative analysis identified probability of the 2D volumetric interpolated breath-hold examination (VIBE) sequence (AUC value, 0.87; 95% CI, 0.77-0.98) as an independent predictor of a type 2 tumor. No difference in the model AUC value was noted when texture features were included in the analysis; however, the model had increased sensitivity and an improved predictive value without loss of specificity. CONCLUSION: The addition of texture analysis to analysis of conventional qualitative MRI features increased the probability of predicting a type 2 papillary RCC tumor, which may be clinically important.

The Effect of Prophylactic Phenylephrine and Ephedrine Infusions on Umbilical Artery Blood pH in Women With Preeclampsia Undergoing Cesarean Delivery With Spinal Anesthesia: A Randomized, Double-Blind Trial.

BACKGROUND: Spinal anesthesia for cesarean delivery is associated with a high incidence of hypotension. Phenylephrine results in higher umbilical artery pH than ephedrine when used to prevent or treat hypotension in healthy women. We hypothesized that phenylephrine compared to ephedrine would result in higher umbilical artery pH in women with preeclampsia undergoing cesarean delivery with spinal anesthesia. METHODS: This study was a randomized double-blind clinical trial. Nonlaboring women with preeclampsia scheduled for cesarean delivery with spinal anesthesia at Prentice Women's Hospital of Northwestern Medicine were randomized to receive prophylactic infusions of phenylephrine or ephedrine titrated to maintain systolic blood pressure >80% of baseline. Spinal anesthesia consisted of hyperbaric 0.75% bupivacaine 12 mg, fentanyl 15 µg, and morphine 150 µg. The primary outcome was umbilical arterial blood pH and the secondary outcome was umbilical artery base excess. RESULTS: One hundred ten women were enrolled in the study and 54 per group were included in the analysis. There were 74 and 72 infants delivered in the ephedrine and phenylephrine groups, respectively. The phenylephrine:ephedrine ratio for umbilical artery pH was 1.002 (95% confidence interval [CI], 0.997-1.007). Mean [standard deviation] umbilical artery pH was not different between the ephedrine 7.20 [0.10] and phenylephrine 7.22 [0.07] groups (mean difference -0.02, 95% CI of the difference -0.06 to 0.07; P = .38). Median (first, third quartiles) umbilical artery base excess was -3.4 mEq/L (-5.7 to -2.0 mEq/L) in the ephedrine group and -2.8 mEq/L (-4.6 to -2.2mEq/L) in the phenylephrine group (difference -0.6 mEq/L, 95% CI of the difference -1.6 to 0.3 mEq/L; P = .10). When adjusted for gestational age and infant gender, umbilical artery pH did not differ between groups. There were also no differences in the umbilical artery pH stratified by magnesium therapy or by the severity of preeclampsia. CONCLUSIONS: We were unable to demonstrate a beneficial effect of phenylephrine on umbilical artery pH compared with ephedrine. Our findings suggest that phenylephrine may not have a clinically important advantage compared with ephedrine with regard to improved neonatal acid-base status when used to prevent spinal anesthesia-induced hypotension in women with preeclampsia undergoing cesarean delivery.

The Association of Targeted Cell Salvage Blood Transfusion During Cesarean Delivery With Allogeneic Packed Red Blood Cell Transfusions in a Maternity Hospital in China.

BACKGROUND: Autologous transfusion of intraoperative cell salvage blood may be a potential method to decrease the need for allogeneic packed red blood cell transfusions after cesarean delivery, although there are limited data on the benefits of this method. This study evaluated the implementation of targeted intraoperative cell salvage during cesarean delivery in women at increased risk for hemorrhage at the Women's and Children's Hospital in Ningbo, China. METHODS: All women who underwent cesarean delivery >28 weeks of gestation were included in the study. The period before intraoperative cell collection (October 1, 2010, to August 31, 2012, n = 11,322) was compared with the postimplementation period (September 1, 2012, to June 30, 2015, n = 17,456) using an interrupted time series analysis. In the postimplementation period, women suspected to be at increased risk of the need for a blood transfusion (1604, 9.2%) underwent intraoperative cell salvage collection. The primary outcomes were the monthly rate of allogeneic packed red blood cell use and the incidence of clinical manifestation of acute blood transfusion reactions. RESULTS: The mean (standard deviation) estimated monthly allogeneic packed blood cell transfusion rate at the end of the 57-month study was 2.2% ± 0.7% with the implementation compared with 2.7% ± 0.9% without, difference -0.5%, 95% CI, -1.4% to 0.3%; P = .22. The mean number of allogeneic units transfused per patient was 4.1 ± 0.4 units with implementation and 3.9 ± 0.9 units without, difference 0.2, 95% CI, -1.7 to 1.1 units; P = .69. Intraoperative cell salvage blood was reinfused in 757 (47%) and wasted in 847 (53%) cases. The monthly intraoperative allogeneic packed red blood cells use rate was lower after implementation (difference -0.7%, 95% CI, -0.1% to -1.4%; P = .03); however, the monthly postpartum allogeneic packed red blood cell use rate was unchanged (difference -0.2%, 95% CI, -0.4% to 0.7%; P = .56). The clinical manifestation of acute blood transfusion reactions rate was unchanged (difference -2%, 99% CI, -9% to 5%; P = .55) between the periods. CONCLUSIONS: Our findings suggest that targeted intraoperative cell salvage in women undergoing cesarean delivery was associated with less allogeneic blood exposure in the operating room, but not in the postoperative period. Intraoperative cell salvage in targeted cesarean deliveries was not associated with a lesser allogeneic red blood cell exposure over the hospital admission period. The lack of adverse events associated with intraoperative cell salvage supports the safety of intraoperative cell salvage in cesarean delivery.

A Prospective Randomized Trial of Prognostic Genicular Nerve Blocks to Determine the Predictive Value for the Outcome of Cooled Radiofrequency Ablation for Chronic Knee Pain Due to Osteoarthritis.

Background and Objectives: Genicular nerve radiofrequency ablation is an effective treatment for patients with chronic pain due to knee osteoarthritis; however, little is known about factors that predict procedure success. The current study evaluated the utility of genicular nerve blocks to predict the outcome of genicular nerve cooled radiofrequency ablation (cRFA) in patients with osteoarthritis. Methods: This randomized comparative trial included patients with chronic knee pain due to osteoarthritis. Participants were randomized to receive a genicular nerve block or no block prior to cRFA. Patients receiving a prognostic block that demonstrated ≥50% pain relief for six hours received cRFA. The primary outcome was the proportion of participants with ≥50% reduction in knee pain at six months. Results: Twenty-nine participants (36 knees) had cRFA following a prognostic block, and 25 patients (35 knees) had cRFA without a block. Seventeen participants (58.6%) in the prognostic block group and 16 (64.0%) in the no block group had ≥50% pain relief at six months (P = 0.34). A 15-point decrease in the Western Ontario and McMaster Universities Osteoarthritis Index at six months was present in 17 of 29 (55.2%) in the prognostic block group and 15 of 25 (60%) in the no block group (P = 0.36). Conclusions: This study demonstrated clinically meaningful improvements in pain and physical function up to six months following cRFA. A prognostic genicular nerve block using a local anesthetic volume of 1 mL at each injection site and a threshold of ≥ 50% pain relief for subsequent cRFA eligibility did not improve the rate of treatment success.

Single dose systemic acetaminophen to improve patient reported quality of recovery after ambulatory segmental mastectomy: A prospective, randomized, double-blinded, placebo controlled, clinical trial.

Few systemic drug interventions are efficacious to improve patient reported quality of recovery after ambulatory surgery. We aimed to evaluate whether a single dose systemic acetaminophen improve quality of recovery in female patients undergoing ambulatory breast surgery. We hypothesized that patients receiving a single dose systemic acetaminophen at the end of the surgical procedure would have a better global quality of postsurgical recovery compared to the ones receiving saline. The study was a prospective randomized double blinded, placebo controlled, clinical trial. Healthy female subjects were randomized to receive 1 g single dose systemic acetaminophen at the end of the surgery or the same volume of saline. The primary outcome was the Quality of Recovery 40 (QOR-40) questionnaire at 24 hours after surgery. Other data collected included opioid consumption and pain scores. Data were analyzed using group t tests and the Wilcoxon exact test. The association between opioid consumption and quality of recovery was evaluated using Spearman rho. P < .05 was used to reject the null hypothesis for the primary outcome. Seventy subjects were randomized and sixty-five completed the study. Patients' baseline characteristics and surgical factors were similar between the study groups. There was a clinically significant difference in the global QoR-40 scores between the acetaminophen and the saline groups, median (IQR) of 189 (183 to 194) and 183 (175 to 190), respectively, P = .01. In addition, there was an inverse relationship (Spearman's rho= -0.33) between oral opioid consumption at home (oral morphine equivalents) and 24 hour postoperative quality of recovery, P = .007. A single dose of systemic acetaminophen improves patient reported quality of recovery after ambulatory breast surgery. The use of systemic acetaminophen is an efficacious strategy to improve patient perceived quality of postsurgical recovery and analgesic outcomes after hospital discharge for ambulatory breast surgery.

The impact of health literacy on shared decision making before elective surgery: a propensity matched case control analysis.

BACKGROUND: Poor health literacy affects over 90 million Americans. The primary aim of the study was to evaluate a possible association between health literacy and decision conflict in surgical patients. METHODS: Patients undergoing a diverse number of elective surgeries were enrolled in the study. Health literacy was measured using the Newest Vital Sign instrument and decision conflict using the low literacy version of the Decision Conflict Scale. RESULTS: 200 patients undergoing elective surgeries were included in the study. Patients who had greater health literacy scores had lower decision conflict scores, Spearman's rho = - 0.43, P < 0.001. Following propensity-score matching to account for potential covariates, the median (IQR) decision conflict score was 20 (0 to 40) for patients with poor health literacy compared to 0 (0 to 5) for patients with adequate literacy, P < 0.001. CONCLUSIONS: Poor health literacy is associated with greater decision conflict in patients undergoing elective surgical procedures. Strategies should be implemented to minimize decision conflict in poor health literacy patients undergoing elective surgical procedures.

Predictive Factors for Developing Chronic Pain After Total Knee Arthroplasty.

Total knee arthroplasty offers substantial improvements for patients as measured by functional status and quality of life; however, 8% to 34% of patients experience chronic postsurgical pain following surgery (CPSP). In addition to disruption in daily activities of life caused by the pain itself, CPSP has been associated with an overall reduction in quality of life following surgery. Risk factors for CPSP can be broadly defined as potentially modifiable or unlikely modifiable. Unlikely modifiable risks include gender, age, medical comorbidities, and socioeconomic status. Potentially modifiable risks include perioperative pain, physical function, psychological state, surgical factors, and possibly genomics. Understanding risks and the magnitude of their effect on outcomes such as CPSP is desirable because interventions designed to affect these factors may be able to dramatically improve outcomes.

The Effect of Intraoperative Systemic Lidocaine on Postoperative Persistent Pain Using Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials Criteria Assessment Following Breast Cancer Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To compare the incidence in postsurgical persistent pain following breast cancer surgery in women receiving intravenous lidocaine compared to saline using validated pain instruments in accordance with the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations. METHODS: The study was a randomized, double-blinded, placebo-controlled, clinical trial. Subjects were randomized into Group 1 (1.5 mg/kg bolus of intravenous lidocaine followed by a 2 mg/kg/hour infusion) or Group 2 (normal saline at the same bolus and infusion rate). Patients were evaluated at 3 and 6 months for the presence of chronic persistent postsurgical pain. RESULTS: One hundred forty-eight patients were included in the study analysis. There were no differences in quality of recovery, pain burden, or opioid consumption between groups at 24 hours. Pain (yes/no) at 6 months attributed to surgery was reported in 29% of Group 2 vs. 13% of Group 1 patients (P = 0.04); however, only 3 subjects (5%) in Group 1 and 2 subjects (3%) in Group 2 met IMMPACT criteria for persistent postoperative pain (P = 0.99). DISCUSSION: Perioperative infusion of lidocaine has been reported to decrease the incidence of postsurgical pain at 3 and 6 months following mastectomy using dichotomous (yes/no) scoring. Although intravenous lidocaine reduced the reported incidence of pain at rest at 6 months, pain with activity, pain qualities, and the physical or emotional impact of the pain were unaffected. Future studies evaluating postsurgical persistent pain should adhere to the IMMPACT recommendations in order to more accurately describe the effect of an intervention on persistent pain.