Effect of Duloxetine on Opioid Use and Pain After Total Knee Arthroplasty: A Triple-Blinded Randomized Controlled Trial.

BACKGROUND: Duloxetine, a serotonin-norepinephrine dual reuptake inhibitor, may improve analgesia after total knee arthroplasty (TKA). Previous studies had one primary outcome, did not consistently use multimodal analgesia, and used patient-controlled analgesia devices, potentially delaying discharge. We investigated whether duloxetine would reduce opioid consumption or pain with ambulation. METHODS: A total of 160 patients received 60 mg duloxetine or placebo daily, starting from the day of surgery and continuing 14 days postoperatively. Patients received neuraxial anesthesia, peripheral nerve blocks, acetaminophen, nonsteroidal anti-inflammatory drugs, and oral opioids as needed. The dual primary outcomes were Numeric Rating Scale (NRS) scores with movement on postoperative days 1, 2, and 14, and cumulative opioid consumption surgery through postoperative day 14. RESULTS: Duloxetine was noninferior to placebo for both primary outcomes and was superior to placebo for opioid consumption. Opioid consumption (mean ± SD) was 288 ± 226 mg OME [94, 385] vs 432 ± 374 [210, 540] (duloxetine vs placebo) P = .0039. Pain scores on POD14 were 4.2 ± 2.0 vs 4.8 ± 2.2 (duloxetine vs placebo) P = .018. Median satisfaction with pain management was 10 (8, 10) and 8 (7, 10) (duloxetine vs placebo) P = .046. Duloxetine reduced interference by pain with walking, normal work, and sleep. CONCLUSION: The 29% reduction in opioid use corresponds to 17 fewer pills of oxycodone, 5 mg, and was achieved without increasing pain scores. Considering the ongoing opioid epidemic, duloxetine can be used to reduce opioid usage after knee arthroplasty in selected patients that can be appropriately monitored for potential side effects of the medication.

A Comprehensive Enhanced Recovery Pathway for Rotator Cuff Surgery Reduces Pain, Opioid Use, and Side Effects.

BACKGROUND: Patients often have moderate to severe pain after rotator cuff surgery, despite receiving analgesics and nerve blocks. There are many suggested ways to improve pain after rotator cuff surgery, but the effects of adopting a pathway that includes formal patient education, a long-acting nerve block, and extensive multimodal analgesia are unclear. QUESTIONS/PURPOSES: (1) Does adoption of a clinical pathway incorporating patient education, a long-acting nerve block, and preemptive multimodal analgesia reduce the worst pain during the first 48 hours after surgery compared with current standard institutional practices? (2) Does adoption of the pathway reduce opioid use? (3) Does adoption of the pathway reduce side effects and improve patient-oriented outcomes? METHODS: From September 2018 to January 2020, 281 patients scheduled for arthroscopic ambulatory rotator cuff surgery were identified for this paired sequential prospective cohort study. Among patients in the control group, 177 were identified, 33% (58) were not eligible, for 11% (20) staff was not available, 56% (99) were approached, 16% (29) declined, 40% (70) enrolled, and 40% (70) were analyzed (2% [4] lost to follow-up for secondary outcomes after postoperative day 2). For patients in the pathway cohort, 104 were identified, 17% (18) were not eligible, for 11% (11) staff was not available, 72% (75) were approached, 5% (5) declined, 67% (70) enrolled, and 67% (70) were analyzed (3% [3] lost to follow-up for secondary outcomes after postoperative day 2). No patients were lost to follow-up for primary outcome; for secondary outcomes, four were lost in the control group and three in the pathway group after postoperative day 2 (p = 0.70). The initial 70 patients enrolled received routine care (control group), and in a subsequent cohort, 70 patients received care guided by a pathway (pathway group). Of the 205 eligible patients, 68% (140) were included in the analysis. This was not a study comparing two tightly defined protocols but rather a study to determine whether adoption of a pathway would alter patient outcomes. For this reason, we used a pragmatic (real-world) study design that did not specify how control patients would be treated, and it did not require that all pathway patients receive all components of the pathway. We developed the pathway in coordination with a group of surgeons and anesthesiologists who agreed to apply the pathway as much as was viewed practical for each individual patient. Patients in both groups received a brachial plexus nerve block with sedation. Major differences between the pathway and control groups were: detailed patient education regarding reasonable pain expectations with a goal of reducing opioid use (no formal educational presentation was given to the control), a long-acting nerve block using bupivacaine with dexamethasone (control patients often received shorter-acting local anesthetic without perineural dexamethasone), and preemptive multimodal analgesia including intraoperative ketamine, postoperative acetaminophen, NSAIDs, and gabapentin at bedtime, with opioids as needed (control patients received postoperative opioids but most did not get postoperative NSAIDS and no controls received gabapentin or separate prescriptions for acetaminophen). The primary outcome was the numerical rating scale (NRS) worst pain with movement 0 to 48 hours after block placement. The NRS pain score ranges from 0 (no pain) to 10 (worst pain possible). The minimum clinically important difference (MCID) [12] for NRS that was used for calculation of the study sample size was 1.3 [18], although some authors suggest 1 [13] or 2 [5] are appropriate; if we had used an MCID of 2, the sample size would have been smaller. Secondary outcomes included NRS pain scores at rest, daily opioid use (postoperative day 1, 2, 7, 14), block duration, patient-oriented pain questions (postoperative day 1, 2, 7, 14), and patient and physician adherence to pathway. RESULTS: On postoperative day 1, pathway patients had lower worst pain with movement (3.3 ± 3.1) compared with control patients (5.6 ± 3.0, mean difference -2.7 [95% CI -3.7 to -1.7]; p < 0.001); lower scores were also seen for pain at rest (1.9 ± 2.3 versus 4.0 ± 2.9, mean difference -2.0 [95% CI -2.8 to -1.3]; p < 0.001). Cumulative postoperative opioid use (0-48 hours) was reduced (pathway oral morphine equivalent use was 23 ± 28 mg versus 44 ± 35 mg, mean difference 21 [95% CI 10 to 32]; p < 0.01). The greatest difference in opioid use was in the first 24 hours after surgery (pathway 7 ± 12 mg versus control 21 ± 21 mg, mean difference -14 [95% CI -19 to -10]; p < 0.01). On postoperative day 1, pathway patients had less interference with staying asleep compared with control patients (0.5 ± 1.6 versus 2.6 ± 3.3, mean difference -2.2 [95% CI -3.3 to -1.1]; p < 0.001); lower scores were also seen for interference with activities (0.9 ± 2.3 versus 1.9 ± 2.9, mean difference -1.1 [95% CI -2 to -0.1]; p = 0.03). Satisfaction with pain treatment on postoperative day 1 was higher among pathway patients compared with control patients (9.2 ± 1.7 versus 8.2 ± 2.5, mean difference 1.0 [95% CI 0.3 to 1.8]; p < 0.001). On postoperative day 2, pathway patients had lower nausea scores compared with control patients (0.3 ± 1.1 versus 1 ± 2.1, mean difference -0.7 [95% CI -1.2 to -0.1]; p = 0.02); lower scores were also seen for drowsiness on postoperative day 1 (1.7 ± 2.7 versus 2.6 ± 2.6, mean difference -0.9 [95% CI - 1.7 to -0.1]; p = 0.03). CONCLUSION: Adoption of the pathway was associated with improvement in the primary outcome (pain with movement) that exceeded the MCID. Patients in the pathway group had improved patient-oriented outcomes and fewer side effects. This pathway uses multiple analgesic drugs, which may pose risks to elderly patients, in particular. Therefore, in evaluating whether to use this pathway, clinicians should weigh the effect sizes against the potential risks that may emerge with large scale use, consider the difficulties involved in adapting a pathway to local practice so that pathway will persist, and recognize that this study only enrolled patients among surgeons and the anesthesiologists that advocated for the pathway; results may have been different with less enthusiastic clinicians. This pathway, based on a long-lasting nerve block, multimodal analgesia, and patient education can be considered for adoption. LEVEL OF EVIDENCE: Level II, therapeutic study.

Chloroprocaine Provides Safe, Effective, Short-Acting Spinal Anesthesia Ideal for Ambulatory Surgeries: A Retrospective Review.

BACKGROUND: The ideal local anesthetic for use in ambulatory spinal anesthesia is safe, with minimal adverse effects, and of a duration that does not impede post-anesthesia care unit (PACU) discharge. Since its approval for use in spinal anesthesia in Europe in 2012, chloroprocaine has seen a resurgence. Recent studies have investigated the safety and efficacy of preservative-free chloroprocaine for use in spinal anesthesia, but few provide the incidence of adverse events such as urinary retention and transient neurologic symptoms. QUESTIONS/PURPOSES: We sought to assess the safety of chloroprocaine for spinal anesthesia, including the incidence of adverse events and the duration and quality of its use, in the initial 6 months of its use at our institution. We hypothesized that chloroprocaine would provide effective spinal anesthesia for orthopedic cases of short duration, with a low rate of complications. METHODS: We conducted a retrospective chart review of all patients from June to December 2016 at our institution who had ambulatory knee arthroscopy or foot procedures in which chloroprocaine spinal anesthesia was used. For all 445 charts analyzed, data were collected on anesthesia characteristics, office visits, nursing PACU assessment, and nursing post-operative day 1 follow-up phone calls. RESULTS: The median chloroprocaine dosage was 44 mg (interquartile range [IQR], 40 to 50). The median duration of sensory block was 156 min (IQR, 128 to 189) and of motor block was 148 min (IQR, 123 to 181). Time to ambulation was 186 min (IQR, 158 to 218) and time to meeting of discharge criteria was 218 min (IQR, 189 to 250). The most common adverse events in the PACU were bradycardia and hypotension. No patients had urinary retention or transient neurologic symptoms. CONCLUSIONS: In 6 months of use at our institution, chloroprocaine provided safe and effective spinal anesthesia for short orthopedic procedures, with no incidence of transient neurologic symptoms, neuropraxia, or urinary retention.

Cerebral Oxygenation in the Sitting Position Is Not Compromised During Spontaneous or Positive-Pressure Ventilation.

BACKGROUND: General anesthesia with neuromuscular blockade may facilitate total shoulder arthroplasty but appears to increase risk of cerebral oxygen desaturation. Cerebral desaturation is undesirable and is a proxy for risk of stroke. PURPOSES/QUESTIONS: This study tested the hypothesis that cerebral oxygen desaturation occurs frequently during general anesthesia with neuromuscular blockade and positive-pressure ventilation but does not occur with spontaneous ventilation. Correlations were sought among cerebral oxygen saturation, blood pressure, and cardiac index. METHODS: We designed a prospective, observational, cohort study to measure cerebral oxygenation in 25 patients during general anesthesia, both with and without positive-pressure ventilation. Patients undergoing elective shoulder arthroplasty in the sitting position received an arterial catheter, near-infrared spectroscopic measurement of cerebral oxygenation, and non-invasive cardiac output measurement. Moderate hypotension was allowed. Blood pressure was supported as needed with ephedrine or low-dose epinephrine (but avoiding phenylephrine). Hypercapnia (45 to 55 mmHg) was targeted during positive-pressure ventilation. RESULTS: No cerebral oxygen desaturations occurred, regardless of ventilation mode. Under positive-pressure ventilation, the median (interquartile range: Q1, Q3) cerebral oxygenation was 110% of baseline (104, 113), the mean arterial pressure was 62% of baseline (59, 69), and the cardiac index was 82% of baseline (71, 104). Cerebral oxygenation did not correlate with blood pressure or cardiac index but had moderate correlation with end-tidal carbon dioxide. No strokes occurred. CONCLUSIONS: There were no signs of inadequate brain perfusion during general anesthesia using paralytic agents. Positive-pressure ventilation with moderate hypotension in the sitting position does not endanger patients, in the context of moderate hypercapnia and hemodynamic support using ephedrine or epinephrine.

A comparison of two different concentrations and infusion rates of ropivacaine in perineural infusion administered at the same total dose for analgesia after foot and ankle surgery: a randomized, double blinded, controlled study.

BACKGROUND: Continuous popliteal nerve block is utilized for postoperative analgesia after foot and ankle surgery. Whether only the total dose of local anesthetic or the combination of concentration and volume determine the characteristics of a continuous popliteal nerve infusion remains currently unknown. We hypothesized a reduction of the incidence of insensate extremity in patients given ropivacaine 0.4% at 4 mL/h compared to patients given ropivacaine 0.2% at 8 mL/h. METHODS: Sixty-four patients scheduled for major foot and ankle surgery requiring a continuous popliteal catheter infusion for postoperative analgesia were studied. Thirty-three patients were randomized to receive a continuous popliteal nerve block with 0.2% (basal 8 mL/h) and thirty-one with 0.4% (basal 4 mL/h) ropivacaine, reaching the same total dose (16 mg/h). The primary outcome was the incidence of persistent sensory block in the distal sciatic nerve distributions in the postoperative period. Secondary outcomes were the incidence of motor block, NRS pain scores at rest in the postoperative period up to 48 hours after surgery, opioid use and related side effects, patients' satisfaction. RESULTS: The incidence of persistent sensory block was similar in patients given 0.2% and in patients receiving 0.4% ropivacaine. The incidence of motor block, postoperative pain scores at rest, use of oral opioids, side effects and patients' satisfaction with the quality of recovery were also similar in both groups. CONCLUSIONS: Our results suggest that local anesthetic total dose is the primary determinant of continuous popliteal perineural infusion effects.

The Incidence of Complications Is Low Following Foot and Ankle Surgery for Which Peripheral Nerve Blocks Are Used for Postoperative Pain Management.

BACKGROUND: The incidence of neurologic complications from foot and ankle surgery utilizing regional anesthesia is not well established. QUESTIONS/PURPOSES: The purpose of this study was to prospectively determine the incidence of neurologic and peripheral nerve block (PNB) site complications on a busy foot and ankle service that utilizes ankle blocks (ABs) and popliteal blocks (POPs). PATIENTS AND METHODS: This prospective observational study included patients undergoing foot and ankle surgery with ABs or POPs. Block choice was determined by surgeon's preference. Patients were assessed for complications during postoperative visits at 2, 6, and 12 weeks. The relation of each complication to the block was scored by a surgeon and anesthesiologist. RESULTS: From October 2012 to October 2014, 2516 patients underwent 2704 surgeries. There were 195 complications (7.2%) considered neurologic or at the PNB site. The incidence of serious complications was 0.7%. A higher complication rate was reported for POPs (8.8%) than for ABs (2.5%). However, when analysis was limited to forefoot surgery, this difference was not significant. Dexamethasone use was associated with increased complications for POPs. Only 5 of the 195 total complications, and 2 of 20 serious complications, were deemed to have been likely caused by the block by both the surgeon and anesthesiologist reviewer. CONCLUSIONS: The incidences of neurologic or block-related complications and serious complications were 7.2 and 0.7%, respectively, most without a clear surgical vs. nerve block etiology. The higher complication rate for POPs using perineural dexamethasone should be interpreted cautiously in light of the lack of randomization and likely confounders.

Readiness for Discharge After Foot and Ankle Surgery Using Peripheral Nerve Blocks: A Randomized Controlled Trial Comparing Spinal and General Anesthesia as Supplements to Nerve Blocks.

BACKGROUND: Neuraxial anesthesia is often viewed as superior to general anesthesia but may delay discharge. Comparisons do not typically use multimodal analgesics and nerve blockade. Combining nerve blockade with general anesthesia may reduce pain, opioid consumption, and nausea. We hypothesized that general anesthesia (with nerve blocks) would lead to earlier readiness for discharge, compared to spinal anesthesia (with nerve blocks). METHODS: All patients underwent ambulatory foot and ankle surgery, with a predicted case duration of 1-3 hours. All patients received popliteal and adductor canal nerve blocks using bupivacaine and dexamethasone. No intraoperative opioids were administered. All patients received ondansetron, dexamethasone, ketamine, and ketorolac. Patients, data collectors, and the data analyst were not informed of group assignment. Patients were randomized to spinal or general anesthesia with concealed allocation. Spinal anesthesia was performed with mepivacaine and accompanied with propofol sedation. After general anesthesia was induced with propofol, a laryngeal mask airway was inserted, followed by sevoflurane and propofol. Time until ready for discharge, the primary outcome, was compared between groups after adjusting for age and surgery time using multivariable unconditional quantile regression. Secondary outcomes compared at multiple timepoints were adjusted for multiple comparisons using the Holm-Bonferroni step-down procedure. RESULTS: General anesthesia patients were ready for discharge at a median of 39 minutes earlier (95% confidence interval, 2-75; P = .038) versus spinal anesthesia patients. Patients in both groups met readiness criteria for discharge substantially before actual discharge. Pain scores at rest were higher among general anesthesia patients 1 hour after leaving the operating room (adjusted difference in means, 2.1 [95% confidence interval, 1.0-3.2]; P < .001). Other secondary outcomes (including opioid use, opioid side effects, nausea, headache, sore throat, and back pain) were not different. CONCLUSIONS: General anesthesia was associated with earlier readiness for discharge, but the difference may not be clinically significant and did not lead to earlier actual discharge. Most secondary outcomes were not different between groups. The choice of spinal or general anesthesia as an adjunct to peripheral nerve blockade can reflect patient, clinician, and institutional preferences.

A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity.

ARL13B encodes for the ADP-ribosylation factor-like 13B GTPase, which is required for normal cilia structure and Sonic hedgehog (Shh) signaling. Disruptions in cilia structure or function lead to a class of human disorders called ciliopathies. Joubert syndrome is characterized by a wide spectrum of symptoms, including a variable degree of intellectual disability, ataxia, and ocular abnormalities. Here we report a novel homozygous missense variant c.[223G>A] (p.(Gly75Arg) in the ARL13B gene, which was identified by whole-exome sequencing of a trio from a consanguineous family with multiple-affected individuals suffering from intellectual disability, ataxia, ocular defects, and epilepsy. The same variant was also identified in a second family. We saw a striking difference in the severity of ataxia between affected male and female individuals in both families. Both ARL13B and ARL13B-c.[223G>A] (p.(Gly75Arg) expression rescued the cilia length and Shh defects displayed by Arl13b hennin (null) cells, indicating that the variant did not disrupt either ARL13B function. In contrast, ARL13B-c.[223G>A] (p.(Gly75Arg) displayed a marked loss of ARL3 guanine nucleotide-exchange factor activity, with retention of its GTPase activities, highlighting the correlation between its loss of function as an ARL3 guanine nucleotide-exchange factor and Joubert syndrome.

Post-Dural Puncture Headache is Uncommon in Young Ambulatory Surgery Patients.

BACKGROUND: The incidence of post-dural puncture headache (PDPH) arising from spinal anesthesia in the general population is low. However, patients under 45 years have been shown to exhibit a higher incidence of PDPH, even with small needles. QUESTIONS/PURPOSES: This study aimed to estimate the incidence of PDPH from a 27G pencil-point needle in ambulatory surgery patients between the ages of 15-45 years and compare incidence of PDPH by age group, sex, and history of headache. METHODS: In this prospective cohort study, 300 patients (15-45 years old) who underwent simple knee arthroscopy under spinal anesthesia with a 27G pencil-point needle were enrolled. Verbal consent was obtained during the initial phone conversation between post-operative days (PODs) 2-5. A PDPH questionnaire was administered during this conversation and between PODs 7-10. Patients who reported a positional headache were contacted by a physician co-investigator, who determined PDPH diagnosis. RESULTS: Five patients were excluded from analysis due to complicated operative procedures or spinal needle size. The overall PDPH incidence was 2.0% (95% CI 0.9-4.4; 6/295). PDPH incidence in 15-19-year-old patients was 16.7% (95% CI 4.7-44.8; 2/12). The crude relative risk of PDPH was 15.4 (95% CI 2.8-114.4) for patients with and without history of headache and 2.5 (95% CI 0.5-14.8) for females vs. males. Overall, 16.3% (95% CI 12.5-20.9) of patients reported post-operative, non-positional headaches. CONCLUSIONS: There was a low overall incidence of PDPH among patients aged 15-45. Pre-planned subgroup analyses of PDPH incidence by age group revealed a high risk of PDPH among a small sample of 15-19-year-olds.

Biochemical characterization of purified mammalian ARL13B protein indicates that it is an atypical GTPase and ARL3 guanine nucleotide exchange factor (GEF).

Primary cilia play central roles in signaling during metazoan development. Several key regulators of ciliogenesis and ciliary signaling are mutated in humans, resulting in a number of ciliopathies, including Joubert syndrome (JS). ARL13B is a ciliary GTPase with at least three missense mutations identified in JS patients. ARL13B is a member of the ADP ribosylation factor family of regulatory GTPases, but is atypical in having a non-homologous, C-terminal domain of ∼20 kDa and at least one key residue difference in the consensus GTP-binding motifs. For these reasons, and to establish a solid biochemical basis on which to begin to model its actions in cells and animals, we developed preparations of purified, recombinant, murine Arl13b protein. We report results from assays for solution-based nucleotide binding, intrinsic and GTPase-activating protein-stimulated GTPase, and ARL3 guanine nucleotide exchange factor activities. Biochemical analyses of three human missense mutations found in JS and of two consensus GTPase motifs reinforce the atypical properties of this regulatory GTPase. We also discovered that murine Arl13b is a substrate for casein kinase 2, a contaminant in our preparation from human embryonic kidney cells. This activity, and the ability of casein kinase 2 to use GTP as a phosphate donor, may be a source of differences between our data and previously published results. These results provide a solid framework for further research into ARL13B on which to develop models for the actions of this clinically important cell regulator.

The abundance of the ARL2 GTPase and its GAP, ELMOD2, at mitochondria are modulated by the fusogenic activity of mitofusins and stressors.

Mitochondria are essential, dynamic organelles that respond to a number of stressors with changes in morphology that are linked to several mitochondrial functions, though the mechanisms involved are poorly understood. We show that the levels of the regulatory GTPase ARL2 and its GAP, ELMOD2, are specifically increased at mitochondria in immortalized mouse embryo fibroblasts deleted for Mitofusin 2 (MFN2), but not MFN1. Elevated ARL2 and ELMOD2 in MEFs deleted for MFN2 could be reversed by re-introduction of MFN2, but only when the mitochondrial fragmentation in these MEFs was also reversed, demonstrating that reversal of elevated ARL2 and ELMOD2 requires the fusogenic activity of MFN2. Other stressors with links to mitochondrial morphology were investigated and several, including glucose or serum deprivation, also caused increases in ARL2 and ELMOD2. In contrast, a number of pharmacological inhibitors of energy metabolism caused increases in ARL2 without affecting ELMOD2 levels. Together we interpret these data as evidence of two ARL2-sensitive pathways in mitochondria, one affecting ATP levels that is independent of ELMOD2 and the other leading to mitochondrial fusion involving MFN2 that does involve ELMOD2.

Duloxetine and Subacute Pain after Knee Arthroplasty when Added to a Multimodal Analgesic Regimen: A Randomized, Placebo-controlled, Triple-blinded Trial.

BACKGROUND: Duloxetine is effective for chronic musculoskeletal and neuropathic pain, but there are insufficient data to recommend the use of antidepressants for postoperative pain. The authors hypothesized that administration of duloxetine for 15 days would reduce pain with ambulation at 2 weeks after total knee arthroplasty. METHODS: In this triple-blinded, randomized, placebo-controlled trial, patients received either duloxetine or placebo for 15 days, starting from the day of surgery. Patients also received a comprehensive multimodal analgesic regimen including neuraxial anesthesia, epidural analgesia, an adductor canal block, meloxicam, and oxycodone/acetaminophen as needed. The primary outcome was the pain score (0 to 10 numeric rating scale) with ambulation on postoperative day 14. RESULTS: One hundred six patients were randomized and analyzed. On day 14, duloxetine had no effect on pain with ambulation; mean pain was 3.8 (SD, 2.3) for placebo versus 3.5 (SD, 2.1) for duloxetine (difference in means [95% CI], 0.4 [-0.5 to 1.2]; P = 0.386). Symptoms potentially attributable to duloxetine discontinuation at study drug completion (nausea, anxiety) occurred among nine patients (duloxetine) and five patients (placebo); this was not statistically significant (P = 0.247). Statistically significant secondary outcomes included opioid consumption (difference in mean milligram oral morphine equivalents [95% CI], 8.7 [3.3 to 14.1], P = 0.002 by generalized estimating equation) over the postoperative period and nausea on day 1 (P = 0.040). There was no difference in other side effects or in anxiety and depression scores. CONCLUSIONS: When included as a part of a multimodal analgesic regimen for knee arthroplasty, duloxetine does not reduce subacute pain with ambulation.

Oligomerization of the Sec7 domain Arf guanine nucleotide exchange factor GBF1 is dispensable for Golgi localization and function but regulates degradation.

Members of the large Sec7 domain-containing Arf guanine nucleotide exchange factor (GEF) family have been shown to dimerize through their NH2-terminal dimerization and cyclophilin binding (DCB) and homology upstream of Sec7 (HUS) domains. However, the importance of dimerization in GEF localization and function has not been assessed. We generated a GBF1 mutant (91/130) in which two residues required for oligomerization (K91 and E130 within the DCB domain) were replaced with A and assessed the effects of these mutations on GBF1 localization and cellular functions. We show that 91/130 is compromised in oligomerization but that it targets to the Golgi in a manner indistinguishable from wild-type GBF1 and that it rapidly exchanges between the cytosolic and membrane-bound pools. The 91/130 mutant appears active as it integrates within the functional network at the Golgi, supports Arf activation and COPI recruitment, and sustains Golgi homeostasis and cargo secretion when provided as a sole copy of functional GBF1 in cells. In addition, like wild-type GBF1, the 91/130 mutant supports poliovirus RNA replication, a process requiring GBF1 but believed to be independent of GBF1 catalytic activity. However, oligomerization appears to stabilize GBF1 in cells, and the 91/130 mutant is degraded faster than the wild-type GBF1. Our data support a model in which oligomerization is not a key regulator of GBF1 activity but impacts its function by regulating the cellular levels of GBF1.

Arl13b and the exocyst interact synergistically in ciliogenesis.

Arl13b belongs to the ADP-ribosylation factor family within the Ras superfamily of regulatory GTPases. Mutations in Arl13b cause Joubert syndrome, which is characterized by congenital cerebellar ataxia, hypotonia, oculomotor apraxia, and mental retardation. Arl13b is highly enriched in cilia and is required for ciliogenesis in multiple organs. Nevertheless, the precise role of Arl13b remains elusive. Here we report that the exocyst subunits Sec8, Exo70, and Sec5 bind preferentially to the GTP-bound form of Arl13b, consistent with the exocyst being an effector of Arl13b. Moreover, we show that Arl13b binds directly to Sec8 and Sec5. In zebrafish, depletion of arl13b or the exocyst subunit sec10 causes phenotypes characteristic of defective cilia, such as curly tail up, edema, and abnormal pronephric kidney development. We explored this further and found a synergistic genetic interaction between arl13b and sec10 morphants in cilia-dependent phenotypes. Through conditional deletion of Arl13b or Sec10 in mice, we found kidney cysts and decreased ciliogenesis in cells surrounding the cysts. Moreover, we observed a decrease in Arl13b expression in the kidneys from Sec10 conditional knockout mice. Taken together, our results indicate that Arl13b and the exocyst function together in the same pathway leading to functional cilia.

The Fibromyalgia Survey Score Correlates With Preoperative Pain Phenotypes But Does Not Predict Pain Outcomes After Shoulder Arthroscopy.

OBJECTIVES: Fibromyalgia (FM) characteristics can be evaluated using a simple, self-reported measure that correlates with postoperative opioid consumption after lower-extremity joint arthroplasty. The purpose of this study was to determine whether preoperative pain history and the FM survey score can predict postoperative outcomes after shoulder arthroscopy, which may cause moderate to severe pain. MATERIALS AND METHODS: In this prospective study, 100 shoulder arthroscopy patients completed preoperative validated self-report measures to assess baseline quality of recovery score, physical functioning, depression, anxiety, and neuropathic pain. FM characteristics were evaluated using a validated measure of widespread pain and comorbid symptoms on a 0 to 31 scale. Outcomes were assessed on postoperative day 2 (opioid consumption [primary], pain, physical functioning, quality of recovery score), and day 14 (opioid consumption, pain). RESULTS: FM survey scores ranged from 0 to 13. The cohort was divided into tertiles for univariate analyses. Preoperative depression and anxiety (P<0.001) and neuropathic pain (P=0.008) were higher, and physical functioning was lower (P<0.001), in higher FM survey score groups. The fibromyalgia survey score was not associated with postoperative pain or opioid consumption; however, it was independently associated with poorer quality of recovery scores (P=0.001). The only independent predictor of postoperative opioid use was preoperative opioid use (P=0.038). DISCUSSION: FM survey scores were lower than those in a previous study of joint arthroplasty. Although they distinguished a negative preoperative pain phenotype, FM scores were not independently associated with postoperative opioid consumption. Further research is needed to elucidate the impact of a FM-like phenotype on postoperative analgesic outcomes.

Patient-controlled epidural analgesia or multimodal pain regimen with periarticular injection after total hip arthroplasty: a randomized, double-blind, placebo-controlled study.

BACKGROUND: The optimal postoperative analgesia after primary total hip arthroplasty remains in question. This randomized, double-blind, placebo-controlled study compared the use of patient-controlled epidural analgesia (PCEA) with use of a multimodal pain regimen including periarticular injection (PAI). We hypothesized that PAI would lead to earlier readiness for discharge, decreased opioid consumption, and lower pain scores. METHODS: Forty-one patients received PAI, and forty-three patients received PCEA. Preoperatively, both groups were administered dexamethasone (6 mg, orally). The PAI group received a clonidine patch and sustained-release oxycodone (10 mg), while the PCEA group had placebo. Both groups received combined spinal-epidural anesthesia and used an epidural pain pump postoperatively; the PAI group had normal saline solution, while the PCEA group had bupivacaine and hydromorphone. The primary outcome, readiness for discharge, required the discontinuation of the epidural, a pain score of <4 (numeric rating scale) without parenteral narcotics, normal eating, minimal nausea, urination without a catheter, a dry surgical wound, no acute medical problems, and the ability to independently transfer and walk 12.2 m (40 ft). RESULTS: The mean time to readiness for discharge (and standard deviation) was 2.4 ± 0.7 days (PAI) compared with 2.3 ± 0.8 days (PCEA) (p = 0.86). The mean length of stay was 3.0 ± 0.8 days (PAI) compared with 3.1 ± 0.7 days (PCEA) (p = 0.46). A significant mean difference in pain score of 0.74 with ambulation (p = 0.01; 95% confidence interval [CI], 0.18 to 1.31) and 0.80 during physical therapy (p = 0.03; 95% CI, 0.09 to 1.51) favored the PCEA group. The mean opioid consumption (oral morphine equivalents in milligrams) was significantly higher in the PAI group on postoperative day 0 (43 ± 21 compared with 28 ± 23; p = 0.002) and postoperative days 0 through 2 (136 ± 59 compared with 90 ± 79; p = 0.004). Opioid-Related Symptom Distress Scale (ORSDS) composite scores for severity and bothersomeness as well as scores for nausea, vomiting, and itchiness were significantly higher in the PCEA group (p < 0.05). Quality of Recovery-40 scores and patient satisfaction were similar. CONCLUSIONS: PAI did not decrease the time to discharge and was associated with higher pain scores and greater opioid consumption but lower ORSDS scores compared with PCEA. The choice for analgesic regimen may depend on a particular patient's threshold for pain and the potential side effects.

Addition of Dexamethasone and Buprenorphine to Bupivacaine Sciatic Nerve Block: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Sciatic nerve block provides analgesia after foot and ankle surgery, but block duration may be insufficient. We hypothesized that perineural dexamethasone and buprenorphine would reduce pain scores at 24 hours. METHODS: Ninety patients received ultrasound-guided sciatic (25 mL 0.25% bupivacaine) and adductor canal (10 mL 0.25% bupivacaine) blockade, with random assignment into 3 groups (30 patients per group): control blocks + intravenous (IV) dexamethasone (4 mg) (control); control blocks + IV buprenorphine (150 µg) + IV dexamethasone (IV buprenorphine); and nerve blocks containing buprenorphine + dexamethasone (perineural). Patients received mepivacaine neuraxial anesthesia and postoperative oxycodone/acetaminophen, meloxicam, pregabalin, and ondansetron. Patients and assessors were blinded to group assignment. The primary outcome was pain with movement at 24 hours. RESULTS: There was no difference in pain with movement at 24 hours (median score, 0). However, the perineural group had longer block duration versus control (45.6 vs 30.0 hours). Perineural patients had lower scores for "worst pain" versus control (median, 0 vs 2). Both IV buprenorphine and perineural groups were less likely to use opioids on the day after surgery versus control (28.6%, 28.6%, and 60.7%, respectively). Nausea after IV buprenorphine (but not perineural buprenorphine) was severe, frequent, and bothersome. CONCLUSIONS: Pain scores were very low at 24 hours after surgery in the context of multimodal analgesia and were not improved by additives. However, perineural buprenorphine and dexamethasone prolonged block duration, reduced the worst pain experienced, and reduced opioid use. Intravenous buprenorphine caused troubling nausea and vomiting. Future research is needed to confirm and extend these observations.

Lower-Dose Mepivacaine Plus Fentanyl May Improve Spinal Anesthesia for Knee Arthroscopy.

BACKGROUND: Previous work indicates that 30 mg isobaric mepivacaine 1.5% plus 10 µg fentanyl produces reliable anesthesia for knee arthroscopy with a more rapid recovery profile than 45 mg mepivacaine. QUESTIONS/PURPOSES: This randomized controlled trial compared plain mepivacaine to three reduced doses of mepivacaine with 10 µg fentanyl for spinal anesthesia. METHODS: Following written informed consent, subjects undergoing outpatient knee arthroscopy were prospectively randomized into one of four groups: mepivacaine 37.5 mg (M37.5); mepivacaine 30 mg plus fentanyl 10 µg (M30/F10); mepivacaine 27 mg plus fentanyl 10 µg (M27/F10); and mepivacaine 24 mg plus fentanyl 10 µg (M24/F10). The spinal was evaluated by the blinded anesthetist and surgeon. In the post-anesthesia care unit, sensory and motor block resolution was assessed. Subjects rated their satisfaction with the overall experience. RESULTS: Group M30/F10 (n = 6) had two "fair" anesthetics, and group M27/F10 (n = 10) had one "fair" and one "inadequate" anesthetic. Both groups were eliminated from further enrollment per study protocol. The recovery profiles showed little difference between groups M37.5 and M30/F10, except for motor block resolution (median (25th percentile, 75th percentile): 171 (135, 195) and 128 (120, 135), respectively). Groups M27/F10 and M24/F10 demonstrated recovery profiles that were faster than group M37.5. Patient satisfaction was 10/10 for all groups. CONCLUSIONS: Adding fentanyl 10 µg to a lower dose of mepivacaine 1.5% can lead to quicker recovery profiles. However, this advantage of a quicker recovery must be weighed against the likelihood of an incomplete anesthetic.

The ARL2 GTPase is required for mitochondrial morphology, motility, and maintenance of ATP levels.

ARF-like 2 (ARL2) is a member of the ARF family and RAS superfamily of regulatory GTPases, predicted to be present in the last eukaryotic common ancestor, and essential in a number of model genetic systems. Though best studied as a regulator of tubulin folding, we previously demonstrated that ARL2 partially localizes to mitochondria. Here, we show that ARL2 is essential to a number of mitochondrial functions, including mitochondrial morphology, motility, and maintenance of ATP levels. We compare phenotypes resulting from ARL2 depletion and expression of dominant negative mutants and use these to demonstrate that the mitochondrial roles of ARL2 are distinct from its roles in tubulin folding. Testing of current models for ARL2 actions at mitochondria failed to support them. Rather, we found that knockdown of the ARL2 GTPase activating protein (GAP) ELMOD2 phenocopies two of three phenotypes of ARL2 siRNA, making it a likely effector for these actions. These results add new layers of complexity to ARL2 signaling, highlighting the need to deconvolve these different cell functions. We hypothesize that ARL2 plays essential roles inside mitochondria along with other cellular functions, at least in part to provide coupling of regulation between these essential cell processes.