Predictors of Citations in Neurosurgical Research.

OBJECTIVE: The number of citations an article receives is an important measure of impact for published research. There are limited published data on predictors of citations in neurosurgery research. We aimed to analyze predictors of citations for neurosurgical articles. METHODS: All articles published in 14 neurosurgical journals in the year 2015 were examined and data collected about their features. The number of citations for each article was tallied using both Web of Science (WoS) and Google Scholar (GS) 2.5 years after their publication in print. Negative binomial regression was then performed to determine the relationship between article features and citation counts for scientific articles. RESULTS: A total of 3923 articles were analyzed, comprising 2867 scientific articles (72.6%) and 1056 nonscientific (editorial, commentary, etc.) articles (27.4%). At 2.5 years, scientific articles had a median [interquartile range] number of citations per article of 3.0 [6.0] and 7.0 [9.0] found in WoS and GS, respectively; nonscientific articles had accumulated median 0.0 [2.0] in both WOS and GS. Articles with the study topic "Spine" had the highest citation count at 4.0 [5.0] and 8.0 [10.0] in WoS and GS, respectively. Significant predictors of citation count in scientific articles were level of evidence, number of centers, number of authors, and impact factor. CONCLUSIONS: This is the largest investigation analyzing predictors of citations in the neurosurgical literature. Factors found to be most influential on citation rates in scientific articles included the study's level of evidence, number of participating centers, number of authors, and the publishing journal's impact factor.

Recovery of physical activity after cesarean delivery and its relationship with pain.

Pain and physical activity are tightly intertwined. Although their relationship has been explored in chronic pain conditions, we know little about the pattern of recovery in activity and its short- and long-term relationship with pain after surgery. We recruited 103 women undergoing elective cesarean delivery and acquired daily pain assessments and hourly steps in 98 of them for 2 months after surgery. Compliance was good, with 78% of subjects missing less than 7 days of activity. Study personnel required daily checking for compliance and 20 minutes per subject per week in study. Activity increased over the first 2 postoperative months in a log(time) manner. The slope of each modeled individual curve for activity was inversely correlated (r = -0.54; P < 0.0001) with worst daily pain. After removing these 2-month trends, pain and activity within an individual day were negatively associated with each point increase in pain being inversely associated with -119 steps (95% confidence interval [CI] = -214 to -25; P = 0.013). A patient's previous experience of pain was not associated with current activity as well as current activity was not associated with future pain scores. These data, although limited by the study of a single operation in a unique social circumstance with low risk of chronic postsurgical pain, demonstrate feasibility of measuring hourly activity for 2 months after surgery. Recovery from pain and inactivity are tightly correlated, and the negative relationship between within-day pain and activity without interday carryover relationships is in stark contrast to findings in chronic pain conditions.

A survey of burnout and professional satisfaction among United States neurointerventionalists.

BACKGROUND: The toll of burnout on healthcare is significant and associated with physician depression and medical errors. OBJECTIVE: To assess the prevalence and risk factors for burnout among neurointerventionalists. METHODS: A 39-question online survey containing questions about neurointerventional practice and the Maslach Burnout Inventory-Human Services Survey for medical personnel was distributed to members of major US neurointerventional physician societies. RESULTS: 320 responses were received. Median (interquartile range) composite scores for emotional exhaustion were 25 (16-35), depersonalization 7 (4-12), and personal accomplishment 39 (35-44). 164/293 respondents (56%) met established criteria for burnout. There was no significant relationship between training background, practice setting, call frequency, or presence of a senior partner on burnout prevalence. Multiple logistic regression analysis showed that feeling underappreciated by hospital leadership (OR=3.71; p<0.001) and covering more than one hospital on call (OR=1.96; p=0.01) were strongly associated with burnout. Receiving additional compensation for a call was independently protective against burnout (OR= 0.70; p=0.005). CONCLUSIONS: This survey of United States neurointerventional physicians demonstrated a self-reported burnout prevalence of 56%, which is similar to the national average among physicians across other specialties. Additional compensation for a call was a significant protective factor against burnout. In addition, feeling underappreciated by departmental or hospital leadership and covering more than one hospital while on call were associated with greater odds of burnout.

Correlation between angiographic stenosis and physiologic venous sinus outflow obstruction in idiopathic intracranial hypertension.

INTRODUCTION: The relationship between degree of angiographic venous sinus stenosis and the trans-stenosis pressure gradient magnitude in idiopathic intracranial hypertension (IIH) is poorly understood. The present study aimed to assess the utility of angiography, venography, and non-invasive imaging (MRV or CTV) for the diagnosis and characterization of clinically significant VSS. METHODS: Retrospective analysis of a prospectively collected database was performed to identify patients with medically refractory IIH who were evaluated by angiography and venous manometry for the presence of VSS with associated clinically significant pressure gradient. Angiographic stenosis was measured by two independent raters using novel methodology. RESULTS: Thirty-seven patients met inclusion criteria for the study. In total, 70% of patients had clinically significant pressure gradients and were selected for stenting. The optimal percentage stenosis for detection of a significant pressure gradient was 34% stenosis on venous phase arteriography (sensitivity 0.81 and specificity 0.91) and 31% stenosis on venography (0.92 and 0.73). For every 10% increase in stenosis, an approximate increase in pressure gradient of 3.5 mmHg is seen. MRV/CTV had a calculated sensitivity of 0.42, and a negative predictive value of 22%. CONCLUSION: The degree of stenosis predictive of a clinically significant pressure gradient (30-35%) in the venous sinuses is considerably lower than the arterial stenosis at which pathologic hemodynamic alterations occur. While highly predictive of a venous pressure gradient when a stenosis is identified, non-invasive imaging does not appear to be a suitable diagnostic evaluation for the purpose of ruling out clinically significant cerebral VSS.

Plasticity and Function of Spinal Oxytocin and Vasopressin Signaling during Recovery from Surgery with Nerve Injury.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Recovery from pain after surgery is faster after cesarean delivery than after other abdominal procedures. The authors hypothesized that recovery in rats after surgery could be reversed by antagonism of spinal oxytocin or vasopressin receptors, that there may be a sex difference, and that spinal oxytocin innervation could change after surgery. METHODS: Male and female rats underwent partial spinal nerve ligation surgery. Effects of nonselective and selective oxytocin and vasopressin 1A receptor antagonists on mechanical hypersensitivity during partial recovery were assessed (n = 8 to 14/group). Oxytocin immunoreactivity in the dorsal horn of the spinal cord (n = 7 to 8/group) and messenger RNA (mRNA) expression for oxytocin-binding receptors in dorsal root ganglia and spinal cord (n = 8/group) were measured. RESULTS: Intrathecal injection of oxytocin and vasopressin receptor antagonists were similarly effective at reducing withdrawal threshold (in all experiments from 22 [19, 26] median [first quartile, third quartile]) g to 8.3 [6.4, 12] g after injection) in both sexes, while having no or minimal effects in animals without surgery. Oxytocin fiber immunoreactivity was 3- to 5-fold greater in lumbar than other regions of the spinal cord and was increased more than 2-fold in lumbar cord ipsilateral to surgery. Injury was also associated with a 6.5-fold increase in oxytocin receptor and a 2-fold increase in vasopressin 1A receptor messenger RNA expression in the L4 dorsal root ganglion ipsilateral to surgery. CONCLUSIONS: These findings suggest that the capacity for oxytocin signaling in the spinal cord increases after surgery and that spinal oxytocin signaling plays ongoing roles in both sexes in recovery from mechanical hypersensitivity after surgery with known nerve injury.

Patterns of recovery from pain after cesarean delivery.

We know very little about the change in pain in the first 2 months after surgery. To address this gap, we studied 530 women scheduled for elective cesarean delivery who completed daily pain diaries for 2 months after surgery through text messaging. Over 82% of subjects missed fewer than 10 diary entries and were included in the analysis. Completers were more likely to be Caucasian, nonsmokers, and with fewer previous pregnancies than noncompleters. Daily worst pain intensity ratings for the previous 24 hours were fit to a log(time) function and allowed to change to a different function up to 3 times according to a Bayesian criterion. All women had at least one change point, occurring 22 ± 9 days postoperatively, and 81% of women had only one change, most commonly to a linear function at 0 pain. Approximately 9% of women were predicted to have pain 2 months after surgery, similar to previous observations. Cluster analysis revealed 6 trajectories of recovery from pain. Predictors of cluster membership included severity of acute pain, perceived stress, surgical factors, and smoking status. These data demonstrate feasibility but considerable challenges to this approach to data acquisition. The form of the initial process of recovery from pain is common to all women, with divergence of patterns at 2 to 4 weeks after cesarean delivery. The change-point model accurately predicts recovery from pain; its parameters can be used to assess predictors of speed of recovery; and it may be useful for future observational, forecasting, and interventional trials.

Gestational Obstructive Sleep Apnea: Biomarker Screening Models and Lack of Postpartum Resolution.

STUDY OBJECTIVES: To measure prevalence and severity of third trimester obstructive sleep apnea and evaluate postpartum resolution. To assess a novel biomarker for screening for obstructive sleep apnea in pregnancy. METHODS: This prospective observational study was performed at Wake Forest School of Medicine obstetrics clinics between April 2014 and December 2015. Fractional exhaled nitric oxide measurements and sleep studies were obtained and compared at 32 0/7 to 35 6/7 weeks gestation and postpartum. Exhaled nitric oxide and risk factors for the development of gestational sleep apnea were evaluated for predictive ability independently and in screening models. RESULTS: Of 76 women enrolled, 73 performed valid sleep studies in pregnancy and 65 had an additional valid study 6 to 15 weeks postpartum. Twenty-four women (37%) had gestational sleep apnea compared with 23 (35%) with postpartum sleep apnea (P > .99). Eight of 11 women (73%) retested 6 to 8 months postpartum had persistent sleep apnea. Exhaled nitric oxide had moderate discrimination screening for sleep apnea in pregnancy (area under the receiver operating characteristic curve = 0.64). A model utilizing exhaled nitric oxide, pregnancy-specific screening, and Mallampati score improved ability to identify women at risk for gestational sleep apnea (sensitivity = 46%, specificity = 91% and likelihood ratio = 5.11, area under receiver operating characteristic curve = 0.75). CONCLUSIONS: Obstructive sleep apnea is common in the early postpartum period and often persisted at least 6 months. Exhaled nitric oxide as a sole biomarker to screen for sleep apnea in pregnancy has only modest discrimination. Combined with additional parameters sensitivity and specificity improved. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Identifier: NCT02100943, Title: Exhaled Nitric Oxide as a Biomarker of Gestational Obstructive Sleep Apnea and Persistence Postpartum, URL: https://clinicaltrials.gov/ct2/show/NCT02100943.

Psychosocial Stress Delays Recovery of Postoperative Pain Following Incisional Surgery in the Rat.

Psychosocial factors such as anxiety, depression and catastrophizing, commonly associated with established chronic pain, also may be associated with an increased risk of chronic postsurgical pain (CPSP) when present preoperatively. We used a repeat social defeat (RSD) paradigm to induce psychosocial stress in rodents prior to incisional surgery of the paw. Mixed effects growth curve models were utilized to examine resolution of mechanical hypersensitivity in rats for four weeks following surgery. Eight days following surgery, immunohistochemistry was conducted to examine glial activation as well as evoked neuronal activation in the spinal cord. Here we document that RSD resulted in reduced weight gain and increased depressive symptoms prior to surgery. Rats exposed to RSD displayed delayed resolution of mechanical hypersensitivity in the ipsilateral paw following surgery compared to non-defeated rats. Prior exposure to RSD significantly increased microglial activation and neuronal sensitization (pERK-IR) within the ipsilateral spinal cord. In conclusion, we found that chronic social stress alters the neurobiological response to surgical injury, resulting in slowed recovery. This model maybe useful for future interventional studies examining the mechanistic interactions between depression and risk of CPSP.

Venous waveform morphological changes associated with treatment of symptomatic venous sinus stenosis.

INTRODUCTION: Venous outflow obstruction is recognized as a contributing factor in a subset of patients with idiopathic intracranial hypertension (IIH). Little is known about venous sinus waveform morphology or how it changes after stenting. METHODS: Fifteen patients with IIH underwent waveform recording during catheter venography and manometry. Ten patients (Group A) with venous sinus stenosis and pressure gradient ≥7 mm Hg underwent waveform recording during awake venography and during stenting under general anesthesia. Five control IIH patients (Group B) without a gradient underwent awake recording only. RESULTS: Group A patients underwent successful stenting with reduction of their gradient from 15.1±6.19 mm Hg to 1.2±0.60 mm Hg. This resulted in an amplitude reduction from 8.3 mm Hg to 2.8 mm Hg (P=0.02). Qualitative evaluation of the waveform yielded a number of novel findings. In Group A before stenting, the observed waveform progressed from an intracranial pressure (ICP)-dominated to central venous pressure (CVP)-dominated waveform. Stenting abolished the high amplitude waveform and smoothed the transition from the intracranial to central venous measurement points. Group B displayed primarily CVP-influenced waveforms distal and proximal to the transverse-sigmoid junction along with respiratory variability of the waveform, absent in 8/10 Group A patients. General anesthesia appeared to blunt the waveform in 5/10 Group A patients. CONCLUSION: The cerebral venous waveform appears to be influenced by both the ICP and CVP waveforms. As measurement moves proximally, the waveform progressively changes to mirror the CVP waveform. Venous sinus stenosis results in a high amplitude waveform which improves with treatment of the stenosis.

Day-to-day experience in resolution of pain after surgery.

We know little about the individual pain experience of patients recovering from surgery in the first weeks after hospital discharge. Here, we examine individual differences in the day-to-day experience after 2 major surgeries: lower limb total major joint arthroplasty (TJA) and cesarean delivery (CD). Fifty-five TJA patients and 157 CD patients were recruited to complete questionnaires and record their daily pain experiences after surgery. After hospital discharge, patients recorded their pain intensity once daily for 60 days (CD) or twice daily for 2 weeks, once daily for 2 weeks, weekly for 8 weeks, and monthly for 3 months (TJA). Pain scores were modeled using growth curve and Bayesian change-point models. Individual differences in the model fits were examined for evidence of day-to-day differences in pain. A log time model was the simplest model that fit the data, but examination of the residuals revealed high autocorrelation representing misspecification. A change-point model fit the data better and revealed that the form of recovery fundamentally changed between days 10 and 21 after surgery. These data add meaningfully to our understanding of recovery from pain after surgery by extending the period of frequent observations a few days after surgery to a 2-month period. These high time resolution data suggest that there is a typical experience of pain resolution after surgery, but that meaningful subpopulations of experience may exist. They also indicate that a transition occurs within 1 month after surgery from 1 pattern of change in pain over time to another.

Pupil responses and pain ratings to heat stimuli: Reliability and effects of expectations and a conditioning pain stimulus.

BACKGROUND: The locus coeruleus (LC) signals salience to sensory stimuli and these responses can modulate the experience of pain stimuli. The pupil dilation response (PDR) to noxious stimuli is thought to be a surrogate for LC responses, but PDR response to Peltier-controlled noxious heat stimuli, the most commonly used method in experimental pain research, has not been described. NEW METHOD: Healthy volunteers were presented with randomly presented heat stimuli of 5 sec duration and provided pain intensity ratings to each stimulus. Pupillometry was performed and a method developed to quantify the PDR relevant to these stimuli. The stimulus response, reliability, and effect of commonly used manipulations on pain experience were explored. RESULTS: A method of artifact removal and adjusting for lag from stimulus initiation to PDR response was developed, resulting in a close correlation between pain intensity rating and PDR across a large range of heat stimuli. A reliable assessment of PDR within an individual was achieved with fewer presentations as heat stimulus intensity increased. The correlation between pain rating and PDR was disrupted when cognitive load is increased by manipulating expectations or presenting a second pain stimulus. COMPARISON WITH EXISTING METHODS: The PDR began later after skin heating than electrical stimuli and this is the first examination of the PDR using standard nociceptive testing and manipulations of expectations and competing noxious stimulation. CONCLUSIONS: A method is described applying PDR to standard heat nociceptive testing, demonstrating stimulus response, reliability, and disruption by cognitive manipulation.

$1.8 Million and counting: how volatile agent education has decreased our spending $1000 per day.

STUDY OBJECTIVE: Volatile anesthetic agents comprise a substantial portion of every hospital's pharmacy budget. Challenged with an initiative to lower anesthetic drug expenditures, we developed an education-based intervention focused on reducing volatile anesthetic costs while preserving access to all available volatile anesthetics. When postintervention evaluation demonstrated a dramatic year-over-year reduction in volatile agent acquisition costs, we undertook a retrospective analysis of volatile anesthetic purchasing data using time series analysis to determine the impact of our educational initiative. DESIGN/SETTING: We obtained detailed volatile anesthetic purchasing data from the Central Supply of Wake Forest Baptist Health from 2007 to 2014 and integrated these data with the time course of our educational intervention. PATIENTS: Aggregate volatile anesthetic purchasing data were analyzed for 7 consecutive fiscal years. INTERVENTION: The educational initiative emphasized tissue partition coefficients of volatile anesthetics in adipose tissue and muscle and their impact on case management. MEASUREMENTS: We used an interrupted time series analysis of monthly cost per unit data using autoregressive integrated moving average modeling, with the monthly cost per unit being the amount spent per bottle of anesthetic agent per month. MAIN RESULTS: The cost per unit decreased significantly after the intervention (t=-6.73, P<.001). The autoregressive integrated moving average model predicted that the average cost per unit decreased $48 after the intervention, with 95% confidence interval of $34 to $62. As evident from the data, the purchasing of desflurane and sevoflurane decreased, whereas that of isoflurane increased. CONCLUSIONS: An educational initiative focused solely on the selection of volatile anesthetic agent per case significantly reduced volatile anesthetic expense at a tertiary medical center. This approach appears promising for application in other hospitals in the rapidly evolving, value-added health care environment. We were able to accomplish this with instruction on tissue partition coefficients and each agent's individual cost per MAC-hour delivered.

Comparing 3 ventilation modalities by measuring several respiratory parameters using the ProSeal laryngeal mask airway in children.

STUDY OBJECTIVE: To determine quantitative differences in several routinely measured ventilation parameters using a standardized anesthetic technique and 3 different ventilation modalities in pediatric patients with a ProSeal laryngeal mask airway (PLMA). DESIGN: Randomized prospective study. SETTING: Pediatric hospital of a tertiary care academic medical center. PATIENTS: Thirty-three, American Society of Anesthesiologists classification 1-2, pediatric patients (12 months to 5 years). INTERVENTIONS: Three different ventilation strategies: spontaneous ventilation (SV), pressure support ventilation (PSV), and pressure-controlled ventilation (PCV) were randomly applied to patients who underwent a standardized mask induction with sevoflurane/oxygen and propofol 3 mg/kg and morphine 0.05 mg/kg administered intravenously followed by PLMA insertion. Patients were maintained on sevoflurane and N2O. MEASUREMENTS: We measured the differences in end-tidal CO2 (Etco2), tidal volume, and respiratory rate over time between SV, PSV, and PCV. These data were recorded at 5-minute intervals. MAIN RESULTS: Etco2 (mm Hg) was significantly higher in the SV vs PSV (P=.016) and vs PCV (P<.001). Tidal volume (mL/kg) was significantly lower in SV vs PSV (P<.001) and vs PCV (P<.001). Respiratory rate (breaths/min) was significantly higher in SV vs PSV (P<.001) and vs PCV (P=.005). CONCLUSIONS: All 3 modes of ventilation using a PLMA were safely used. Our SV group was noted to have a significantly higher Etco2 when compared with PSV and PCV with a mean Etco2 over time in excess of 55 mm Hg. PSV and PCV were found to be more appropriate ventilation strategies to more optimally control Etco2 over time in these patients.

Disruption of Spinal Noradrenergic Activation Delays Recovery of Acute Incision-Induced Hypersensitivity and Increases Spinal Glial Activation in the Rat.

UNLABELLED: Results of clinical studies suggest that descending inhibitory controls from the brainstem are important for speeding recovery from pain after surgery. We examined the effects of destroying spinally projecting noradrenergic neurons via intrathecally administered antibody to dopamine ß-hydroxylase conjugated to saporin (DßH-saporin) on recovery in an acute incisional pain model. Mechanical and thermal paw withdrawal thresholds and nonevoked spontaneous guarding scores were tested for several weeks postoperatively and analyzed using mixed effects growth curve modeling. DßH-saporin treatment resulted in a significant prolongation in the duration of mechanical and to a lesser degree thermal hypersensitivity in the ipsilateral paw of incised rats but did not increase the duration of spontaneous guarding. DßH-saporin treatment was also associated with increased microglial and astrocyte activation in the ipsilateral spinal cord 21 days after incision compared with immunoglobulin G-saporin treated controls. Chronic intrathecal administration of the α2 adrenergic receptor antagonist atipamezole (50-200 µg/d) produced similar effects. These data suggest that spinally projecting noradrenergic pathways and spinal α2 adrenergic receptor activation are important for speeding recovery from hypersensitivity after surgical incision possibly by reducing spinal glial activation. Interventions that augment the noradrenergic system might be important to speed recovery from pain after surgery. PERSPECTIVE: Endogenous descending spinal noradrenergic activation promotes resolution of incision-induced hypersensitivity and inhibits spinal microglial and astrocyte activation in part through α2 adrenergic receptors.

Uncovering the History of Operating Room Attire through Photographs.

BACKGROUND: Although early proponents for each of the four basic articles of operating room clothing--gowns, caps, masks, and gloves--can be identified, it is unclear from historical commentaries when each article achieved general acceptance and was consistently worn by surgeons and by anesthesia providers. METHODS: Historical photographs were identified from the Web sites of the National Library of Medicine, Google, and the archives of the Wood Library-Museum of Anesthesiology for the 11 decades 1860 to 1970. The presence or absence of each article of clothing was then determined for the surgical and anesthesia providers depicted. RESULTS: Over 1,000 photographs were identified and examined. Photographs were then eliminated for repetition, lack of available dating, questionable dating, and poor quality. In 338 remaining photographs that met inclusion criteria, 640 surgical providers and 219 anesthesia providers were depicted and used in the analysis. Statistical definitions for historical terms general acceptance and routine use were proposed. The probability that a surgeon was wearing nonstreet clothes (gown) was 0.66 (95% CI, 0.22 to 0.93) in 1863. The years (95% lower bound to 95% upper bound) associated with a 0.5 probability for wearing cap, gloves, and mask were 1900 (1896 to 1904), 1907 (1903 to 1910), and 1916 (1913 to 1919), respectively. The years associated with a 0.5 probability that an anesthesia provider would be wearing nonstreet clothes (gown), cap, and mask were 1883 (1863 to 1889), 1905 (1900 to 1911), and 1932 (1929 to 1937), respectively. CONCLUSION: Timelines for the adoption of each basic article of surgical attire by surgeons and anesthesia providers were determined by analysis of historical operating room photographs from 1863 to 1969.

Individual differences in acute pain-induced endogenous analgesia predict time to resolution of postoperative pain in the rat.

BACKGROUND: Chronic postsurgical pain, a significant public health problem, occurs in 10 to 50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of chronic postsurgical pain. The relation between CPM and recovery from surgery has not been examined in preclinical models. METHODS: CPM was assessed in individual rats and correlated with each animal's time course of recovery of hypersensitivity after partial spinal nerve ligation. The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine ß-hydroxylase-conjugated saporin to ablate these pathways. Behavioral hypersensitivity, static weight bearing, and spinal glial activation were measured after partial spinal nerve ligation. RESULTS: The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001; r = 0.660). CPM induced the release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or dopamine ß-hydroxylase-saporin. Dopamine ß-hydroxylase-saporin also slowed recovery and enhanced spinal glial activation after partial spinal nerve ligation surgery. Ongoing activation of these pathways was critical to sustained recovery because intrathecal dopamine ß-hydroxylase-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery. CONCLUSION: Collectively, these studies provide a clear back-translation from clinical observations of CPM and chronic postsurgical pain and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

Nerve injury induces a new profile of tactile and mechanical nociceptor input from undamaged peripheral afferents.

Chronic pain after nerve injury is often accompanied by hypersensitivity to mechanical stimuli, yet whether this reflects altered input, altered processing, or both remains unclear. Spinal nerve ligation or transection results in hypersensitivity to mechanical stimuli in skin innervated by adjacent dorsal root ganglia, but no previous study has quantified the changes in receptive field properties of these neurons in vivo. To address this, we recorded intracellularly from L4 dorsal root ganglion neurons of anesthetized young adult rats, 1 wk after L5 partial spinal nerve ligation (pSNL) or sham surgery. One week after pSNL, hindpaw mechanical withdrawal threshold in awake, freely behaving animals was decreased in the L4 distribution on the nerve-injured side compared with sham controls. Electrophysiology revealed that high-threshold mechanoreceptive cells of A-fiber conduction velocity in L4 were sensitized, with a seven-fold reduction in mechanical threshold, a seven-fold increase in receptive field area, and doubling of maximum instantaneous frequency in response to peripheral stimuli, accompanied by reductions in after-hyperpolarization amplitude and duration. Only a reduction in mechanical threshold (minimum von Frey hair producing neuronal activity) was observed in C-fiber conduction velocity high-threshold mechanoreceptive cells. In contrast, low-threshold mechanoreceptive cells were desensitized, with a 13-fold increase in mechanical threshold, a 60% reduction in receptive field area, and a 40% reduction in instantaneous frequency to stimulation. No spontaneous activity was observed in L4 ganglia, and the likelihood of recording from neurons without a mechanical receptive field was increased after pSNL. These data suggest massively altered input from undamaged sensory afferents innervating areas of hypersensitivity after nerve injury, with reduced tactile and increased nociceptive afferent response. These findings differ importantly from previous preclinical studies, but are consistent with clinical findings in most patients with chronic neuropathic pain.

Modeling individual recovery after peripheral nerve injury in rats and the effects of parturition.

BACKGROUND: Recovery from pain after surgery exhibits large interindividual variability, with very slow recovery equated to chronic pain. Surgical injury in the postpartum period modestly increases initial recovery after major nerve injury. In this study, the authors use a nerve injury that recovers over 2 to 3 months and apply growth curve modeling to further understand the effect of the postpartum period on speed of recovery. METHODS: Withdrawal threshold to mechanical stimulus on the hind paw was determined in 41 Sprague-Dawley rats before and for 10 weeks after partial spinal nerve ligation. Age-matched male and female rats and postpartum females with pups or those separated from pups at delivery were studied. Growth curve analyses were applied to model recovery after surgery despite varying timing of measurements across groups and missing data, and these results were compared with those of two-way repeated-measures ANOVA. RESULTS: The recovery time course was similar between males and females. In contrast, recovery was hastened in the postpartum groups, with nonoverlapping 95% CIs of modeled trajectories between days 6 and 66 after surgery. CIs were more precise at most time periods with growth curve analysis compared with ANOVA. CONCLUSIONS: The authors describe a method of analysis to quantify recovery from hypersensitivity after surgery in rats with several distinct advantages over traditionally used methods. Study results do not support a sex difference in trajectory of recovery but confirm and extend previous observations that injury at the time of obstetric delivery is associated with an abnormally rapid recovery.

Nociceptor-selective peripheral nerve block induces delayed mechanical hypersensitivity and neurotoxicity in rats.

BACKGROUND: Long-lasting, sensory-specific peripheral nerve blockade would advance perioperative analgesia. Perineural injection of a combination of transient receptor potential vanilloid 1 channel agonists and lidocaine or its hydrophilic derivative, QX-314, produces prolonged sensory or nociceptor-selective nerve block in rodents. In this study, the authors tested the efficacy of these combinations in peripheral nerve block after incisional surgery in rats. METHODS: The authors administered perisciatic lidocaine (2%), QX-314 (0.2%) followed by dilute capsaicin (0.05%, 10 min later), or vehicle in rats and the duration of motor and sensory block to thermal and mechanical stimuli assessed in normal animals and those after incisional surgery to the hind paw. Other animals receiving these injections were evaluated 7 weeks later by behavior and histology for potential neurotoxicity. RESULTS: Perineural injection of the combination not only attenuated mechanical hypersensitivity for 72 h after incision but also resulted in delayed onset mechanical hypersensitivity several weeks later, accompanied by degeneration of central terminals of isolectin B4 (nonpeptidergic) and calcitonin gene-related peptide-containing (peptidergic) afferents in the ipsilateral spinal cord. Dorsal root ganglia ipsilateral to injection of the combination showed increased expression of activating transcription factor-3 and satellite cell activation. CONCLUSIONS: Combined administration of local anesthetics with the transient receptor potential vanilloid 1 agonist capsaicin induced a near complete blockade of incision-induced hypersensitivity for several days. However, the same combination induced delayed mechanical hypersensitivity and neurotoxicity in naïve rats. Combination of these drugs in these concentrations is likely to result in neurotoxicity, and the safety of other concentrations warrants further study.