Insights into the pathophysiology and response of persistent spinal pain syndrome type 2 to spinal cord stimulation: a human genome-wide association study.

BACKGROUND: Spinal cord stimulation (SCS) provides pain relief for some patients with persistent spinal pain syndrome type 2 (PSPS 2), but the precise mechanisms of action and prognostic factors for a favorable pain response remain obscure. This in vivo human genome-wide association study provides some pathophysiological clues. METHODS: We performed a high-density oligonucleotide microarray analysis of serum obtained from both PSPS 2 cases and pain-free controls who had undergone lower back spinal surgery at the study site. Using multivariate discriminant analysis, we tried to identify different expressions between mRNA transcripts from PSPS 2 patients relative to controls, SCS responders to non-responders, or SCS responders to themselves before starting SCS. Gene ontology enrichment analysis was used to identify the biological processes that best discriminate between the groups of clinical interest. RESULTS: Thirty PSPS 2 patients, of whom 23 responded to SCS, were evaluated together with 15 pain-free controls. We identified 11 significantly downregulated genes in serum of PSPS 2 patients compared with pain-free controls and two significantly downregulated genes once the SCS response became apparent. All were suggestive of enhanced inflammation, tissue repair mechanisms and proliferative responses among the former. We could not identify any gene differentiating patients who responded to SCS from those who did not respond. CONCLUSIONS: This study points out various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response, inflammation and restorative processes.

Effect of Conventional Spinal Cord Stimulation on Serum Protein Profile in Patients With Persistent Spinal Pain Syndrome: A Case-Control Study.

BACKGROUND: Spinal cord stimulation (SCS) provides pain relief for most patients with persistent spinal pain syndrome type 2 (PSPS 2). Evidence is mounting on molecular changes induced by SCS as one of the mechanisms to explain pain improvement. We report the SCS effect on serum protein expression in vivo in patients with PSPS 2. MATERIALS AND METHODS: Serum proteins were identified and quantified using mass spectrometry. Proteins with significantly different expression among patients with PSPS 2 relative to controls, responders, and nonresponders to SCS, or significantly modulated by SCS relative to baseline, were identified. Those most correlated with the presence and time course of pain were selected using multivariate discriminant analysis. Bioinformatic tools were used to identify related biological processes. RESULTS: Thirty patients with PSPS 2, of whom 23 responded to SCS, were evaluated, together with 14 controls with no pain who also had undergone lumbar spinal surgery. A significant improvement in pain intensity, disability, and quality of life was recorded among responders. Five proteins differed significantly at baseline between patients with PSPS 2 and controls, with three proteins, mostly involved in immune processes and inflammation, being downregulated and two, mostly involved in vitamin metabolism, synaptic transmission, and restorative processes, being upregulated. In addition, four proteins, mostly related to immune processes and inflammation, decreased significantly, and three, mostly related to iron metabolism and containment of synaptic sprouting, increased significantly during SCS. CONCLUSION: This study identifies various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response and inflammation, synaptic sprouting, vitamin and iron metabolism, and restorative processes.

Peri-operative Hemi-diaphragmatic Variations After Brachial Plexus Block Above the Clavicle: A Prospective Observational Study of the Contralateral Side.

OBJECTIVE: Hemi-diaphragm palsy after brachial plexus block above the clavicle (BPBAC) occurs frequently, but few patients develop post-operative pulmonary complications (PPC). We hypothesized that contralateral hemidiaphragm function increases after BPBAC. This contralateral function preserves global diaphragmatic function, avoiding PPC in the case of ipsilateral hemi-diaphragm palsy. METHODS: This prospective observational cohort study included 64 adult patients undergoing shoulder surgery with planned BPBAC (interscalene brachial plexus block and supraclavicular block). The Thickening Fraction (TF) was measured by ultrasound in both hemi-diaphragms, ipsilateral (TF ipsilateral) and contralateral (TFcontralateral) to the BPBAC, before and after the surgery. TFglobal is the sum of TFipsilateral and TFcontralateral. PPC were defined as occurrences of dyspnea, tachypnea, SpO2 <90% or SpO2/FiO2 <315. RESULTS: TFcontralateral increased significantly (an average of 40%) after BPBAC (p = 0.001), and TFipsilateral decreased (an average of 72%). After BPBAC, 86% of patients had a decreased TFipsilateral and 59% of patients an increased TFcontralateral at post-operatively. Only 17% of patients have PPC. CONCLUSION: After BPBAC, global diaphragm function decreases because of ipsilateral hemi-diaphragm reduction, but less than expected because of increased contralateral hemi-diaphragm function. As a part of diaphragm function, contralateral hemi-diaphragm function must be checked.

Is Sedation of Choice in Thyroplasty Surgery? A Study on the Effects of Sedatives on Voice Quality.

OBJECTIVE: In order to establish the ideal anesthetic protocol in thyroplasty type I surgery, where the intraoperative voice test is used to guide the medialization of the paralyzed fold, we have studied the effects of a sedation with midazolam premedication and adjusted intravenous doses of propofol and remifentanil on voice quality in patients without vocal fold pathology undergoing otorhinolaryngology surgery other than thyroplasty. STUDY DESIGN: Prospective cross-sectional study included 40 adult patients. METHOD: A voice recording was performed when the patient was fully awake and when an appropriate level of conscious sedation was reached. Following premedication with midazolam at anxiolytic doses, remifentanil and propofol were administrated by target controlled infusion pumps (TCI). These results were compared with those obtained in a previous study carried out by the same team using intravenous bolus (IV) according to weight. The recorded voice analysis was performed using the computer program Praat (v.5.3.39) for a sustained vowel. RESULTS: All the parameters obtained from the acoustic analysis of the voice were altered after sedation with target controlled infusion in a statistically significant way. Comparing with bolus intravenous, harmonic and noise ratio (HNR) was the only parameter that decreased less in the TCI group. CONCLUSION: The state of sedation obtained using midazolam premedication, propofol and remifentanil adjusted intravenous doses alters significantly all the voice parameters, although this alteration is considerably less than the changes produced by the medication administered in bolus IV. According to these results, the sedation and the voice test during thyroplasty surgery would present a series of limitations when it comes to guiding the medialization of the paralyzed vocal fold and therefore it could not be considered as the ideal anesthetic protocol in thyroplasty surgery.

Intrathecal Drug Delivery: Advances and Applications in the Management of Chronic Pain Patient.

Advances in our understanding of the biology of spinal systems in organizing and defining the content of exteroceptive information upon which higher centers define the state of the organism and its role in the regulation of somatic and automatic output, defining the motor response of the organism, along with the unique biology and spatial organization of this space, have resulted in an increased focus on therapeutics targeted at this extracranial neuraxial space. Intrathecal (IT) drug delivery systems (IDDS) are well-established as an effective therapeutic approach to patients with chronic non-malignant or malignant pain and as a tool for management of patients with severe spasticity and to deliver therapeutics that address a myriad of spinal pathologies. The risk to benefit ratio of IDD makes it a useful interventional approach. While not without risks, this approach has a significant therapeutic safety margin when employed using drugs with a validated safety profile and by skilled practioners. The present review addresses current advances in our understanding of the biology and dynamics of the intrathecal space, therapeutic platforms, novel therapeutics, delivery technology, issues of safety and rational implementation of its therapy, with a particular emphasis upon the management of pain.

Intubation with vivasight double-lumen tube versus conventional double-lumen tube in adult patients undergoing lung resection: A retrospective analysis.

Objectives: The present study was designed to compare outcomes in patients undergoing thoracic surgery using the VivaSight double-lumen tube (VDLT) or the conventional double-lumen tube (cDLT). Design: A retrospective analysis of 100 patients scheduled for lung resection recruited over 21 consecutive months (January 2018-September 2019). Setting: Single-center university teaching hospital investigation. Participants: A randomized sample of 100 patients who underwent lung resection during this period were selected for the purpose to compare 50 patients in the VDLT group and 50 in the cDLT group. Interventions: After institutional review board approval, patients were chosen according to inclusion and exclusion criteria and we created a general database. The 100 patients have been chosen through a random process with the Microsoft Excel program (Microsoft 2018, Version 16.16.16). Measurements and Main Results: The primary endpoint of the study was to analyze the need to use fiberoptic bronchoscopy to confirm the correct positioning of VDLT or the cDLT used for lung isolation. Secondary endpoints were respiratory parameters, admission to the intensive care unit, length of hospitalization, postoperative complications, readmission, and 30-day mortality rate. The use of fiberoptic bronchoscopy was lower in the VDLT group, and the size of the tube was smaller. The intraoperative respiratory and hemodynamics parameters were optimal. There were no other preoperative, intraoperative, or postoperative differences between both groups. Conclusions: The VDLT reduces the need for fiberoptic bronchoscopy, and it seems that a smaller size is needed. Finally, VDLT is cost-effective using disposable fiberscopes.

A new strategy in lung/lobe isolation in patients with a lung abscess or a previous lung resection using double lumen tubes combined with bronchial blockers.

The combined use of a double-lumen tube and a bronchial blocker can be very helpful in two different clinical scenarios: (1) in isolating not only the contralateral lung, but also the lobe/s of the same lung in which the infected lobe must be resected, (2) in preventing/treating hypoxemia because of the presence of a contralateral lobectomy. A cardiothoracic anesthesiologist must expertise this technique to avoid complications during surgery.

Clinical characteristics of COVID-19 hospitalized patients associated with mortality: A cohort study in Spain.

Background: The heterogeneity of patients with COVID-19 may explain the wide variation of mortality rate due to the population characteristics, presence of comorbidities and clinical manifestations. Methods: In this study, we analyzed 5342 patients' recordings and selected a cohort of 177 hospitalized patients with a poor prognosis at an early stage. We assessed during 6 months their symptomatology, coexisting health conditions, clinical measures and health assistance related to mortality. Multiple Cox proportional hazards models were built to identify the associated factors with mortality risk. Results: We observed that cough and kidney failure triplicate the mortality risk and both bilirubin levels and oncologic condition are shown as the most associated with the demise, increasing in four and ten times the risk, respectively. Other clinical characteristics such as fever, diabetes mellitus, breathing frequency, neutrophil-lymphocyte ratio, oxygen saturation, and troponin levels, were also related to mortality risk of in-hospital death. Conclusions: The present study shows that some symptomatology, comorbidities and clinical measures could be the target of prevention tools to improve survival rates.

Adjacent segment syndrome after failed back surgery: biomechanics, diagnosis, and treatment.

The adjacent segment syndrome is defined as the changes in the adjacent structures of an operated spinal level that produce symptoms of pain and disability, which worsen the quality of life of a patient. Pain management specialists must be aware of these biomechanical changes brought by spinal surgeries, as well as of the symptoms associated with pain after surgery, to reach an appropriate diagnosis and provide an adequate treatment. Specialized pain literature contains few reports on specific management of patients using the terms "adjacent segment syndrome, degeneration or disease;" most of the literature comes from surgical journals. It is necessary to perform studies with a population sample comprising patients with adjacent segment syndrome after spinal surgery, since almost all treatments applied in this group are extrapolated from those used in patients with pain originating in the same area but who have not previously undergone spine surgery. Therefore, we consider necessary for pain physicians to understand the underlying biomechanics, promote the diagnosis of this condition, and analyze possible treatments in patients with adjacent segment disease to alleviate their pain and improve their quality of life.

Predictive Clinical Decision Support System Using Machine Learning and Imaging Biomarkers in Patients With Neurostimulation Therapy: A Pilot Study.

BACKGROUND: Chronic pain is correlated with alterations in brain structure and function. The selection process for the ideal candidate for spinal cord stimulation (SCS) therapy is based on functional variables analysis and pain evaluation scores. In addition to the difficulties involved in the initial selection of patients and the predictive analysis of the trial phase, the large rate of explants is one of the most important concerns in the analysis of the suitability of implanted candidates. OBJECTIVE: To investigate the usefulness of imaging biomarkers, functional connectivity (FC) and volumetry of the whole brain in patients with Failed back surgery syndrome (FBSS) and to create a clinical patient-based decision support system (CDSS) combining neuroimaging and clinical data for predicting the effectiveness of neurostimulation therapy after a trial phase. STUDY DESIGN: A prospective, consecutive, observational, single center study. SETTING: The Multidisciplinary Pain Management Department of the General University Hospital in Valencia, Spain. METHODS: A prospective, consecutive, and observational single-center study. Using Resting-state functional magnetic resonance imaging (rs-fMRI) and Region of interest (ROI) to ROI analysis, we compared the functional connectivity between regions to detect differences in FC and volume changes. Basal magnetic resonance images were obtained in a 1.5T system and clinical variables were collected twice, at the basal condition and at 6-months post-SCS implant. We also conducted a seed-to-voxel analysis with 9 items as seed-areas characterizing the functional connectivity networks. A decreased in 10 units in the Pain Detect Questionnaire (PD-Q) score was established to define the subgroup of Responders Group (R-G) to neurostimulation therapy. The clinical variables collected and the imaging biomarkers obtained (FC and volumes) were tested on a set of 6 machine learning approaches in an effort to find the best classifier system for predicting the effectiveness of the neurostimulator. RESULTS: Twenty-four patients were analyzed and only seven were classified in the R-G. Volumetric differences were found in the left putamen, F = 34.06, P = 0.02. Four pairwise brain areas showed statistical differences in the rs-fMRI including the right insular cortex. Linear Discriminant Analysis showed the best performance for building the CDSS combining clinical variables and significant imaging biomarkers, the prediction increased diagnostic accuracy in the R-G patients from 29% in current practice to 96% of long-term success. CONCLUSION: These findings confirm a major role of the left putamen and the four pairs of brain regions in FBBS patients and suggest that a CDSS would be able to select patients susceptible to benefitting from SCS therapy adding imaging biomarkers.

Peripheral nerve block anesthesia/analgesia for patients undergoing primary hip and knee arthroplasty: recommendations from the International Consensus on Anesthesia-Related Outcomes after Surgery (ICAROS) group based on a systematic review and meta-analysis of current literature.

BACKGROUND: Evidence-based international expert consensus regarding the impact of peripheral nerve block (PNB) use in total hip/knee arthroplasty surgery. METHODS: A systematic review and meta-analysis: randomized controlled and observational studies investigating the impact of PNB utilization on major complications, including mortality, cardiac, pulmonary, gastrointestinal, renal, thromboembolic, neurologic, infectious, and bleeding complications.Medline, PubMed, Embase, and Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, were queried from 1946 to August 4, 2020.The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess evidence quality and for the development of recommendations. RESULTS: Analysis of 122 studies revealed that PNB use (compared with no use) was associated with lower ORs for (OR with 95% CIs) for numerous complications (total hip and knee arthroplasties (THA/TKA), respectively): cognitive dysfunction (OR 0.30, 95% CI 0.17 to 0.53/OR 0.52, 95% CI 0.34 to 0.80), respiratory failure (OR 0.36, 95% CI 0.17 to 0.74/OR 0.37, 95% CI 0.18 to 0.75), cardiac complications (OR 0.84, 95% CI 0.76 to 0.93/OR 0.83, 95% CI 0.79 to 0.86), surgical site infections (OR 0.55 95% CI 0.47 to 0.64/OR 0.86 95% CI 0.80 to 0.91), thromboembolism (OR 0.74, 95% CI 0.58 to 0.96/OR 0.90, 95% CI 0.84 to 0.96) and blood transfusion (OR 0.84, 95% CI 0.83 to 0.86/OR 0.91, 95% CI 0.90 to 0.92). CONCLUSIONS: Based on the current body of evidence, the consensus group recommends PNB use in THA/TKA for improved outcomes. RECOMMENDATION: PNB use is recommended for patients undergoing THA and TKA except when contraindications preclude their use. Furthermore, the alignment of provider skills and practice location resources needs to be ensured. Evidence level: moderate; recommendation: strong.

Radiation safety and knowledge: an international survey of 708 interventional pain physicians.

INTRODUCTION: Interventional pain procedures have increased in complexity, often requiring longer radiation exposure times and subsequently higher doses. The practicing physician requires an in-depth knowledge and evidence-based knowledge of radiation safety to limit the health risks to themselves, patients and healthcare staff. The objective of this study was to examine current radiation safety practices and knowledge among interventional pain physicians and compare them to evidence-based recommendations. MATERIALS AND METHODS: A 49-question survey was developed based on an extensive review of national and international guidelines on radiation safety. The survey was web-based and distributed through the following professional organizations: Association of Pain Program Directors, American Academy of Pain Medicine, American Society of Regional Anesthesia and Pain Medicine, European Society of Regional Anesthesia and Pain Therapy, International Neuromodulation Society, and North American Neuromodulation Society. Responses to radiation safety practices and knowledge questions were evaluated and compared with evidence-based recommendations. An exploratory data analysis examined associations with radiation safety training/education, geographical location, practice type, self-perceived understanding, and fellowship experience. RESULTS: Of 708 responding physicians, 93% reported concern over the health effects of radiation, while only 63% had ever received radiation safety training/education. Overall, ≥80% physician compliance with evidence-based radiation safety practice recommendations was demonstrated for only 2/15 survey questions. Physician knowledge of radiation safety principles was low, with 0/10 survey questions having correct response rates ≥80%. CONCLUSION: We have identified deficiencies in the implementation of evidence-based practices and knowledge gaps in radiation safety. Further education and training are warranted for both fellowship training and postgraduate medical practice. The substantial gaps identified should be addressed to better protect physicians, staff and patients from unnecessary exposure to ionizing radiation during interventional pain procedures.

Differences in Gene Expression of Endogenous Opioid Peptide Precursor, Cannabinoid 1 and 2 Receptors and Interleukin Beta in Peripheral Blood Mononuclear Cells of Patients With Refractory Failed Back Surgery Syndrome Treated With Spinal Cord Stimulation: Markers of Therapeutic Outcomes?

OBJECTIVE: The use of spinal cord stimulation for patients with failed back surgery syndrome (FBSS) is very common. In order to better understand the mechanisms of action of spinal cord stimulation (SCS), our aim was to determine potential changes in relative gene and protein expression in the peripheral blood mononuclear cells (PBMCs) of patients as potential biomarkers of disease outcomes and potential new targets for therapy. METHODS: Twenty-four patients with diagnosis of FBSS refractory to conservative therapy for at least six months were included in the study. Clinical evaluation in this study included validated questionnaires. Blood samples (10 mL) were collected five times from baseline until two months after implant of the leads. Proenkephalin (PENK), cannabinoid receptors CB1 and CB2, and interleukin 1ß (IL 1ß) were analyzed. Each patient served as his/her own control by comparing the samples collected at different time points against the baseline sample collected at T0. RESULTS: A total of 16 patients met all relevant criteria during the whole study and were assessed. Only PENK showed significant changes over time (Friedman p = 0.000). A positive correlation was observed between changes in visual analog scale (VAS) scores and PENK and a negative correlation between changes in PENK and Short Form-12 (SF-12) mental component score (MCS) scores, as well as between changes in IL 1ß and Pain Detect Questionnaire (PD-Q) scores. As PENK changes increased, so did pain (VAS). As changes in PENK increased, SF-12 MCS health worsened. As changes in IL 1ß increased, PD-Q values decreased. No severe adverse events occurred. CONCLUSIONS: Previously unknown effects of SCS on levels of PBMCs biomarkers are demonstrated. The findings of our research suggest a potential for useful integration of genome analysis and lymphocyte expression in the daily practice of neurostimulation for pain management and represent a novel road map in the light of the important questions that remain unanswered.

Effects of spinal cord stimulation on voxel-based brain morphometry in patients with failed back surgery syndrome.

OBJECTIVE: Despite the clinical effectiveness of Spinal Cord Stimulation (SCS), potential structural brain modifications have not been explored. Our aim was to identify structural volumetric changes during subsensory SCS, in patients with Failed Back Surgery Syndrome (FBSS). METHODS: In this cohort study, twenty-two FBSS patients underwent a magnetic resonance imaging protocol before SCS and 3 months after SCS. Clinical parameters were correlated with volumetric changes, calculated with voxel-based morphometry. RESULTS: After 3 months, a significant volume decrease was found in the inferior frontal gyrus, precuneus, cerebellar posterior lobe and middle temporal gyrus. Significant increases were found in the inferior temporal gyrus, precentral gyrus and the middle frontal gyrus after SCS. Additionally, significant increases in volume of superior frontal and parietal white matter and a significant decrease in volume of white matter underlying the premotor/middle frontal gyrus were revealed after SCS. A significant correlation was highlighted between white matter volume underlying premotor/middle frontal gyrus and leg pain relief. CONCLUSIONS: This study revealed for the first time that SCS is able to induce volumetric changes in gray and white matter, suggesting the reversibility of brain alterations after chronic pain treatment. SIGNIFICANCE: Volumetric brain alterations are observable after 3 months of subsensory SCS in FBSS patients.

Intrathecal Drug Delivery.

Targeted intrathecal (IT) drug delivery systems (IDDS) are well established as an effective treatment of patients with chronic nonmalignant or malignant pain, and as a tool for management of patients with severe spasticity. The risk to benefit ratio of IDD makes it a relatively safe therapy for both cancer- and noncancer-related pain, but it is not free of risks, so it should be managed at specific centers. Recent technological advances, new therapeutic applications, reported complications, and the costs as well as maintenance required for this therapy require the need to stay up to date about new recommendations that may improve outcomes. This chapter reviews all technological issues regarding IDDS implantation with follow-up and pharmacological recommendations published during recent years that provide evidence-based decision-making process in the management of chronic pain and spasticity in patients.

Anaesthetic care of patients undergoing primary hip and knee arthroplasty: consensus recommendations from the International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS) based on a systematic review and meta-analysis.

BACKGROUND: Evidence-based international expert consensus regarding anaesthetic practice in hip/knee arthroplasty surgery is needed for improved healthcare outcomes. METHODS: The International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS) systematic review, including randomised controlled and observational studies comparing neuraxial to general anaesthesia regarding major complications, including mortality, cardiac, pulmonary, gastrointestinal, renal, genitourinary, thromboembolic, neurological, infectious, and bleeding complications. Medline, PubMed, Embase, and Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, from 1946 to May 17, 2018 were queried. Meta-analysis and Grading of Recommendations Assessment, Development and Evaluation approach was utilised to assess evidence quality and to develop recommendations. RESULTS: The analysis of 94 studies revealed that neuraxial anaesthesia was associated with lower odds or no difference in virtually all reported complications, except for urinary retention. Excerpt of complications for neuraxial vs general anaesthesia in hip/knee arthroplasty, respectively: mortality odds ratio (OR): 0.67, 95% confidence interval (CI): 0.57-0.80/OR: 0.83, 95% CI: 0.60-1.15; pulmonary OR: 0.65, 95% CI: 0.52-0.80/OR: 0.69, 95% CI: 0.58-0.81; acute renal failure OR: 0.69, 95% CI: 0.59-0.81/OR: 0.73, 95% CI: 0.65-0.82; deep venous thrombosis OR: 0.52, 95% CI: 0.42-0.65/OR: 0.77, 95% CI: 0.64-0.93; infections OR: 0.73, 95% CI: 0.67-0.79/OR: 0.80, 95% CI: 0.76-0.85; and blood transfusion OR: 0.85, 95% CI: 0.82-0.89/OR: 0.84, 95% CI: 0.82-0.87. CONCLUSIONS: Recommendation: primary neuraxial anaesthesia is preferred for knee arthroplasty, given several positive postoperative outcome benefits; evidence level: low, weak recommendation. RECOMMENDATION: neuraxial anaesthesia is recommended for hip arthroplasty given associated outcome benefits; evidence level: moderate-low, strong recommendation. Based on current evidence, the consensus group recommends neuraxial over general anaesthesia for hip/knee arthroplasty. TRIAL REGISTRY NUMBER: PROSPERO CRD42018099935.