An Explorative Study of CYP2D6's Polymorphism in a Sample of Chronic Pain Patients.

BACKGROUND: A proper antalgic treatment is based on the use of titrated drugs to provide adequate relief and a good tolerability profile. Therapies have a variable effectiveness among subjects depending on medical and genetic conditions. CYP2D6 variations determine a different clinical response to most analgesic drugs commonly used in daily clinical practice by influencing the drugs' pharmacokinetics. This study was a monocentric clinical trial exploring the CYP2D6 variants in 100 patients with a diagnosis of chronic pain. METHODS: DNA was extracted to evaluate the genotype and to classify patients as normal-fast (gNMs-F), normal-slow (gNMs-S), ultrarapid (gUMs), intermediate (gIMs), and poor metabolizers (gPMs) using the Activity Score (AS). Information on therapies and general side effects experienced by patients was collected. Nongenetic co-factors were evaluated to examine the discrepancy between metabolic profile predicted from genotype (gPh) and metabolic profile (phenocopying). RESULTS: The distribution of our data underlined the prevalence of the gNMs-F (67%), whereas gNMs-S were 24%, gIMs 6%, gPMs 3%, and no gUMs were found, resulting in 33% of patients with reduced metabolic activity. In the analyzed population sample, 86% and 56% of patients, respectively, took at least one or two drugs inhibiting in vitro activity of the CYP2D6 enzyme. CONCLUSIONS: Over one-third of the enrolled patients showed altered CYP2D6 enzymatic metabolic activity, with a risk of phenocopying potentially due to polypharmacology. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03411759.

An Embedded Device for Real-Time Noninvasive Intracranial Pressure Estimation.

OBJECTIVE: The monitoring of intracranial pressure (ICP) is indicated for diagnosing and guiding therapy in many neurological conditions. Current monitoring methods, however, are highly invasive, limiting their use to the most critically ill patients only. Our goal is to develop and test an embedded device that performs all necessary mathematical operations in real-time for noninvasive ICP (nICP) estimation based on a previously developed model-based approach that uses cerebral blood flow velocity (CBFV) and arterial blood pressure (ABP) waveforms. MATERIALS AND METHODS: The nICP estimation algorithm along with the required preprocessing steps were implemented on an NXP LPC4337 microcontroller unit (MCU). A prototype device using the MCU was also developed, complete with display, recording functionality, and peripheral interfaces for ABP and CBFV monitoring hardware. RESULTS: The device produces an estimate of mean ICP once per minute and performs the necessary computations in 410 ms, on average. Real-time nICP estimates differed from the original batch-mode MATLAB implementation of theestimation algorithm by 0.63 mmHg (root-mean-square error). CONCLUSIONS: We have demonstrated that real-time nICP estimation is possible on a microprocessor platform, which offers the advantages of low cost, small size, and product modularity over a general-purpose computer. These attributes take a step toward the goal of real-time nICP estimation at the patient's bedside in a variety of clinical settings.

A Waveform Archiving System for the GE Solar 8000i Bedside Monitor.

OBJECTIVES: Our objective was to develop, deploy, and test a data-acquisition system for the reliable and robust archiving of high-resolution physiological waveform data from a variety of bedside monitoring devices, including the GE Solar 8000i patient monitor, and for the logging of ancillary clinical and demographic information. MATERIALS AND METHODS: The data-acquisition system consists of a computer-based archiving unit and a GE Tram Rac 4A that connects to the GE Solar 8000i monitor. Standard physiological front-end sensors connect directly to the Tram Rac, which serves as a port replicator for the GE monitor and provides access to these waveform signals through an analog data interface. Together with the GE monitoring data streams, we simultaneously collect the cerebral blood flow velocity envelope from a transcranial Doppler ultrasound system and a non-invasive arterial blood pressure waveform along a common time axis. All waveform signals are digitized and archived through a LabView-controlled interface that also allows for the logging of relevant meta-data such as clinical and patient demographic information. RESULTS: The acquisition system was certified for hospital use by the clinical engineering team at Boston Medical Center, Boston, MA, USA. Over a 12-month period, we collected 57 datasets from 11 neuro-ICU patients. The system provided reliable and failure-free waveform archiving. We measured an average temporal drift between waveforms from different monitoring devices of 1 ms every 66 min of recorded data. CONCLUSIONS: The waveform acquisition system allows for robust real-time data acquisition, processing, and archiving of waveforms. The temporal drift between waveforms archived from different devices is entirely negligible, even for long-term recording.

Effects of anaesthesia and analgesia on long-term outcome after total knee replacement: A prospective, observational, multicentre study.

BACKGROUND: Perioperative regional anaesthesia may protect from persistent postsurgical pain (PPSP) and improve outcome after total knee arthroplasty (TKA). OBJECTIVES: Aim of this study was to evaluate the impact of regional anaesthesia on PPSP and long-term functional outcome after TKA. DESIGN: A web-based prospective observational registry. SETTING: Five Italian Private and University Hospitals from 2012 to 2015. PATIENTS: Undergoing primary unilateral TKA, aged more than 18 years, informed consent, American Society of Anesthesiologists (ASA) physical status classes 1 to 3, no previous knee surgery. INTERVENTION(S): Personal data (age, sex, BMI and ASA class), preoperative pain assessed by numerical rating scale (NRS) score, and risk factors for PPSP were registered preoperatively. Data on anaesthetic and analgesic techniques were collected. Postoperative pain (NRS), analgesic consumption, major complications and patient satisfaction were registered up to the time of discharge. PPSP was assessed by a blinded investigator during a phone call after 1, 3 and 6 months, together with patient satisfaction, quality of life (QOL) and walking ability. MAIN OUTCOME MEASURES: Experience of PPSP according to the type of peri-operative analgesia. RESULTS: Five hundred sixty-three patients completed the follow-up. At 6 months, 21.6% of patients experienced PPSP, whereas autonomy was improved only in 56.3%; QOL was worsened or unchanged in 30.7% of patients and improved in 69.3%. Patients receiving continuous regional anaesthesia (epidural or peripheral nerve block) showed a lower NRS through the whole peri-operative period up to 1 month compared with both single shot peripheral nerve block and those who did not receive any type of regional anaesthesia. No difference was found between these latter two groups. Differences in PPSP at 3 or 6 months were not significantly affected by the type of anaesthesia or postoperative analgesia. A higher NRS score at 1 month, younger age, history of anxiety or depression, pro-inflammatory status, higher BMI and a lower ASA physical status were associated with a higher incidence of PPSP and worsened QOL at 6 months. CONCLUSION: Continuous regional anaesthesia provides analgesic benefit for up to 1 month after surgery, but did not influence PPSP at 6 months. Better pain control at 1 month was associated with reduced PPSP. Patients with higher expectations from surgery, enhanced basal inflammation and a pessimistic outlook are more prone to develop PPSP. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02147730.

Transversus Abdominis Plane Block for Postoperative Analgesia in Patients Undergoing Total Laparoscopic Hysterectomy: A Randomized, Controlled, Observer-Blinded Trial.

BACKGROUND: In this randomized, controlled, observer-blinded study, we evaluated analgesia provided by transversus abdominis plane (TAP) block after elective total laparoscopic hysterectomy in terms of reduced postoperative morphine consumption as the primary end point. METHODS: Fifty-two patients were randomly divided into 2 groups: patients in group T (TAP, n = 26) received an ultrasound-guided bilateral TAP block with 40 mL of 0.375% levobupivacaine and morphine patient-controlled analgesia, whereas patients in group C (control, n = 26) received morphine patient-controlled analgesia. Secondary outcomes included pain measurements (Numeric Rating Scale from 0 to 10) during the first 24 hours postoperatively, times to postanesthesia care unit discharge, times to surgical ward discharge, incidence of postoperative nausea and vomiting, functional capacity measurements in terms of 2-minute walking test, and first oral solid intake. RESULTS: Demographic and anthropometric variables were similar in the 2 groups. The total dose of morphine consumed by patients during postanesthesia care unit stay was 6 (0-8) mg in group T vs 8 (5.5-8.5) mg in group C (P = 0.154). Postoperative morphine consumption during the first 24 hours was 10.55 ± 10.24 mg in group C vs 10.73 ± 13.45 mg in group T (P = 0.950). The 95% confidence interval of the difference between means of 24-hour morphine consumption was -7.45 to +7.09. The 2 groups were comparable. There were no significant differences in secondary outcome variables between groups. CONCLUSIONS: TAP block did not reduce morphine consumption during the first postoperative 24 hours after elective total laparoscopic hysterectomy.

Use of ultrasound for lower extremity.

PURPOSE OF REVIEW: To explore the recent advances in the use of ultrasound for lower extremity blocks, including approaches to the lumbar and sacral plexus blocks. RECENT FINDINGS: Procedures of the lower extremity often require blocks of the lumbar and sacral plexuses. The use of ultrasound offers some advantages, including the possibility to directly visualize the distribution of local anesthetics. SUMMARY: Lower extremity blocks under ultrasound guidance often require advanced skills because of the depth of target nerves. This review summarizes the recent advances in the use of ultrasound guidance over traditional techniques.

Is spinal anaesthesia a suitable technique for ultra-short outpatient procedures?

Spinal anaesthesia is an easy and reliable technique. Factors limiting its use in the ambulatory setting include delayed ambulation, risk of urinary retention and pain after block regression. On the contrary, general anaesthesia with fast-acting drugs provides a fast recovery that facilitates an early discharge. Although recovery after spinal anaesthesia has been improved by reducing the dose of the commonly used longacting local anaesthetics, discharge times are still prolonged compared with general anaesthesia. 2-Chloroprocaine is an amino-ester local anaesthetic with a very short half-life and a favourable evolution of spinal block for ultra-short outpatient procedures. Moreover, the preservative free 2-chloroprocaine solution showed a very low risk of urinary retention and transient neurological symptoms when compared with bupivacaine and lidocaine. The aim of this article is to evaluate if the neuraxial administration of short-acting local anaesthetics renders spinal anaesthesia a suitable technique for ultra-short surgical procedures.

Nonsteroideal Anti-inflammatory Drugs (NSAIDs) in clinical practice: managing gastric and cardiovascular risks.

For many years, non-steroidal inflammatory drugs (NSAIDs) were commonly used in the treatment of acute pain due to inflammation.With the arrival on the market of NSAIDs with selective action on COX-2 there was a reduction of side effects in the stomach, but not eliminating the possible cardiovascular complications. The availability of NSAIDs such self-medication can aggravate this type of problem, it is therefore the clinician a fair and accurate assessment of the risk \ benefit based on the characteristics of the individual patient.

Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk.

NSAIDs are largely used for the treatment of a huge variety of clinical conditions in order to relieve symptoms related to inflammation.The use of NSAIDs is associated with a potential increased risk of gastrointestinal and cardiovascular complications.The cardiovascular risk related to NSAIDs administration is often underestimated and it is frequently believed to be less important than the gastrointestinal risk. Adverse effects of NSAIDs are specifically related to their underlying mechanisms of action.The most plausible mechanism underlying the cardiovascular risk of NSAIDs has been identified in the profound inhibition of COX-2-dependent PGI2 in the presence of incomplete and intermittent inhibition of platelet COX-1. Nevertheless, the cardiovascular risk related to the use of NSAIDs is not only due to the COX-2 selectivity. An important determinant of the clinical effects of NSAIDs depends on the pharmacokinetic features of the different drugs such as half-life, and type of formulations, which can influence the extent and duration of patient exposure to COXisozyme inhibition. The aim of this review is to analyse the mechanisms behind the cardiovascular risk of different NSAIDs.

Acute and chronic pain management in sport medicine: an expert opinion looking at an alternative mechanism-based approach to the pharmacological treatment.

In the last decades there has been a huge increase in people who practice sports requesting an increase of the performance. Consequently, also incidence of acute and chronic pain is highly increased in this population of "healthy" people. Pain represents not only a signal of a lesion occurred during the sportive activity, but also (and almost) an unbalance of posture or an overuse of specific articulations or muscles, that has to be resolved not only with a correct physiotherapeutic approach, but also with a careful diagnosis of the complex mechanisms that sustain the pain. Furthermore, many drugs, commonly used in patients with acute pain, can cause side effects in people who practice sports, or they cannot be used as classified in the doping list. Hence, the pain therapist assumes a pivotal role in the management of pain in people who practice sports, for his skills in pain diagnosis, and for the possibility to introduce new mechanism-based therapies. In the last decade, these new therapies, such as regenerative medicine and peripheral neuromodulation, have demonstrated their effectiveness not only to reduce pain, but also to facilitate the healing process and the faster return to the sportive activity. In this expert opinion we summarize the most recent data to support this approach, focalizing not only on how to treat specific pain syndromes but also on how pain therapist could drive, through a careful diagnosis of the pain mechanism, to a new simultaneous mechanism-based disease modifying approach in people with pain practicing sport.

Regional anesthesia techniques and postoperative delirium: systematic review and meta-analysis.

INTRODUCTION: Postoperative delirium is a frequent occurrence in the elderly surgical population. As a comprehensive list of predictive factors remains unknown, an opioid-sparing approach incorporating regional anesthesia techniques has been suggested to decrease its incidence. Due to the lack of conclusive evidence on the topic, we conducted a systematic review and meta-analysis to investigate the potential impact of regional anesthesia and analgesia on postoperative delirium. EVIDENCE ACQUISITION: PubMed, Embase, and the Cochrane central register of Controlled trials (CENTRAL) databases were searched for randomized trials comparing regional anesthesia or analgesia to systemic treatments in patients having any type of surgery. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We pooled the results separately for each of these two applications by random effects modelling. Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the certainty of evidence and strength of conclusions. EVIDENCE SYNTHESIS: Eighteen trials (3361 subjects) were included. Using regional techniques for surgical anesthesia failed to reduce the risk of postoperative delirium, with a relative risk (RR) of 1.21 (95% CI: 0.79 to 1.85); P=0.3800. In contrast, regional analgesia reduced the relative risk of perioperative delirium by a RR of 0.53 (95% CI: 0.42 to 0.68; P<0.0001), when compared to systemic analgesia. Post-hoc subgroup analysis for hip fracture surgery yielded similar findings. CONCLUSIONS: These results show that postoperative delirium may be decreased when regional techniques are used in the postoperative period as an analgesic strategy. Intraoperative regional anesthesia alone may not decrease postoperative delirium since there are other factors that may influence this outcome.

The opioid sparing effect of erector spinae plane block for various surgeries: a meta-analysis of randomized-controlled trials.

INTRODUCTION: The erector spinae plane block (ESPB) is a newer fascial plane block which has been broadly applied for postoperative analgesia after various surgeries, but the effectiveness in these populations is not well established. EVIDENCE ACQUISITION: A systematic database search was conducted in PubMed, PMC, Embase, and Scopus for randomized controlled trials (RCTs) comparing ESPB with control, placebo, or other blocks. The primary outcome was intravenous opioid consumption in milligram morphine equivalents 24 h after surgery. Standardized mean differences (SMDs) with 95% confidence intervals (CI) were calculated using a random-effects model. EVIDENCE SYNTHESIS: A total of 29 RCTs were included. An analysis was conducted by subgroups differentiated by surgery type, 'no block' vs. ESPB, and other blocks vs. ESPB. ESPB was effective in reducing opioid consumption against no block for breast surgery (SMD -1.13; 95% CI), thoracic surgery (SMD -3.00; 95% CI), and vertebral surgery (SMD -1.78; 95% CI). ESPB was effective against alternative blocks for breast surgery (vs. paravertebral, SMD -1.07; 95% CI) and abdominal surgery (SMD -1.77; 95% CI). ESPB showed moderate effect in thoracic surgery against paravertebral (SMD 0.58; 95% CI) and against no block in abdominal surgery (SMD 0.80; 95% CI). In only one case did ESPB perform worse than another block: vs. PECS block for breast surgery (SMD 1.66; 95% CI). CONCLUSIONS: ESPB may be a useful addition to the multimodal analgesic regimen for a variety of surgeries especially when the alternative is no block. Unanswered questions include determining of the mechanism of action, refining of the EPSB technique, and establishing recommended local anesthetic dose and volume.

The Role of Regional Anesthesia During the SARS-CoV2 Pandemic: Appraisal of Clinical, Pharmacological and Organizational Aspects.

The severe acute respiratory syndrome coronavirus SARS-CoV2 is spreading over millions of people worldwide, leading to thousands of deaths, even among the healthcare providers. Italy has registered the deaths of 337 physicians and more than 200 nurses as of March 14, 2021. Anesthesiologists are at higher risk as they are the care providers in both ICU and operating rooms.Although the vaccination of healthcare providers has been the prioirity, physicians are still continually exposed to the virus and potentially risk contagion and must thus protect themselves and their patients from the risks of infection while providing the best care to their surgical patients.Regional anesthesia allows for a reduction in airway manipulation, reducing environmental contamination as a result. Furthermore, regional anesthesia reduces the opioid requirements as well as the muscle paralysis due to muscle-relaxants and should be recommended whenever possible in COVID-19 patients. Our aim is to evaluate the advantages and criticisms of regional anesthesia in the management of surgical patients in the pandemic age.

Opportunities and challenges for nonaddictive interventions in chronic pain.

The worlds of chronic pain and addiction continue to intersect too often in many ways. Chronic pain significantly impairs and disrupts the quality of life of millions of people worldwide. Opioids remain the most prescribed pharmacotherapy offered to patients to alleviate chronic pain. The extensive and often unnecessary prescription of opioids has created a surge in the prevalence of opioid use disorders and opioid overdose-related deaths. In this brief review, we aim to provide a bench-to-bedside overview of promising biomarkers, therapeutic targets, and challenges related to treating patients with chronic pain. We hope this review will inspire new opportunities and insights into the development of novel, nonaddictive treatments for chronic pain that will be available to patients in the near future.

An Exploratory Pilot Study of Changes in Global DNA Methylation in Patients Undergoing Major Breast Surgery Under Opioid-Based General Anesthesia.

This study aimed to investigate DNA methylation levels in patients undergoing major breast surgery under opioid-based general anesthesia. Blood samples were collected from eleven enrolled patients, before, during and after anesthesia. PBMC were isolated and global DNA methylation levels as well as DNA methyltransferase (DNMT) and cytokine gene expression were assessed. DNA methylation levels significantly declined by 26%, reversing the direction after the end of surgery. Likewise, DNMT1a mRNA expression was significantly reduced at all time points, with lowest level of -68%. DNMT3a and DNMT3b decreased by 65 and 71%, respectively. Inflammatory cytokines IL6 and TNFα mRNA levels showed a trend for increased expression at early time-points to end with a significant decrease at 48 h after surgery. This exploratory study revealed for the first time intraoperative global DNA hypomethylation in patients undergoing major breast surgery under general anesthesia with fentanyl. The alterations of global DNA methylation here observed seem to be in agreement with DNMTs gene expression changes. Furthermore, based on perioperative variations of IL6 and TNFα gene expression, we hypothesize that DNA hypomethylation may occur as a response to surgical stress rather than to opiate exposure.

A Review of the Clinical and Therapeutic Implications of Neuropathic Pain.

Understanding neuropathic pain presents several challenges, given the various mechanisms underlying its pathophysiological classification and the lack of suitable tools to assess its diagnosis. Furthermore, the response of this pathology to available drugs is still often unpredictable, leaving the treatment of neuropathic pain still questionable. In addition, the rise of personalized treatments further extends the ramified classification of neuropathic pain. While a few authors have focused on neuropathic pain clustering, by analyzing, for example, the presence of specific TRP channels, others have evaluated the presence of alterations in microRNAs to find tailored therapies. Thus, this review aims to synthesize the available evidence on the topic from a clinical perspective and provide a list of current demonstrations on the treatment of this disease.

Serum sodium alterations in SARS CoV-2 (COVID-19) infection: impact on patient outcome.

OBJECTIVE: Hyponatremia is the most common electrolyte disorder in hospitalized patients and occurs in about 30% of patients with pneumonia. Hyponatremia has been associated with a worse outcome in several pathologic conditions The main objective of this study was to determine whether serum sodium alterations may be independent predictors of the outcome of hospitalized COVID-19 patients. DESIGN AND METHODS: In this observational study, data from 441 laboratory-confirmed COVID-19 patients admitted to a University Hospital were collected. After excluding 61 patients (no serum sodium at admission available, saline solution infusion before sodium assessment, transfer from another hospital), data from 380 patients were analyzed. RESULTS: 274 (72.1%) patients had normonatremia at admission, 87 (22.9%) patients had hyponatremia and 19 (5%) patients had hypernatremia. We found an inverse correlation between serum sodium and IL-6, whereas a direct correlation between serum sodium and PaO2/FiO2 ratio was observed. Patients with hyponatremia had a higher prevalence of non-invasive ventilation and ICU transfer than those with normonatremia or hypernatremia. Hyponatremia was an independent predictor of in-hospital mortality (2.7-fold increase vs normonatremia) and each mEq/L of serum sodium reduction was associated with a 14.4% increased risk of death. CONCLUSIONS: These results suggest that serum sodium at admission may be considered as an early prognostic marker of disease severity in hospitalized COVID-19 patients.

Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study.

Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71-93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. Controlled clinical trials are necessary to establish efficacy of ruxolitinib in COVID-19.