Peri-operative pain management in adults: a multidisciplinary consensus statement from the Association of Anaesthetists and the British Pain Society.

BACKGROUND: Nearly half of adult patients undergoing surgery experience moderate or severe postoperative pain. Inadequate pain management hampers postoperative recovery and function and may be associated with adverse outcomes. This multidisciplinary consensus statement provides principles that might aid postoperative recovery, and which should be applied throughout the entire peri-operative pathway by healthcare professionals, institutions and patients. METHODS: We conducted a directed literature review followed by a four-round modified Delphi process to formulate recommendations for organisations and individuals. RESULTS: We make recommendations for the entire peri-operative period, covering pre-admission; admission; intra-operative; post-anaesthetic care unit; ward; intensive care unit; preparation for discharge; and post-discharge phases of care. We also provide generic principles of peri-operative pain management that clinicians should consider throughout the peri-operative pathway, including: assessing pain to facilitate function; use of multimodal analgesia, including regional anaesthesia; non-pharmacological strategies; safe use of opioids; and use of protocols and training for staff in caring for patients with postoperative pain. CONCLUSIONS: We hope that with attention to these principles and their implementation, outcomes for adult patients having surgery might be improved.

Anaesthesia role in enhanced recovery after surgery: a revolution in care outcomes.

PURPOSE OF REVIEW: Enhanced recovery after surgery (ERAS) has revolutionized care outcomes. The purpose of this review is to provide an overview of how ERAS changed healthcare outcomes. RECENT FINDINGS: Development of multidisciplinary evidence-based ERAS guidelines for specific surgical specialties and systematic implementation of these guidelines resulted in improved healthcare outcomes, reduction in length of stay, reduction in complications and improved survival. The value of audit of the outcomes is essential for implementation and to improve healthcare. Healthcare economics analysis related to the implementation of ERAS showed significant cost savings up to a return to investment ratio of more than seven. SUMMARY: ERAS has revolutionized healthcare by developing evidence-based ERAS guidelines and systematic implementation of these guidelines. Audit of outcomes is essential, not only to improve healthcare but also to significantly save healthcare expenditures.

Oral Pretreatment with Galantamine Effectively Mitigates the Acute Toxicity of a Supralethal Dose of Soman in Cynomolgus Monkeys Posttreated with Conventional Antidotes.

Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible acetylcholinesterase (AChE) inhibitors can serve as adjunct pretreatments against poisoning by organophosphorus compounds, including the nerve agent soman. The present study was designed to determine whether pretreatment with a clinically relevant oral dose of galantamine HBr mitigates the acute toxicity of 4.0×LD50 soman (15.08 µg/kg) in Macaca fascicularis posttreated intramuscularly with the conventional antidotes atropine (0.4 mg/kg), 2-pyridine aldoxime methyl chloride (30 mg/kg), and midazolam (0.32 mg/kg). The pharmacokinetic profile and maximal degree of blood AChE inhibition (∼25%-40%) revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr in these nonhuman primates (NHPs) translate to human-equivalent doses that are within the range used for AD treatment. Subsequent experiments demonstrated that 100% of NHPs pretreated with either dose of galantamine, challenged with soman, and posttreated with conventional antidotes survived 24 hours. By contrast, given the same posttreatments, 0% and 40% of the NHPs pretreated, respectively, with vehicle and pyridostigmine bromide (1.2 mg/kg, oral), a peripherally acting reversible AChE inhibitor approved as pretreatment for military personnel at risk of exposure to soman, survived 24 hours after the challenge. In addition, soman caused extensive neurodegeneration in the hippocampi of saline- or pyridostigmine-pretreated NHPs, but not in the hippocampi of galantamine-pretreated animals. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supralethal doses of soman in NHPs. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a clinically relevant oral dose of galantamine effectively prevents lethality and neuropathology induced by a supralethal dose of the nerve agent soman in Cynomolgus monkeys posttreated with conventional antidotes. These findings are of major significance for the continued development of galantamine as an adjunct pretreatment against nerve agent poisoning.

Guidelines for vulvar and vaginal surgery: Enhanced Recovery After Surgery Society recommendations.

This is the first collaborative Enhanced Recovery After Surgery Society guideline for optimal perioperative care for vulvar and vaginal surgeries. An Embase and PubMed database search of publications was performed. Studies on each topic within the Enhanced Recovery After Surgery vulvar and vaginal outline were selected, with emphasis on meta-analyses, randomized controlled trials, and prospective cohort studies. All studies were reviewed and graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. All recommendations on the Enhanced Recovery After Surgery topics are based on the best available evidence. The level of evidence for each item is presented.

Recommendations for Managing Opioid-Tolerant Surgical Patients within Enhanced Recovery Pathways.

PURPOSE OF REVIEW: One of the consequences of the opioid epidemic is an increase in the number of opioid-tolerant patients. These patients are at higher risk for readmission and longer hospital stays following surgery. Enhanced recovery after surgery (ERAS) pathways can be used as a framework for providing high-quality comprehensive care to patient population. It is estimated that as many as 15% of all surgery patients in the USA are receiving opioids going into surgery. The number of patients on medication maintenance therapy with long-acting opioids such as methadone or partial mu receptor agonists like buprenorphine is rising, which poses a challenge for perioperative healthcare providers. RECENT FINDINGS: Preoperative opioid tolerance is an independent predictor for increased length of hospital stays, high costs, and increased readmission rates following surgery. Given the recent trends, it is likely that more opioid-tolerant patients will require surgery in near future. Enhanced recovery programs can be used to provide a framework for high-quality care to opioid-tolerant patients throughout all phases of the perioperative process. To improve the quality of care of opioid-tolerant patients, we present five general recommendations for clinicians to consider and possibly incorporate into ERAS programs and care protocols. Recommendations include the following: opioid-tolerant patients should not be excluded from ERAS programs; opioid-tolerant patients should be identified preoperatively; programs should establish standard practices for patients on medication maintenance therapy and buprenorphine; opioid-tolerant patients should receive multimodal analgesia perioperatively; and opioid-tolerant patients should receive coordinated follow up after surgery.

Guidelines for postoperative care in cesarean delivery: Enhanced Recovery After Surgery (ERAS) Society recommendations (part 3).

BACKGROUND: This Enhanced Recovery After Surgery Guideline for postoperative care in cesarean delivery will provide best practice, evidenced-based recommendations for postoperative care with primarily a maternal focus. OBJECTIVE: The pathway process for scheduled and unscheduled cesarean delivery for this Enhanced Recovery After Surgery cesarean delivery guideline will consider time from completion of cesarean delivery until maternal hospital discharge. STUDY DESIGN: The literature search (1966-2017) used Embase and PubMed to search medical subject headings that included "Cesarean Section," "Cesarean Delivery," "Cesarean Section Delivery," and all postoperative Enhanced Recovery After Surgery items. Study selection allowed titles and abstracts to be screened by individual reviewers to identify potentially relevant articles. Metaanalyses, systematic reviews, randomized controlled studies, nonrandomized controlled studies, reviews, and case series were considered for each individual topic. Quality assessment and data analyses evaluated the quality of evidence, and recommendations were evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation system as used and described in previous Enhanced Recovery After Surgery Guidelines. RESULTS: The Enhanced Recovery After Surgery cesarean delivery guideline/pathway has created a pathway for postoperative care. Specifics include sham feeding, nausea and vomiting prevention, postoperative analgesia, nutritional care, glucose control, thromboembolism prophylaxis, early mobilization, urinary drainage, and discharge counseling. A number of elements of postoperative care of women who undergo cesarean delivery are recommended, based on the evidence. CONCLUSION: As the Enhanced Recovery After Surgery cesarean delivery pathway (elements/processes) are studied, implemented, audited, evaluated, and optimized by the maternity care teams, there will be an opportunity for focused and optimized areas of care and recommendations to be further enhanced.

The Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist: A Joint Statement by the ERAS® and ERAS® USA Societies.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs are multimodal care pathways designed to minimize the physiological and psychological impact of surgery for patients. Increased compliance with ERAS guidelines is associated with improved patient outcomes across surgical types. As ERAS programs have proliferated, an unintentional effect has been significant variation in how ERAS-related studies are reported in the literature. METHODS: To improve the quality of ERAS reporting, ERAS® USA and the ERAS® Society launched an effort to create an instrument to assist authors in manuscript preparation. Criteria to include were selected by a combination of literature review and expert opinion. The final checklist was refined by group consensus. RESULTS: The Societies present the Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist. The tool contains 20 items including best practices for reporting clinical pathways, compliance auditing, and formatting guidelines. CONCLUSIONS: The RECOvER Checklist is intended to provide a standardized framework for the reporting of ERAS-related studies. The checklist can also assist reviewers in evaluating the quality of ERAS-related manuscripts. Authors are encouraged to include the RECOvER Checklist when submitting ERAS-related studies to peer-reviewed journals.

Guidelines for intraoperative care in cesarean delivery: Enhanced Recovery After Surgery Society Recommendations (Part 2).

The Enhanced Recovery After Surgery Society guideline for intraoperative care in cesarean delivery will provide best practice, evidenced-based, recommendations for intraoperative care, with primarily a maternal focus. The "focused" pathway process for scheduled and unscheduled cesarean delivery for this Enhanced Recovery After Surgery cesarean delivery guideline will consider procedure from the decision to operate (starting with the 30-60 minutes before skin incision) through the surgery. The literature search (1966-2017) used Embase and PubMed to search medical subject headings including "cesarean section," "cesarean section," "cesarean section delivery," and all pre- and intraoperative Enhanced Recovery After Surgery items. Study selection allowed titles and abstracts to be screened by individual reviewers to identify potentially relevant articles. Metaanalyses, systematic reviews, randomized controlled studies, nonrandomized controlled studies, reviews, and case series were considered for each individual topic. Quality assessment and data analyses evaluated the quality of evidence and recommendations were evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation system as used and described in previous Enhanced Recovery After Surgery Society guidelines. The Enhanced Recovery After Surgery cesarean delivery guideline/pathway has created a maternal focused pathway (for scheduled and unscheduled surgery starting from 30-60 minutes before skin incision to maternal discharge) with Enhanced Recovery After Surgery-directed preoperative elements, intraoperative elements, and postoperative elements. Specifics of the intraoperative care included the use of prophylactic antibiotics before the cesarean delivery, appropriate patient warming intraoperatively, blunt expansion of the transverse uterine hysterotomy, skin closure with subcuticular sutures, and delayed cord clamping. A number of specific elements of intraoperative care of women who undergo cesarean delivery are recommended based on the evidence. The Enhanced Recovery After Surgery Society guideline for intraoperative care in cesarean delivery will provide best practice, evidenced-based, recommendations for intraoperative care with primarily a maternal focus. When the cesarean delivery pathway (elements/processes) is studied, implemented, audited, evaluated, and optimized by maternity care teams, this will create an opportunity for the focused and optimized areas of care and recommendations to be further enhanced.

Guidelines for Antenatal and Preoperative care in Cesarean Delivery: Enhanced Recovery After Surgery Society Recommendations (Part 1).

This Enhanced Recovery After Surgery (ERAS) Guideline for perioperative care in cesarean delivery will provide best practice, evidenced-based, recommendations for preoperative, intraoperative, and postoperative phases with, primarily, a maternal focus. The focused pathway process for scheduled and unscheduled cesarean delivery for this ERAS Cesarean Delivery Guideline will consider from the time from decision to operate (starting with the 30-60 minutes before skin incision) to hospital discharge. The literature search (1966-2017) used Embase and PubMed to search medical subject headings that included "Cesarean Section," "Cesarean Section," "Cesarean Section Delivery" and all pre- and intraoperative ERAS items. Study selection allowed titles and abstracts to be screened by individual reviewers to identify potentially relevant articles. Metaanalyses, systematic reviews, randomized controlled studies, nonrandomized controlled studies, reviews, and case series were considered for each individual topic. Quality assessment and data analyses that evaluated the quality of evidence and recommendations were evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation system, as used and described in previous ERAS Guidelines. The ERAS Cesarean Delivery Guideline/Pathway has created a maternal focused pathway (for scheduled and unscheduled surgery starting from 30-60 minutes before skin incision to maternal discharge) with ERAS cesarean delivery consensus recommendations preoperative elements (anesthetic medications, fasting, carbohydrate supplementation, prophylactic antibiotics/skin preparation, ), intraoperative elements (anesthetic management, maternal hypothermia prevention, surgical technique, hysterotomy creation and closure, management of peritoneum, subcutaneous space, and skin closure), perioperative fluid management, and postoperative elements (chewing gum, management of nausea and vomiting, analgesia, timing of food intake, glucose management, antithrombotic prophylaxis, timing of ambulation, urinary management, and timing of maternal and neonate discharge). Limited topics for optimized care and for antenatal education and counselling and the immediate neonatal needs at delivery are discussed. Strong recommendations for element use were given for preoperative (antenatal education and counselling, use of antacids and histamine, H2 receptor antagonists, 2-hour fasting and small meal within 6 hours surgery, antimicrobial prophylaxis and skin preparation/chlorhexidine-alcohol), intraoperative (regional anesthesia, prevention of maternal hypothermia [forced warm air, warmed intravenous fluids, room temperature]), perioperative (fluid management for euvolemia and neonatal immediate care needs that include delayed cord clamping), and postoperative (fluid management to prevent nausea and vomiting, antiemetic use, analgesia with nonsteroidal antiinflammatory drugs/paracetamol, regular diet within 2 hours, tight capillary glucose control, pneumatic compression stocking for venous thromboembolism prophylaxis, immediate removal of urinary catheter). Recommendations against the element use were made for preoperative (maternal sedation, bowel preparation), intraoperative (neonatal oral suctioning or increased inspired oxygen), and postoperative (heparin should not be used routinely venous thromboembolism prophylaxis). Because these ERAS cesarean delivery pathway recommendations (elements/processes) are studied, implemented, audited, evaluated, and optimized by the maternity care teams, this will create an opportunity for the focused and optimized areas of care research with further enhanced care and recommendation.

Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms.

Organophosphorus (OP) insecticides are pest-control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh). Prolonged exposures to levels of OP insecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short- and long-term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure to OP insecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity of OP insecticides. Most of the discussion will be focused on chlorpyrifos, the top-selling OP insecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

Opportunities and Challenges for the Next Phase of Enhanced Recovery After Surgery: A Review.

Importance: Enhanced Recovery After Surgery (ERAS) is a global surgical quality improvement initiative now firmly entrenched within the field of perioperative care. Although ERAS is associated with significant clinical outcome improvements and cost savings in numerous surgical specialties, several opportunities and challenges deserve further discussion. Observations: Uptake and implementation of ERAS Society guidelines, together with ERAS-related research, have increased exponentially since the inception of the ERAS movement. Opportunities to further improve patient outcomes include addressing frailty, optimizing nutrition, prehabilitation, correcting preoperative anemia, and improving uptake of ERAS worldwide, including in low- and middle-income countries. Challenges facing enhanced recovery today include implementation, carbohydrate loading, reversal of neuromuscular blockade, and bowel preparation. The COVID-19 pandemic poses both a challenge and an opportunity for ERAS. Conclusions and Relevance: To date, ERAS has achieved significant benefit for patients and health systems; however, improvements are still needed, particularly in the areas of patient optimization and systematic implementation. During this time of global crisis, the ERAS method of delivering care is required to take surgery and anesthesia to the next level and bring improvements in outcomes to both patients and health systems.

Consensus statement for perioperative care in lumbar spinal fusion: Enhanced Recovery After Surgery (ERAS®) Society recommendations.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) evidence-based protocols for perioperative care have led to improvements in outcomes in numerous surgical areas, through multimodal optimization of patient pathway, reduction of complications, improved patient experience and reduction in the length of stay. ERAS represent a relatively new paradigm in spine surgery. PURPOSE: This multidisciplinary consensus review summarizes the literature and proposes recommendations for the perioperative care of patients undergoing lumbar fusion surgery with an ERAS program. STUDY DESIGN: This is a review article. METHODS: Under the impetus of the ERAS® society, a multidisciplinary guideline development group was constituted by bringing together international experts involved in the practice of ERAS and spine surgery. This group identified 22 ERAS items for lumbar fusion. A systematic search in the English language was performed in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Systematic reviews, randomized controlled trials, and cohort studies were included, and the evidence was graded according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Consensus recommendation was reached by the group after a critical appraisal of the literature. RESULTS: Two hundred fifty-six articles were included to develop the consensus statements for 22 ERAS items; one ERAS item (prehabilitation) was excluded from the final summary due to very poor quality and conflicting evidence in lumbar spinal fusion. From these remaining 21 ERAS items, 28 recommendations were included. All recommendations on ERAS protocol items are based on the best available evidence. These included nine preoperative, eleven intraoperative, and six postoperative recommendations. They span topics from preoperative patient education and nutritional evaluation, intraoperative anesthetic and surgical techniques, and postoperative multimodal analgesic strategies. The level of evidence for the use of each recommendation is presented. CONCLUSION: Based on the best evidence available for each ERAS item within the multidisciplinary perioperative care pathways, the ERAS® Society presents this comprehensive consensus review for perioperative care in lumbar fusion.

Evidence for positive allosteric modulation of cognitive-enhancing effects of nicotine in healthy human subjects.

RATIONALE: Cognitive benefits of nicotinic acetylcholine receptor (nAChR) agonists are well established but have generally been of small magnitude and uncertain clinical significance. A way of raising the effect size may be to facilitate agonist-induced responses by co-administering a nAChR positive allosteric modulator (PAM). OBJECTIVE: The aim was to test whether galantamine, a PAM at several nAChR subtypes, can potentiate the cognitive-enhancing effects of nicotine. METHODS: Twenty-six adult never-smokers were treated, in a double-blind counterbalanced sequence, with nicotine (7 mg/24 h, transdermally) and galantamine (4 mg, p.o.) combined, nicotine alone, galantamine alone, and double placebo. A low dose of galantamine was chosen to minimize acetylcholinesterase inhibition, which was verified in blood assays. In each condition, participants were tested with three cognitive tasks. RESULTS: Nicotine significantly improved reaction time (RT) and signal detection in a visuospatial attention task and the Rapid Visual Information Processing Task. Galantamine did not modulate these effects. A trend toward RT reduction by galantamine correlated with acetylcholinesterase inhibition. In a change detection task, there were no effects of nicotine or galantamine alone on accuracy or RT. However, both drugs combined acted synergistically to reduce RT. This effect was not associated with acetylcholinesterase inhibition. CONCLUSIONS: A pattern consistent with allosteric potentiation of nicotine effects by galantamine was observed on one of six performance measures. This may reflect specific nAChR subtype involvement, or additional pharmacological actions of galantamine may have overshadowed similar interactions on other measures. The finding suggests that allosteric potentiation of nAChR agonist-induced cognitive benefits is possible in principle.

Learning and memory retention deficits in prepubertal guinea pigs prenatally exposed to low levels of the organophosphorus insecticide malathion.

High doses of malathion, an organophosphorus (OP) insecticide ubiquitously used in agriculture, residential settings, and public health programs worldwide, induce a well-defined toxidrome that results from the inhibition of acetylcholinesterase (AChE). However, prenatal exposures to malathion levels that are below the threshold for AChE inhibition have been associated with increased risks of neurodevelopmental disorders, including autism spectrum disorder with intellectual disability comorbidity. The present study tested the hypothesis that prenatal exposures to a non-AChE-inhibiting dose of malathion are causally related to sex-biased cognitive deficits later in life in a precocial species. To this end, pregnant guinea pigs were injected subcutaneously with malathion (20 mg/kg) or vehicle (peanut oil, 0.5 ml/kg) once daily between approximate gestational days 53 and 63. This malathion dose regimen caused no significant AChE inhibition in the brain or blood of dams and offspring and had no significant effect on the postnatal growth of the offspring. Around postnatal day 30, locomotor activity and habituation, a form of non-associative learning, were comparable between malathion- and peanut oil-exposed offspring. However, in the Morris water maze, malathion-exposed offspring presented significant sex-dependent spatial learning deficits in addition to memory impairments. These results are far-reaching as they indicate that: (i) malathion is a developmental neurotoxicant and (ii) AChE inhibition is not an adequate biomarker to derive safety limits of malathion exposures during gestation. Continued studies are necessary to identify the time and dose dependence of the developmental neurotoxicity of malathion and the mechanisms underlying the detrimental effects of this insecticide in the developing brain.

Guidelines for Perioperative Care in Cytoreductive Surgery (CRS) with or without hyperthermic IntraPEritoneal chemotherapy (HIPEC): Enhanced Recovery After Surgery (ERAS®) Society Recommendations - Part II: Postoperative management and special considerations.

BACKGROUND: Enhanced recovery after surgery (ERAS) pathways have been shown to considerably reduce complications, length of stay and costs after most of surgical procedures by standardised application of best evidence-based perioperative care. The aim was to elaborate dedicated recommendations for cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC) in a two-part series of guidelines based on expert consensus. The present part II of the guidelines highlights postoperative management and special considerations. METHODS: The core group assembled a multidisciplinary panel of 24 experts involved in peritoneal surface malignancy surgery representing the fields of general surgery (n = 12), gynaecological surgery (n = 6), and anaesthesia (n = 6). Experts systematically reviewed and summarized the available evidence on 72 identified perioperative care items, following the GRADE (grading of recommendations, assessment, development, evaluation) system. Final consensus (defined as ≥50%, or ≥70% of weak/strong recommendations combined) was reached by a standardised 2-round Delphi process, regarding the strength of recommendations. RESULTS: Response rates were 100% for both Delphi rounds. Quality of evidence was evaluated high, moderate low and very low, for 15 (21%), 26 (36%), 29 (40%) and 2 items, respectively. Consensus was reached for 71/72(98.6%) items. Strong recommendations were defined for 37 items. No consensus could be reached regarding the preemptive use of fresh frozen plasma. CONCLUSION: The present ERAS recommendations for CRS ± HIPEC are based on a standardised expert consensus process providing clinicians with valuable guidance. There is an urgent need to produce high quality studies for CRS ± HIPEC and to prospectively evaluate recommendations in clinical practice.