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BACKGROUND Given that variation exists in health care utilization, expenditure, and medical practice, there is a paucity of data on variation within the practice of anesthesia. The Pediatric Regional Anesthesia Network (PRAN) data lend itself to explore whether different medical practice patterns exist and if there are nerve blocks with more local anesthetic dosing variation than others. The primary aim of this study was to quantify variation in single injection caudal block dosing, and the secondary aim was to explore possible causes for variation (eg, number of blocks performed versus geographic location). METHODS We queried the PRAN database for single injection caudal blocks in children

Cannabinoids, cannabis, and cannabis-based medicines (CBMs) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We summarised efficacy and adverse events (AEs) of these types of drugs for treating pain using randomised controlled trials: in people of any age, with any type of pain, and for any treatment duration. Primary outcomes were 30% and 50% reduction in pain intensity, and AEs. We assessed risk of bias of included studies, and the overall quality of evidence using GRADE. Studies of 7 days treatment duration were analysed separately. We included 36 studies (7217 participants) delivering cannabinoids (8 studies), cannabis (6 studies), and CBM (22 studies); all had high and/or uncertain risk of bias. Evidence of benefit was found for cannabis 7 days (risk difference 0.06, 95% confidence interval 0.01-0.12; 6 trials, 1484 patients, very low-quality evidence). No other beneficial effects were found for other types of cannabinoids, cannabis, or CBM in our primary analyses; 81% of subgroup analyses were negative. Cannabis, nabiximols, and delta-9-tetrahydrocannabinol had more AEs than control. Studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. We have little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.

The President of the International Association for the Study of Pain (IASP) established a Taskforce on Cannabis and Cannabinoid Analgesia, to systematically examine the evidence on (i) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain, (ii) the clinical efficacy of cannabis, cannabinoids and cannabis-based medicines (CBM) for pain, (iii) harms related to long-term use of cannabinoids, as well as (iv) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the Taskforce outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high quality clinical trials with cannabinoids are needed. Important remaining questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal and policy challenges associated with medicinal and non-medicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.

The increase in opioid-related deaths in the United States (and other countries) has prompted a national debate in medicine about the appropriateness of opioids for the treatment of acute and chronic pain, and specifically in children, if medical opioid use causes or increases the risk of opioid use disorder (OUD) later in life. Some in the medical community and in government advocate withholding opioids from children after an arbitrary number of days of treatment, regardless of diagnosis. Here, I argue that opioid experimentation and misuse is no more common in children and adolescents today than 2 or 3 decades ago, that there is no compelling evidence that appropriate medical use of opioids leads to OUD, and that the epidemic of inadequately treated pain in children remains the more compelling issue.

Fewer randomized clinical trials (RCTs) are conducted for chronic or recurrent pain in pediatric populations compared with adult populations; thus, data to support treatment efficacy in children are limited. This article evaluates the design features and reporting practices of RCTs for chronic and recurrent pain that are likely unique to, or particularly important in, a pediatric population to promote improvements in the evidence base for pediatric pain treatments. Areas covered include outcome measure selection and reporting and reporting of adverse events and challenges to recruitment and retention. A search of PubMed and EMBASE identified primary publications describing RCTs of treatments for select chronic and recurrent pain conditions in children or adolescents published between 2000 and 2017. Only 49% of articles identified a primary outcome measure. The primary outcome measure assessed pain intensity in 38% of the trials, specifically measure by verbal rating scale (13%), faces pain scale (11%), visual analogue scale (9%), or numeric rating scale (5%). All of the CONSORT harms reporting recommendations were fulfilled by 10%. The goal of this article is to promote comprehensive reporting of pediatric pain RCTs to improve the design of future trials, facilitate conduction of systematic reviews and meta-analyses, and better inform clinical practice. PERSPECTIVE: This review of chronic and recurrent pediatric pain trials demonstrates inadequacies in the reporting quality of key features specifically important to pediatric populations. It provides recommendations that address these shortcomings to promote continued efforts toward improving the quality of the design and publication of future pediatric clinical pain trials.

This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.

Supplemental Digital Content is Available in the Text. Most patients with childhood-onset complex regional pain syndrome continue to have some complex regional pain syndrome–related pain into young adulthood and have a lower health-related quality of life., Introduction: Complex regional pain syndrome (CRPS) is a neuropathic pain condition of unknown etiology. Little is known of long-term outcomes of young adults who were diagnosed with CRPS as children. Methods: In this study, surveys were mailed to adults who were treated for childhood CRPS at the Lucile Packard Children's Hospital between 1994 and 2018. Completed surveys were analyzed for pain symptoms. Health-related quality-of-life surveys, the Optum SF-8, were analyzed based on norm-based scoring. Results: This study had a 50% response rate. Patients were treated with physical and occupational therapy, peripheral or sympathetic nerve blocks, medication for neuropathic pain, and psychotherapy. Sixty-eight percent of the subjects reported pain. Each 1-year increase in the patient's age at the time of CRPS diagnosis increased the odds of having at least mild pain as an adult by 61% (P = 0.005). Most patients had slightly lower quality-of-life scores than the US population average in both the mental component score (43.4, 95%, confidence interval 3.4) and the physical component score (44.4, 95%, confidence interval 3.3). Conclusions: Young adults in our sample had long-lasting pain symptoms. More than two-thirds of adult patients reported some degree of pain, and these patients had a lower quality of life. Encouraging was that the majority did not have CRPS spreading to other areas, and their pain did not warrant further treatment. Understanding long-term outcomes may lead to risk stratification earlier in the disease to improve future quality of life.

Children and adolescents with chronic pain are best managed by an interdisciplinary team. In cases of complex regional pain syndrome (CRPS), the interdisciplinary team consists of a pain management specialist, such as an anesthesiologist or physiatrist, a physical therapist, an occupational therapist, a pain psychologist, and an orthopaedist. It may also include other professions, such as a gastroenterologist, psychiatrist, nurse practitioner, nutritionist, endocrinologist, acupuncturist, or social worker. Key factors include rapid recognition of CRPS and the initiation of appropriate treatment, both for the pain syndrome as well as for the orthopaedic injury. Intensive therapies have been shown to be effective in treating CRPS in children. Children often are more responsive to noninvasive treatments than adults.

Supplemental Digital Content is Available in the Text., We report a systematic review and meta-analysis of studies that assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference effect size for each comparison and performed a random-effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86%). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective cannabinoid type 1, cannabinoid type 2, nonselective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol) and peroxisome proliferator-activated receptor-alpha agonists (predominantly palmitoylethanolamide) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low; therefore, the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models, and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.

Hip denervation comprising radiofrequency lesioning of the obturator and femoral articular branches is used in adults with refractory hip pain who are not surgical candidates. Persistent hip pain occurs infrequently in pediatric patients, and there are limited data on the safety and efficacy of this procedure in a pediatric population. We provide a case report of a successful ultrasound and fluoroscopic-guided hip denervation procedure in an 11-year-old girl with persistent right hip pain after septic arthritis refractory to conservative and surgical management. At an 18-week follow-up, hip denervation provided improvement in pain, mobility, and reduced opioid consumption by 20%.

Telehealth has emerged as a promising healthcare delivery modality due to its ability to ameliorate traditional access-level barriers to treatment. In response to the onset of the novel coronavirus (COVID-19) pandemic, multidisciplinary pain clinics either rapidly built telehealth infrastructure from the ground up or ramped up existing services. As the use of telehealth increases, it is critical to develop data collection frameworks that guide implementation. This applied review provides a theoretically-based approach to capitalize on existing data sources and collect novel data to inform virtually delivered care in the context of pediatric pain care. Reviewed multisource data are (1) healthcare administrative data; (2) electronic chart review; (3) clinical health registries; and (4) stakeholder feedback. Preliminary telehealth data from an interdisciplinary pediatric chronic pain management clinic (PPMC) serving youth ages 8–17 years are presented to illustrate how relevant implementation outcomes can be extracted from multisource data. Multiple implementation outcomes were assessed, including telehealth adoption rates, patient clinical symptoms, and mixed-method patient-report telehealth satisfaction. This manuscript provides an applied roadmap to leverage existing data sources and incorporate stakeholder feedback to guide the implementation of telehealth in pediatric chronic pain settings through and beyond COVID-19. Strengths and limitations of the modeled data collection approach are discussed within the broader context of implementation science.

Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts-neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on the levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts.

Objective Postdural puncture headache (PDPH) is an uncommon sequel of lumbar puncture in children. When conservative treatment with bed rest, hydration, and caffeine are ineffective, epidural blood patches are recommended and are generally effective. The purpose of this report was to highlight that when lumbar epidural blood patches fail to eliminate PDPH, diagnostic evaluation should be performed and alternative treatment sought. Case Report An unusual case is described of an 11-year-old boy with PDPH, which was successfully managed with a ventral (anterior) epidural blood patch and epidural saline infusion after headache and other symptoms failed to resolve after conservative treatment and conventionally performed blood patches. Conclusions Ineffectiveness of conservative measures and epidural blood patches performed posteriorly to resolve PDPH should lead the physician both to question the diagnosis of PDPH by pursuing radiographic confirmation of a cerebral spinal fluid leak and, furthermore, identification of its location to best direct further therapy.

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.

* Abbreviations: CDC — : Centers for Disease Control and Prevention SUD — : substance use disorder It is impossible to watch broadcast news or read a newspaper without encountering a story of the “opioid epidemic,” an unfortunate phrase used by the Centers for Disease Control and Prevention (CDC)1 from whom “epidemic” carries an emotive connotation. The national interest in the opioid epidemic began when the New England Journal of Medicine,2 followed by other sources,3–7 documented increasing opioid-related deaths in the United States. With media attention (Fig 1) the topic became politicized, later followed by regulations, statutes, and litigation against the pharmaceutical industry in an attempt to solve the “crisis,” while punishing pharmaceutical manufacturers for causing this epidemic. FIGURE 1 The number of media publications using the word “opioid” from May 2008 to May 2018, as reported by Google Trends. Media attention produced many experts, pundits, and politicians who offer simplistic blameworthy origins for the problem (eg, overprescription of opioids, deceptive marketing of opioids, The Joint Commission, and/or an inability of Americans to endure discomfort), as well as simplistic solutions (eg, draconian restriction of prescribing, mandatory use of prescription drug monitoring programs, nonopioid alternatives to opioids, acupuncture, meditation, and/or yoga). Against this background, Chung et al8 have contributed a publication in this journal, “Outpatient Opioid Prescriptions for Children and Opioid-Related Adverse Events.” In this editorial, we will comment on their findings and put them into what we believe is the proper context. But before we do, there are 2 caveats: First is that the authors of this editorial are not champions of opioid use, per se. We know that opioids are associated with many untoward side effects and are potentially lethal. But we believe there is a reason why opioids have been used to treat pain since the Sumerians 5000 years ago: no other analgesics equal in potency and effect have been discovered … Address correspondence to Elliot J. Krane, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Dr, Stanford, CA 94305. E-mail: ekrane{at}stanford.edu

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Complications in pediatric regional anesthesia are rare, so a large sample size is necessary to quantify risk. The Pediatric Regional Anesthesia Network contains data on more than 100,000 blocks administered at more than 20 children’s hospitals. This study analyzed the risk of major complications associated with regional anesthesia in children. Methods This is a prospective, observational study of routine clinical practice. Data were collected on every regional block placed by an anesthesiologist at participating institutions and were uploaded to a secure database. The data were audited at multiple points for accuracy. Results There were no permanent neurologic deficits reported (95% CI, 0 to 0.4:10,000). The risk of transient neurologic deficit was 2.4:10,000 (95% CI, 1.6 to 3.6:10,000) and was not different between peripheral and neuraxial blocks. The risk of severe local anesthetic systemic toxicity was 0.76:10,000 (95% CI, 0.3 to 1.6:10,000); the majority of cases occurred in infants. There was one epidural abscess reported (0.76:10,000, 95% CI, 0 to 4.8:10,000). The incidence of cutaneous infections was 0.5% (53:10,000, 95% CI, 43 to 64:10,000). There were no hematomas associated with neuraxial catheters (95% CI, 0 to 3.5:10,000), but one epidural hematoma occurred with a paravertebral catheter. No additional risk was observed with placing blocks under general anesthesia. The most common adverse events were benign catheter-related failures (4%). Conclusions The data from this study demonstrate a level of safety in pediatric regional anesthesia that is comparable to adult practice and confirms the safety of placing blocks under general anesthesia in children.

Background and Objectives Some topics in the clinical management of regional anesthesia in children remain controversial. To evaluate and come to a consensus regarding some of these topics, The European Society of Regional Anaesthesia and Pain Therapy (ESRA) and the American Society of Regional Anesthesia and Pain Medicine (ASRA) developed a joint committee practice advisory on pediatric regional anesthesia (PRA). Methods Representatives from both ASRA and ESRA comprised the joint committee practice advisory on PRA. Evidence-based recommendations were based on a systematic search of the literature. In cases where no literature was available, expert opinion was elicited. Experts selected controversial topics in PRA. Results The performance of PRA under general anesthesia or deep sedation is associated with acceptable safety and should be viewed as the standard of care (Evidence B2 and Evidence B3). Because of the difficulty interpreting a negative test dose, the use of test dosing should remain discretionary (Evidence B4). The use of either air–loss of resistance or saline–loss of resistance techniques is supported by expert opinion, but the literature supporting one technique over the other is sparse and controversial; when used appropriately, each technique may be safely used in children. There are no current evidence-based data that the use of RA increases the risk for acute compartment syndrome or delays its diagnosis in children. Conclusions High-level evidence is not yet available for the topics evaluated, and most recommendations are based on Evidence B studies. The ESRA/ASRA recommendations intend to provide guidance for the safe practice of regional anesthesia in children.

It is increasingly common for children with mitochondrial disease to undergo surgery and anesthesia. Although many different anesthetics have been used successfully for these patients, serious, unexpected complications have occurred during and following anesthetic exposure. This has led to the widespread opinion among anesthesiologists that mitochondrial patients are at increased risk from the stress of surgery and anesthesia. Defects in function of the mitochondrial electron transport chain can lead to striking hypersensitivity to volatile anesthetics in children. Despite this striking finding, the connection between mitochondrial function and response to anesthetics is unknown. We review here the anesthetic considerations for patients with mitochondrial defects. In addition, we present an approach to anesthetic care of these patients at our institutions.

Background Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents. As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can occur in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) relating to genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and for other unknown reasons. Antiepileptic (anticonvulsant) drugs, which were originally developed to treat convulsions in people with epilepsy, have in recent years been used to provide pain relief in adults for many chronic painful conditions and are now recommended for the treatment of chronic pain in the WHO list of essential medicines. Known side effects of antiepileptic drugs range from sweating, headache, elevated temperature, nausea, and abdominal pain to more serious effects including mental or motor function impairment. Objectives To assess the analgesic efficacy and adverse events of antiepileptic drugs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews as well as online clinical trial registries. Selection criteria Randomised controlled trials, with or without blinding, by any route, treating chronic non-cancer pain in children and adolescents, comparing any antiepileptic drug with placebo or an active comparator. Data collection and analysis Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods if data were available. We assessed the evidence using GRADE and created two 'Summary of findings' tables. Main results We included two studies with a total of 141 participants (aged 7 to 18 years) with chronic neuropathic pain, complex regional pain syndrome type 1 (CRPS-I), or fibromyalgia. One study investigated pregabalin versus placebo in participants with fibromyalgia (107 participants), and the other study investigated gabapentin versus amitriptyline in participants with CRPS-I or neuropathic pain (34 participants). We were unable to perform any quantitative analysis. Risk of bias for the two included studies varied, due to issues with randomisation (low to unclear risk), blinding of outcome assessors (low to unclear risk), reporting bias (low to unclear risk), the size of the study populations (high risk), and industry funding in the 'other' domain (low to unclear risk). We judged the remaining domains of sequence generation, blinding of participants and personnel, and attrition as low risk of bias. Primary outcomes One study (gabapentin 900 mg/day versus amitriptyline 10 mg/day, 34 participants, for 6 weeks) did not report our primary outcomes (very low-quality evidence). The second study (pregabalin 75 to 450 mg/day versus placebo 75 to 450 mg/day, 107 participants, for 15 weeks) reported no significant change in pain scores for pain relief of 30% or greater between pregabalin 18/54 (33.3%), and placebo 16/51 (31.4%), P = 0.83 (very low-quality evidence). This study also reported Patient Global Impression of Change, with the percentage of participants feeling "much or very much improved" with pregabalin 53.1%, and placebo 29.5% (very low-quality evidence). We downgraded the evidence by three levels to very low for one of two reasons: due to the fact that there was no evidence to support or refute the use of the intervention, or that there were too few data and the number of events was too small to be meaningful. Secondary outcomes In one small study, adverse events were uncommon: gabapentin 2 participants (2 adverse events); amitriptyline 1 participant (1 adverse event) (6-week trial). The second study reported a higher number of adverse events: pregabalin 38 participants (167 adverse events); placebo 34 participants (132 adverse events) (15-week trial) (very low-quality evidence). Withdrawals due to adverse events were infrequent in both studies: pregabalin (4 participants), placebo (4 participants), gabapentin (2 participants), and amitriptyline (1 participant) (very low-quality evidence). Serious adverse events were reported in both studies. One study reported only one serious adverse event (cholelithiasis and major depression resulting in hospitalisation in the pregabalin group) and the other study reported no serious adverse events (very low-quality evidence). There were few or no data for our remaining secondary outcomes (very low-quality evidence). We downgraded the evidence by three levels to very low due to too few data and the fact that the number of events was too small to be meaningful. Authors' conclusions This review identified only two small studies, with insufficient data for analysis. As we could undertake no meta-analysis, we were unable to comment about efficacy or harm from the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents. Similarly, we could not comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life. We know from adult randomised controlled trials that some antiepileptics, such as gabapentin and pregabalin, can be effective in certain chronic pain conditions. We found no evidence to support or refute the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents.

Background Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.Opioids are used worldwide for the treatment of pain. They bind to opioid receptors in the central nervous system (mu, kappa, delta, and sigma) and can be agonists, antagonists, mixed agonist-antagonists, or partial agonists. Opioids are generally available in healthcare settings across most high-income countries, but access may be restricted in low- and middle-income countries. For example, opioids currently available in the UK include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are used in varying doses (generally based on body weight for paediatric patients) by means of parenteral, transmucosal, transdermal, or oral administration (immediate release or modified release). To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is a lower dose gradually titrated to effect in the child. Objectives To assess the analgesic efficacy and adverse events of opioids used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. Selection criteria Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing opioids with placebo or an active comparator. Data collection and analysis Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. Main results No studies were eligible for inclusion in this review. We rated the quality of the evidence as very low. We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome. Authors' conclusions There was no evidence from randomised controlled trials to support or refute the use of opioids to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of opioids to treat chronic non-cancer pain in children and adolescents.We know from adult randomised controlled trials that some opioids, such as morphine and codeine, can be effective in certain chronic pain conditions.This means that no conclusions could be made about efficacy or harm in the use of opioids to treat chronic non-cancer pain in children and adolescents.

We describe an instance in which complete paraplegia was evident immediately postoperatively after apparently uneventful lumbar epidural-general anesthesia in a patient with Morquio Type A syndrome (Morquio A) with moderate thoracic spinal stenosis.A 16-yr-old male with Morquio A received lumbar epidural-general anesthesia for bilateral distal femoral osteotomies. Preoperative imaging had revealed a stable cervical spine and moderate thoracic spinal stenosis with a mild degree of spinal cord compression. Systolic blood pressure (BP) was maintained within 20% of the pre-anesthetic baseline value. The patient sustained a severe thoracic spinal cord infarction. The epidural anesthetic contributed to considerable delay in the recognition of the diagnosis of paraplegia.This experience leads us to suggest that, in patients with Morquio A, it may be prudent to avoid the use of epidural anesthesia without very firm indication, to support BP at or near baseline levels in the presence of even moderate spinal stenosis, and to avoid flexion or extension of the spinal column in intraoperative positioning. If the spinal cord/column status is unknown or if the patient is known to have any degree of spinal stenosis, we suggest that the same rigorous BP support practices that are typically applied in other patients with severe spinal stenosis, especially stenosis with myelomalacia, should apply to patients with Morquio A and that spinal cord neurophysiological monitoring should be employed. In the event that cord imaging is not available, e.g., emergency procedures, it would be prudent to assume the presence of spinal stenosis.

Current approaches to classification of chronic pain conditions suffer from the absence of a systematically implemented and evidence-based taxonomy. Moreover, existing diagnostic approaches typically fail to incorporate available knowledge regarding the biopsychosocial mechanisms contributing to pain conditions. To address these gaps, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration and the American Pain Society (APS) have joined together to develop an evidence-based chronic pain classification system called the ACTTION-APS Pain Taxonomy. This paper describes the outcome of an ACTTION-APS consensus meeting, at which experts agreed on a structure for this new taxonomy of chronic pain conditions. Several major issues around which discussion revolved are presented and summarized, and the structure of the taxonomy is presented. ACTTION-APS Pain Taxonomy will include the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. In coming months, expert working groups will apply this taxonomy to clusters of chronic pain conditions, thereby developing a set of diagnostic criteria that have been consistently and systematically implemented across nearly all common chronic pain conditions. It is anticipated that the availability of this evidence-based and mechanistic approach to pain classification will be of substantial benefit to chronic pain research and treatment. Perspective The ACTTION-APS Pain Taxonomy is an evidence-based chronic pain classification system designed to classify chronic pain along the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.

Background and Objectives The impact of the patient state at time of placement of regional blocks on the risk of complications is unknown. Current opinion is based almost entirely on case reports, despite considerable interest in the question. Analyzing more than 50,000 pediatric regional anesthesia blocks from an observational prospective database, we determined the rate of adverse events in relation to the patient’s state at the time of block placement. Primary outcomes considered were postoperative neurologic symptoms (PONSs) and local anesthetic systemic toxicity (LAST). Secondary outcome was extended hospital stay due to a block complication. Methods The Pediatric Regional Anesthesia Network is a multi-institutional research consortium that was created with an emphasis on rigorous, prospective, and complete data collection including a data validation and audit process. For the purpose of the analysis, blocks were divided in major groups by single injection versus continuous and by block location. Rates were determined in aggregate for these groups and classified further based on the patient’s state (general anesthesia [GA] without neuromuscular blockade [NMB], GA with NMB, sedated, and awake) at the time of block placement. Results Postoperative neurological symptoms occurred at a rate of 0.93/1000 (confidence interval [CI], 0.7–1.2) under GA and 6.82/1000 (CI, 4.2–10.5) in sedated and awake patients. The only occurrence of PONSs lasting longer than 6 months (PONSs-L) was a small sensory deficit in a sedated patient (0.019/1000 [CI, 0–0.1] for all, 0.48/1000 [CI, 0.1–2.7] for sedated patients). There were no cases of paralysis. There were 5 cases of LAST or 0.09/1000 (CI, 0.03–0.21). The incidence of LAST in patients under GA (both with and without NMB) was 0.08/1000 (CI, 0.02–0.2) and 0.34/1000 (CI, 0–1.9) in awake/sedated patients. Extended hospital stays were described 18 times (0.33/1000 [CI, 0.2–0.53]). The rate for patients under GA without NMB was 0.29/1000 (CI, 0.13–0.48); GA with NMB, 0.29/1000 (CI, 0.06–0.84); sedated, 1.47/1000 (CI, 0.3–4.3); and awake, 1.15/1000 (CI, 0.02–6.4). Conclusions The placement of regional anesthetic blocks in pediatric patients under GA is as safe as placement in sedated and awake children. Our results provide the first prospective evidence for the pediatric anesthesia community that the practice of placing blocks in anesthetized patients should be considered safe and should remain the prevailing standard of care. Prohibitive recommendations based on anecdote and case reports cannot be supported.

Background and Objectives A practice advisory on regional anesthesia in children in 2008, published in this journal, supported the placement of regional blocks in children under general anesthesia (GA). Interscalene brachial plexus (IS) blocks were specifically excluded, based on case reports (level 3 evidence) of injury, which occurred predominantly in heavily sedated or anesthetized adult patients. Apart from case reports, there is a paucity of data that explore the safety of IS blocks placed in patients under GA, and the level of evidence available on which to base recommendations is limited. Methods Querying the database of the Pediatric Regional Anesthesia Network (PRAN), we report on the incidence of postoperative neurological symptoms, local anesthetic systemic toxicity, and other reported adverse events in children receiving IS blocks under GA or sedated. Results A total of 518 interscalene blocks were performed, 390 under GA and 123 with the patient sedated or awake (5 cases had missing status); 472 of these were single injection, and 46 involved the placement of infusion catheters. Eighty-eight percent of blocks were placed with ultrasound guidance, 7.7% with no location device, and 2.5% with a nerve stimulator. No local anesthetic systemic toxicity, postoperative neurological symptoms, cardiovascular complications, or dural puncture was reported in this cohort. There were 1 vascular puncture and 1 postoperative infection. These negative results are compatible with 0 to 7.7/1000 events for each of these complications for IS blocks placed under GA. There was no paralysis, motor block, or sensory deficit beyond the expected block duration time. Conclusions Analyzing interscalene blocks in children placed under GA, we identified no serious adverse events. The upper limit of the confidence interval for these events is similar to that in awake or sedated adults receiving IS blocks. Based on these prospectively collected data, placement of IS blocks under GA in children is no less safe than placement in awake adults, calling into question the American Society of Regional Anesthesia and Pain Medicine advisory proscribing GA during IS block in pediatric patients.

Supplemental Digital Content is Available in the Text., Pain is an experience that affects many people worldwide and is associated with higher mortality and lower quality of life. Cannabinoid, cannabis, and cannabis-based medicines (CBMs) are thought to reduce pain, but a proliferation of different products has led to variability in trials, creating a challenge when determining the assessment of efficacy in systematic reviews. We will conduct 2 systematic reviews commissioned by the International Association for the Study of Pain Task Force on the use of cannabinoids, cannabis, and CBMs for pain management: first, an overview review of systematic reviews to summarise the evidence base and second, a systematic review of randomised controlled trials of cannabinoids, cannabis, and CBMs. In these reviews we will determine the harm and benefit of CBM from the current literature and will interpret the findings in light of the quality of evidence and reviews included. We will search online databases and registries in any language for systematic reviews and randomised controlled trials. We will include studies that evaluate any cannabinoid or CBM vs any control for people with acute and chronic pain. Our primary outcomes for both reviews are the number of participants achieving (1) a 30% and (2) 50% reduction in pain intensity, (3) moderate improvement, and (4) substantial improvement. A number of secondary outcome measures will also be included. We will assess risk of bias and quality of evidence. We will analyse data using fixed and random effect models, with separate comparators for cannabis and CBMs. Prospero ID (CRD42019124710; CRD42019124714).

The DØ experiment enjoyed a very successful data-collection run at the Fermilab Tevatron collider between 1992 and 1996. Since then, the detector has been upgraded to take advantage of improvements to the Tevatron and to enhance its physics capabilities. We describe the new elements of the detector, including the silicon microstrip tracker, central fiber tracker, solenoidal magnet, preshower detectors, forward muon detector, and forward proton detector. The uranium/liquid-argon calorimeters and central muon detector, remaining from Run I, are discussed briefly. We also present the associated electronics, triggering, and data acquisition systems, along with the design and implementation of software specific to DØ. © 2006 Elsevier B.V. All rights reserved.

Neuropathic pain is relatively uncommon in children. Although some syndromes closely resemble those found in adults, the incidence and course of the condition can vary substantially in children, depending on developmental status and contextual factors. There are some neuropathic pain syndromes that are rare and relatively unique to the pediatric population. This article discusses the array of neuropathic pain conditions in children and available treatment strategies. Data are limited by small numbers and few randomized controlled trials. Research and clinical implications are discussed.

BACKGROUND: Difficulty assessing pain has been cited as one of the primary reasons for infrequent and inadequate assessment and analgesia for children with cognitive impairment (CI). Several behavioral observational pain tools have been shown to have good psychometric properties for pain assessment in this population; however, routine clinical use may depend largely on their pragmatic qualities. We designed this study to evaluate pragmatic attributes or clinical utility properties of three recently developed pain assessment tools for children with CI. METHODS: A sample of clinicians from three medical centers were asked to review 15 videotaped observations of children with CI, recorded during their first three postoperative days during participation in a previous study. Participants scored pain using the revised-Face, Legs, Activity, Cry, Consolability (r-FLACC) tool (individualized for the child during the previous study) for five observations, the noncommunicative Non-Communicating Children’s Pain Checklist-Postoperative Version (NCCPC-PV) for five, and the Nursing Assessment of Pain Intensity (NAPI) for five observations. After their review of all segments, participants completed the Clinical Utility Attributes Questionnaire (CUAQ) ranking three attributes of clinical utility; complexity, compatibility, and relative advantage. RESULTS: Five physicians and 15 nurses comprised the sample. There was excellent agreement between the coded pain scores (i.e., mild, moderate, severe pain) assigned using all tools and r-FLACC scores assigned by original observers (88%–98% exact agreement; 0.71–0.96). The internal consistency or reliability of the CUAQ was supported by high values for each of the subscales ( 0.84–0.93). Subscale and total CUAQ scores were higher for the r-FLACC and NAPI compared with the NCCPC-PV. The r-FLACC had similar scores for complexity, but slightly higher scores for compatibility, relative advantage, and total utility compared with the NAPI. CONCLUSIONS: We found that clinicians rated the complexity, compatibility, relative advantage, and overall clinical utility higher for the r-FLACC and NAPI compared with the NCCPC-PV, suggesting that these tools may be more readily adopted into clinical practice. (Anesth Analg 2008;106:72‐8)

In the last 25 years there has been an increase in the use of regional blocks in children. This is due to several converging factors: a better knowledge of the pharmacology of local anesthetic agents in the child, the availability of equipment adapted for children’s anatomy, the recognition of the remarkable hemodynamic stability of the young child during an neuraxial block, as well as the recognition of the need to treat pain not just in the operative period, but in the postoperative period of time as well. The safety of performing regional anesthetic blocks in children depends on the practitioner’s recognition of three important differences between adults and children: (1) their frequent inability to allow the performance of a regional anesthetic block unless under general anesthesia (which is a subject of controversy that is beyond the scope of this review), (2) the anatomic differences between adults and children, and (3) the pharmacologic/pharmacodynamic differences between adults and children. The purpose of this review is to examine the pharmacology of the local anesthetic agents commonly used in children.

An ideal taxonomy of chronic pain would be applicable to people of all ages. Developmental sciences focus on lifespan developmental approaches, and view the trajectory of processes in the life course from birth to death. In this article we provide a review of lifespan developmental models, describe normal developmental processes that affect pain processing, and identify deviations from those processes that lead to stable individual differences of clinical interest, specifically the development of chronic pain syndromes. The goals of this review were 1) to unify what are currently separate purviews of “pediatric pain,” “adult pain,” and “geriatric pain,” and 2) to generate models so that specific elements of the chronic pain taxonomy might include important developmental considerations. Perspective A lifespan developmental model is applied to the forthcoming Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks—American Pain Society Pain Taxonomy to ascertain the degree to which general “adult” descriptions apply to pediatric and geriatric populations, or if age- or development-related considerations need to be invoked.

Dear Editor, The following letter describes two pilot studies testing the feasibility of immersive virtual reality therapy on pediatric patients with unilateral lower limb complex regional pain syndrome (CRPS). In these studies, patients completed target-hitting tasks in virtual reality using novel avatar bodies. Patients completed all sessions without adverse effects and both patients and parents were enthusiastic about the treatment. We discuss how function was tracked within and across sessions, and next steps. Because virtual reality (VR) replaces sensory information from the physical world, users may partially replace their sense of presence in the physical world, or in their physical body. This quality of presence was first used to treat pain using distraction ⇓ and has also been used to produce relaxation or increased engagement (e.g., in physical therapy). A second quality that may be utilized in pain treatment is flexibility: the ability to change the relationship between a participant's appearance and/or actions in the physical world, and the appearance and actions that this participant perceives virtually ⇓. Leveraging the flexibility of virtual reality allows the creation of avatars whose movements differ from that of the participants' own, allowing more radical interventions than mirroring the unaffected limb. Following Lanier's concept of homuncular flexibility ⇓, researchers have demonstrated that users can learn to identify with avatars that have very different bodies ⇓ and learn to control these avatars very rapidly ⇓. We propose that using such novel bodies may also be therapeutic for pain. Four patients with pediatric CRPS, confirmed by Budapest Criteria ⇓, were enrolled in this study, after institutional review board (IRB) approval, consent, and assent. All patients were receiving concurrent multidisciplinary therapy including physical and occupational therapy, psychological support, and medical visits. All therapies, including medications, were kept constant throughout the study …

Rosenfeld et al in their recent article "Office Insertion of Tympanostomy Tubes without Anesthesia in Young Children" describe using a "papoose board for restraint" while performing a procedure resulting in severe pain for a significant number of children: a myringotomy and tube insertion. In 2016, it is inappropriate to perform elective painful procedures in children without treatment to avoid or minimize pain. We strongly disagree with the authors' conclusion "that office insertion of tubes in young children is a feasible alternative to general anesthesia for caregivers and clinicians who are comfortable with this choice."

A premature newborn infant is being treated in a neonatal intensive care unit, quite ill and subject to an array of invasive procedures. We wish to do all we can to minimize that individual’s suffering. Which analgesics may be effective? Are they safe? Are they metabolized by the youngest of human beings in a predictable way? Clearly, to answer these questions it is necessary to conduct clinical trials on children within this population. But is it ethical? Is it feasible? That is the tension experienced by pediatric practitioners who wish to invoke evidence to ease children’s pain in a safe and effective manner. The magnitude of the problem may be appreciated when one examines the epidemiology of pain in children. A prospective study conducted in neonatal intensive care settings showed that over the first 14 days of admission, each premature infant experienced a median of 75 (range: 3–364) painful procedures and ten (range: 0–51) painful procedures per day of hospitalization. Among the total of 42,413 painful procedures observed, newborns were provided with pharmacologic therapy specifically targeting the procedural pain only 2.1% of the time [1]. This study, and others in the field, tells us little about other, more ongoing pain in neonates, such as disease-related and postoperative pain. Of course, beyond the neonatal period, infants and children commonly experience acute pain due to surgery or injuries. In addition to acute pain, 5–23% of school-age children experience significant recurrent pain, such as headache, chest pain, abdominal pain and limb pain [2–4]. Children also endure chronic daily pain from headache disorders, neurodegenerative diseases, inflammatory and autoimmune disease, post-traumatic neuropathic pain conditions including complex regional pain syndrome, small fiber neuropathies and pain due to malignancies and other life-limiting diseases.

Purpose: Human and animal studies have shown that filling, contraction and emptying produce cyclical changes in bladder blood flow. The mechanism of these hemodynamic changes remains unclear. We studied the regulation of bladder blood flow in the rabbit model.Materials and Methods: A total of 18 male New Zealand White rabbits were anesthetized. Arterial pressure, intravesical pressure, and dome and base blood flow were measured simultaneously in the empty bladder, at 25 and 50 ml. intravesical volume, and after draining. These measurements were recorded before and then after intravenous administration of atropine, phentolamine, propranolol, L-arginine or N-nitro-L-arginine. Changes in dome and base microcirculation resistance, and blood flow after treatment were compared with those recorded before treatment.Results: In the empty bladder dome microcirculation resistance was greater than at the base and base blood flow was greater than at the dome. Filling increased dome microcirculation resistance,...

Little debate exists regarding the effectiveness of regional anesthesia in improving surgical outcomes and providing pain management for patients after surgery, trauma, or for certain medical illnesses. There is also little debate regarding the desirability of extending these benefits to patients in the pediatric age range. However, contention arises regarding the safety of such an extrapolation, particularly when one contemplates performing certain regional anesthetics on children rendered pharmacologically unconscious to overcome their fear and lack of voluntary cooperation. Here we will review the ethical issues that surround this consideration. Copyright 2002, Elsevier Science (USA). All rights reserved.

Molecular testing of routinely available thyroid nodule fine needle aspiration (FNA) material has many advantages. Recently, we described the molecular testing of air-dried smears. Now, we performed molecular testing on liquid based FNA material and analyzed the remaining CytoLyt-FNA material for BRAF, RAS, RET/PTC and PAX8/PPARG mutations. Thyroid FNAs were classified according to the Bethesda System for Reporting Thyroid Cytopathology after routine cytological examination. The remaining material from all available cases was used for blinded analysis of BRAF, NRAS, HRAS, KRAS point mutations and RET/PTC and PAX8/PPARG rearrangements by high resolution melting PCR/pyrosequencing, and qPCR, respectively. A total of 597 consecutive cases were collected and stored at 8 °C for up to 6 months. Molecular analysis was possible for 391 cases. Higher volumes of remaining material (> 2 ml) were associated with higher diagnostic success rates (23% vs. 79%, p < 0.001, chi-squared test). Mutations and rearrangements were detected in 11.5% of atypias of undetermined significance, 33% suspicious cases, 47.1% malignant cases, 7.1% follicular neoplasms, 9.3% benign cases, and 2.5% non-diagnostic (molecular analysis possible for 63.2%) samples. Compared to histology (available for 211 samples), cytology and molecular analysis increased sensitivity, specificity, PPV, and NPV compared to cytology alone to 86.7%, 98.1%, 98.7%, and 81.5%, respectively, considering 13 mutation-positive but histologically benign cases as true positives. Mutational analysis is feasible on residual ThinPrep material and has the advantage of not requiring additional FNA procedures or dedicated passes, special preservation, or storage. Its reflex use can be valuable in the preoperative determination of the extent of surgery for mutation-positive cases, help to clarify 12% of AUS cases, decrease the rate of false negatives for benign cases, and allow molecular diagnostics for 63.2% of the non-diagnostic samples.

Although former preterm birth infants are at risk for postoperative apnea after surgery, it is unclear whether the same is true of full-term birth infants. We evaluated the incidence of apnea in 60 full-term neonates and infants undergoing pyloromyotomy both before and after anesthesia. All subjects were randomized to a remifentanil- or halothane-based anesthetic. Apnea was defined by the presence of prolonged apnea (>15 s) or frequent brief apnea, as observed on the pneumocardiogram. Apnea occurred before surgery in 27% of subjects and after surgery in 16% of subjects, with no significant difference between subjects randomized to remifentanil or halothane anesthesia. This apnea was primarily central in origin, occurred throughout the recording epochs, and was associated with severe desaturation in some instances. Of the subjects with normal preoperative pneumocardiograms, new onset postoperative apnea occurred in 3 (23%) of 13 subjects who received halothane-based anesthetics versus 0 (0%) of 22 subjects who received remifentanil-based anesthetics (P = 0.04). Thus, postoperative apnea can follow anesthesia in otherwise healthy full-term infants after pyloromyotomy and is occasionally severe with desaturation. New-onset postoperative apnea was not seen with a remifentanil-based anesthetic.

Pyloric stenosis is sometimes associated with hemodynamic instability and postoperative apnea. In this multicenter study we examined the hemodynamic response and recovery profile of remifentanil and compared it with that of halothane in infants undergoing pyloromyotomy. After atropine, propofol, and succinylcholine administration and tracheal intubation, patients were randomized (2:1 ratio) to receive either remifentanil with nitrous oxide and oxygen or halothane with nitrous oxide and oxygen as the maintenance anesthetic. Pre- and postoperative pneumograms were done and evaluated by an observer blinded to the study. Intraoperative hemodynamic data and postanesthesia care unit (PACU) discharge times, PACU recovery scores, pain medications, and adverse events (vomiting, bradycardia, dysrhythmia, and hypoxemia) were recorded by the study's research nurse. There were no significant differences in patient age or weight between the two groups. There were no significant differences in hemodynamic values between the two groups at the various intraoperative stress points. The extubation times, PACU discharge times, pain medications, and adverse events were similar for both groups. No patient anesthetized with remifentanil who had a normal preoperative pneumogram had an abnormal postoperative pneumogram, whereas three patients with a normal preoperative pneumogram who were anesthetized with halothane had abnormal pneumograms after.The use of ultra-short-acting opioids may be an appropriate technique for infants less than 2 mo old when tracheal extubation after surgery is anticipated.

Purpose: Autopsy studies performed in men older than 80 years old have demonstrated that 90% have histological evidence of benign prostatic hyperplasia. Despite this fact pressure flow studies in men of this age who are referred for the evaluation of lower urinary tract symptoms have shown that only 40% have evidence of bladder outlet obstruction. To our knowledge the specific features of benign prostatic hyperplasia responsible for bladder outlet obstruction are not known. To investigate the possible etiological factors responsible for bladder outlet obstruction we determined whether chronic ischemia alters the structural and functional properties of the prostate.Materials and Methods: Male New Zealand White rabbits weighing 3.5 to 4 kg. were divided into a chronic prostate ischemia (12), hypercholesterolemia (8) and age matched control (8) group. The chronic prostate ischemia group underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet, the hypercholesterolemia g...

Isoprostane 8-epi PGF2alpha is a product of oxidative stress that causes potent smooth muscle contraction. Its production increases in conditions associated with oxidative stress such as in diabetes, smoking, and aging. The aim was to study whether the urinary bladder synthesizes isoprostane 8-epi PGF2alpha and releases to the urine and whether isoprostane 8-epi PGF2alpha causes bladder smooth muscle contraction. Urine samples were obtained transurethrally from 12 male New Zealand white rabbits for measurement of isoprostane 8-epi PGF2alpha levels. To examine whether bladder synthesizes isoprostane 8-epi PGF2alpha, both ureters were ligated, then the bladder was washed 5 times by filling and emptying with normal saline. Bladder was refilled with normal saline, and at 5 minutes a bladder washout sample was taken. After this, the bladder was contracted by nerve stimulation periodically for 30 minutes, and then another washout sample was taken. Strips of bladder tissues were processed for study of isoprostane 8-epi PGF2alpha production in tissue culture chambers and for isometric tension measurements in the organ bath. Enzyme immunoassay (EIA) revealed a remarkable amount of isoprostane 8-epi PGF2alpha in the rabbit urine. EIA of washout samples showed that the bladder synthesizes isoprostane 8-epi PGF2alpha and its production increases with nerve stimulation-induced contractions. EIA of samples from the tissue culture media showed that bladder strips synthesize isoprostane 8-epi PGF2alpha in vitro. Electrical field stimulation (EFS) significantly increased the synthesis and release of isoprostane 8-epi PGF2alpha by the bladder strips. In the organ bath, isoprostane 8-epi PGF2alpha caused concentration-dependent contraction of bladder tissue. While the threshold contraction required smaller concentration of isoprostane 8-epi PGF2alpha (3 nmol) than carbachol (10 nmol), the amplitude of contraction to carbachol was greater than isoprostane 8-epi PGF2alpha. Our studies show that the rabbit bladder synthesizes isoprostane 8-epi PGF2alpha and releases it to the urine. Production of isoprostane 8-epi PGF2alpha in the bladder increases with nerve stimulation-induced contraction. Exogenous isoprostane 8-epi PGF2alpha causes significant bladder smooth muscle contraction. Our findings necessitate further studies to evaluate the possible role of oxidative stress and increased isoprostane 8-epi PGF2alpha production in bladder dysfunction. Neurourol. Urodynam. 19:43-51, 2000.

Axial penile buckling forces vs Rigiscan™ radial rigidity as a function of intracavernosal pressure: why Rigiscan does not predict functional erections in individual patients

Purpose:: Our aim was to study the effect of chronic ischemia on bladder contraction and detrusor smooth muscle reactivity. The relationship between structural damage and functional changes in the chronically ischemic bladder was also investigated.Material and Methods:: Male New Zealand White rabbits were divided into arterial injury (AI), hypercholesterolemia (Hch) and control groups. The AI group (n = 18) underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet. The Hch group (n = 8) received a 0.5% cholesterol diet alone. The control group (n = 8) received a regular diet. After 16 weeks, iliac artery and bladder wall blood flows were recorded. Cystometrograms and arteriography were obtained and bladder tissues were processed for isometric tension measurement in the organ bath and for histological evaluation.Results:: At 16 weeks, blood flow through the iliac arteries was significantly reduced in the AI group compared with the Hch and control groups. In the AI grou...

The pleotropic cytokine TGF-beta1 which induces connective tissue synthesis, and inhibits the growth of smooth muscle cells, has been implicated in corpus cavernosum fibrosis. The objective of this study was to determine the dose and time dependence of TGF-beta1 as an active agent in penile corporal fibrosis in an animal model.A time release method of delivery was developed using sodium alginate microspheres containing recombinant human (rh) TGF-beta1. New Zealand White rabbits were injected intracorporally with a single alginate microsphere either with or without rh-TGF-beta1. Dosage was varied from 325 to 1500 ng./bead. Animals were sacrificed at either three or five days post injection and the penises removed en bloc, examined, and processed for quantitative histomorphometric analysis, staining the sections with Masson's trichrome.Alginate microspheres containing [125I]-rh-TGF-beta1 showed slow-release kinetics (t1/2 = 10.5 hours). Histomorphometric analysis of 60 sets of high powered fields/treatment/ animal showed dose dependent decreases in percentage of corporal smooth muscle with TGF-beta1 treatment (750 to 1500 ng./bead). Placebo (alginate microspheres alone) had trabecular smooth muscle content comparable to values previously reported for untreated rabbit corpus cavernosum.This study confirms that TGF-beta1 induces fibrosis in situ by altering connective tissue synthesis and hence the structure of the corpus cavernosum. Injection of rh-TGF-beta1 impregnated alginate microspheres into the corpus cavernosum resulted in dose-dependent decreases in percentage of corporal smooth muscle.

Objectives To project the likely worldwide increase in the prevalence of erectile dysfunction (ED) over the next 25 years, and to identify and discuss some possible health-policy consequences using the recent developments in the UK as a case study. Methods Using the United Nations projected male population distributions by quinquennial age groups for 2025, the prevalence rates for ED were applied from the Massachusetts Male Aging Study (MMAS) to calculate the likely incidence of ED. The MMAS has the advantage of being the first study to provide population-based rates rather than rates based on clinical samples. All the projections were age-adjusted. Results It is estimated that in 1995 there were over 152 million men worldwide who experienced ED; the projections for 2025 show a prevalence of ≈322 million with ED, an increase of nearly 170 million men. The largest projected increases were in the developing world, i.e. Africa, Asia and South America. Discussion The likely worldwide increase in the prevalence of ED (associated with rapidly ageing populations) combined with newly available and highly publicized medical treatments, will raise challenging policy issues in nearly all countries. Already under-funded national health systems will be confronted with unanticipated resource requests and challenges to existing government funding priorities. The projected trends represent a serious challenge for healthcare policy makers to develop and implement policies to prevent or alleviate ED.

Purpose: To study the mechanism of chronic ischemia-induced increased cavernosal smooth muscle contraction in an animal model of vasculogenic erectile dysfunction.Materials and Methods: New Zealand White rabbits were divided into control (n = 6, fed with a regular diet), hypercholesterolemic (n = 9, fed with a diet containing 0.5% cholesterol) and chronic cavernosal ischemia (CCI, n = 10, underwent balloon de-endothelialization of iliac arteries and received a diet containing 0.5% cholesterol) groups. After 16 weeks, the relationship between iliac artery blood flow and cavernosal smooth muscle contraction was studied. The roles of cyclooxygenase and nitric oxide (NO) pathways in chronic ischemia-induced increased smooth muscle contraction were also examined.Results: Iliac artery blood flow in the CCI group was significantly reduced compared with the control and hypercholesterolemic groups. Hypercholesterolemia alone did not affect cavernosal smooth muscle contraction. Atherosclerosis-induced chron...