Updates in our understanding of local anaesthetic systemic toxicity: a narrative review.

Despite advances in clinical practice, local anaesthetic systemic toxicity continues to occur with the therapeutic use of local anaesthesia. Patterns of presentation have evolved over recent years due in part to the increasing use of ultrasound which has been demonstrated to reduce risk. Onset of toxicity is increasingly delayed, a greater proportion of clinical reports are secondary to fascial plane blocks, and cases are increasing where non-anaesthetist providers are involved. The evolving clinical context presents a challenge for diagnosis and requires education of all physicians, nurses and allied health professionals about these changing patterns and risks. This review discusses: mechanisms; prevention; diagnosis; and treatment of local anaesthetic systemic toxicity. The local anaesthetic and dose used, site of injection and block conduct and technique are all important determinants of local anaesthetic systemic toxicity, as are various patient factors. Risk mitigation is discussed including the care of at-risk groups, such as: those at the extremes of age; patients with cardiac, hepatic and specific metabolic diseases; and those who are pregnant. Advances in the changing clinical landscape with novel applications and settings for the use of local anaesthesia are also described. Finally, we signpost future directions to potentially improve the management of local anaesthetic systemic toxicity. The utility of local anaesthetics remains unquestionable in clinical practice, and thus maximising the safe and appropriate use of these drugs should translate to improvements in patient care.

The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety.

Intravenous lidocaine is used widely for its effect on postoperative pain and recovery but it can be, and has been, fatal when used inappropriately and incorrectly. The risk-benefit ratio of i.v. lidocaine varies with type of surgery and with patient factors such as comorbidity (including pre-existing chronic pain). This consensus statement aims to address three questions. First, does i.v. lidocaine effectively reduce postoperative pain and facilitate recovery? Second, is i.v. lidocaine safe? Third, does the fact that i.v. lidocaine is not licensed for this indication affect its use? We suggest that i.v. lidocaine should be regarded as a 'high-risk' medicine. Individual anaesthetists may feel that, in selected patients, i.v. lidocaine may be beneficial as part of a multimodal peri-operative pain management strategy. This approach should be approved by hospital medication governance systems, and the individual clinical decision should be made with properly informed consent from the patient concerned. If i.v. lidocaine is used, we recommend an initial dose of no more than 1.5 mg.kg-1 , calculated using the patient's ideal body weight and given as an infusion over 10 min. Thereafter, an infusion of no more than 1.5 mg.kg-1 .h-1 for no longer than 24 h is recommended, subject to review and re-assessment. Intravenous lidocaine should not be used at the same time as, or within the period of action of, other local anaesthetic interventions. This includes not starting i.v. lidocaine within 4 h after any nerve block, and not performing any nerve block until 4 h after discontinuing an i.v. lidocaine infusion.

Maternal folate status and obesity/insulin resistance in the offspring: a systematic review.

OBJECTIVE: Prenatal folic acid supplementation or maternal folate sufficiency may protect the offspring from obesity and insulin resistance. This study aims to summarize the findings of association between prenatal folic acid supplementation/maternal folate sufficiency and obesity/insulin resistance in the offspring. METHODS: Twelve databases were searched for both published and unpublished work of prenatal folic acid supplementation/maternal folate status up to 1 July 2014. Experimental and observational studies on animals and human beings were included based on the eligibility criteria. There were no limits to the time period and language of publication. The study quality was assessed with a 10-Point Scale for Scientific Methodology. RESULTS: The search identified 2548 records. Nine animal studies and five human studies satisfied search criteria were included. Five of these nine animal studies showed a protective effect of folic acid. Of the five human studies, one showed a protective effect of folic acid, two showed a harmful effect and two showed uncertain results. CONCLUSIONS: Data from both animal studies and human studies are inconsistent. Future researches with sophisticated designs are needed to demonstrate the potential protective effect of maternal folate on obesity/insulin resistance in the offspring in animal models and human pregnancies.

Wide differences in mode of delivery within Europe: risk-stratified analyses of aggregated routine data from the Euro-Peristat study.

OBJECTIVE: To use data from routine sources to compare rates of obstetric intervention in Europe both overall and for subgroups at higher risk of intervention. DESIGN: Retrospective analysis of aggregated routine data. SETTING: Thirty-one European countries or regions contributing data on mode of delivery to the Euro-Peristat project. POPULATION: Births in participating countries in 2010. METHODS: Countries provided aggregated data about overall rates of obstetric intervention and about caesarean section rates for specified subgroups. MAIN OUTCOME MEASURES: Mode of delivery. RESULTS: Rates of caesarean section ranged from 14.8% to 52.2% of all births and rates of instrumental vaginal delivery ranged from 0.5% to 16.4%. Overall, there was no association between rates of instrumental vaginal delivery and rates of caesarean section, but similarities were observed between some countries that are geographically close and may share common traditions of practice. Associations were observed between caesarean section rates for women with breech and vertex births and with singleton and multiple births but patterns of association for women who had and had not had previous caesarean sections were more complex. CONCLUSIONS: The persisting wide variations in caesarean section and instrumental vaginal delivery rates point to a lack of consensus about practice and raise questions for further investigation. Further research is needed to explore the impact of differences in clinical guidelines, healthcare systems and their financing and parents' and professionals' attitudes to care at delivery.

Linking databases on perinatal health: a review of the literature and current practices in Europe.

BACKGROUND: International comparisons of perinatal health indicators are complicated by the heterogeneity of data sources on pregnancy, maternal and neonatal outcomes. Record linkage can extend the range of data items available and thus can improve the validity and quality of routine data. We sought to assess the extent to which data are linked routinely for perinatal health research and reporting. METHODS: We conducted a systematic review of the literature by searching PubMed for perinatal health studies from 2001 to 2011 based on linkage of routine data (data collected continuously at various time intervals). We also surveyed European health monitoring professionals about use of linkage for national perinatal health surveillance. RESULTS: 516 studies fit our inclusion criteria. Denmark, Finland, Norway and Sweden, the US and the UK contributed 76% of the publications; a further 29 countries contributed at least one publication. Most studies linked vital statistics, hospital records, medical birth registries and cohort data. Other sources were specific registers for: cancer (70), congenital anomalies (56), ART (19), census (19), health professionals (37), insurance (22) prescription (31), and level of education (18). Eighteen of 29 countries (62%) reported linking data for routine perinatal health monitoring. CONCLUSION: Research using linkage is concentrated in a few countries and is not widely practiced in Europe. Broader adoption of data linkage could yield substantial gains for perinatal health research and surveillance.

Diversity and stability of cultured vaginal lactobacilli in pregnant women from a multi-ethnic urban UK population.

AIM: To determine the diversity and stability of cultured vaginal lactobacilli in a multi-ethnic population of pregnant women. METHODS AND RESULTS: A single-centre, prospective, cohort study was performed in a tertiary perinatal centre in East London, UK. Self-collected vaginal swabs at 13 and 20 weeks gestation were obtained from women attending for routine antenatal care and cultured for lactobacilli. In women who provided both swabs, 37 of 203 (18%) had no lactobacilli cultured at either time. Only 53 (26%) had the same species at both times. Black women were less likely to have lactobacilli cultured at 13 weeks (P = 0·014), and Black and Asian women were less likely to have lactobacilli cultured at 20 weeks (P = 0·002) compared with those in the White and Other groups. CONCLUSIONS: Significant differences exist between ethnic groups in the carriage and stability of vaginal lactobacilli. SIGNIFICANCE AND IMPACT OF THE STUDY: These differences have implications for the design of interventions aimed at normalizing the vaginal microbiota in pregnant women.

Does regional anaesthesia improve outcome after total hip arthroplasty? A systematic review.

Total hip arthroplasty (THA) is amenable to a variety of regional anaesthesia (RA) techniques that may improve patient outcome. We sought to answer whether RA decreased mortality, cardiovascular morbidity, deep venous thrombosis (DVT) and pulmonary embolism (PE), blood loss, duration of surgery, pain, opioid-related adverse effects, cognitive defects, and length of stay. We also questioned whether RA improved rehabilitation. To do so, we performed a systematic review of the contemporary literature to compare general anaesthesia (GA) and RA and also systemic and regional analgesia for THA. To reflect contemporary surgical and anaesthetic practice, only randomized controlled trials (RCTs) from 1990 onward were included. We identified 18 studies involving 1239 patients. Only two of the 18 trials were of Level I quality. There is insufficient evidence from RCTs alone to conclude if anaesthetic technique influenced mortality, cardiovascular morbidity, or the incidence of DVT and PE when using thromboprophylaxis. Blood loss may be reduced in patients receiving RA rather than GA for THA. Our review suggests that there is no difference in duration of surgery in patients who receive GA or RA. Compared with systemic analgesia, regional analgesia can reduce postoperative pain, morphine consumption, and nausea and vomiting. Length of stay is not reduced and rehabilitation does not appear to be facilitated by RA or analgesia for THA.

Folic acid supplementation reduces multigenerational sperm miRNA perturbation induced by in utero environmental contaminant exposure.

Persistent organic pollutants (POPs) can induce epigenetic changes in the paternal germline. Here, we report that folic acid (FA) supplementation mitigates sperm miRNA profiles transgenerationally following in utero paternal exposure to POPs in a rat model. Pregnant founder dams were exposed to an environmentally relevant POPs mixture (or corn oil) ± FA supplementation and subsequent F1-F4 male descendants were not exposed to POPs and were fed the FA control diet. Sperm miRNA profiles of intergenerational (F1, F2) and transgenerational (F3, F4) lineages were investigated using miRNA deep sequencing. Across the F1-F4 generations, sperm miRNA profiles were less perturbed with POPs+FA compared to sperm from descendants of dams treated with POPs alone. POPs exposure consistently led to alteration of three sperm miRNAs across two generations, and similarly one sperm miRNA due to POPs+FA; which was in common with one POPs intergenerationally altered sperm miRNA. The sperm miRNAs that were affected by POPs alone are known to target genes involved in mammary gland and embryonic organ development in F1, sex differentiation and reproductive system development in F2 and cognition and brain development in F3. When the POPs treatment was combined with FA supplementation, however, these same miRNA-targeted gene pathways were perturbed to a lesser extend and only in F1 sperm. These findings suggest that FA partially mitigates the effect of POPs on paternally derived miRNA in a intergenerational manner.

Caesarean section using total intravenous anaesthesia in a patient with Ebstein's anomaly complicated by supraventricular tachycardia.

Ebstein's anomaly is a rare congenital cardiac defect associated with both displacement and incompetence of the tricuspid valve. The condition is commonly complicated by supraventricular tachycardias. We describe the management of a patient with this condition undergoing caesarean section. Propofol and remifentanil total intravenous anaesthesia resulted in haemodynamic stability and delivery of a healthy baby who breathed spontaneously after two minutes.

Recent trends in the incidence of multiple births and associated mortality.

The overall incidence of multiple births in England and Wales, which had been declining since the early 1950s, started to increase in the early 1980s in all age groups except for women under 20. This followed a rise in the incidence of triplet and higher order multiple births which had started in the late 1970s. Analyses of data for births between 1978 and 1983 showed that while stillbirth, perinatal, neonatal, and post-neonatal mortalities among multiple births fell considerably, they remained consistently higher than those for singleton births. Differences in the distribution of birth weight do not wholly explain these differences. Analyses of certified causes of stillbirth and death are difficult to interpret because a considerable proportion were attributed to 'multiple pregnancy'.

Sudden infant deaths and cold weather: was the rise in infant mortality in 1986 in England and Wales due to the weather?

Using the daily number of deaths due to sudden infant death syndrome in England and Wales from 1979 to 1985, and the daily temperature recorded at the London Weather Centre, two models were constructed, one including a temperature term and one without it, and the models used to predict the mortality in 1986. It was found that the model using temperature had a slightly better predictive power and successfully accounted for the increased mortality in February 1986. Thus, we conclude that the excess mortality of February 1986 was associated with the unusually cold weather during that month.

Does poor communication contribute to stillbirths and infant deaths? A review.

BACKGROUND: Assessors from the Confidential Enquiry into Stillbirths and Deaths in Infancy (CESDI) have cited poor communication as a contributory factor in a proportion of such deaths. This review assesses what research evidence exists to support or explain this. METHODS: A structured review was carried out, including all studies of sub-optimal care in stillbirth or infant death and studies of litigation in perinatal care. The following databases were searched: MEDLINE, PsycLIT, The Cochrane Library, BIDS Science and Social Science Citation Indexes, Cinahl and Embase. For included studies, information was extracted on the type of study, the selection criteria and number of cases studied, other methods used and results relevant to the question. RESULTS: One hundred and four studies of potential relevance to the review were identified. Of these, 52 did not meet the inclusion criteria and were excluded. Of the remaining 52 studies, 11 considered communication failure explicitly as a factor in sub-optimal care leading to stillbirth or infant death. In three out of the four studies that presented their findings in terms of numbers of cases, communication failure was noted in between 24 and 29 per cent of cases. There was some consistency across different types of study in the types of communication problems noted. CONCLUSION: Poor communication may contribute to a proportion of stillbirths and infant deaths. However, given the small number of papers that looked explicitly at poor communication as a factor in sub-optimal care and the lack of comparative information on communication in cases that do not end in poor outcome, caution is needed in drawing conclusions based on the findings of these papers.

Is the clinical trial evidence about new drugs statistically adequate?

The statistical adequacy of all papers published in the period 1976-80 describing clinical trials of five non-steroidal anti-inflammatory and two analgesic drugs introduced into the UK market in 1978 and 1979 has been assessed using a checklist of simple criteria. Most trials were reported to be randomised and double-blind. Trial designs were less satisfactory in other important respects; the sample size of most trials was inadequate to demonstrate superiority of the new drug compared with an active control therapy. The period of treatment assessment was short in view of the likelihood of prolonged prescription of drugs in these classes. It is suggested that licensing authorities should demand higher standards of clinical trial evidence offered in support of new drugs.

Sputum cysteinyl leukotrienes increase 24 hours after allergen inhalation in atopic asthmatics.

We have used the relatively noninvasive technique of induced sputum to measure allergen-induced changes in the concentration of eicosanoid mediators in bronchial secretions from atopic asthmatics. Sputum induction was performed before and 24 h after inhalational allergen challenge in 14 atopic asthmatics who developed a late asthmatic reaction (LAR). Differential cell counts were made on sputum cytospins and eicosanoid (cysteinyl leukotrienes [cys LTs], prostaglandin D(2) [PGD(2)], and PGE(2)) concentrations were measured in the sputum supernatants. The percentage of eosinophils at baseline correlated with the concentration of cys LTs (r = 0.84, p < 0.001) but not prostanoid mediators. Allergen challenge produced a significant increase in the concentration of sputum cys LTs from 3. 45 ng/ml sputum to 11.95 ng/ml (p = 0.002), which correlated with the increase in sputum eosinophils (r = 0.55, p < 0.05). There were no significant changes in PGD(2) or PGE(2) concentrations in sputum supernatants in response to challenge. Thus, the noninvasive technique of induced sputum has been used to demonstrate increased cys LTs, but not prostanoids associated with LAR after allergen challenge. The correlation between eosinophil numbers and cys LT concentrations at baseline values and 24 h after allergen challenge is consistent with these cells being a principal source of cys LTs within the airways at these time points.

Molecular cloning of F4/80, a murine macrophage-restricted cell surface glycoprotein with homology to the G-protein-linked transmembrane 7 hormone receptor family.

F4/80 is a monoclonal antibody that recognizes a murine macrophage-restricted cell surface glycoprotein and has been extensively used to characterize macrophage populations in a wide range of immunological studies. Apart from the tightly regulated pattern of expression of the F4/80 antigen, little is known about its possible role in macrophage differentiation and function. We have sought to characterize the molecule at the molecular level, through the isolation of cDNA clones, and now describe the sequence of the F4/80 protein. The primary amino acid sequence demonstrates homology to two protein superfamilies. The NH2-terminal region consists of seven epidermal growth factor-like domains, separated by approximately 300 amino acids from a COOH-terminal region that shows homology to members of the seven transmembrane-spanning family of hormone receptors. The potential role of these distinct domains is discussed with respect to the possible function of the F4/80 molecule.