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.

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.

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.

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.

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.

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.

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.

Attenuation of the allergen-induced late asthmatic reaction by cyclosporin A is associated with inhibition of bronchial eosinophils, interleukin-5, granulocyte macrophage colony-stimulating factor, and eotaxin.

The allergen-induced late asthmatic reaction (LAR) is associated with increases in bronchial eosinophils and basophils as well as upregulation of several eosinophil active cytokines and C-C chemokines. Cyclosporin A (CsA) was previously shown to inhibit the LAR, but not the early asthmatic reaction (EAR), and this was associated with a decrease in blood eosinophils. For these reasons, we determined whether CsA inhibited the allergen-induced increases in bronchial eosinophils, basophils, eotaxin, interleukin-5 (IL-5), and granulocyte macrophage colony-stimulating factor (GM-CSF). Subjects with a demonstrable LAR underwent bronchoscopy with biopsy and bronchoalveolar lavage (BAL) at baseline and then were randomly allocated to receive either CsA (n = 13) or placebo (n = 11) before challenge. A second bronchoscopy was performed 24 h later. The LAR, but not the EAR, was significantly attenuated in the CsA group compared with placebo (p < 0.05). CsA significantly inhibited the allergen-induced increases in IL-5 (p = 0.02) and GM-CSF (p = 0. 0028) in mRNA+ cells in BAL, and in a mAB against human activated eosinophils (EG2+) (p = 0.0227). We conclude that inhibition of the LAR by CsA may be related to its inhibitory effects on eosinophil-associated cytokines and chemokines. The beneficial effect of CsA in asthma may also be the result of inhibition of eosinophil accumulation.

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.

Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin.

BACKGROUND: Previous studies used indirect methods to identify basophils in the bronchi in asthma, and the numbers were not compared with eosinophils and mast cells. Furthermore, differences in basophil numbers between atopic and nonatopic asthma at baseline and between late-phase skin and asthmatic reactions have not been previously documented. OBJECTIVE: The basophil granule-specific mAb BB1 was used to identify basophils in (1) bronchial biopsy specimens from atopic asthmatic subjects and nonatopic asthmatic subjects and control subjects, (2) biopsy specimens from atopic asthmatic subjects before and after inhalational allergen challenge, and (3) late-phase skin reactions. Basophil numbers were compared with EG2(+) eosinophils and tryptase(+) mast cells. METHODS: Cells were enumerated in bronchial and skin biopsy specimens by means of immunohistochemistry with the alkaline phosphatase-antialkaline phosphatase method. RESULTS: There were elevated numbers of basophils in baseline biopsy specimens in atopic asthmatic subjects compared with atopic control subjects or normal control subjects, although eosinophils and mast cells were 10-fold higher. There was an intermediate number of basophils in nonatopic asthmatic subjects. Basophils increased after allergen inhalation, but again basophils were less than 10% of eosinophils. In contrast, basophils in cutaneous late-phase reactions were approximately 40% of infiltrating eosinophils. The peak of basophil accumulation was at 24 hours, whereas maximal eosinophil infiltration occurred at 6 hours. One third of cutaneous basophils had morphologic appearances suggestive of degranulation. CONCLUSION: Numerous basophils infiltrated cutaneous late-phase reactions in atopic subjects. However, this cell was not prominent in bronchial biopsy specimens of asthmatic subjects, either at baseline or after allergen challenge.

Increases in eotaxin-positive cells in induced sputum from atopic asthmatic subjects after inhalational allergen challenge.

BACKGROUND: Eosinophils are believed to be critical proinflammatory cells in airway mucosal damage in asthma. Eotaxin is a C-C chemokine with selective activity for eosinophils and basophils. Previous studies have shown increased expression of eotaxin in the airways of asthmatics at baseline. We aimed to investigate eotaxin expression during the late-phase reaction to allergen inhalation in atopic asthmatics. METHODS: Sputum induction was performed before and 24 h after inhalational allergen challenge in atopic asthmatics, and eotaxin protein was detected immunocytochemically. RESULTS: Thirteen patients with a mean decrease in forced expiratory volume in 1 s of 28% (+/-1.5) during the early asthmatic reaction, and 39% (+/-4.7) during the late asthmatic reaction produced sufficient sputum for study. The percentage of eosinophils in sputum was increased 24 h after allergen challenge (P<0.004), and eosinophil percentages in sputum after challenge correlated with the magnitude of the late-phase reaction (r=0.56, P=0.05). The percentage of eotaxin-positive cells increased from 12.6% (range 2-43.8) to 24.3% (8.1-47.1, P<0.005). Allergen-induced increases in eotaxin-positive cells correlated with increases in eosinophils (r=0.63, P<0.01). CONCLUSIONS: These findings suggest that eotaxin may contribute to allergen-induced recruitment of eosinophils to the airway in asthmatic subjects.