Neuroinflammation is a putative target for the prevention and treatment of perioperative neurocognitive disorders.

INTRODUCTION: The demographics of aging of the surgical population has increased the risk for perioperative neurocognitive disorders in which trauma-induced neuroinflammation plays a pivotal role. SOURCES OF DATA: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. AREAS OF AGREEMENT: Neuroinflammation is a sine qua non for development of perioperative neurocognitive disorders. AREAS OF CONTROVERSY: What is the best method for ameliorating trauma-induced neuroinflammation while preserving inflammation-based wound healing. GROWING POINTS: This review considers how to prepare for and manage the vulnerable elderly surgical patient through the entire spectrum, from preoperative assessment to postoperative period. AREAS TIMELY FOR DEVELOPING RESEARCH: What are the most effective and safest interventions for preventing and/or reversing Perioperative Neurocognitive Disorders.

Past, present, and future of nitrous oxide.

Introduction: For a drug that has been omnipresent for nearly 200 years, nitrous oxide's (N2O) future seems less certain than its illustrious past. Environmental concerns are coming to the fore and may yet outweigh important clinical benefits. Sources of data: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. Areas of agreement: The analgesic and anaesthetic advantages of N2O remain despite a plethora of newer agents. Areas of controversy: N2O greenhouse gas effect and its inhibition of key enzymes involved in protein and DNA synthesis have provided further fuel for those intent on eliminating its further clinical use. Growing points: The use of N2O for treatment-resistant depression has gained traction. Areas timely for developing research: Comparative studies for N2O role in combatting the prescription opioid analgesic epidemic may well provide further clinical impetus.

Interleukin-6 is both necessary and sufficient to produce perioperative neurocognitive disorder in mice.

BACKGROUND: Perioperative neurocognitive disorders (PND) result in long-term morbidity and mortality with no effective interventions available. Because interleukin-6 (IL-6), a pro-inflammatory cytokine, is consistently up-regulated by trauma, including after surgery, we determined whether IL-6 is a putative therapeutic target for PND in a mouse model. METHODS: Following institutional approval, adult (12-14 weeks) male C57/Bl6 mice were pretreated with the IL-6 receptor (IL6R) blocking antibody tocilizumab prior to open tibia fracture with internal fixation under isoflurane anaesthesia. Inflammatory and behavioural responses in a trace fear conditioning (TFC) paradigm were assessed postoperatively. Separately, the effects of IL-6 administration or of depletion of bone marrow-derived monocytes (BM-DMs) with clodrolip on the inflammatory and behavioural responses were assessed. Blood brain barrier disruption, hippocampal microglial activation, and infiltration of BM-DMs were each assessed following IL-6 administration. RESULTS: The surgery-induced decrement in freezing time in the TFC assay, indicative of cognitive decline, was attenuated by tocilizumab (P<0.01). The surgery-induced increase in pro-inflammatory mediators was significantly reduced by tocilizumab. Exogenously administered IL-6 significantly impaired freezing behaviour (P<0.05) and up-regulated pro-inflammatory cytokines; both responses were prevented by depletion of BM-DMs. IL-6 disrupted the blood brain barrier, and increased hippocampal activation of microglia and infiltration of BM-DMs. CONCLUSIONS: IL-6 is both necessary and sufficient to produce cognitive decline. Following further preclinical testing of its perioperative safety, the IL6R blocker tocilizumab is a candidate for prevention and/or treatment of PND.

The hip fracture surgery in elderly patients (HIPELD) study to evaluate xenon anaesthesia for the prevention of postoperative delirium: a multicentre, randomized clinical trial.

BACKGROUND: Postoperative delirium occurs frequently in elderly hip fracture surgery patients and is associated with poorer overall outcomes. Because xenon anaesthesia has neuroprotective properties, we evaluated its effect on the incidence of delirium and other outcomes after hip fracture surgery. METHODS: This was a phase II, multicentre, randomized, double-blind, parallel-group, controlled clinical trial conducted in hospitals in six European countries (September 2010 to October 2014). Elderly (≥75yr-old) and mentally functional hip fracture patients were randomly assigned 1:1 to receive either xenon- or sevoflurane-based general anaesthesia during surgery. The primary outcome was postoperative delirium diagnosed through postoperative day 4. Secondary outcomes were delirium diagnosed anytime after surgery, postoperative sequential organ failure assessment (SOFA) scores, and adverse events (AEs). RESULTS: Of 256 enrolled patients, 124 were treated with xenon and 132 with sevoflurane. The incidence of delirium with xenon (9.7% [95% CI: 4.5 -14.9]) or with sevoflurane (13.6% [95% CI: 7.8 -19.5]) were not significantly different (P=0.33). Overall SOFA scores were significantly lower with xenon (least-squares mean difference: -0.33 [95% CI: -0.60 to -0.06]; P=0.017). For xenon and sevoflurane, the incidence of serious AEs and fatal AEs was 8.0% vs 15.9% (P=0.05) and 0% vs 3.8% (P=0.06), respectively. CONCLUSIONS: Xenon anaesthesia did not significantly reduce the incidence of postoperative delirium after hip fracture surgery. Nevertheless, exploratory observations concerning postoperative SOFA-scores, serious AEs, and deaths warrant further study of the potential benefits of xenon anaesthesia in elderly hip fracture surgery patients. CLINICAL TRIAL REGISTRATION: EudraCT 2009-017153-35; ClinicalTrials.gov NCT01199276.

Perioperative management of the obese surgical patient.

INTRODUCTION: The escalation in the prevalence of obesity throughout the world has led to an upsurge in the number of obese surgical patients to whom perioperative care needs to be delivered. SOURCES OF DATA: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. AREAS OF AGREEMENT: There were no controversies regarding preoperative management and the intraoperative care of the obese surgical patient. AREAS OF CONTROVERSY: Is there a healthy obese state that gives rise to the obesity paradox regarding postoperative complications? GROWING POINTS: This review considers how to prepare for and manage the obese surgical patient through the entire spectrum, from preoperative assessment to possible postoperative intensive care. AREAS TIMELY FOR DEVELOPING RESEARCH: What results in an obese patient developing 'unhealthy' obesity?

Relation between acute and long-term cognitive decline after surgery: Influence of metabolic syndrome.

INTRODUCTION: The relationship between persistent postoperative cognitive decline and the more common acute variety remains unknown; using data acquired in preclinical studies of postoperative cognitive decline we attempted to characterize this relationship. METHODS: Low capacity runner (LCR) rats, which have all the features of the metabolic syndrome, were compared postoperatively with high capacity runner (HCR) rats for memory, assessed by trace fear conditioning (TFC) on the 7th postoperative day, and learning and memory (probe trial [PT]) assessed by the Morris water-maze (MWM) at 3 months postoperatively. Rate of learning (AL) data from the MWM test, were estimated by non-linear mixed effects modeling. The individual rat's TFC result at postoperative day (POD) 7 was correlated with its AL and PT from the MWM data sets at postoperative day POD 90. RESULTS: A single exponential decay model best described AL in the MWM with LCR and surgery (LCR-SURG) being the only significant covariates; first order AL rate constant was 0.07 s(-1) in LCR-SURG and 0.16s(-1) in the remaining groups (p<0.05). TFC was significantly correlated with both AL (R=0.74; p<0.0001) and PT (R=0.49; p<0.01). CONCLUSION: Severity of memory decline at 1 week after surgery presaged long-lasting deteriorations in learning and memory.

Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model.

BACKGROUND: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. METHODS: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 µg/kg and maintenance infusion at doses from 10 to 0.6 µg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. RESULTS: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 µg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 µg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. CONCLUSIONS: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.

Xenon treatment protects against cold ischemia associated delayed graft function and prolongs graft survival in rats.

Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia-hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival.

Outcomes of infected abdominal aortic grafts managed with antimicrobial therapy and graft retention in an unselected cohort.

OBJECTIVE: To document the treatment of all patients with infected aortic grafts at Christchurch Hospital between 1999 and 2010, focussing on the mortality and morbidity of those treated without graft explantation. METHODS: Cases of infected aortic grafts were reviewed. Cases required a compatible clinical syndrome, CT imaging and tissue/blood culture results. RESULTS: Eighteen patients were identified. Organisms isolated at diagnosis from blood or graft site were Staphylococcus aureus 6 (MRSA 1), beta haemolytic streptococci 2, enteric organisms 9.There was no isolate from 2. One case had graft explantation and brief antimicrobial therapy. Seventeen patients had the graft retained. Of these, 14 received intravenous antimicrobial therapy for 6 weeks and 14 lifelong oral therapy. None died during their initial admission or within 30 days. During a mean follow-up of 57 months, 10 (59%) relapsed (median time 31 months, range 0--98), 4 (24%) underwent graft explantation and 10 (59%) died (median 40 months, range 1e 198). Four of 10 who relapsed had organisms isolated (all enteric). CONCLUSION: Patients treated with lifelong antimicrobial therapy and graft retention survived a median of 41 months, with low early mortality although over half relapsed. Empiric therapy should cover skin organisms and enteric organisms, even for those outside the post-operative period.

Nucleic Acid Amplification of the opa Gene for Detection of Neisseria gonorrhoeae: experience from a diagnostic laboratory.

We report results of Neisseria gonorrhoeae nucleic acid amplification testing (NAAT) with the Abbott m2000 PCR at a tertiary laboratory 6 months after its introduction. Of 5,475 specimens tested, 45 samples (0.82%) tested positive for N. gonorrhoeae. Eight were not cultured, but seven tested positive with a porA pseudogene NAAT.

Adverse effects and duration of treatment of TB in Canterbury, New Zealand.

BACKGROUND Treatment of TB is often extended beyond the recommended duration. The aim of this study was to assess prevalence of extended treatment and to identify associated risk factors. We also aimed to determine the frequency and type of adverse drug reactions (ADR) experienced by this study population.METHODS We performed a retrospective cohort study of all patients treated for active TB at Christchurch Hospital, Christchurch, New Zealand, between 1 March 2012 and 31 December 2018. Data for 192 patients were collected on patient demographics, disease characteristics and treatment characteristics, including planned and actual duration of treatment and ADRs.RESULTS Of 192 patients, 35 (18.2%) had treatment extended, and 85 (46.5%) of 183 with fully drug-susceptible TB received ≥9 months treatment. The most common reasons for extension were persistent or extensive disease and ADR. Extended treatment duration was not associated with any patient or disease characteristics. We found 35 (18.2%) patients experienced at least one ADR. The most common ADRs were hepatitis, rash and peripheral neuropathy.CONCLUSION TB treatment extension beyond WHO guidelines is common. Further research is needed to guide management of those with slow response to treatment. Methods for early detection of ADR, systems to improve adherence and therapeutic drug monitoring are potentially useful strategies.

Ochroconis gallopava peritonitis in a cardiac transplant patient on continuous ambulatory peritoneal dialysis.

Ochroconis gallopava has rarely been isolated in immunosuppressed patients. We report the first case to our knowledge of O. gallopava peritonitis in a cardiac transplant patient on continuous ambulatory peritoneal dialysis. A 58-year-old man who had undergone cardiac transplant 8 years earlier alerted his dialysis nurses to the presence of black material in his catheter lumen. Fungal hyphae were seen on direct microscopy of the black material and from the dialysate effluent, and O. gallopava was cultured from both after 1 day. He was treated successfully with a single dose of intravenous voriconazole, followed by 2 weeks of oral voriconazole.

Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain.

BACKGROUND: Recent evidence has demonstrated the anti-apoptotic of dexmedetomidine in different brain injury models. Herein, we investigated whether dexmedetomidine could directly protect against cortical injury in vitro and in vivo. METHODS: Apoptosis was induced by staurosporine or wortmannin treatment in cortical neuronal cultures in vitro or by 6 h of isoflurane (0.75%) administration to post-natal day 7 rat pups in vivo. Dexmedetomidine was then applied in escalating doses to assess the neuroprotective potential of this agent. Cell survival was quantified using an MTT assay in vitro and in vivo apoptosis was assessed using cleaved caspase-3 immunohistochemistry. Cortical Western blots were conducted for the cellular survival proteins Bcl-2 and phosphorylated extracellular signal-regulated protein kinase (pERK)1 and 2. RESULTS: In vitro dexmedetomidine dose-dependently prevented both staurosporine- and wortmannin-induced injury in cortical neuronal cultures, indicating that dexmedetomidine can prevent apoptosis when applied directly. In vivo isoflurane induced cortical neuroapoptosis compared with air (327+/-80 vs. 34+/-9 caspase-3-positive neurons; P<0.05). Dexmedetomidine inhibited isoflurane-induced caspase-3 expression (P<0.05), although the protection achieved did not completely attenuate the isoflurane injury (P<0.05 vs. air). Isoflurane treatment decreased Bcl-2 and pERK protein expression relative to air, an effect reversed by dexmedetomidine treatment. CONCLUSIONS: Dexmedetomidine prevents cortical apoptosis in vitro and in vivo. However, using higher doses of dexmedetomidine does not further increase protection against isoflurane injury in the cortex than previously observed.

Diagnostic accuracy of leptospirosis whole-cell lateral flow assays: a systematic review and meta-analysis.

BACKGROUND: Leptospirosis is under-diagnosed by clinicians in many high-incidence countries, because reference diagnostic tests are largely unavailable. Lateral flow assays (LFA) that use antigen derived from heat-treated whole cell Leptospira biflexa serovar Patoc have the potential to improve leptospirosis diagnosis in resource-limited settings. OBJECTIVES: We sought to summarize estimates of sensitivity and specificity of LFA by conducting a systematic review and meta-analysis of evaluations of the accuracy of LFA to diagnose human leptospirosis. DATA SOURCES: On 4 July 2017 we searched three medical databases. Study eligibility criteriaArticles were included if they were a study of LFA sensitivity and specificity. PARTICIPANTS: Patients with suspected leptospirosis. INTERVENTIONS: Nil. METHODS: For included articles, we assessed study quality, characteristics of participants and diagnostic testing methods. We estimated sensitivity and specificity for each study against the study-defined case definition as the reference standard, and performed a meta-analysis using a random-effects bivariate model. RESULTS: Our search identified 225 unique reports, of which we included nine (4%) published reports containing 11 studies. We classified one (9%) study as high quality. Nine (82%) studies used reference tests with considerable risk of misclassification. Our pooled estimates of sensitivity and specificity were 79% (95% CI 70%-86%) and 92% (95% CI 85%-96%), respectively. CONCLUSIONS: As the evidence base for determining the accuracy of LFA is small and at risk of bias, pooled estimates of sensitivity and specificity should be interpreted with caution. Further studies should use either reference tests with high sensitivity and specificity or statistical techniques that account for an imperfect reference standard.

Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity.

Logistical and ethical reasons make conducting clinical research in paediatric practice difficult, and therefore safe and efficacious advances are dependent on good preclinical research. For example, notable advances have been made in preclinical studies of pain processing that correlate well with patient data. Other areas of paediatric anaesthetic research remain in their infancy including mechanisms of anaesthesia and anaesthetic neuroprotection and neurotoxicity. Animal data have identified the potential 'double-edged' sword of administering anaesthetic agents in the young; although these agents can be neuroprotective in certain circumstances, they can be neurotoxic in others. The potential for this toxicity must be balanced against the importance of providing adequate anaesthesia for which there can be no compromise. We review the current state of preclinical research in paediatric anaesthesia and identify areas which require further exploration in order to provide the foundations for well-conducted clinical trials.

G-protein-coupled receptors.

G-Protein-coupled receptors mediate many of the hypnotic and analgesic actions of the drugs employed in anesthesia. Notably, opioid agonists represent the most successful and efficacious class of analgesic agents employed over the last century. Also, major clinical advances have been made by the study of alpha(2) adrenoceptor agonists, which possess both hypnotic and analgesic qualities that are being increasingly exploited in both anesthetic and critical care settings. Furthermore orexin, gamma-aminobutyric acid (GABA) (B), and muscarinic cholinergic receptors have been identified as potential anesthetic targets; clinical exploitation of ligands at these receptors may lead to important advances in anesthetic pharmacology. In this review we discuss the relevant molecular and neural network pharmacology of anesthetic agents acting at G-protein-coupled receptors.

The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway.

We investigated the role of regionally discrete GABA (gamma-aminobutyric acid) receptors in the sedative response to pharmacological agents that act on GABA(A) receptors (muscimol, propofol and pentobarbital; 'GABAergic agents') and to ketamine, a general anesthetic that does not affect GABA(A) receptors. Behavioral studies in rats showed that the sedative response to centrally administered GABAergic agents was attenuated by the GABA(A) receptor antagonist gabazine (systemically administered). The sedative response to ketamine, by contrast, was unaffected by gabazine. Using c-Fos as a marker of neuronal activation, we identified a possible role for the tuberomammillary nucleus (TMN): when gabazine was microinjected directly into the TMN, it attenuated the sedative response to GABAergic agents. Furthermore, the GABA(A) receptor agonist muscimol produced a dose-dependent sedation when it was administered into the TMN. We conclude that the TMN is a discrete neural locus that has a key role in the sedative response to GABAergic anesthetics.

The epidemiology of febrile illness in sub-Saharan Africa: implications for diagnosis and management.

BACKGROUND: Fever is among the most common symptoms of people living in Africa, and clinicians are challenged by the similar clinical features of a wide spectrum of potential aetiologies. AIM: To summarize recent studies of fever aetiology in sub-Saharan Africa focusing on causes other than malaria. SOURCES: A narrative literature review by searching the MEDLINE database, and recent conference abstracts. CONTENT: Studies of multiple potential causes of fever are scarce, and for many participants the infecting organism remains unidentified, or multiple co-infecting microorganisms are identified, and establishing causation is challenging. Among ambulatory patients, self-limiting arboviral infections and viral upper respiratory infections are common, occurring in up to 60% of children attending health centres. Among hospitalized patients there is a high prevalence of potentially fatal infections requiring specific treatment. Bacterial bloodstream infection and bacterial zoonoses are major causes of fever. In recent years, the prevalence of antimicrobial resistance among bacterial isolates has increased, notably with spread of extended spectrum ß-lactamase-producing Enterobacteriaceae and fluoroquinolone-resistant Salmonella enterica. Among those with human immunodeficiency virus (HIV) infection, Mycobacterium tuberculosis bacteraemia has been confirmed in up to 34.8% of patients with sepsis, and fungal infections such as cryptococcosis and histoplasmosis remain important. IMPLICATIONS: Understanding the local epidemiology of fever aetiology, and the use of diagnostics including malaria and HIV rapid-diagnostic tests, guides healthcare workers in the management of patients with fever. Current challenges for clinicians include assessing which ambulatory patients require antibacterial drugs, and identifying hospitalized patients infected with organisms that are not susceptible to empiric antibacterial regimens.

Antisense technology reveals the alpha2A adrenoceptor to be the subtype mediating the hypnotic response to the highly selective agonist, dexmedetomidine, in the locus coeruleus of the rat.

Alpha2 adrenergic agonists are used in the anesthetic management of the surgical patient for their sedative/hypnotic properties although the alpha2 adrenoceptor subtype responsible for these anesthetic effects is not known. Using a gene-targeting strategy, it is possible to specifically reduce the expression of the individual adrenoceptors expressed in the central nervous system and to thereby determine their role in hypnotic action. Stably transfected cell lines (PC 124D for rat alpha2A; NIH3T3 for rat alpha2C adrenoceptors) were exposed to 5 microM antisense oligodeoxynucleotides (ODNs) for alpha2A and alpha2C adrenergic receptor subtypes for 3 d. Individual receptor subtype expression, as determined by radiolabeled ligand binding, was selectively decreased only by the appropriate antisense ODNs and not by the "scrambled" ODNs. These antisense ODNs were then administered three times, on alternate days, into the locus coeruleus of chronically cannulated rats and their hypnotic response to dexmedetomidine (an alpha2 agonist) was determined. Only the alpha2A antisense ODNs significantly change the hypnotic response causing both an increase in latency to, and a decrease in duration of, the loss of righting reflex following dexmedetomidine; hypnotic response had normalized 8 d after stopping the ODNs. Therefore, the alpha2A adrenoceptor subtype is responsible for the hypnotic response to dexmedetomidine in the locus coeruleus of the rat.