Articaine: dental practitioner use, basis of perception and evidence-based dentistry-a cross-sectional study.

BACKGROUND: Limited data exist on dental practitioner use and perceptions of articaine. This study is a cross-sectional survey of dental practitioners from January, 2021 to ascertain the extent of their use of the dental local anaesthetic, articaine, the basis of their perceptions about articaine and whether current practices are in line with recent evidence regarding articaine safety and efficacy. METHOD: An anonymous survey was designed using the SAP Qualtrics Core XM software platform and a survey link was disseminated from December 2020 to January 2021 via social media. The survey was designed as a five minute, anonymous, online questionnaire including a plain language information sheet, request for participant consent and 14 questions. Data were entered onto a Microsoft™ Excel spreadsheet and analysed qualitatively, isolating the answers into recurrent themes. RESULTS: Sixty percent of the surveyed dental practitioner used articaine as their preferred dental anaesthetic. Twenty-three percent of the dental practitioner surveyed used articaine for all of their dental procedures including inferior alveolar nerve blocks, while 40% of respondents used articaine for all their dental procedures except inferior alveolar nerve blocks. The predominant basis of dental practitioner uses and perception of articaine were their countries dental guidelines. CONCLUSION: Despite the latest findings that articaine is as safe and more efficacious as lidocaine for all routine dental treatment, 40% of survey respondents avoided articaine use for inferior alveolar blocks. Our study recognises a discrepancy between reported clinical practice and current research evidence. Further research and clarifications are needed to achieve ubiquitous practice of evidence-based dentistry.

Articaine in dentistry: an overview of the evidence and meta-analysis of the latest randomised controlled trials on articaine safety and efficacy compared to lidocaine for routine dental treatment.

OBJECTIVES: To comprehensively review the existing studies of articaine in dentistry and conduct a systematic review and meta-analysis to answer the following Population, Intervention, Comparison and Outcome question: "Is articaine a safe and efficacious local anaesthetic for routine dental treatment compared to lidocaine?" METHODS: Database searches were conducted in Medline Ovid, Medline Pubmed, Scopus, Emcare, Proquest and the Cochrane Central register of Controlled Trials. Inclusion criteria were all existing English, human, randomised controlled trials of interventions involving 4% articaine and 2% lidocaine in routine dental treatment. Twelve studies were included for meta-analysis using Cochrane Review Manager 5 software. Anaesthetic success odds ratios were calculated using a random-effects model. RESULTS: Articaine had a higher likelihood of achieving anaesthetic success than lidocaine overall and in all subgroup analyses with varying degrees of significance. Overall (OR: 2.17, 95% CI: 1.50, 3.15, I2 = 62%) articaine had 2.17 times the likelihood of anaesthetic success of lidocaine (P < 0.0001). For mandibular blocks (OR: 1.50, 95% CI: 1.14, 1.98, I2 = 0%) articaine had 1.5 times the likelihood of anaesthetic success of lidocaine (P = 0.004). For all infiltrations, maxillary and mandibular (OR: 2.78, 95% CI: 1.61, 4.79, I2 = 66%) articaine had 2.78 times the likelihood of anaesthetic success of lidocaine (P = 0.0002). None of the studies reported any major local anaesthetic-related adverse effects as a result of the interventions. CONCLUSIONS: Articaine is a safe and efficacious local anaesthetic for all routine dental procedures in patients of all ages, and more likely to achieve successful anaesthesia than lidocaine in routine dental treatment. Neither anaesthetic has a higher association with anaesthetic-related adverse effects.

Improving intravenous-to-oral antibiotic switch in children: a team-based audit and implementation approach.

Children in hospital are frequently prescribed intravenous antibiotics for longer than needed. Programmes to optimise timely intravenous-to-oral antibiotic switch may limit excessive in-hospital antibiotic use, minimise complications of intravenous therapy and allow children to go home faster. Here, we describe a quality improvement approach to implement a guideline, with team-based education, audit and feedback, for timely, safe switch from intravenous-to-oral antibiotics in hospitalised children. Eligibility for switch was based on evidence-based guidelines and supported by education and feedback. The project was conducted over 12 months in a tertiary paediatric hospital. Primary outcomes assessed were the proportion of eligible children admitted under paediatric and surgical teams switched within 24 hours, and switch timing prior to and after guideline launch. Secondary outcomes were hospital length of stay, recommencement of intravenous therapy or readmission. The percentage of children switched within 24 hours of eligibility significantly increased from 32/50 (64%) at baseline to 203/249 (82%) post-implementation (p=0.006). The median time to switch fell from 15 hours 42 min to 4 hours 20 min (p=0.0006). In addition, there was a 14-hour median reduction in hospital length of stay (p=0.008). Readmission to hospital and recommencement of intravenous therapy did not significantly change postimplementation. This education, audit and feedback approach improved timely intravenous-to-oral switch in children and also allowed for more timely discharge from hospital. The study demonstrates proof of concept for this implementation with a methodology that can be readily adapted to other paediatric inpatient settings.

Comparison of Attitudes of Wisconsin Health Care Providers and Pharmacists Toward Vaccine Administration and Perceived Barriers.

OBJECTIVE: To measure the attitudes of pharmacists and other health care providers towards vaccine administration, overall acceptance of pharmacists as immunization providers, and perceived immunization barriers in Wisconsin. METHODS: The authors conducted a cross-sectional study utilizing an online survey to assess the attitudes of pharmacists and other health care providers toward their role as immunization providers and perceived barriers to providing immunizations. The survey was distributed between November 2018 and February 2019. RESULTS: Two hundred thirty-six pharmacists and 51 other health care providers completed the survey. Of the pharmacists who responded, 203 (86%) provided immunizations. Most respondents (97.9% of pharmacists and 90.2% of other health care providers) see vaccinations as a shared professional responsibility. Both pharmacists (82.6%) and other health care providers (79.6%) believe pharmacists have adequate training to administer vaccines to patients. Immunizing pharmacists identified 2 primary barriers to providing immunizations: patients refusing vaccines for financial reasons (55%) and patients not having insurance coverage for vaccines received in a pharmacy (55%). In contrast, the primary barrier identified by non-immunizing pharmacists is other responsibilities taking precedence over vaccinating (75%). Other health care providers identified determining whether their patients' insurance will reimburse for a vaccine (52%) as their primary barrier toward providing immunizations. CONCLUSION: These surveys provide a baseline measure of the attitudes of Wisconsin pharmacists and other health care providers toward immunization provision and offer opportunities for comparison. Our findings highlight barriers, such as insurance coverage for immunizations, that may prevent pharmacists from increasing vaccination rates in Wisconsin.

Immunizations at Wisconsin Pharmacies: Results of a statewide vaccine registry analysis and pharmacist survey.

BACKGROUND: There is currently limited data in the United States on the proportion of immunization doses given at pharmacies outside the influenza vaccine. This study aims to obtain baseline information on the percentage of vaccine doses administered at pharmacies in Wisconsin and to understand the immunization barriers for Wisconsin pharmacists, to inform interventions to increase immunization access at pharmacies. METHODS: Aggregated data from the Wisconsin Immunization Registry (WIR) was obtained for all vaccines administered at pharmacies to patients over the age of six from July 2017 through June 2018. In addition, a survey on attitudes towards and barriers to vaccination was sent to 2000 Wisconsin pharmacists with 236 respondents yielding a 12% response rate. RESULTS: WIR data demonstrates that zoster and influenza vaccines have the highest proportion of doses administered at pharmacies (39% and 20%, respectively). Human papillomavirus (HPV) vaccines have the lowest proportion of doses at 0.2%. Pharmacy survey shows that 86% provide immunizations. Most stock influenza vaccines (84%), whereas much fewer stock HPV vaccines (21%). The greatest immunization barriers for the pharmacy respondents include billing and reimbursement challenges and competing demands for staff. CONCLUSIONS: Despite the barriers, community pharmacies have significant potential to address vaccination gaps. Physicians, patients, and legislative bodies are generally well-accepting of pharmacists as immunizers. Pharmacists, in order to be fully utilized as immunizers, must engage in active communication with patients and be willing to collaborate with physicians. Legislative policy and health insurance reimbursement reforms are also necessary to facilitate further pharmacist participation in immunization.

Timeliness of data entry in Wisconsin Immunization Registry by Wisconsin pharmacies.

OBJECTIVE: To assess the association of various immunization- and pharmacy-related factors with the timeliness of pharmacy data entry in a state immunization information system. DESIGN: A cross-sectional study was conducted. SETTING AND PARTICIPANTS: Data for 2,040,248 immunizations administered by pharmacies in Wisconsin during 2012-2017 were collected from the Wisconsin Immunization Registry (WIR). Variables, including the submission method, immunization administration year, vaccine type, and recipient age, were analyzed through multivariate logistic regression to determine if they had a relationship with data entry timeliness. Pharmacists were surveyed on immunization data entry practices to corroborate analysis findings. OUTCOME MEASURES: Timeliness of immunization data entry in WIR was measured as a binary variable: 7 days or fewer or more than 7 days after immunization. RESULTS: Influenza immunizations were statistically significantly less likely to be timely compared with noninfluenza immunizations (odds ratio [OR] 0.719 [95% CI 0.712-0.726]; P < 0.0001). Immunizations administered to individuals aged more than 18 years were less timely compared with immunizations administered to individuals aged 6-18 years. The magnitude showed a slight difference in timeliness but without statistical significance (0.989 [95% CI 0.972-1.006]; P > 0.05). For submission method, flat-file submission was less likely to be timely compared with manual entry (0.48 [95% CI 0.475-0.486]; P < 0.0001). Health Level-7 submission, involving the electronic exchange of information with electronic health systems, was much more likely to be timely compared with manual entry (1.989 [95% CI 1.972-2.007]; P < 0.0001). With each successive year, from 2012 to 2017, immunizations were entered in a less timely manner (0.981 [95% CI 0.979-0.983]; P < 0.0001). CONCLUSIONS: Timeliness of pharmacy data entry in WIR was associated with entry method, vaccine type, and immunization administration year. We hope to identify ways to help pharmacies improve immunization data entry in WIR and facilitate the communication of immunization information among providers.

Advancing Community Pharmacy Practice - A Technician Product Verification Pilot to Optimize Care.

Elevating the technical role of pharmacy technicians to perform Technician Product Verification (TPV) is one strategy that has shown promise to optimize pharmacy practice models. This is done by better positioning pharmacists to provide clinical care, in line with their education and expertise. TPV permits a Validated Pharmacy Technician, as defined by the Wisconsin Pharmacy Examining Board, to verify the accuracy of a product filled by another technician. The pharmacist maintains responsibility for assessing the clinical appropriateness of the prescription, including drug utilization review, data entry, and patient counseling. During the study period, 12,891 pharmacist-verified prescriptions (baseline) and 27,447 Validated Pharmacy Technician-verified prescriptions were audited for accuracy. The aggregate verification error rate for pharmacist-verified prescriptions was 0.16% and 0.01% for Validated Pharmacy Technician-verified prescriptions. The mean error rate was significantly less for Validated Pharmacy Technician-verified prescriptions than for pharmacist-verified prescriptions (0.19 ± 0.174 % vs 0.03 ± 0.089 %, p=0.020) (Figure 3). This suggests TPV in the community pharmacy setting maintained patient safety. In this study, Validated Pharmacy Technicians were shown to be more accurate than pharmacists at performing product verification. The ability to delegate the product verification task holds the potential to free up pharmacist time for increased direct patient care. Increasing direct patient care by pharmacists in community pharmacies may have significant implications for improving patient outcomes and pharmacy quality.

Factors influencing treatment team recommendations to review tribunals for forensic psychiatric patients.

It is the responsibility of forensic psychiatric hospitals to detain and treat patients, gradually reintegrating them into society; decisions to release patients must balance risk to the public with maintaining the least restrictive environment for patients. Little is known about the factors considered when making such decisions and whether these factors have been empirically linked to future risk of violence. The current study explores the factors predictive of forensic treatment teams' recommendations for patients under the care of the Ontario Review Board (ORB). Factors differ depending on level of security; decisions on medium secure units were influenced by the presence of active symptoms and patients' overall violence risk level and decisions made on minimum secure units were influenced by the number of critical incidents that occurred within the recommendation year. Understanding the factors used to make recommendations to the ORB tribunal helps treatment teams to reflect on their own decision-making practices. Furthermore, the results serve to inform us about factors that influence length of stay for forensic psychiatric patients. Copyright © 2016 John Wiley & Sons, Ltd.

Cerebrospinal fluid from patients with subarachnoid haemorrhage and vasospasm enhances endothelin contraction in rat cerebral arteries.

INTRODUCTION: Previous studies have suggested that cerebrospinal fluid from patients with subarachnoid hemorrhage (SAH) leads to pronounced vasoconstriction in isolated arteries. We hypothesized that only cerebrospinal fluid from SAH patients with vasospasm would produce an enhanced contractile response to endothelin-1 in rat cerebral arteries, involving both endothelin ETA and ETB receptors. METHODS: Intact rat basilar arteries were incubated for 24 hours with cerebrospinal fluid from 1) SAH patients with vasospasm, 2) SAH patients without vasospasm, and 3) control patients. Arterial segments with and without endothelium were mounted in myographs and concentration-response curves for endothelin-1 were constructed in the absence and presence of selective and combined ETA and ETB receptor antagonists. Endothelin concentrations in culture medium and receptor expression were measured. RESULTS: Compared to the other groups, the following was observed in arteries exposed to cerebrospinal fluid from patients with vasospasm: 1) larger contractions at lower endothelin concentrations (p<0.05); 2) the increased endothelin contraction was absent in arteries without endothelium; 3) higher levels of endothelin secretion in the culture medium (p<0.05); 4) there was expression of ETA receptors and new expression of ETB receptors was apparent; 5) reduction in the enhanced response to endothelin after ETB blockade in the low range and after ETA blockade in the high range of endothelin concentrations; 6) after combined ETA and ETB blockade a complete inhibition of endothelin contraction was observed. CONCLUSIONS: Our experimental findings showed that in intact rat basilar arteries exposed to cerebrospinal fluid from patients with vasospasm endothelin contraction was enhanced in an endothelium-dependent manner and was blocked by combined ETA and ETB receptor antagonism. Therefore we suggest that combined blockade of both receptors may play a role in counteracting vasospasm in patients with SAH.

Tracheostomy in mechanical ventilation.

Airway access for mechanical ventilation (MV) can be provided either by orotracheal intubation (OTI) or tracheostomy tube. During episodes of acute respiratory failure, patients are commonly ventilated through an orotracheal tube that represents an easy and rapid initial placement of the airway device. OTI avoids acute surgical complications such as bleeding, nerve and posterior tracheal wall injury, and late complications such as wound infection and tracheal lumen stenosis that may emerge due to tracheostomy tube placement. Tracheostomy is often considered when MV is expected to be applied for prolonged periods or for the improvement of respiratory status, as this approach provides airway protection, facilitates access for secretion removal, improves patient comfort, and promotes progression of care in and outside the intensive care unit (ICU). The aim of this review is to assess the frequency and performance of different surgical or percutaneous dilational tracheostomy and timing and safety procedures associated with the use of fiberoptic bronchoscopy and ultrasounds. Moreover, we analyzed the performance based on National European surveys to assess the current tracheostomy practice in ICUs.

Characteristics of Native Americans with HIV and implications for care.

Limited data have been published about HIV infections and response to antiretroviral therapy in the Native American population. We reviewed baseline characteristics of 112 Native American patients to determine if there were any shared characteristics that would dictate the best treatment for this population. Metabolic diseases and psychiatric disorders were common findings among our patients. Native American patients should be monitored and screened as appropriate for comorbid conditions, and these disease states should be considered when choosing an antiretroviral regimen.

Does total manual rescreening of negative pap tests screened by the ThinPrep imaging system add any value?

We compared the performance of utilizing the ThinPrep® Imaging System (TIS) according to the manufacturer's directions to screening with the TIS plus total manual rescreening in Pap tests that were initially diagnosed as NIL to determine whether manual rescreening decreases the false-negative rate for epithelial lesions. Three thousand three hundred forty cases were diagnosed as NIL on the 22 fields of view selected by the TIS and subsequently manually rescreened by the same cytotechnologist. Six hundred seventy-four cases were sent to a cytopathologist for final diagnosis based on review criteria. Biopsy follow-up and Human Papilloma Virus (HPV) test results were noted if available for cases with a diagnosis of ASCUS or above. Three thousand one hundred fifty-nine (94.6%) were confirmed NIL and 181 cases were diagnosed as abnormal on manual rescreen. There were 147 ASCUS, 6 ASCH, 9 AGC, 19 LSIL, and 0 HSIL cases. The overall false-negative rate of screening for atypia/SIL with the TIS was 5.4%. Of the 147 cases with HPV results, 43 (29%) were positive. Only 1 cervical intraepithelial neoplasia 2 was found on biopsy follow-up, in a case of ASCUS with a positive HPV. Based on our data, the TIS for screening of Pap tests is reliable in NIL cases as compared to total manual rescreening. The majority of the false-negative cases were diagnosed as ASCUS on subsequent review, with 0 HSIL cases. Our results confirm that the TIS is highly accurate in excluding HSIL, negating the need for total manual rescreening of NIL Pap tests.

Oportunidad diagnóstica en el recién nacido con cardiopatía congénita / Diagnostic opportunities in the newborn with congenital heart defects

Introducción: Las cardiopatías congénitas (CC) son la primera causa de mortalidad en los pacientes con malformaciones congénitas, y el diagnóstico temprano modifica su pronóstico.En nuestro país las CC representan el 13% de la mortalidadinfantil, en tercer lugar luego de la prematurez y las infecciones. Objetivo: describir el proceso diagnóstico de los reciénnacidos con cardiopatía congénita ingresados a la terapiacardiovascular. Pacientes y métodos: estudio descriptivo, retrospectivo. Se incluyeron los menores de 45 días ingresadosen la unidad de recuperación cardiovascular del 1/1 al 31/12/10. Se registraron variables demográficas, presentación clínica, edad al diagnóstico, tipo de cardiopatía y lugar de procedencia. Se consideró diagnóstico precoz al prenatal o antes de las 72 hs de vida. Resultados: ingresaron 46 recién nacidos, de 18.7±15.3 días de edad a la cirugía y un peso de 3.39±0.4 kg y. La trasposición de grandes vasos, anomalía del retorno venoso e hipoplasia de corazón izquierdo fueron las patologías más frecuentes. Sólo 3 tuvieron diagnóstico prenatal y 21 en las primeras 72 hs. La forma de presentación más frecuente fue la cianosis (29/42), pero en menos del 50% el diagnóstico se realizó dentro de las 72 hs de vida. Conclusión: Sólo en el 52% de los neonatos el diagnóstico de cardiopatía congénita se realizó antes de las 72 hs. de vida. El diagnóstico prenatal fue excepcional en esta serie. La cianosis fue mal reconocida como índice de sospecha de cardiopatía congénita.

Introduction: Congenital heart defects (CHD) are the leading cause of death in patients with congenital malformations and early diagnosis may improve the prognosis. In Argentina, CHD account for 13% of infant mortality, being the third most-common cause following prematurity and infections. Objective: To describe the diagnostic work-up of newborns with CHD admitted to cardiac intensive care. Patients and methods: A retrospective, descriptive study was conducted, including infants younger than 45 days admitted to the cardiac inten-sive care unit between January 1 and December 31, 2010. Demographic and clinical features, age at diagnosis, type of heart defect, and place of origin were assessed. Early diag-nosis was defined as a diagnosis made prenatally or within 72 hours of life. Results: 46 newborns were admitted to the cardiac intensive care unit. Age at surgery was 18.7±15.3 days and weight was 3.39±0.4 kg. Transposition of the great arteries, anomalous pulmonary venous return, and hypoplastic left heart syndrome were the most commonly found patholo-gies. Diagnosis was made prenatally in only three and within the first 72 hours of life in 21. The most common presenting symptom was cyanosis (29/42), however, in less than 50% of these patients diagnosis was made within the first 72 hours of life. Conclusion: In only 52% of the newborns, the diagnosis of CHD was made before 72 hours of life. Prenatal diagnosis was exceptional in this series. Cyanosis was not always recognized as symptom of CHD.

Regulation of advance directives in Italy: a bad law in the making.

PURPOSE: The Advance Directives (ADs) have been adopted in many countries to defend patients' autonomy. In Italy, the role of ADs has recently been the subject of heated debate involving political parties and the Roman Catholic Church. In February 2009, the conservative government coalition presented a bill of law on this issue. It has been passed by the Low Chamber and is now being discussed in the Senate. The purpose of the article is to highlight any possible bill's contradiction with Italian Constitution, Italian Code of Medical Ethics (ICME), and Oviedo Convention contents, relevant for intensivists. METHODS: Analysis of bill's content in the light of Italian Constitution, ICME, Oviedo Convention articles and in comparison with French legislation regarding end of life (Leonetti law). RESULTS: In the Authors' point of view the bill's articles -limit the moral and judicial importance of four main issues as informed consent, permanent incapacity, artificial nutrition/hydration, and withdraw/withhold treatments. CONCLUSIONS: In the Authors' opinion the ADs must represent informed preferences made freely by patients within the relationship with their physicians, as part of an advance care planning. When this relationship develops in accordance with the ICME rules, it contains all of the ethical/professional dimensions to legitimate right choices in each case. The law should draw inspiration from ICME principles, assigning them a juridical power, acknowledging their validity in legitimating end-of-life decisions, and defining a framework of juridical legitimacy for these decisions without infringing on patients' right to autonomy with prescriptions on the care.

Phosphorylation mechanisms in intensive care medicine.

INTRODUCTION: The phosphorylation states of proteins, lipids, carbohydrates, amino acids, and nucleotides control the mechanisms behind nearly all cellular functions. Therefore, not surprisingly, recent findings have shown that alterations in these phosphorylation pathways play a central role in the development and progression of many disease states. This review provides a brief summary of the function and activity of various phosphorylation mechanisms, outlines some of the major phosphorylation signaling cascades, and describes the role of these phosphorylation mechanisms in intensive care medicine. METHODS: This article will comprise a comprehensive review of the literature in the context of intensive care medicine. Specifically, we will discuss the involvement of phosphorylation in the pathogenesis, diagnosis, and treatment of heart failure, myocardial infarction, stroke, respiratory failure, ventilation-induced lung injury, traumatic brain injury, acute organ failure, systemic sepsis, and shock. CONCLUSION: Phosphorylation mechanisms clearly play an important role in many pathologies and treatment strategies of intensive care and therefore further understanding of these mechanisms may lead to the development of novel therapies and improved patient care.

Effect of a lung protective strategy for organ donors on eligibility and availability of lungs for transplantation: a randomized controlled trial.

CONTEXT: Many potential donor lungs deteriorate between the time of brain death and evaluation for transplantation suitability, possibly because of the ventilatory strategy used after brain death. OBJECTIVE: To test whether a lung protective strategy increases the number of lungs available for transplantation. DESIGN, SETTING, AND PATIENTS: Multicenter randomized controlled trial of patients with beating hearts who were potential organ donors conducted at 12 European intensive care units from September 2004 to May 2009 in the Protective Ventilatory Strategy in Potential Lung Donors Study. Interventions Potential donors were randomized to the conventional ventilatory strategy (with tidal volumes of 10-12 mL/kg of predicted body weight, positive end-expiratory pressure [PEEP] of 3-5 cm H(2)O, apnea tests performed by disconnecting the ventilator, and open circuit for airway suction) or the protective ventilatory strategy (with tidal volumes of 6-8 mL/kg of predicted body weight, PEEP of 8-10 cm H(2)O, apnea tests performed by using continuous positive airway pressure, and closed circuit for airway suction). MAIN OUTCOME MEASURES: The number of organ donors meeting eligibility criteria for harvesting, number of lungs harvested, and 6-month survival of lung transplant recipients. RESULTS: The trial was stopped after enrolling 118 patients (59 in the conventional ventilatory strategy and 59 in the protective ventilatory strategy) because of termination of funding. The number of patients who met lung donor eligibility criteria after the 6-hour observation period was 32 (54%) in the conventional strategy vs 56 (95%) in the protective strategy (difference of 41% [95% confidence interval {CI}, 26.5% to 54.8%]; P <.001). The number of patients in whom lungs were harvested was 16 (27%) in the conventional strategy vs 32 (54%) in the protective strategy (difference of 27% [95% CI, 10.0% to 44.5%]; P = .004). Six-month survival rates did not differ between recipients who received lungs from donors ventilated with the conventional strategy compared with the protective strategy (11/16 [69%] vs 24/32 [75%], respectively; difference of 6% [95% CI, -22% to 32%]). CONCLUSION: Use of a lung protective strategy in potential organ donors with brain death increased the number of eligible and harvested lungs compared with a conventional strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00260676.

Pulmonary-derived phosphoinositide 3-kinase gamma (PI3Kγ) contributes to ventilator-induced lung injury and edema.

BACKGROUND: Ventilator-induced lung injury (VILI) occurs in part by increased vascular permeability and impaired alveolar fluid clearance. Phosphoinositide 3-kinase gamma (PI3Kγ) is activated by mechanical stress, induces nitric oxide (NO) production, and participates in cyclic adenosine monophosphate (cAMP) hydrolysis, each of which contributes to alveolar edema. We hypothesized that lungs lacking PI3Kγ or treated with PI3Kγ inhibitors would be protected from ventilation-induced alveolar edema and lung injury. METHODS: Using an isolated and perfused lung model, wild-type (WT) and PI3Kγ-knockout (KO) mice underwent negative-pressure cycled ventilation at either -25 cmH2O and 0 cmH2O positive end-expiratory pressure (PEEP) (HIGH STRESS) or -10 cmH2O and -3 cmH2O PEEP (LOW STRESS). RESULTS: Compared with WT, PI3Kγ-knockout mice lungs were partially protected from VILI-induced derangement of respiratory mechanics (lung elastance) and edema formation [bronchoalveolar lavage (BAL) protein concentration, wet/dry ratio, and lung histology]. In PI3Kγ-knockout mice, VILI induced significantly less phosphorylation of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), production of nitrate and nitrotyrosine, as well as hydrolysis of cAMP, compared with wild-type animals. PI3Kγ wild-type lungs treated with AS605240, an inhibitor of PI3Kγ kinase activity, in combination with enoximone, an inhibitor of phosphodiesterase-3 (PDE3)-induced cAMP hydrolysis, were protected from VILI at levels comparable to knockout lungs. CONCLUSIONS: Phosphoinositide 3-kinase gamma in resident lung cells mediates part of the alveolar edema induced by high-stress ventilation. This injury is mediated via altered Akt, eNOS, NO, and/or cAMP signaling. Anti-PI3Kγ therapy aimed at resident lung cells represents a potential pharmacologic target to mitigate VILI.

Endotoxin removal by polymyxin B immobilized cartridge inactivates circulating proapoptotic factors.

BACKGROUND/AIMS: Severe sepsis and septic shock continue to be major clinical challenges due to high associated mortality. Lipopolysaccharide (LPS) is a component of the cell membrane of Gram-negative bacteria, and is believed to initiate septic-induced signaling, inflammation and organ damage, including acute renal failure. Polymyxin B (PMX-B) hemoperfusion of septic patients can improve survival and decreasing organ dysfunction by removing circulating LPS. Unfortunately, some clinicians have been slow to adopt this novel therapy due to the lack of understanding of the cellular mechanisms involved in this treatment. Apoptosis, or programmed cell death, is known to contribute to acute renal failure and overall organ dysfunction during sepsis, and can be activated by LPS-initiated signaling pathways. Therefore, the protective renal effects associated with PMX-B hemoperfusion of septic patients may result from alterations in cellular apoptosis. This chapter will review recent data regarding the role of apoptosis prevention in the mechanism leading to the improved outcome and decreased acute renal failure associated with PMX-B hemoperfusion during sepsis. METHODS: Blood was collected, upon inclusion and following 72 h, from conventionally treated patients and patients receiving two PMX-B hemoperfusion treatments. Plasma was subsequently used to stimulate renal tubule cells or glomerular podocytes to assess their ability to induce apoptosis. RESULTS: All plasma collected upon inclusions, as well as plasma from conventionally treated patients at 72 h, significantly increased apoptosis, while plasma collected from patients following PMX-B treatment induced significantly less apoptosis than time 0 or conventionally treated controls. This decreased proapoptotic signal resulted from decreased extrinsic and intrinsic apoptotic signaling determined by decreased caspase activity, Fas expression and Bax/Bcl-2 balance. CONCLUSION: The protective effects of extracorporeal therapy with PMX-B on the development of acute renal failure result, in part, through its ability to reduce the systemic proapoptotic activity of septic patients on renal cells.