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OBJECTIVES: Postoperative delirium (POD) remains the most common complication in older adults, with cognitive impairment being the main risk factor. Patients with mild cognitive impairment, in particular, have much to lose from delirium; despite this, their cognitive impairment might be clinically overlooked. Understanding which cognitive domains are particularly predictive in this regard may improve the sensitivity of preoperative testing and allow for a more targeted application of resource-intensive measures to prevent delirium in the perioperative period. The authors conducted this study with the aim of identifying the most indicative cognitive domains. DESIGN: A secondary analysis of a randomized controlled trial. SETTING: At a single center, the University Medical Centre Hamburg in Hamburg, Germany. PARTICIPANTS: Patients ≥60 years without major neurocognitive disorders (dementia, Mini-Mental State Examination score ≤23) scheduled for cardiovascular surgery. MEASUREMENTS AND MAIN RESULTS: Preoperative neuropsychologic testing and delirium screening were performed twice daily until postoperative day 5. A multiple logistic regression model was applied to determine the predictive ability of test performances for the development of delirium. RESULTS: A total of 541 patients were included in the analysis; the delirium rate was 15.6%. After controlling for confounders, only low performance within the Trail Making Test B/A (odds ratio [OR] = 1.32; 95% CI: 1.05-1.66) and letter fluency (OR = 0.66; 95% CI: 0.45-0.96) predicted a particularly high risk for delirium development. The discriminative ability of the final multiple logistic regression model to predict POD had an area under the curve of 0.786. CONCLUSIONS: Impairment in the cognitive domains of executive function and language skills associated with memory, inhibition, and access speed seem to be particularly associated with the development of delirium after surgery in adults ≥65 years of age without apparent preoperative neurocognitive impairment.
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Disfunción Cognitiva , Delirio , Delirio del Despertar , Humanos , Anciano , Delirio del Despertar/diagnóstico , Delirio del Despertar/epidemiología , Delirio del Despertar/etiología , Delirio/diagnóstico , Delirio/epidemiología , Delirio/etiología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Cognición/fisiología , Factores de RiesgoRESUMEN
BACKGROUND: In elderly patients following surgery, postoperative delirium (POD) is the most frequent complication and is associated with negative outcomes. The 2017 European Society of Anaesthesiology guideline on POD aims to improve patient care by implementing structured delirium prevention, diagnosis and treatment. However, these recommendations, especially systematic delirium screening, are still incompletely adopted in clinical practice. The aim of this study was to evaluate the feasibility and acceptance of validated delirium screening tools and to identify barriers to their implementation on nonintensive care unit wards. METHODS: Screening rates, as well as practicability, acceptance and the interprofessional handling of positive results, were assessed for each group. Screening rates were calculated as a percentage of the total potential testing episodes completed (up to 15 per patient). Patients were considered eligible when aged 65âyears and above. Barriers and motivating factors were assessed in a mixed method approach by utilising questionnaires and focus group discussions. INTERVENTION: In a 3-month phase, a guideline-compliant screening protocol involving screening for POD three times daily for 5 days following surgery was introduced in five wards: both the 4-item assessment test (4AT) and the nursing delirium screening scale (NuDESC) were used. Before commencing the study and again after 6âweeks, medical staff of the respective wards underwent a 45âmin training session. RESULTS: Of a total of 3183 potential testing episodes, 999 (31.4%) were completed, with more NuDESC observational tests (43%) than 4AT bedside tests completed (20%). The 4AT was considered more difficult to integrate into daily working routines, it took longer to administer, and nurses felt uncomfortable conducting the screening (53 vs. 13%). Screening results indicating delirium were often not discussed within the team (47%), and nurses felt that often such results were not taken seriously by physicians (54%). CONCLUSION: The observational NuDESC showed a higher completion rate than the bedside 4AT, although overall testing rates were low. The necessary time needed to conduct the screening, the negative reactions by patients, insufficient team communication and a lack of initiation of any therapy were identified as major barriers in the implementation of the guideline-compliant screening protocol. For all staff, further education and awareness of the importance of POD diagnosis and treatment might improve the screening rates. The NuDesc received better results concerning acceptance, practicability and introduction into daily work routine, leading to higher screening rates compared with the 4AT. The latter instrument, which was intended to be used rather selectively or when POD is suspected, might therefore not be suitable for guideline-compliant regular and repeated screening for POD.
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Delirio , Anciano , Delirio/diagnóstico , Hospitales , Humanos , Tamizaje Masivo , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
Bacterial pneumonia is a global health challenge that causes up to 2 million deaths each year. Purinergic signaling plays a pivotal role in healthy alveolar epithelium. Here, we used fluorophore-based analysis and live-cell calcium imaging to address the question of whether the bacterial pathogen Streptococcus pneumoniae directly interferes with purinergic signaling in alveolar epithelial cells. Disturbed purinergic signaling might result in pathophysiologic changes like edema formation and atelectasis, which are commonly seen in bacterial pneumonia. Purine receptors are mainly activated by ATP, mediating a cytosolic calcium response. We found that this purinergic receptor P2Y2-mediated response is suppressed in the presence of S. pneumoniae in A549 and isolated primary alveolar cells in a temperature-dependent manner. Downstream inositol 3-phosphate (IP3) signaling appeared to be unaffected, as calcium signaling via protease-activated receptor 2 remained unaltered. S. pneumoniae-induced suppression of the P2Y2-mediated calcium response depended on the P2Y2 phosphorylation sites Ser-243, Thr-344, and Ser-356, which are involved in receptor desensitization and internalization. Spinning-disk live-cell imaging revealed that S. pneumoniae induces P2Y2 translocation into the cytosol. In conclusion, our results show that S. pneumoniae directly inhibits purinergic signaling by inducing P2Y2 phosphorylation and internalization, resulting in the suppression of the calcium response of alveolar epithelial cells to ATP, thereby affecting cellular integrity and function.
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Células Epiteliales Alveolares/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Streptococcus pneumoniae/metabolismo , Células A549 , Adenosina Trifosfato/metabolismo , Animales , Señalización del Calcio , Células Cultivadas , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2Y2/genéticaRESUMEN
Despite its fundamental role in providing an extensive surface for gas exchange, the alveolar epithelium (AE) serves as an immunological barrier through, e.g., the release of proinflammatory cytokines and secretion of surfactant to prevent alveolar collapse. Thus, AE is important for sustaining lung homeostasis. Extracellular ATP secreted by alveolar epithelial cells (AECs) is involved in physiological and pathological conditions and acts mainly through the activation of purine receptors (P2Rs). When studying P2R-mediated processes, primary isolated type II AECs (piAECs) still represent the gold standard in in vitro research, although their preparation is time-consuming and requires the sacrifice of many animals. Hence, cultivated immortalized and tumor-derived AEC lines may constitute a valuable alternative. In this work, we examined P2R expression and functionality in piAECs, in immortalized and tumor-derived AEC lines with the purpose of gaining a better understanding of purinergic signaling in different cell systems and assisting researchers in the choice of a suitable cell line with a certain P2R in demand. We combined mRNA and protein analysis to evaluate the expression of P2R. For pharmacological testing, we conducted calcium ([Ca2+]) measurements and siRNA receptor knockdown. Interestingly, the mRNA and protein levels of P2Y2, P2Y6, and P2X4 were detected on all cell lines. Concerning functionality, P2XR could be narrowed to L2 and piAECs while P2YR were active in all cell lines.
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Células Epiteliales Alveolares/metabolismo , Células Epiteliales/metabolismo , Purinas/metabolismo , Receptores Purinérgicos/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Células Cultivadas , Expresión Génica/fisiología , Humanos , Pulmón/metabolismo , RatasRESUMEN
PURPOSE OF REVIEW: Alterations in cognitive functions are common in the perioperative course. Although often unnoticed by physicians, these alterations might have distinct long-term consequences for the patient with regard to everyday functioning, self-dependency, and quality of life. In recent years, however, perioperative cognition has gained increased interest, both by clinicians and scientists, and knowledge of the preventive measures of postoperative cognitive decline has become mandatory for anesthetists and surgeons. RECENT FINDINGS: This review offers a brief overview of the current state of knowledge concerning perioperative changes in cognition, including its pathophysiology and prevention strategies. SUMMARY: Postoperative neurocognitive disorders are frequent complications, especially in elderly patients, with postoperative delirium being its most pronounced and acute postoperative form, predisposing the patient for long-term cognitive impairment. The incidence of postoperative cognitive decline can be reduced by implementing preventive measures during perioperative patient care as recommended by national and international guidelines.
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Anestesia , Trastornos del Conocimiento , Delirio , Anciano , Anestesia/efectos adversos , Trastornos del Conocimiento/etiología , Humanos , Complicaciones Posoperatorias , Periodo Posoperatorio , Calidad de VidaRESUMEN
BACKGROUND: In acute respiratory distress syndrome (ARDS), pulmonary perfusion failure increases physiologic dead space ventilation (VD/VT), leading to a decline of the alveolar CO2 concentration [CO2]iA. Although it has been shown that alveolar hypocapnia contributes to formation of atelectasis and surfactant depletion, a typical complication in ARDS, the underlying mechanism has not been elucidated so far. METHODS: In isolated perfused rat lungs, cytosolic or mitochondrial Ca2+ concentrations ([Ca2+]cyt or [Ca2+]mito, respectively) of alveolar epithelial cells (AECs), surfactant secretion and the projected area of alveoli were quantified by real-time fluorescence or bright-field imaging (n=3-7 per group). In ventilated White New Zealand rabbits, the left pulmonary artery was ligated and the size of subpleural alveoli was measured by intravital microscopy (n=4 per group). Surfactant secretion was determined in the bronchoalveolar lavage (BAL) by western blot. RESULTS: Low [CO2]iA decreased [Ca2+]cyt and increased [Ca2+]mito in AECs, leading to reduction of Ca2+-dependent surfactant secretion, and alveolar ventilation in situ. Mitochondrial inhibition by ruthenium red or rotenone blocked these responses indicating that mitochondria are key players in CO2 sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO2 to the inspiratory gas inhibited these responses. CONCLUSIONS: Accordingly, we provide evidence that alveolar hypocapnia leads to a Ca2+ shift from the cytosol into mitochondria. The subsequent decline of [Ca2+]cyt reduces surfactant secretion and thus regional ventilation in lung regions with high VD/VT. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO2 application.
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Hipocapnia/etiología , Mitocondrias/fisiología , Surfactantes Pulmonares/metabolismo , Síndrome de Dificultad Respiratoria/etiología , Volumen de Ventilación Pulmonar/fisiología , Animales , Modelos Animales de Enfermedad , Alveolos Pulmonares/irrigación sanguínea , Ratas , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/fisiopatologíaRESUMEN
PURPOSE OF REVIEW: Neurocognitive dysfunction after surgery is highly relevant in the elderly. The multifactorial manner of this syndrome has made it hard to define an ideal biomarker to predict individual risk and assess diagnosis and severity of delirium [postoperative delirium (POD)] and subsequent postoperative cognitive decline (POCD). This review summarizes recent literature on blood biomarkers for POD/POCD. RECENT FINDINGS: Markers for delirium have been searched for in the cerebrospinal fluid to examine the pathologic cascade. However, cerebrospinal fluid cannot be easily obtained in the perioperative setting. Thus, attention shifts toward prediction markers from patients' blood to determine the individual risk. In this regard, three major groups of peripheral blood markers could be distinguished: first, global, but unspecific markers associated with POD/POCD; second, specific and established markers related to neurocognitive function; and third, upcoming or newly described markers with less evidence. Solely neuron-specific enolase is an adequate biomarker based on recent literature. SUMMARY: Single markers for postoperative cognitive impairment cannot predict POD/POCD in geriatric patients. However, a wisely arranged battery of promising biomarkers might achieve a satisfying sensitivity and specificity for the preoperative assessment of subsequent cognitive decline. Adequately powered studies to prove this hypothesis are required.
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Anestesia/efectos adversos , Disfunción Cognitiva/diagnóstico , Delirio del Despertar/diagnóstico , Procedimientos Quirúrgicos Operativos/efectos adversos , Factores de Edad , Anciano , Envejecimiento/fisiología , Biomarcadores/análisis , Cognición/efectos de los fármacos , Disfunción Cognitiva/etiología , Delirio del Despertar/etiología , Estudios de Factibilidad , Humanos , Periodo Posoperatorio , Valor Predictivo de las Pruebas , Pronóstico , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
Background: It remains unknown whether there is a causal relationship between intraoperative hypotension and postoperative neurocognitive disorders. We tested the hypothesis that personalised-compared to routine-intraoperative blood pressure management reduces the incidence of postoperative neurocognitive disorders in patients having major noncardiac surgery. Methods: In this single-centre trial, 328 elective major noncardiac surgery patients were randomly allocated to receive personalised blood pressure management (i.e. maintaining intraoperative mean arterial pressure [MAP] above preoperative baseline MAP from automated 24-h blood pressure monitoring) or routine blood pressure management (i.e. maintaining MAP above 65 mm Hg). The primary outcome was the incidence of neurocognitive disorders (composite of delayed neurocognitive recovery and delirium) between postoperative days 3 and 7. Results: The primary outcome, neurocognitive disorders, occurred in 18 of 147 patients (12%) assigned to personalised and 21 of 148 patients (14%) assigned to routine blood pressure management (odds ratio [OR]=0.84, 95% confidence interval [CI]: 0.40-1.75, P=0.622). Delayed neurocognitive recovery occurred in 17 of 146 patients (12%) assigned to personalised and 17 of 145 patients (12%) assigned to routine blood pressure management (OR=0.99, 95% CI: 0.45-2.17, P=0.983). Delirium occurred in 2 of 157 patients (1%) assigned to personalised and 4 of 158 patients (3%) assigned to routine blood pressure management (OR=0.50, 95% CI: 0.04-3.53, P=0.684). Conclusions: Personalised intraoperative blood pressure management maintaining preoperative baseline MAP neither reduced the incidence of the composite primary outcome neurocognitive disorders between postoperative days 3 and 7 nor the incidences of the components of the composite primary outcome-delayed neurocognitive recovery and delirium-compared to routine blood pressure management in patients having major noncardiac surgery. Clinical trial registration: ClinicalTrials.gov (NCT03442907).
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As octogenarians in the operation room are no longer an exemption but the norm, perioperative management needs to be adopted to meet the special requirements of this group of patients. Anesthesia does not need to be re-invented to fit the elderly. However, as elderly patients are among those most affected by adverse postoperative outcomes, the same diligence that is as a matter of course exercised in anesthesiologic care of the youngest patients' needs to be exercised for the eldest as well. Aging is associated with characteristic physiologic changes and an overall reduction in compensation width. However, the individual relevance of these changes varies distinctly. A comprehensive preoperative assessment is therefore essential to identify those at high risk. Maintaining functionality and preventing cognitive decline are central elements of perioperative care for frail elders, often only requiring unspectacular, but effective adjustments to established routine care processes. This review focuses on current recommendations in the perioperative anesthesiologic management of elderly patients with a view towards assisting clinical anesthesiologists in implementing respective structures in their setting and adjusting care pathways to meet the needs of this vulnerable but growing group of patients and improve their postoperative outcome.
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Anestesia , Disfunción Cognitiva , Anciano , Anciano de 80 o más Años , Envejecimiento , Humanos , Atención PerioperativaRESUMEN
Recently, we reported on three patients with chronic hepatitis B virus (HBV) infection for whom adefovir (ADF) therapy virologically failed, most likely due to a preexisting rtI233V HBV polymerase mutation. Here, we describe two further patients with chronic HBV infection who were found to develop the rtI233V mutation after initiation of ADF therapy. These patients represent the first cases known so far in which the rtI233V ADF resistance mutation evolved under persistent HBV replication during HBV therapy with ADF. Interestingly, one of the previously described patients, who was initially successfully switched from ADF to tenofovir (TDF) and became virologically suppressed subsequently, experienced a moderate but remarkable rebound of HBV viremia after switching from TDF to entecavir, due to the emergence of renal toxicity. Thus, we provide evidence for the selection and counterselection of the rtI233V ADF resistance mutation during antiviral therapy.
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Adenina/análogos & derivados , Antivirales/uso terapéutico , Farmacorresistencia Viral , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Mutación Missense , Organofosfonatos/uso terapéutico , Adenina/farmacología , Adenina/uso terapéutico , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Antivirales/farmacología , Femenino , Guanina/análogos & derivados , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/aislamiento & purificación , Humanos , Masculino , Datos de Secuencia Molecular , Organofosfonatos/farmacología , Selección Genética , Alineación de Secuencia , Tenofovir , Insuficiencia del Tratamiento , Viremia , Adulto JovenRESUMEN
BACKGROUND: The share of elderly patients undergoing emergency surgery is constantly increasing. Their postoperative outcome remains poor, even if surgery itself is survived in the short or medium term. OBJECTIVES: Important aspects of anesthesiologic care for older emergency patients based upon recent literature and guideline recommendations are presented. METHODS: Selective review of the literature, considering national and international guidelines, meta-analysis and Cochrane reviews. CONCLUSION: Anesthesiologic care can significantly influence the perioperative outcome of elderly emergency surgery patients. In this context, emergency anesthesiology exceeds mere anesthesia itself and applies to the overall perioperative management.
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Anestesia Dental , Anestesiología , Servicio de Urgencia en Hospital , Anciano , Urgencias Médicas , Humanos , Metaanálisis como Asunto , Complicaciones PosoperatoriasRESUMEN
INTRODUCTION: With increasing age, the risk of complications after surgery rises in elderly patients. Furthermore, the prevalence of multimorbidity and polypharmacy rises with age, making this elderly population especially vulnerable for drug-related problems and posing an additional risk for postoperative complications. Still, only few studies have concentrated on investigating how medication safety can be improved in these patients. The aim of this pilot study is to examine the impact of a comprehensive intervention (interprofessional systematic medication therapy management) on medication appropriateness in elderly polymedicated, multimorbid patients during hospital stay for elective surgery. METHODS AND ANALYSIS: This pilot study will include a total number of 140 patients. Surgical high-risk patients ≥65 years taking more than five chronic systemic drugs will be recruited consecutively for 9 months in the control group capturing usual care regarding medication history and in-hospital medication therapy management without any study intervention. Recruitment of the intervention group will be conducted for another 9 months. The intervention consists of the following components: an additional medication history by a hospital pharmacist before admission, a subsequent medication review, optimisation of the long-term medication and recommendations to the patient's general practitioner. A follow-up will be performed 3 months after surgery. As the primary study outcome, medication appropriateness will be measured using the Medication Appropriateness Index.Secondary outcomes are postoperative complications, incidence and frequency of adverse drug reactions and potentially inappropriate medication in the elderly, satisfaction with inpatient and outpatient care, medication reconciliation and health-related quality of life. Multivariable analyses will be used to analyse all quantitative research questions. ETHICS AND DISSEMINATION: Ethics approval was obtained by the medical ethics committee of the Medical Chamber of Hamburg (study ID: PV5754). Data will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: The study is registered at www.drks.de: DRKS00014621.
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Calidad de Vida , Anciano , Humanos , Prescripción Inadecuada , Preparaciones Farmacéuticas , Proyectos Piloto , Polifarmacia , Reproducibilidad de los ResultadosRESUMEN
The reverse-transcriptase inhibitor lamivudine (Zeffix, GlaxoSmithKline) is often used to treat chronic infection with hepatitis B virus (HBV) until resistance develops. Treatment may then be switched to the reverse-transcriptase inhibitor adefovir (Hepsera, Gilead), which has a lower frequency of resistance. Here, we describe three cases of primary adefovir resistance that were sensitive to tenofovir (Viread, Gilead). All three cases involved a rare HBV variant with a valine at position 233 of the reverse-transcriptase domain instead of isoleucine (rtI233V), as in the wild-type virus. This HBV variant also displayed resistance to adefovir and sensitivity to tenofovir in vitro.
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Adenina/análogos & derivados , Farmacorresistencia Viral , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Organofosfonatos/uso terapéutico , ADN Polimerasa Dirigida por ARN/genética , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adenina/farmacología , Adenina/uso terapéutico , Secuencia de Aminoácidos , Antivirales/farmacología , Antivirales/uso terapéutico , ADN Viral/biosíntesis , Farmacorresistencia Viral/genética , Femenino , Hepatitis B Crónica/virología , Humanos , Lamivudine/farmacología , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Organofosfonatos/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Tenofovir , ViremiaRESUMEN
BACKGROUND: Elderly patients are a growing and vulnerable group with an elevated perioperative risk. Perioperative treatment pathways that take these patients' special risks and requirements into account are often not implemented in routine clinical practice. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, the AWMF guideline database, and the Cochrane database for guidelines from Germany and abroad, meta-analyses, and Cochrane reviews. RESULTS: The care of elderly patients who need surgery calls for an interdisciplinary, interprofessional treatment concept. One component of this concept is preoperative preparation of the patient ("prehabilitation"), which is best initiated before hospital admission, e.g., correction of deficiency states, optimization of chronic drug treatment, and respiratory training. Another important component consists of pre-, intra-, and postoperative measures to prevent delirium, which can lower the frequency of this complication by 30-50%: these include orientation aids, avoidance of inappropriate drugs for elderly patients, adequate analgesia, early mobilization, short fasting times, and a perioperative nutrition plan. Preexisting cognitive impairment predisposes to postoperative delirium (odds ratios [OR] ranging from 2.5 to 4.5). Frailty is the most important predictor of the postoperative course (OR: 2.6-11). It follows that preoperative assessment of the patient's functional and cognitive status is essential. CONCLUZION: The evidence-based and guideline-consistent care of elderly patients requires not only close interdisciplinary, interprofessional, and cross-sectoral collaboration, but also the restructuring and optimization of habitual procedural pathways in the hospital. Elderly patients' special needs can only be met by a treatment concept in which the entire perioperative phase is considered as a single, coherent process.
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Atención Perioperativa , Anciano , HumanosRESUMEN
BACKGROUND: Older patients are undergoing surgery in increasing numbers. Frailty is a key risk factor associated with higher rates of complications and mortality, longer hospital stays, and functional impairment. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, including guidelines from Germany and abroad. RESULTS: Many studies have been published on the assessment of frailty and its consequences, but the scientific investigation of this topic and the clinical utility of the findings are made more difficult by the lack of a uniform definition and of uniform instruments for assessment. Some definitions of frailty include only physical aspects, while others encompass cognitive, emotional, and social factors as well. Despite this variability, the assessment of frailty enables better estimation of the perioperative risk so that the patient can be optimally prepared for the operation. Especially for frail elderly patients, an interdisciplinary approach is called for over the entire perioperative treatment period. CONCLUSION: In the future, the definition of frailty will need to be standardized so that this parameter can be properly assessed and investigated in comparative studies.
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Anciano Frágil , Atención Perioperativa , Anciano , Humanos , Resultado del TratamientoRESUMEN
INTRODUCTION: Geriatric patients have a pronounced risk to suffer from postoperative complications. While effective risk-specific perioperative measures have been studied in controlled experimental settings, they are rarely found in routine healthcare. This study aims (1) to implement a multicomponent preoperative and intraoperative intervention, and investigate its feasibility, and (2) exploratorily assess the effectiveness of the intervention in routine healthcare. METHODS AND ANALYSIS: Feasibility and exploratory effectiveness of the intervention will be investigated in a monocentric, prospective, non-randomised, controlled trial. The intervention includes systematic information for patients and family about measures to prevent postoperative complications; preoperative screening for frailty, malnutrition, strength and mobility with nutrient supplementation and physical exercise (prehabilitation) as needed. Further components focus on potentially inadequate medication, patient blood-management and carbohydrate loading prior to surgery, retainment of orientation aids in the operating room and a geriatric anaesthesia concept. Data will successively be collected from control, implementation and intervention groups. Patients aged 65+ with impending surgery will be included. A sample size of 240, n=80 per group, is planned. Assessments will take place at inclusion and 2, 30 and 180 days after surgery. Mixed-methods analyses will be performed. Exploratory effectiveness will be assessed using mixed segmented regressions. The primary endpoint is functional status. Secondary endpoints include cognitive performance, health-related quality of life, length of inpatient stay and occurrence of postoperative complications. Feasibility will be assessed through semi-structured interviews with staff and patients and quantitative analyses of the data quality, focussing on practicability, acceptance, adoption and fidelity to protocol. ETHICS AND DISSEMINATION: The study will be carried out in accordance with the Helsinki Declaration and to principles of good scientific practice. The Ethics Committee of the Medical Association Hamburg, Germany, approved the protocol (study ID: PV5596). Results will be disseminated in scientific journals and healthcare conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03325413.
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Ensayos Clínicos Controlados como Asunto/métodos , Atención Perioperativa/normas , Complicaciones Posoperatorias/prevención & control , Anciano , Estudios de Factibilidad , Humanos , Estudios ProspectivosRESUMEN
INTRODUCTION: Hip fracture surgery is associated with high in-hospital and 30-day mortality rates and serious adverse patient outcomes. Evidence from randomised controlled trials regarding effectiveness of spinal versus general anaesthesia on patient-centred outcomes after hip fracture surgery is sparse. METHODS AND ANALYSIS: The iHOPE study is a pragmatic national, multicentre, randomised controlled, open-label clinical trial with a two-arm parallel group design. In total, 1032 patients with hip fracture (>65 years) will be randomised in an intended 1:1 allocation ratio to receive spinal anaesthesia (n=516) or general anaesthesia (n=516). Outcome assessment will occur in a blinded manner after hospital discharge and inhospital. The primary endpoint will be assessed by telephone interview and comprises the time to the first occurring event of the binary composite outcome of all-cause mortality or new-onset serious cardiac and pulmonary complications within 30 postoperative days. In-hospital secondary endpoints, assessed via in-person interviews and medical record review, include mortality, perioperative adverse events, delirium, satisfaction, walking independently, length of hospital stay and discharge destination. Telephone interviews will be performed for long-term endpoints (all-cause mortality, independence in walking, chronic pain, ability to return home cognitive function and overall health and disability) at postoperative day 30±3, 180±45 and 365±60. ETHICS AND DISSEMINATION: iHOPE has been approved by the leading Ethics Committee of the Medical Faculty of the RWTH Aachen University on 14 March 2018 (EK 022/18). Approval from all other involved local Ethical Committees was subsequently requested and obtained. Study started in April 2018 with a total recruitment period of 24 months. iHOPE will be disseminated via presentations at national and international scientific meetings or conferences and publication in peer-reviewed international scientific journals. TRIAL REGISTRATION NUMBER: DRKS00013644; Pre-results.
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Anestesia General/métodos , Anestesia Raquidea/métodos , Protocolos de Ensayos Clínicos como Asunto , Fracturas de Cadera/cirugía , Complicaciones Posoperatorias/prevención & control , Anciano , Artroplastia de Reemplazo de Cadera , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Dolor Postoperatorio/prevención & control , Ensayos Clínicos Pragmáticos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de InvestigaciónRESUMEN
In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (VD/VT) correlating with mortality. High VD/VT results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.