Beneficial Effects of Halogenated Anesthetics in Cardiomyocytes: The Role of Mitochondria.

In the last few years, the use of anesthetic drugs has been related to effects other than those initially related to their fundamental effect, hypnosis. Halogenated anesthetics, mainly sevoflurane, have been used as a therapeutic tool in patients undergoing cardiac surgery, thanks to the beneficial effect of the cardiac protection they generate. This effect has been described in several research studies. The mechanism by which they produce this effect has been associated with the effects generated by anesthetic preconditioning and postconditioning. The mechanisms by which these effects are induced are directly related to the modulation of oxidative stress and the cellular damage generated by the ischemia/reperfusion procedure through the overexpression of different enzymes, most of them included in the Reperfusion Injury Salvage Kinase (RISK) and the Survivor Activating Factor Enhancement (SAFE) pathways. Mitochondria is the final target of the different routes of pre- and post-anesthetic conditioning, and it is preserved from the damage generated in moments of lack of oxygen and after the recovery of the normal oxygen concentration. The final consequence of this effect has been related to better cardiac function in this type of patient, with less myocardial damage, less need for inotropic drugs to achieve normal myocardial function, and a shorter hospital stay in intensive care units. The mechanisms through which mitochondrial homeostasis is maintained and its relationship with the clinical effect are the basis of our review. From a translational perspective, we provide information regarding mitochondrial physiology and physiopathology in cardiac failure and the role of halogenated anesthetics in modulating oxidative stress and inducing myocardial conditioning.

The Role of Anesthetic Drugs and Statins in Prostate Cancer Recurrence: Starting at the Actual Knowledge and Walking through a New Paradigm.

Prostate cancer has become a major health problem in men. Its incidence is increasing as the average age of the affected population tends to be higher. Of all the possible treatments, surgery is the gold standard in its treatment. Surgery produces a deregulation in the immune system that can favour the development of distant metastases. Different anesthetic techniques have raised the hypothesis that different anesthetic drugs influence tumor recurrence and prognosis. Some mechanisms are beginning to be understood by which halogenated agents in cancer patients and the use of opioids may negatively affect patients. In this document, we group together all the available evidence on how the different anesthetic drugs affect tumor recurrence in prostate cancer.

Anesthesia and Cancer: Something More than Avoiding Stress Response.

Currently, an increasing prevalence has been reported in incidences of tumor pathologies. The influence of anesthetics drugs has been the subject of numerous studies. It has been reported that the use of certain drugs may have an impact on prognosis and survival. By investigating the action of these drugs on different metabolic pathways and their mechanisms of action, we can better understand how they influence various hallmarks of carcinogenesis and determine their potential impact on cancer progression. Some of the action pathways are widely known within oncology, being targets of specific treatments, such as PI3k/AKT/mTOR, EGFR, and Wnt/ ß-catenin. This review performs a thorough dissection of the interaction between anesthetic drugs and oncological cell lines through cell signaling pathways and genetic, immune, and transcriptomic pathways. Through these underlying mechanisms, it aims to clarify the effect of the choice of anesthetic drug and its potential influence on the prognosis of oncological surgery.

Opioid-Free Anaesthesia Improves Anaesthesia Recovery when Compared with that of Opioid-Based Anaesthesia. Systematic Review and Meta-Analysis of Clinical Trials.

INTRODUCTION: Opioid Free Anesthesia (OFA) is a relatively new technique that has been questioned due to the lack of evidence regarding its benefit-risk balance. METHODS: Four international databases were searched for clinical trials comparing OFA with opioid based anesthesia. The primary outcome was pain control and the secondary included postoperative nausea and vomiting (PONV), gastrointestinal recovery, respiratory depression, urinary retention, length of hospital stay, surgical complications, number of patients with cessation of the intervention and other side effects. RESULTS: Pain was better controlled in the OFA group in all the measurements made (VAS 1h: Md = -0.81, CI95% = -0.48- -1.14, VAS 24h: Md = -1.25, CI95% =-2.41- -0.1, VAS >24h: Md = -1.36, CI95% = -1.73- -1). In the opioid group there was an increase in the risk of nausea (RR=2.69, CI95% = 2-3.61) and vomiting (RR = 3.99, CI95% = 2.06-7.74), whilst in the OFA group, there was an increased risk of bradycardia (RR= 1.62, CI95% = 1.02-2.57). The rest of the variables showed no differences between groups or could not be analyzed. CONCLUSION: There is a clear benefit of OFA in pain control and PONV, but there is also a higher risk of bradycardia. This technique should be considered in patients with a special risk of difficult postoperative pain control or PONV. However, the best drug combination to perform OFA is still unknown, as well as the type of patient that benefits more with less risk.

The Prognostic Value of Previous Coronary Stent Implantation in Patients Undergoing Myocardial Revascularization Surgery.

BACKGROUND: Currently, studies are underway to determine whether coronary stent implantation with percutaneous transluminal coronary angioplasty before a coronary artery bypass graft (CABG) influences the prognosis of surgery. This study aimed to assess the need for future revascularisation or all-cause mortality as a composite endpoint after CABG surgery among patients with previous stent implantation. METHODS: A retrospective, non-randomised study was performed on 721 patients who underwent CABGin our centre between 2012 and 2017. This single-centre study compared two groups: 1) the previous stent group, patients with previous stent implantation (n=144), and 2) the non-previous stent group, patients without previous stent implantation (n=577). RESULTS: After a median follow-up of 36 months, the previous stent group presented a decreased combined event-free survival at 1, 3 and 5 years compared with the non-previous stent group (67.4, 43.5 and 23.0% vs. 91.0, 80.3 and 63.0%, respectively; p<0.01). There was also higher mortality in the previous stent group than in the non-previous stent group (96.1, 90.5 and 79.4 vs. 91.9, 75.9 and 51.0, respectively; p=0.01). The multivariable analysis of demographics, baseline comorbidity and surgical data showed previous stent implantation as an independent predictor of the composite endpoint (Hazard Ratio=3.00 and 95% confident interval=2.09-4.32; p<0.01). CONCLUSION: Patients with percutaneous coronary intervention before CABG present higher comorbidities and clinical events during follow-up than those who do not undergo stenting.

Comparison of the Use of Desflurane vs. Propofol in Aortic Valve Replacement Surgery: Differences in Nephroprotection: An Explorative and Hypothesis-Generating Study.

Introduction: The cardioprotective effect of halogenated drugs in cardiac surgery has been the subject of several studies. However, there is scarcity of data on their potential nephroprotective effects. Aortic valve replacement and coronary revascularization are the most frequent cardiac surgery procedures. The objective of this explorative study was to examine the effect of desflurane vs. propofol on renal function, when administered in aortic valve replacement surgery, including the extracorporeal circulation period. Method: A quasi-experimental prospective study was performed in 60 patients, who were allocated to receive either desflurane or propofol intraoperatively during aortic valve replacement surgery. As a hypnotic, group 1 received propofol, whereas group 2 received desflurane. Markers of renal function and level of cardiac preservation were determined based on biochemical parameters (troponin I, NTProBNP). Results: In the propofol group, there were significant variations between postoperative values of urinary NGAL and creatinine and baseline values. In contrast, no variations were found in the desflurane group in terms of hemodynamic parameters and myocardial damage. Conclusions: The use of propofol vs. desflurane during aortic valve replacement surgery is associated with a decrease in renal function.

COVID-19 pandemic and nurse teaching: Our experience.

In this letter to the editor, we would like to show in our hospital how our nurse team manage formation during coronavirus disease 2019 pandemic.

Clevidipine and COVID 19: From Hypertension to Inflammatory Response.

Globally, more than 4 million have died from COVID-19, World Health Organization (WHO) to declare COVID-19 a pandemic. The COVID 19 pathology, produced by SARS-COV2, a virus from the coronavirus family, emerged at the end of 2019. The majority of cases usually have a mild or moderate form, characterized by fever, cough, intense asthenia and multiple symptoms derived from the initial replicative effect and subsequent hyperimmune effect. Severe cases present with Acute Respiratory Distress Syndrome (ARDS), due to pneumonia with bilateral involvement, which lead to hospital admission of patients and the need for admission to intensive care units (ICU) of approximately 10‒20%. According to the different series; the mortality of the condition once the patient is admitted to the ICU is close to 35‒45%. Currently, more than 4 million people have died in the world due to this pathology. The volume of infections generated the declaration by the World Health Organization (WHO) of the pandemic situation. Factors associated with a higher risk of progression into severe disease include age and comorbidities, especially systemic arterial hypertension due to its high incidence in the general population. Clevidipine can be rapidly and effectively adjusted to the clinical status of the patient, since it can be withdrawn and its effects reversed in just a few minutes, and contains high concentrations of lipids, and it could reduce the inflammatory response induced by SARS-COV2, which is key to progression into severe disease. However, its application in pro-inflammatory settings has not yet been explored, although it must play a key role in inflammation as a scavenger molecule.

Heart Failure after Cardiac Surgery: The Role of Halogenated Agents, Myocardial Conditioning and Oxidative Stress.

Heart disease requires a surgical approach sometimes. Cardiac-surgery patients develop heart failure associated with ischemia induced during extracorporeal circulation. This complication could be decreased with anesthetic drugs. The cardioprotective effects of halogenated agents are based on pre- and postconditioning (sevoflurane, desflurane, or isoflurane) compared to intravenous hypnotics (propofol). We tried to put light on the shadows walking through the line of the halogenated anesthetic drugs' effects in several enzymatic routes and oxidative stress, waiting for the final results of the ACDHUVV-16 clinical trial regarding the genetic modulation of this kind of drugs.

Identification of miRNAs as Biomarkers of Cardiac Protection in Non-Genetically Modified Primary Human Cardiomyocytes Exposed to Halogenated Hypnotics in an In Vitro Model of Transfection and Ischemia/Reperfusion: A New Model in Translational Anesthesia.

BACKGROUND: Many clinical studies have identified some circulating micro-RNAs (miRNAs) as potential biomarkers with regard to the cardioprotective effects of halogenated agents administered perioperatively during myocardial conditioning procedures. However, there is a major methodological difficulty in identifying these potential miRNA targets in cardiac cells. METHODS: We developed an in vitro protocol to analyze the differential expression of target miRNAs at the intracellular level in non-genetically modified primary human cardiomyocytes (HCMs) through their exposure to different hypnotic compounds (i.e., halogenated versus non-halogenated). For this purpose, we performed a validated in vitro model of "ischemia and reperfusion" with the transfection of specific miRNA mimics (MIMICs) designed to simulate naturally occurring mature miRNAs as a functional study. Afterwards, next-generation sequencing (NGS) was used to identify and quantify miRNAs and elucidate their function. The differences in miRNA expression between HCMs exposed to different hypnotic drugs, along with the prediction of functional miRNA targets, were assessed using a meticulous in-house bioinformatics pipeline in order to derive diagnostic biomarkers and possible therapeutic targets. CONCLUSION: In brief, this methodological procedure was designed to investigate whether the cardioprotective effects of halogenated agents are a phenomenon mediated by either the activation or the suppression of miRNAs targeted by halogenated anesthetics.

Breast Cancer and Anaesthesia: Genetic Influence.

Breast cancer is the leading cause of mortality in women. It is a heterogeneous disease with a high degree of inter-subject variability even in patients with the same type of tumor, with individualized medicine having acquired significant relevance in this field. The clinical and morphological heterogeneity of the different types of breast tumors has led to a diversity of staging and classification systems. Thus, these tumors show wide variability in genetic expression and prognostic biomarkers. Surgical treatment is essential in the management of these patients. However, the perioperative period has been found to significantly influence survival and cancer recurrence. There is growing interest in the pro-tumoral effect of different anaesthetic and analgesic agents used intraoperatively and their relationship with metastatic progression. There is cumulative evidence of the influence of anaesthetic techniques on the physiopathological mechanisms of survival and growth of the residual neoplastic cells released during surgery. Prospective randomized clinical trials are needed to obtain quality evidence on the relationship between cancer and anaesthesia. This document summarizes the evidence currently available about the effects of the anaesthetic agents and techniques used in primary cancer surgery and long-term oncologic outcomes, and the biomolecular mechanisms involved in their interaction.

Case Report: COVID-19 with cytokine storm in a 16-year-old patient: if heart failures comes think about levosimendan.

Introduction: Our case is unique because the differential diagnosis was a challenge. At first, the patient presented with septic shock and multi-organ failure in the context of a suspected lymphoproliferative syndrome. Once the lymphoproliferative process had been ruled out, hemophagocytic syndrome due to COVID-19 infection was suspected, so he is probably one of the few patients with such an exhaustive study that could contribute to our understanding of COVID-19. We followed therapeutic guidelines that differ from the usual, using adrenalin and levosimendan. Corticosteroids helped to modulate the cytokine storm. Case report: A 16-year-old adolescent was admitted to the intensive care unit with fever, diarrhea, multiorgan failure and septic shock. He was IgG positive for COVID-19 and IgM negative. Thoraco-abdominal computed tomography demonstrated multiple para-aortic and peri-pancreatic lymphadenopathy and acute respiratory distress syndrome. The first suspected diagnosis was a lymphoproliferative syndrome and bacterial infection. The second possibility was a hemophagocytic syndrome in a patient recovering from COVID-19. He was treated with broad spectrum antibiotics because the differential diagnosis was difficult, and we removed them when the microbiological screening was negative. During the course of the disease he presented with severe biventricular dysfunction, probably due to the cytokine storm, so we used inotropic drugs (adrenaline, levosimendan). Infection with Salmonella species group B was diagnosed later, when the patient was in the Internal Medicine ward, although he was asymptomatic. Conclusion: The severity of COVID-19 infection ranges from mild to severe, causing serious disease in some people. Although the pathophysiology is not well known, it seems that in some cases an immune storm is triggered, and it is related to more serious and prolonged disease. In our case, heart failure was important, because it could have worsened the prognosis. Fortunately, the response to levosimendan and corticosteroids was adequate and he recovered favorably until discharge.

Anesthesia in Combination with Propofol Increases Disease-Free Survival in Bladder Cancer Patients Who Undergo Radical Tumor Cystectomy as Compared to Inhalational Anesthetics and Opiate-Based Analgesia.

BACKGROUND: The effect of anesthetic techniques on cancer recurrence has been the subject of intensive research in the past years, as it affects a large proportion of the population. The use of opioids and halogenated agents in cancer patients during the perioperative period may be related to higher rates of cancer recurrence and reduced disease-free survival. METHODS: This was a prospective study. The sample was composed of 100 patients who underwent a radical cystectomy for infiltrating bladder cancer in a reference center. We compared disease-free survival associated with combined anesthesia versus opiate-based analgesia. The relationship between the administered hypnotic and disease-free survival was also investigated. RESULTS: The median disease-free survival of the patients who received combined anesthesia was 585 (240-1,005) days versus 210 (90-645) days in the other group. A significant difference was observed between the two groups (p = 0.01). Combined analysis of all groups revealed significant differences in disease-free survival between patients who received combined anesthesia with propofol (510 [315-1,545] disease-free days) and those who received sevoflurane and opioids (150 [90-450] disease-free days) (p = 0.02). CONCLUSIONS: Anesthesia may play a crucial role in tumor relapse, as it is administered at the moment of the greatest risk of dissemination: surgical handling of the tumor. Opioids and volatile agents have been related to an increased risk for cancer recurrence. We compared the use of propofol + local anesthesia versus sevoflurane + opioids and also found that disease-free survival was longer among patients who received propofol + local anesthesia. Disease-free survival increases with the use of propofol in combination with epidural anesthesia in patients who undergo surgery for infiltrating bladder cancer.

Anesthetic-induced Myocardial Conditioning: Molecular Fundamentals and Scope.

BACKGROUND: The pre- and post-conditioning effects of halogenated anesthetics make them most suitable for cardiac surgery. Several studies have demonstrated that the mechanism of drug-induced myocardial conditioning is enzyme-mediated via messenger RNA and miRNA regulation. The objective of this study was to investigate the role that miRNAs play in the cardioprotective effect of halogenated anesthetics. For such purpose, we reviewed the literature to determine the expression profile of miRNAs in ischemic conditioning and in the complications prevented by these phenomena. METHODS: A review was conducted of more than 100 studies to identify miRNAs involved in anesthetic-induced myocardial conditioning. Our objective was to determine the miRNAs that play a relevant role in ischemic disease, heart failure and arrhythmogenesis, which expression is modulated by the perioperative administration of halogenated anesthetics. So far, no studies have been performed to assess the role of miRNAs in anesthetic-induced myocardial conditioning. The potential of miRNAs as biomarkers and miRNAs-based therapies involving the synthesis, inhibition or stimulation of miRNAs are a promising avenue for future research in the field of cardiology. RESULTS: Each of the cardioprotective effects of myocardial conditioning is related to the expression of several (not a single) miRNAs. The cumulative evidence on the role of miRNAs in heart disease and myocardial conditioning opens new therapeutic and diagnostic opportunities. CONCLUSION: Halogenated anesthetics regulate the expression of miRNAs involved in heart conditions. Further research is needed to determine the expression profile of miRNAs after the administration of halogenated drugs. The results of these studies would contribute to the development of new hypnotics for cardiac surgery patients.

Preservation of renal function in cardiac surgery patients with low cardiac output syndrome: levosimendan vs beta agonists.

BACKGROUND: Some studies have been performed to assess the effects of levosimendan on cardiac function when administered to cardiac surgery patients with low cardiac output syndrome (LCOS) in the immediate postoperative period. Levosimendan is an inotropic agent for the treatment of low cardiac output syndrome that seems to have a protective effect on renal function. METHODS: It is a quasi-experimental study. A total of 100 patients with LCOS received either beta-agonists or levosimendan. We assessed the incidence of postoperative kidney failure in cardiac surgery patients. In patients who had kidney failure at diagnosis of LCOS, we examined whether differences existed in the evolution of kidney failure based on the treatment administered for LCOS. The parameters measured included haemodynamics, oxygen supply, and renal function as assessed by the AKI scale. ANOVA, Student's t-test and Wilcoxon or Friedman tests were used. RESULTS: Up to 30% of cardiac surgery patients had kidney failure at diagnosis of LCOS. Kidney failure at discharge from the ICU was more frequent in patients who received beta-agonist drugs as compared to those who received levosimendan (p < 0.05). CONCLUSION: The incidence of kidney failure decreased with the postoperative administration of levosimendan to cardiac surgery patients with LCOS, as compared to beta-agonists. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 46058317. Date of registration: 7/10/2019. Retrospectively registered.

How Anesthetic, Analgesic and Other Non-Surgical Techniques During Cancer Surgery Might Affect Postoperative Oncologic Outcomes: A Summary of Current State of Evidence.

The question of whether anesthetic, analgesic or other perioperative intervention during cancer resection surgery might influence long-term oncologic outcomes has generated much attention over the past 13 years. A wealth of experimental and observational clinical data have been published, but the results of prospective, randomized clinical trials are awaited. The European Union supports a pan-European network of researchers, clinicians and industry partners engaged in this question (COST Action 15204: Euro-Periscope). In this narrative review, members of the Euro-Periscope network briefly summarize the current state of evidence pertaining to the potential effects of the most commonly deployed anesthetic and analgesic techniques and other non-surgical interventions during cancer resection surgery on tumor recurrence or metastasis.

Cardioprotection with halogenated gases: how does it occur?

Numerous studies have studied the effect of halogenated agents on the myocardium, highlighting the beneficial cardiac effect of the pharmacological mechanism (preconditioning and postconditioning) when employed before and after ischemia in patients with ischemic heart disease. Anesthetic preconditioning is related to the dose-dependent signal, while the degree of protection is related to the concentration of the administered drug and the duration of the administration itself. Triggers for postconditioning and preconditioning might have numerous pathways in common; mitochondrial protection and a decrease in inflammatory mediators could be the major biochemical elements. Several pathways have been identified, including attenuation of NFκB activation and reduced expression of TNFα, IL-1, intracellular adhesion molecules, eNOS, the hypercontraction reduction that follows reperfusion, and antiapoptotic activating kinases (Akt, ERK1/2). It appears that the preconditioning and postconditioning triggers have numerous similar paths. The key biochemical elements are protection of the mitochondria and reduction in inflammatory mediators, both of which are developed in various ways. We have studied this issue, and have published several articles on cardioprotection with halogenated gases. Our results confirm greater cardioprotection through myocardial preconditioning in patients anesthetized with sevoflurane compared with propofol, with decreasing levels of troponin and N-terminal brain natriuretic peptide prohormone. The difference between our studies and previous studies lies in the use of sedation with sevoflurane in the postoperative period. The results could be related to a prolonged effect, in addition to preconditioning and postconditioning, which could enhance the cardioprotective effect of sevoflurane in the postoperative period. With this review, we aim to clarify the importance of various mechanisms involved in preconditioning and postconditioning with halogenated gases, as supported by our studies.

Cardiac, renal, and neurological benefits of preoperative levosimendan administration in patients with right ventricular dysfunction and pulmonary hypertension undergoing cardiac surgery: evaluation with two biomarkers neutrophil gelatinase-associated lipocalin and neuronal enolase.

PURPOSE: To evaluate if the preoperative administration of levosimendan in patients with right ventricular (RV) dysfunction, pulmonary hypertension, and high perioperative risk would improve cardiac function and would also have a protective effect on renal and neurological functions, assessed using two biomarkers neutrophil gelatinase-associated lipocalin (N-GAL) and neuronal enolase. METHODS: This is an observational study. Twenty-seven high-risk cardiac patients with RV dysfunction and pulmonary hypertension, scheduled for cardiac valve surgery, were prospectively followed after preoperative administration of levosimendan. Levosimendan was administered preoperatively on the day before surgery. All patients were considered high risk of cardiac and perioperative renal complications. Cardiac function was assessed by echocardiography, renal function by urinary N-GAL levels, and the acute kidney injury scale. Neuronal damage was assessed by neuron-specific enolase levels. RESULTS: After surgery, no significant variations were found in mean and SE levels of N-GAL (14.31 [28.34] ng/mL vs 13.41 [38.24] ng/mL), neuron-specific enolase (5.40 [0.41] ng/mL vs 4.32 [0.61] ng/mL), or mean ± SD creatinine (1.06±0.24 mg/dL vs 1.25±0.37 mg/dL at 48 hours). RV dilatation decreased from 4.23±0.7 mm to 3.45±0.6 mm and pulmonary artery pressure from 58±18 mmHg to 42±19 mmHg at 48 hours. CONCLUSION: Preoperative administration of levosimendan has shown a protective role against cardiac, renal, and neurological damage in patients with a high risk of multiple organ dysfunctions undergoing cardiac surgery.