The Impact of General Anesthesia on Redox Stability and Epigenetic Inflammation Pathways: Crosstalk on Perioperative Antioxidant Therapy.

Worldwide, the prevalence of surgery under general anesthesia has significantly increased, both because of modern anesthetic and pain-control techniques and because of better diagnosis and the increased complexity of surgical techniques. Apart from developing new concepts in the surgical field, researchers and clinicians are now working on minimizing the impact of surgical trauma and offering minimal invasive procedures due to the recent discoveries in the field of cellular and molecular mechanisms that have revealed a systemic inflammatory and pro-oxidative impact not only in the perioperative period but also in the long term, contributing to more difficult recovery, increased morbidity and mortality, and a negative financial impact. Detailed molecular and cellular analysis has shown an overproduction of inflammatory and pro-oxidative species, responsible for augmenting the systemic inflammatory status and making postoperative recovery more difficult. Moreover, there are a series of changes in certain epigenetic structures, the most important being the microRNAs. This review describes the most important molecular and cellular mechanisms that impact the surgical patient undergoing general anesthesia, and it presents a series of antioxidant therapies that can reduce systemic inflammation.

Multiparametric Monitoring of Hypnosis and Nociception-Antinociception Balance during General Anesthesia-A New Era in Patient Safety Standards and Healthcare Management.

The development of general anesthesia techniques and anesthetic substances has opened new horizons for the expansion and improvement of surgical techniques. Nevertheless, more complex surgical procedures have brought a higher complexity and longer duration for general anesthesia, which has led to a series of adverse events such as hemodynamic instability, under- or overdosage of anesthetic drugs, and an increased number of post-anesthetic events. In order to adapt the anesthesia according to the particularities of each patient, the multimodal monitoring of these patients is highly recommended. Classically, general anesthesia monitoring consists of the analysis of vital functions and gas exchange. Multimodal monitoring refers to the concomitant monitoring of the degree of hypnosis and the nociceptive-antinociceptive balance. By titrating anesthetic drugs according to these parameters, clinical benefits can be obtained, such as hemodynamic stabilization, the reduction of awakening times, and the reduction of postoperative complications. Another important aspect is the impact on the status of inflammation and the redox balance. By minimizing inflammatory and oxidative impact, a faster recovery can be achieved that increases patient safety. The purpose of this literature review is to present the most modern multimodal monitoring techniques to discuss the particularities of each technique.

Impact of General Anesthesia Guided by State Entropy (SE) and Response Entropy (RE) on Perioperative Stability in Elective Laparoscopic Cholecystectomy Patients-A Prospective Observational Randomized Monocentric Study.

Laparoscopic cholecystectomy is one of the most frequently performed interventions in general surgery departments. Some of the most important aims in achieving perioperative stability in these patients is diminishing the impact of general anesthesia on the hemodynamic stability and the optimization of anesthetic drug doses based on the individual clinical profile of each patient. The objective of this study is the evaluation of the impact, as monitored through entropy (both state entropy (SE) and response entropy (RE)), that the depth of anesthesia has on the hemodynamic stability, as well as the doses of volatile anesthetic. A prospective, observational, randomized, and monocentric study was carried out between January and December 2019 in the Clinic of Anesthesia and Intensive Care of the "Pius Brînzeu" Emergency County Hospital in Timișoara, Romania. The patients included in the study were divided in two study groups: patients in Group A (target group) received multimodal monitoring, which included monitoring of standard parameters and of entropy (SE and RE); while the patients in Group B (control group) only received standard monitoring. The anesthetic dose in group A was optimized to achieve a target entropy of 40-60. A total of 68 patients met the inclusion criteria and were allocated to one of the two study groups: group A (N = 43) or group B (N = 25). There were no statistically significant differences identified between the two groups for both demographical and clinical characteristics (p > 0.05). Statistically significant differences were identified for the number of hypotensive episodes (p = 0.011, 95% CI: [0.1851, 0.7042]) and for the number of episodes of bradycardia (p < 0.0001, 95% CI: [0.3296, 0.7923]). Moreover, there was a significant difference in the Sevoflurane consumption between the two study groups (p = 0.0498, 95% CI: [-0.3942, 0.9047]). The implementation of the multimodal monitoring protocol, including the standard parameters and the measurement of entropy for determining the depth of anesthesia (SE and RE) led to a considerable improvement in perioperative hemodynamic stability. Furthermore, optimizing the doses of anesthetic drugs based on the individual clinical profile of each patient led to a considerable decrease in drug consumption, as well as to a lower incidence of hemodynamic side-effects.

Cannabis Sativa Revisited-Crosstalk between microRNA Expression, Inflammation, Oxidative Stress, and Endocannabinoid Response System in Critically Ill Patients with Sepsis.

Critically ill patients with sepsis require a multidisciplinary approach, as this situation implies multiorgan distress, with most of the bodily biochemical and cellular systems being affected by the condition. Moreover, sepsis is characterized by a multitude of biochemical interactions and by dynamic changes of the immune system. At the moment, there is a gap in our understanding of the cellular, genetic, and molecular mechanisms involved in sepsis. One of the systems intensely studied in recent years is the endocannabinoid signaling pathway, as light was shed over a series of important interactions of cannabinoid receptors with biochemical pathways, specifically for sepsis. Furthermore, a series of important implications on inflammation and the immune system that are induced by the activity of cannabinoid receptors stimulated by the delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been noticed. One of the most important is their ability to reduce the biosynthesis of pro-inflammatory mediators and the modulation of immune mechanisms. Different studies have reported that cannabinoids can reduce oxidative stress at mitochondrial and cellular levels. The aim of this review paper was to present, in detail, the important mechanisms modulated by the endocannabinoid signaling pathway, as well as of the molecular and cellular links it has with sepsis. At the same time, we wish to present the possible implications of cannabinoids in the most important biological pathways involved in sepsis, such as inflammation, redox activity, immune system, and epigenetic expression.

Retraction Note to: Implications of Entropy and Surgical Pleth Index-guided general anaesthesia on clinical outcomes in critically ill polytrauma patients. A prospective observational non-randomized single centre study.

The authors have retracted this article [1]. After publication it was discovered that Table 1 which reports the clinical and demographical characteristics of the patients in the study contains a number of statistical and typographical errors. The data reported in this article are therefore unreliable. All authors agree with this retraction.

Assessment of Metabolic and Nutritional Imbalance in Mechanically Ventilated Multiple Trauma Patients: From Molecular to Clinical Outcomes.

The critically ill polytrauma patient is characterized by a series of metabolic changes induced by inflammation, oxidative stress, sepsis, and primary trauma, as well as associated secondary injuries associated. Metabolic and nutritional dysfunction in the critically ill patient is a complex series of imbalances of biochemical and genetic pathways, as well as the interconnection between them. Therefore, the equation changes in comparison to other critical patients or to healthy individuals, in which cases, mathematical equations can be successfully used to predict the energy requirements. Recent studies have shown that indirect calorimetry is one of the most accurate methods for determining the energy requirements in intubated and mechanically ventilated patients. Current research is oriented towards an individualized therapy depending on the energy consumption (kcal/day) of each patient that also takes into account the clinical dynamics. By using indirect calorimetry, one can measure, in real time, both oxygen consumption and carbon dioxide production. Energy requirements (kcal/day) and the respiratory quotient (RQ) can be determined in real time by integrating these dynamic parameters into electronic algorithms. In this manner, nutritional therapy becomes personalized and caters to the patients' individual needs, helping patients receive the energy substrates they need at each clinically specific time of treatment.

MicroRNA Expression is Associated with Sepsis Disorders in Critically Ill Polytrauma Patients.

A critically ill polytrauma patient is one of the most complex cases to be admitted to the intensive care unit, due to both the primary traumatic complications and the secondary post-traumatic interactions. From a molecular, genetic, and epigenetic point of view, numerous biochemical interactions are responsible for the deterioration of the clinical status of a patient, and increased mortality rates. From a molecular viewpoint, microRNAs are one of the most complex macromolecular systems due to the numerous modular reactions and interactions that they are involved in. Regarding the expression and activity of microRNAs in sepsis, their usefulness has reached new levels of significance. MicroRNAs can be used both as an early biomarker for sepsis, and as a therapeutic target because of their ability to block the complex reactions involved in the initiation, maintenance, and augmentation of the clinical status.

Analysis of oxidative stress-related markers in critically ill polytrauma patients: An observational prospective single-center study.

Critically ill polytrauma patients have increased production of free radicals (FRs) and consequent alterations in biochemical pathways, as well as disruption of cellular integrity, due to increased lipid peroxidation. The aim of this study was to investigate several biomarkers associated with increased oxidative stress in critically ill polytrauma patients, and to evaluate the effect of antioxidant treatment on the clinical outcome in these patients. A total of 67 polytrauma patients from an intensive care unit met the selection criteria. Antiox group included 35/67 patients who received antioxidant therapy, while 32/67 patients without antioxidant treatment were considered as control group. Antioxidant therapy consisted of simultaneous administration of Vitamin C (sodium ascorbate) and N-acetylcysteine, through continuous intravenous infusion. Clinical and paraclinical evaluation of the patients was performed daily until discharge or death. At admission, laboratory parameters did not differ significantly between two groups. At discharge/upon death, statistically significant differences in favor of Antiox group were observed in the following parameters: thrombocytes, activated partial thromboplastin time, prothrombin time, total bilirubin, total cholesterol, high-density lipoproteins, low-density lipoproteins, erythrocyte sedimentation rate, interleukin 6 (all p = 0.0001), total protein (p = 0.0005), serum albumin (p = 0.0004), lactate dehydrogenase (p = 0.0006), and C-reactive protein (p = 0.0014). Starting from day 5, the APACHE II score was significantly decreased in Antiox versus control group (p < 0.05). Finally, the sepsis incidence and mortality rate were significantly lower in Antiox group (p < 0.05). Decreasing the level of oxidative stress by antioxidant substances significantly correlated with a better prognosis and outcome in our patients. Further studies should elucidate more clearly the mechanism of action of antioxidants in critically ill polytrauma patients.

Implications of Entropy and Surgical Pleth Index-guided general anaesthesia on clinical outcomes in critically ill polytrauma patients. A prospective observational non-randomized single centre study.

Being highly unstable, the critically ill polytrauma patient represents a challenge for the anaesthesia team. The aim of this study was to compare the Entropy and Surgical Pleth Index (SPI)-guided general anaesthesia with standard haemodynamic monitoring methods used in the critically ill polytrauma patients and to evaluate the incidence of hemodynamic events, as well as the opioid and vasopressor demand. 72 patients were included in this prospective observational study, divided in two groups, the ESPI Group (N = 37, patients that benefited from Entropy and SPI monitoring) and the STDR Group (N = 35 patients that benefited from standard hemodynamic monitoring). In the ESPI Group general anaesthesia was modulated in order to maintain the Entropy levels between 40 and 60. Analgesia control was achieved by maintaining the SPI levels between 20 and 50. In the STDR Group hypnosis and analgesia were maintained using the standard criteria based on hemodynamic changes. ClinicalTrials.gov identifier NCT03095430. The incidence of hypotension episodes was significantly lower in the ESPI Group (N = 3), compared to the STDR Group (N = 71) (p < 0.05). Moreover, the Fentanyl demand was significantly lower in the ESPI Group (p < 0.0001, difference between means 5.000 ± 0.038, 95% confidence interval 4.9250-5.0750), as well as vasopressor medication demand (p < 0.0001, difference between means 0.960 ± 0.063, 95% confidence interval 0.8.334-1.0866). The implementation of multimodal monitoring in the critically ill polytrauma patient brings substantial benefits both to the intraoperative clinical status and to the clinical outcome of these patients by reducing the incidence of anesthesia-related complications.

The influence of metabolic imbalances and oxidative stress on the outcome of critically ill polytrauma patients: a review.

The critically ill polytrauma patient presents with a series of associated pathophysiologies secondary to the traumatic injuries. The most important include systemic inflammatory response syndrome (SIRS), sepsis, oxidative stress (OS), metabolic disorders, and finally multiple organ dysfunction syndrome (MODS) and death. The poor outcome of these patients is related to the association of the aforementioned pathologies. The nutrition of the critically ill polytrauma patient is a distinct challenge because of the rapid changes in terms of energetic needs associated with hypermetabolism, sepsis, SIRS, and OS. Moreover, it has been proven that inadequate nutrition can prolong the time spent on a mechanical ventilator and the length of stay in an intensive care unit (ICU). A series of mathematical equations can predict the energy expenditure (EE), but they have disadvantages, such as the fact that they cannot predict the EE accurately in the case of patients with hypermetabolism. Indirect calorimetry (IC) is another method used for evaluating and monitoring the energy status of critically ill patients. In this update paper, we present a series of pathophysiological aspects associated with the metabolic disaster affecting the critically ill polytrauma patient. Furthermore, we present different non-invasive monitoring methods that could help the intensive care physician in the adequate management of this type of patient.

The Use of Exosomes as Biomarkers for Evaluating and Monitoring Critically Ill Polytrauma Patients with Sepsis.

Regarding genetic biomarkers for early assessment and monitoring the clinical course in polytrauma patients with sepsis, in recent years a remarkable evolution has been highlighted. One of the main representatives is the exosome miRNAs. In this paper, we would like to present in more details the various methods of using exosome miRNAs as a biomarker for monitoring polytrauma patients with sepsis, as well as establishing a belated outcome by aggregating the entire clinical aspects. The use of exosome miRNAs for late evaluating and monitoring the clinical evolution of polytrauma patients can bring significant improvements in current clinical practice through the optimization and modulation of intensive care according to the needs of each patient individually.

New perspectives of volemic resuscitation in polytrauma patients: a review.

Nowadays, fluid resuscitation of multiple trauma patients is still a challenging therapy. Existing therapies for volume replacement in severe haemorrhagic shock can lead to adverse reactions that may be fatal for the patient. Patients presenting with multiple trauma often develop hemorrhagic shock, which triggers a series of metabolic, physiological and cellular dysfunction. These disorders combined, lead to complications that significantly decrease survival rate in this subset of patients. Volume and electrolyte resuscitation is challenging due to many factors that overlap. Poor management can lead to post-resuscitation systemic inflammation causing multiple organ failure and ultimately death. In literature, there is no exact formula for this purpose, and opinions are divided. This paper presents a review of modern techniques and current studies regarding the management of fluid resuscitation in trauma patients with hemorrhagic shock. According to the literature and from clinical experience, all aspects regarding post-resuscitation period need to be considered. Also, for every case in particular, emergency therapy management needs to be rigorously respected considering all physiological, biochemical and biological parameters.

The Use of Redox Expression and Associated Molecular Damage to Evaluate the Inflammatory Response in Critically Ill Patient with Severe Burn.

The patient with severe burns always represents a challenge for the trauma team due to the severe biochemical and physiopathological disorders. Although there are many resuscitation protocols of severe burn patient, systemic inflammatory response, oxidative stress, decreased immune response, infections, and multiple organ dysfunction syndromes are still secondary complications of trauma, present at maximum intensity in this type of patients. Currently there are numerous studies regarding the evaluation, monitoring, and minimizing the side effects induced by free radicals through antioxidant therapy. In this study, we want to introduce biochemical and physiological aspects of oxidative stress in patients with severe burns and to summarize the biomarkers used presently in the intensive care units. Systemic inflammations and infections are according to the literature the most important causes of death in these type of patients, being directly involved in multiple organ dysfunction syndrome and death.

The Use of Circulating miRNAs as Biomarkers for Oxidative Stress in Critically Ill Polytrauma Patients.

BACKGROUND: The diversity of primary and secondary traumatic injuries specific for the critically ill polytrauma patient is complicating the therapeutic management in the absence of a strict assessment of the biological changes. Inflammation, redox imbalance, and immunosuppression can be quantified by various biochemical parameters; however, they do not fully respond to the current requirements. Another phenomenon responsible for worsening the clinical status and for the development of complications in such patients is oxidative stress. Its aggressiveness combined with biochemical and physiological imbalances leads to increased morbidity and mortality. To minimize the effects induced by free radicals, various substances are administered with high antioxidant capacity. However, the dosage optimization for each patient is difficult without strict monitoring of oxidative stress. In this paper we will summarize and present the pathophysiology of oxidative stress, as well as the specificity of miRNAs for a series of molecular changes at the cellular level. METHODS: For this study the available literature on specific databases such as PubMed, Embase and Scopus was thoroughly analyzed. Each article has been carefully reviewed, extracting useful information for this study. The keywords used to select the relevant articles were "oxidative stress", "antioxidant therapy", "microRNAs biomarkers", and "critically ill patients". RESULTS: For this study, 121 scientific articles relevant to our topic were analyzed. Currently, quantification of oxidative stress is achieved through indirect correlations with plasma levels of specific biomarkers. For a more specific evaluation of the redox status, numerous studies were conducted on the use of circulating miRNAs as biomarkers in this regard. CONCLUSIONS: Introducing miRNAs can revolutionize both monitoring and therapy modulation in these patients, adapting to the organic damage.

The Expression of Nuclear Transcription Factor Kappa B (NF-κB) in the Case of Critically Ill Polytrauma Patients with Sepsis and Its Interactions with microRNAs.

Critical polytrauma patients present a series of pathophysiological disturbances, biochemical and molecular dysfunction, which comprise to be the major cause of intensive care unit admission. In regard to molecular damage, there exists a series of factors, which all together contribute to the aggravation of the clinical status leading to increased mortality rate in these patients. One of the most important biochemical factors involved is the nuclear transcription factor B (NF-κB). Impaired NF-κB functioning is reflected on the clinical status of the patient through increased production of pro-inflammatory molecule, leading to multiple organ dysfunction syndrome. In addition to this, through microRNAs interactions, various pathophysiological as well as biochemical disturbances are produced, which altogether further reduce the patient's survival rate. In this paper, we would like to present the modifications seen in the expression of NF-κB in critically polytraumatized patients with sepsis. In additions to this, we would like to discuss the correlation between the microRNAs and its further implications in clinical status of these patients.

An in vitro study of the release capacity of the local anaesthetics from siloxane matrices.

AIMS: In the field of anaesthesia and intensive care, the controlled release systems capable of delivering constantly local anaesthetics are of interest because of the advantages brought to pain management. In this paper we presented the release profiles by usage of siloxane matrices of two common local anaesthetics, lidocaine and bupivacaine, analysed in vitro. METHODS: The siloxane matrices were obtained in accordance with the methods described in the specialized literature, tetraethoxysilane (TEOS) and tetramethoxysilane (TMOS) were used as precursors. Lidocaine and bupivacaine were encapsulated in the synthesized gels. The controlled release was performed in vitro artificial systems in which temperature (30°C, 36.5°C, 40°C) and pH (6, 7, 8) have varied. RESULTS: Following the analysis of the artificial systems similar profiles were highlighted for both local anaesthetics. Statistically significant differences were identified (p < 0.05) for systems where the release occurred at temperatures above 36.5°C. There were no statistically significant differences regarding the influence of pH, the type of the entrapped anaesthetic or the type of the precursor used in the synthesis of siloxane matrices. CONCLUSIONS: According to this experimental study, the pH, the type of precursor or the type of anaesthetic does not statistically influence the release profile from the studied system. In conclusion, these systems are promising for obtaining pharmaceutical preparations which can be used in current clinical practice. Several studies on controlled release siloxane systems should be carried out both in vitro and in vivo in order to exclude possible toxicity and histopathological effects.

Redox Changes Induced by General Anesthesia in Critically Ill Patients with Multiple Traumas.

The critically ill polytrauma patient is a constant challenge for the trauma team due to the complexity of the complications presented. Intense inflammatory response and infections, as well as multiple organ dysfunctions, significantly increase the rate of morbidity and mortality in these patients. Moreover, due to the physiological and biochemical imbalances present in this type of patients, the bioproduction of free radicals is significantly accelerated, thus installing the oxidative stress. In the therapeutic management of such patients, multiple surgical interventions are required and therefore they are being subjected to repeated general anesthesia. In this paper, we want to present the pathophysiological implications of oxidative stress in critically ill patients with multiple traumas and the implications of general anesthesia on the redox mechanisms of the cell. We also want to summarize the antioxidant treatments able to reduce the intensity of oxidative stress by modulating the biochemical activity of some cellular mechanisms.

Use of miRNAs as biomarkers in sepsis.

Sepsis is one of the most common causes of death in critical patients. Severe generalized inflammation, infections, and severe physiological imbalances significantly decrease the survival rate with more than 50%. Moreover, monitoring, evaluation, and therapy management often become extremely difficult for the clinician in this type of patients. Current methods of diagnosing sepsis vary based especially on the determination of biochemical-humoral markers, such as cytokines, components of the complement, and proinflammatory and anti-inflammatory compounds. Recent studies highlight the use of new biomarkers for sepsis, namely, miRNAs. miRNAs belong to a class of small, noncoding RNAs with an approximate content of 19-23 nucleotides. Following biochemical and physiological imbalances, the expression of miRNAs in blood or other body fluids changes significantly. Moreover, its stability, specificity, and selectivity make miRNAs ideal candidates for sepsis biomarkers. In conclusion, we can affirm that stable species of circulating miRNAs represent potential biomarkers for monitoring the evolution of sepsis.

Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma--a review.

Multiple trauma patients require extremely good management and thus, the trauma team needs to be prepared and to be up to date with the new standards of intensive therapy. Oxidative stress and free radicals represent an extremely aggressive factor to cells, having a direct consequence upon the severity of lung inflammation. Pulmonary tissue is damaged by oxidative stress, leading to biosynthesis of mediators that exacerbate inflammation modulators. The subsequent inflammation spreads throughout the body, leading most of the time to multiple organ dysfunction and death. In this paper, we briefly present an update of biochemical effects of oxidative stress and free radical damage to the pulmonary tissue in patients in critical condition in the intensive care unit. Also, we would like to present a series of active substances that substantially reduce the aggressiveness of free radicals, increasing the chances of survival.

Influence of antioxidant therapy on the clinical status of multiple trauma patients. A retrospective single center study.

INTRODUCTION: The biochemical processes of bioproduction of free radicals (FR) are significantly increasing in polytrauma patients. Decreased plasma concentrations of antioxidants, correlated with a disturbance of the redox balance are responsible for the installation of the phenomenon called oxidative stress (OS). OS action is associated with a series of secondary complications with direct implications in reducing the rate of survival, as well as in increasing morbidity The objectives of this study were to reveal possible relations between antioxidant therapy and a number of serum biochemical variables (ALT, AST, APPT, LDH, urea, leukocytes, platelets), the length of mechanical ventilation, the time spent in the ICU, and the mortality rate in major trauma patients. MATERIALS AND METHODS: In this retrospective study from a single center, 64 medical files of polytrauma patients admitted to the ICU "Casa Austria" were analysed. The selection criteria were: the Injury Severity Score (ISS) > 16 and a systolic arterial pressure (SAP) < 89 mmHg. The selected patients (n = 34) were divided into two groups: Antiox group, 20 patients who benefited from antioxidant therapy and the Contr group, 14 patients who did not received antioxidant therapy and served as a control group. The antioxidant therapy consisted of the simultaneous administration of vitamin C (i.v.), vitamin B1 (i.v.) and N-acetylcysteine (i.v.). The clinical and the biological evaluation were performed repeatedly until discharge from the ICU or the death of the patient. RESULTS: No significant differences were highlighted concerning the demographic data, the magnitude or the trauma mechanism between the two groups. In comparison with patients from the Contr group, the patients submitted to antioxidant therapy showed lower values after the treatment for leukocytes (p = 0.0066), urea (p = 0.0076), LDH (p = 0.0238), AST (p = 0.0070) and ALT (p < 0.0001). No statistically significant differences were evidenced regarding the incidence of sepsis or the development of multiple organ dysfunction syndrome (MODS). The period of mechanical ventilation was longer in patients from the Contr group (p = 0.0498), with no differences concerning the ICU length of stay (p = 0.7313). The mortality rate was lower in the Contr group (p = 0.0475). CONCLUSION: In multiple trauma patients a prolonged antioxidant therapy improved the posttraumatic laboratory tests.