Clinical characteristics and factors associated with ICU mortality during the first year of the SARS-Cov-2 pandemic in Romania: A prospective, cohort, multicentre study of 9000 patients.

BACKGROUND: The epidemiology of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be different worldwide. Despite similarities in medicine quality and formation, there are also significant differences concerning healthcare and ICU organisation, staffing, financial resources and population compliance and adherence. Large cohort data of critically ill patients from Central and Eastern Europe are also lacking. OBJECTIVES: The study objectives were to describe the clinical characteristics of patients admitted to Romanian ICUs with SARS-CoV-2 infection and to identify the factors associated with ICU mortality. DESIGN: Prospective, cohort, observational study. SETTING: National recruitment, multicentre study, between March 2020 to March 2021. PATIENTS: All patients with SARS-CoV-2 infection admitted to Romanian ICUs were eligible. There were no exclusion criteria. INTERVENTION: None. MAIN OUTCOME MEASURE: ICU mortality. RESULTS: The statistical analysis included 9058 patients with definitive ICU outcome. The multivariable mixed effects logistic regression model found that age [odds ratio (OR) 1.27; 95% confidence interval (CI), 1.23 to 1.31], male gender (OR 1.21; 95% CI 1.05 to 1.4), medical history of neoplasia (OR 1.74; 95% CI, 1.36 to 2.22), chronic kidney disease (OR 1.54; 95% CI, 1.27 to 1.88), type II diabetes (OR 1.23; 95% CI, 1.06 to 1.43), chronic heart failure (OR 1.24; 95% CI, 1.03 to 1.49), dyspnoea (OR 1.3; 95% CI, 1.1 to 1.5), SpO2 less than 90% (OR 3; 95% CI, 2.5 to 3.5), admission SOFA score (OR 1.07; 95% CI, 1.05 to 1.09), acute respiratory distress syndrome (ARDS) on ICU admission (OR 1.35; 95% CI, 1.1 to 1.63) and the need for noninvasive (OR 1.8, 95% CI, 1.5 to 1.22) or invasive ventilation (OR 28; 95% CI, 22 to 35) and neuromuscular blockade (OR 3.5; 95% CI, 2.6 to 4.8), were associated with larger ICU mortality.Higher GCS on admission (OR 0.81; 95% CI, 0.79 to 0.83), treatment with hydroxychloroquine (OR 0.78; 95% CI, 0.64 to 0.95) and tocilizumab (OR 0.58; 95% CI, 0.48 to 0.71) were inversely associated with ICU mortality. CONCLUSION: The SARS-CoV-2 critically ill Romanian patients share common personal and clinical characteristics with published European cohorts. Public health measures and vaccination campaign should focus on patients at risk.

General Anesthesia as a Multimodal Individualized Clinical Concept.

In the last decades, several new and modern techniques have been developed for the continuous monitoring of vitals for patients undergoing surgery under general anesthesia. These complex methods are meant to come as an adjunct to classical monitoring protocols used in general anesthesia to increase patient safety. The main objectives of multimodal monitoring are avoiding the over- or underdosing of anesthetic drugs, adapting the concentration for the substances in use, reducing post-anesthetic complications, and increasing patient comfort. Recent studies have shown a series of benefits with significant clinical impact such as a reduced incidence of nausea and vomiting, shorter reversal times, a reduction in opioid consumption, shorter hospital stays, and an increase in patient satisfaction.

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.

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.

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.

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 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.

microRNAs Expression as Novel Genetic Biomarker for Early Prediction and Continuous Monitoring in Pulmonary Cancer.

One of the main causes of death in the world is lung cancer. According to the World Health Organization, the annual incidence of lung cancer increases significantly. Moreover, lung cancer accounts for one of the highest mortality rates, mainly due to late detection. Numerous studies have been conducted in order to identify new biomarkers for early diagnosis and for monitoring and evaluation of lung cancer stages. An ideal biomarker candidate is represented by the analysis of microRNAs expression. In this paper, we want to summarize microRNAs expressions in lung cancer. We also want to present the expression of microRNAs depending on the evolution of lung cancer. For this study, we analyzed the studies available in scientific databases, such as PubMed and Scopus. The studies were selected using the search keywords "microRNAs expression," "lung cancer," and "genetic biomarkers." The most significant articles were selected for the study, following rigorous analysis. To evaluate and monitor lung cancer, the expression of microRNAs may be used successfully due to increased specificity and selectivity. However, further studies are needed on the assignment and validation of microRNAs for each type of lung cancer, respectively, for each stage of evolution.

Early Prediction of Sepsis Incidence in Critically Ill Patients Using Specific Genetic Polymorphisms.

Several diagnostic methods for the evaluation and monitoring were used to find out the pro-inflammatory status, as well as incidence of sepsis in critically ill patients. One such recent method is based on investigating the genetic polymorphisms and determining the molecular and genetic links between them, as well as other sepsis-associated pathophysiologies. Identification of genetic polymorphisms in critical patients with sepsis can become a revolutionary method for evaluating and monitoring these patients. Similarly, the complications, as well as the high costs associated with the management of patients with sepsis, can be significantly reduced by early initiation of intensive care.

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 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 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.

Genetic and Epigenetic Biomarkers of Molecular Alterations in Oral Carcinogenesis.

Worldwide, oral cancers represent the 6th most common type of cancer. Oral squamous cell carcinoma (OSCC), which is the most common type of oral cancer, is present in about 90% of the patients with this malignancy. OSCC presents a survival rate up to 80%, if it is detected in an early stage (T1), but if detected at later stages (T3 - T4) the survival rate decreases to 20 - 30%. Due to these survival rates, it is obvious that there is an urgent need to introduce new molecular biomarkers for the early, noninvasive diagnosis of oral cancers from saliva. These biomarkers will aid in increasing the survival rate of the patients for the long-term. MicroRNAs are part of a class of small, non-coding RNAs that contain 19 - 23 nucleotides. MicroRNAs play an important role in the regulation of biochemical mechanisms, cell proliferation, and other cellular mechanisms in the human body. Recently, due to the developments in the field of molecular genetics, salivary microRNAs became important biomarkers in early detection and monitoring of oral cancers by noninvasive methods. We want to present in this review the most important genetic and epigenetic biomarkers involved in oral carcinogenesis, focusing especially on the salivary microRNAs as biomarkers in early diagnosis of OSCC.

Circulating MicroRNAs as Promising Biomarkers in Forensic Body Fluids Identification.

In the last 20 years, DNA molecular analysis has become an important tool in forensic investigations. Currently, it is possible to genotype all types of biological traces or micro-traces containing nucleated cells if they are not entirely destroyed, chemically or bacterial. The DNA profiling is based on the short tandem repeats (STR) and aids in human identification from biological samples, but due to the recent advances in molecular genetics, other biomarkers have been proposed to be used in forensic identifications, such as: messenger RNA(mRNA), microRNA (miRNA), and DNA methylation. MicroRNAs are part of a class of small, non-coding RNAs that contain 19 - 23 nucleotides. MicroRNAs play an important role in the regulation of biochemical mechanisms, cell proliferation and other cellular mechanisms in the human body. The level of microRNAs in blood and other body fluids (urine, saliva, sweat) increases as a consequence of altered pathophysiological mechanisms and tissue insult. Moreover, the stability and specificity of microRNAs make them ideal candidates for circulating biomarkers in forensic bioanalytical procedures. In this review, we want to present a brief overview of biogenesis, functions, and applications of miRNAs in the identification of forensic body fluids.

Multimodal Diagnostic Methods of Sepsis in Critically Ill Patients.

The Special Issue "Multimodal Diagnostic Methods in Sepsis in the Critically Ill Patients" published in Diagnostics, Section "Pathology and Molecular Diagnostics", reports a series of scientific works from varying international authors regarding different methods of diagnosis and identification of clinical signs in critical patients with sepsis [...].

Bacterial and Fungal Superinfections in COVID-19 Patients Hospitalized in an Intensive Care Unit from Timișoara, Romania.

Purpose: Critically ill patients hospitalized in the intensive care unit (ICU) have an increased infection risk. The aim of this study was to determine the bacterial and fungal superinfections rate in Coronavirus disease 2019 (COVID-19) patients stationed in the ICU, identify risk factors associated with their development and to determine whether superinfection plays a role in patients' outcome in this population. Patients and Methods: In this retrospective, non-interventional, single centre, cohort study, medical records of 302 consecutive patients with SARS-COV-2 pneumonia admitted into the COVID-19 ICU of the largest university hospital from Western Romania between October 2020 and May 2021, were reviewed, of whom 236 patients met the inclusion criteria. Results: One hundred and nineteen patients developed a superinfection ≥48 h after being admitted to the hospital. Superinfection rate in the ICU was 50.42%. Coagulase-negative Staphylococci (CoNS) and Enterococcus spp. were predominantly isolated from blood cultures, while Acinetobacter baumannii, Staphylococcus aureus and Candida spp. from tracheobronchial aspirates. Significant independent risk factors regarding bacterial/fungal superinfection in COVID-19 patients were obtained for the following variables: number of days of central venous catheter (HR = 1.13 [1.07-1.20], p < 0.001) and prior administration of corticosteroids (HR = 2.80 [1.33-5.93], p = 0.007). Four independent predictive risk factors were associated with unfavorable outcome: age (HR = 1.07 [95% CI 1.03-1.12], p = 0.001); Carmeli Score (HR = 6.09 [1.18-31.50], p = 0.031); body mass index (HR = 1.11 [1.02-1.21], p = 0.011) and the presence of a central venous catheter (HR = 6.49 [1.93-21.89], p = 0.003). Conclusion: The superinfection rate in COVID-19 patients was high in this study group. Exogenous risk factors were associated with superinfection more than endogenous factors. Only a small percentage of uninfected COVID-19 patients were not prescribed antibiotics during their hospitalization, raising serious concerns regarding the judicious prescribing of antibiotics in viral infections.

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.

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.

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.

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.