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.

The Impact of Therapeutic Plasma Exchange on Inflammatory Markers and Acute Phase Reactants in Patients with Severe SARS-CoV-2 Infection.

Background and Objectives: Due to the poor prognosis and the very high mortality rate associated with severe SARS-CoV-2 infections, various regimens have been tried to stop the evolution of the inflammatory cascade, such as immunomodulatory therapy and plasma clearance of the acute phase reactants involved. Therefore, the objective of this review was to analyze the effects of using therapeutic plasma exchange (TPE), also known as plasmapheresis, on the inflammatory markers of critically ill COVID-19 patients admitted to the intensive care unit (ICU). Materials and Methods: A thorough scientific database search was performed, and it included a review of articles published on PubMed, Cochrane Database, Scopus, and Web of Science from the beginning of the COVID-19 pandemic in March 2020 until September 2022 that focused on the treatment of SARS-CoV-2 infections using plasma exchange for patients admitted to the ICU. The current study included original articles, reviews, editorials, and short or special communications regarding the topic of interest. Results: A total of 13 articles were selected after satisfying the inclusion criterion of three or more patients enrolled with clinically severe COVID-19 that were eligible for TPE. From the included articles, it was observed that TPE was used as a last-resort salvage therapy that can be regarded as an alternative treatment method when the standard management for these patients fails. TPE significantly decreased the inflammatory status as measured by Interleukin-6 (IL-6), C-reactive protein (CRP), lymphocyte count, and D-dimers, as well as improving the clinical status measured with PaO2/FiO2 and duration of hospitalization. The pooled mortality risk reduction after TPE was 20%. Conclusions: There are sufficient studies and evidence to show that TPE reduces inflammatory mediators and improves coagulation function and the clinical/paraclinical status. Nevertheless, although it was shown that TPE decreases the severe inflammatory status without significant complications, the improvement of survival rate remains unclear.

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.

The Successful Recovery of a Critically Ill COVID-19 Patient, Following the Combination of Therapeutic Plasma Exchange and Convalescent Plasma Transfusion: A Case Report.

With an intricate symptom pattern involving a dysregulated host response to infection, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause severe inflammation and cytokine storms, acute respiratory distress syndrome, coagulopathy, multi-organ failure, and finally death. The uniqueness of this case report lies in the nature of the therapeutic intervention performed. While numerous studies are available on both the use of therapeutic plasma exchange in coronavirus disease 2019 (COVID-19) patients and convalescent plasma transfusion as separate treatment methods, there is very little information regarding the combination of these procedures. We present the case of a 52-year-old male, unvaccinated for COVID-19, who tested positive on reverse transcriptase polymerase chain reaction for SARS-CoV-2 for the first time and presented in the emergency room with fever, chills, severe cough, tachypnea, tachycardia, and dyspnea that started two days before presentation. Upon rapid assessment, the patient showed signs of acute respiratory failure, so it was decided to transfer the patient to the intensive care unit, COVID-19 ward, after preliminary radiological examination. For the next 24 days, the patient was stationed in the intensive care unit, where he was closely monitored and treated. Invasive mechanical ventilation was required following the initial worsening of his respiratory status. We performed therapeutic plasma exchange on the first day of his stay in the intensive care unit, and immediately after the procedure, the patient was transfused with 500 mL of convalescent plasma from healthy donors. The patient's condition improved over the next few days, which led to the cessation of mechanical ventilation and, after treating the superinfection, the patient was discharged home, making a full recovery. The early initiation of therapeutic plasma exchange followed by transfusion of convalescent plasma in severe and critical forms of COVID-19 may reduce the risk of the progression of the disease and ultimately reduce the risk of negative outcomes in a selected group of patients.

Efficacy of Therapeutic Plasma Exchange in Severe Acute Respiratory Distress Syndrome in COVID-19 Patients from the Western Part of Romania.

Background and Objectives: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has surprised the medical world with its devastating effects such as severe acute respiratory distress syndrome (ARDS) and cytokine storm, but also with the scant therapeutic solutions which have proven to be effective against the disease. Therapeutic plasma exchange (TPE) has been proposed from the very beginning as a possible adjuvant treatment in severe cases. Our objective was to analyze the evolution of specific biological markers of the COVID-19 disease before and one day after a therapeutic plasma exchange session, how a change in these parameters influences the patient's respiratory status, as well as the impact of TPE on the survival rate. Materials and Methods: In this retrospective study, we include 65 patients with COVID-19 admitted to the intensive care unit department of our hospital between March 2020 and December 2021, and who received a total of 120 sessions of TPE. Results: TPE significantly reduced the following inflammation markers (p < 0.001): interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), fibrinogen, ferritin, and erythrocyte sedimentation rate. This procedure significantly increased the number of lymphocytes and decreased D-dimers levels (p = 0.0024). TPE significantly improved the PaO2/FiO2 ratio (p < 0.001) in patients with severe acute respiratory distress syndrome (PaO2/FiO2 < 100). Survival was improved in intubated patients who received TPE. Conclusions: TPE involved the reduction in inflammatory markers in critical patients with COVID-19 disease and the improvement of the PaO2/FiO2 ratio in patients with severe ARDS and had a potential benefit on the survival of patients with extremely severe COVID-19 disease.

Cerebrolysin after moderate to severe traumatic brain injury: prospective meta-analysis of the CAPTAIN trial series.

INTRODUCTION: This prospective meta-analysis summarizes results from the CAPTAIN trial series, evaluating the effects of Cerebrolysin for moderate-severe traumatic brain injury, as an add-on to usual care. MATERIALS AND METHODS: The study included two phase IIIb/IV prospective, randomized, double-blind, placebo-controlled clinical trials. Eligible patients with a Glasgow Coma Score (GCS) between 6 and 12 received study medication (50 mL of Cerebrolysin or physiological saline solution per day for ten days, followed by two additional treatment cycles with 10 mL per day for 10 days) in addition to usual care. The meta-analysis comprises the primary ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses based on multivariate, directional tests. RESULTS: A total 185 patients underwent meta-analysis (mean admission GCS = 10.3, mean age = 45.3, and mean Baseline Prognostic Risk Score = 2.8). The primary endpoint, a multidimensional ensemble of functional and neuropsychological outcome scales indicated a "small-to-medium" sized effect in favor of Cerebrolysin, statistically significant at Day 30 and at Day 90 (Day 30: MWcombined = 0.60, 95%CI 0.52 to 0.66, p = 0.0156; SMD = 0.31; OR = 1.69; Day 90: MWcombined = 0.60, 95%CI 0.52 to 0.68, p = 0.0146; SMD = 0.34, OR = 1.77). Treatment groups showed comparable safety and tolerability profiles. DISCUSSION: The meta-analysis of the CAPTAIN trials confirms the safety and efficacy of Cerebrolysin after moderate-severe TBI, opening a new horizon for neurorecovery in this field. Integration of Cerebrolysin into existing guidelines should be considered after careful review of internationally applicable criteria.

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.

New Molecular and Epigenetic Expressions as Novel Biomarkers in Critically Ill Polytrauma Patients with Acute Kidney Injury (AKI).

BACKGROUND: A high percentage of the critically ill polytrauma patients develop acute kidney injury (AKI) secondary to trauma and are therefore prone to high morbidity and mortality rates. One of the main objectives in these cases is the fast detection of the condition and continuous rigorous monitoring of the patients. Currently the panel of biomarkers available for monitoring and for the prognosis of AKI is limited. Numerous studies have proven the importance of microRNAs in this field. In this actualization paper we wish to summarize the most relevant microRNAs that can be used as biomarkers for patients with AKI. METHODS: For this paper, we looked into the studies available in scientific databases such as PubMed and Scopus. For the analysis we used the following key words: "miRNAs biomarker", "acute kidney injury AKI", "genetic expression in AKI", and "epigenetic microRNAs biomarkers in AKI". RESULTS: Numerous studies have shown high specificity for certain microRNA species in the case of patients with AKI. Moreover, they have reported a series of microRNAs that present high specificity and that have a strong expression in fluids that can be sampled through non-invasive methods, such as urine and saliva. CONCLUSIONS: The expression of microRNAs can be successfully used in the future as a non-invasive method for the evaluation and monitoring of AKI 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.

Antimicrobial consumption, costs and resistance patterns: a two year prospective study in a Romanian intensive care unit.

BACKGROUND: Due to the vulnerable nature of its patients, the wide use of invasive devices and broad-spectrum antimicrobials used, the intensive care unit (ICU) is often called the epicentre of infections. In the present study, we quantified the burden of hospital acquired pathology in a Romanian university hospital ICU, represented by antimicrobial agents consumption, costs and local resistance patterns, in order to identify multimodal interventional strategies. METHODS: Between 1st January 2012 and 31st December 2013, a prospective study was conducted in the largest ICU of Western Romania. The study group was divided into four sub-samples: patients who only received prophylactic antibiotherapy, those with community-acquired infections, patients who developed hospital acquired infections and patients with community acquired infections complicated by hospital-acquired infections. The statistical analysis was performed using the EpiInfo version 3.5.4 and SPSS version 20. RESULTS: A total of 1596 subjects were enrolled in the study and the recorded consumption of antimicrobial agents was 1172.40 DDD/ 1000 patient-days. The presence of hospital acquired infections doubled the length of stay (6.70 days for patients with community-acquired infections versus 16.06/14.08 days for those with hospital-acquired infections), the number of antimicrobial treatment days (5.47 in sub-sample II versus 11.18/12.13 in sub-samples III/IV) and they increased by 4 times compared to uninfected patients. The perioperative prophylactic antibiotic treatment had an average length duration of 2.78 while the empirical antimicrobial therapy was 3.96 days in sample II and 4.75/4.85 days for the patients with hospital-acquired infections. The incidence density of resistant strains was 8.27/1000 patient-days for methicilin resistant Staphylococcus aureus, 7.88 for extended spectrum ß-lactamase producing Klebsiella pneumoniae and 4.68/1000 patient-days for multidrug resistant Acinetobacter baumannii. CONCLUSIONS: Some of the most important circumstances collectively contributing to increasing the consumption of antimicrobials and high incidence densities of multidrug-resistant bacteria in the studied ICU, are represented by prolonged chemoprophylaxis and empirical treatment and also by not applying the definitive antimicrobial therapy, especially in patients with favourable evolution under empirical antibiotic treatment. The present data should represent convincing evidence for policy changes in the antibiotic therapy.

Intensive care antibiotic consumption and resistance patterns: a cross-correlation analysis.

BACKGROUND: Over recent decades, a dramatic increase in infections caused by multidrug-resistant pathogens has been observed worldwide. The aim of the present study was to investigate the relationship between local resistance bacterial patterns and antibiotic consumption in an intensive care unit in a Romanian university hospital. METHODS: A prospective study was conducted between 1st January 2012 and 31st December 2013. Data covering the consumption of antibacterial drugs and the incidence density for the main resistance phenotypes was collected on a monthly basis, and this data was aggregated quarterly. The relationship between the antibiotic consumption and resistance was investigated using cross-correlation, and four regression models were constructed, using the SPSS version 20.0 (IBM, Chicago, IL) and the R version 3.2.3 packages. RESULTS: During the period studied, the incidence of combined-resistant and carbapenem-resistant P. aeruginosa strains increased significantly [(gradient = 0.78, R2 = 0.707, p = 0.009) (gradient = 0.74, R2 = 0.666, p = 0.013) respectively], mirroring the increase in consumption of ß-lactam antibiotics with ß-lactamase inhibitors (piperacillin/tazobactam) and carbapenems (meropenem) [(gradient = 10.91, R2 = 0.698, p = 0.010) and (gradient = 14.63, R2 = 0.753, p = 0.005) respectively]. The highest cross-correlation coefficients for zero time lags were found between combined-resistant vs. penicillins consumption and carbapenem-resistant P. aeruginosa strains vs. carbapenems consumption (0.876 and 0.928, respectively). The best model describing the relation between combined-resistant P. aeruginosa strains and penicillins consumption during a given quarter incorporates both the consumption and the incidence of combined-resistant strains in the hospital department during the previous quarter (multiple R2 = 0.953, p = 0.017). The best model for explaining the carbapenem resistance of P. aeruginosa strains based on meropenem consumption during a given quarter proved to be the adjusted model which takes into consideration both previous consumption and incidence density of strains during the previous quarter (Multiple R2 = 0.921, p = 0.037). CONCLUSIONS: The cross-correlation coefficients and the fitted regression models provide additional evidence that resistance during the a given quarter depends not only on the consumption of antibacterial chemotherapeutic drugs in both that quarter and the previous one, but also on the incidence of resistant strains circulating during the previous quarter.

Circulating microRNAs Expressions as Genetic Biomarkers in Pancreatic Cancer Patients Continuous Non-Invasive Monitoring.

BACKGROUND: Pancreatic cancer is one of the most important causes of death worldwide. The main cause is late detection. Also, an important factor playing a role in altering the clinical status of these patients is the lack of methods for the evaluation of therapeutic response. A marker that can be useful, both in early diagnosis and in evaluating and monitoring non-invasive treatment response, is analyzing the expression of miRNAs. In this paper, we summarize genetic and epigenetic aspects of miRNAs in pancreatic cancer. Moreover, we want to emphasize potential miRNAs expressions that can be used as biomarkers for the management of patients with pancreatic cancer. METHODS: Studies available in scientific databases, such as PubMed and Scopus, were analyzed for conducting the present study. The keywords "miRNAs expression", "pancreatic cancer", and "genetic biomarkers" were used in the search engine. RESULTS: Following the searches, 187 primary scientific articles were analyzed. After rigorous analysis 40 articles were selected for the study. A high percentage of papers highlight the importance of using microRNAs as modern, non-invasive, and accurate biomarkers, designed for the early diagnosis and continuous monitoring of both the clinical outcome and treatment response of the patient. CONCLUSIONS: The expression of miRNAs can be successfully used for the evaluation and non-invasive monitoring of patients with pancreatic cancer.

miRNAs Expressions and Interaction with Biological Systems in Patients with Alzheimer`s Disease. Using miRNAs as a Diagnosis and Prognosis Biomarker.

BACKGROUND: A high percentage of patients develop Alzheimer`s disease (AD). The main signs are loss of memory and cognitive functions which have a significant impact on lifestyle. Numerous studies have been conducted to identify new biomarkers for early diagnosis of patients with AD. An ideal biomarker is represented by the expression of miRNAs. In this paper, we want to summarize expressions miRNAs in AD. We also want to present the pathophysiological and genetic interactions of miRNAs with protein systems in these patients. METHODS: For the study, we examined available studies in scientific databases, such as PubMed and Scopus. The studies were searched using the keywords "miRNAs expression", "Alzheimer`s disease", "genetic polymorphisms", and "genetic biomarkers". RESULTS: For the assessment and monitoring of patients with AD, the expression of miRNAs can be used successfully due to increased specificity and selectivity. Moreover, the expression of miRNAs can provide important answers regarding possible genetic interactions and genetic therapeutic regimens. CONCLUSIONS: For the evaluation and non-invasive monitoring of patients with Alzheimer`s disease the expression of miRNAs can be successfully used.

Phase 2, Dose-Ranging Study of Relebactam with Imipenem-Cilastatin in Subjects with Complicated Intra-abdominal Infection.

Relebactam (REL [MK-7655]) is a novel class A/C ß-lactamase inhibitor intended for use with imipenem for the treatment of Gram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were ≥18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains.

Using Circulating miRNAs as Biomarkers for the Evaluation and Monitoring of the Mitochondrial Damage in the Critically Ill Polytrauma Patients.

BACKGROUND: The multiple-traumatic critical patient presents a variety of pathophysiological, cellular, and molecular dysfunctions. One of the most important is represented by mitochondrial damage which afterwards is responsible for the augmentation and worsening of a series of pathologies that lead to the worsening of the clinical status of the patient. The severe inflammatory response, sepsis, and the redox imbalance are other pathologies that together with the multiple traumas are responsible for the mitochondrial dysfunctions. As an overview, we can say that both the mitochondrial damage as well as the clinical statuses of those patients are responsible for an increase in the chances of multiple organ dysfunction syndrome and death of critical patients with multiple trauma from the Intensive Care Units (ICU). In this paper we wish to summarize the microRNAs that can be used as biomarkers for evaluation and monitoring of the mitochondrial activity in critical patients with multiple traumas. METHODS: For the paper, literature available in the international databases PubMed and Scopus until the year 2015 has been consulted. The key words used for the article search were "mitochondrial damage", "microRNAs biomarkers", and "critically ill polytrauma patients". RESULTS: As a result of the research based on the key words presented above, we found 234 papers. From those, after rigorous analysis 64 were selected as being in conformity with the needs of this paper. CONCLUSIONS: The critical polytrauma patient needs a specific evaluation and monitoring due to the complexity of the dysfunctions that appear at the cellular level. The use of microRNAs as biomarkers for the mitochondrial damage can be of real use for intensive care medicine. Nevertheless, more studies are required in order to determine a larger panel of microRNAs which can have an impact on mitochondrial damage.

Using the Expression of miRNAs as Biomarkers for the Evaluation Acute Respiratory Distress Syndrome in the Critically Ill Polytrauma Patient.

BACKGROUND: A high percentage of critically ill polytrauma patients develop acute respiratory distress syndrome (ARDS), both because of the primary traumatic injuries and because of the secondary post-traumatic injuries. For adequate management of these patients, new complex evaluation and monitoring methods are needed, methods that could answer as many questions as possible regarding the pathophysiological changes associated with ARDS. Currently, a series of clinical and biochemical markers are being used which unfortunately do not respond to the needs of an intensive care clinician. Therefore, the changes of miRNAs have been intensely researched in the case of patients with ARDS. Moreover, using them as biomarkers for ARDS brings a series of answers regarding the pathophysiological changes associated to ARDS, making them biomarkers of the future in laboratory medicine. METHODS: In order for this research study to be carried out the literature found on Scopus and PubMed on the topic was consulted, up to the year 2015. The key words used for the articles were "acute respiratory distress syndrome ARDS", "biomarkers for ARDS", "critically ill polytrauma patients", "miRNAs expression in ARDS", "miRNAs expression in sepsis", "miRNAs in critically ill patients" and "miRNAs biomarker". Research articles in English, German, and French were included in the search. RESULTS: Following the search using the above mentioned key words, 567 articles were found. After a rigorous analysis of these articles 55 of them were selected for our study. CONCLUSIONS: Using miRNAs for the evaluation and monitoring of ARDS makes them a biomarker of the future, because of the complex answers they bring to questions related both to the main injury caused by ARDS and to the associated pathophysiology.

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.

Advances in Biomarkers in Critical Ill Polytrauma Patients.

BACKGROUND: The complexity of the cases of critically ill polytrauma patients is given by both the primary, as well as the secondary, post-traumatic injuries. The severe injuries of organ systems, the major biochemical and physiological disequilibrium, and the molecular chaos lead to a high rate of morbidity and mortality in this type of patient. The 'gold goal' in the intensive therapy of such patients resides in the continuous evaluation and monitoring of their clinical status. Moreover, optimizing the therapy based on the expression of certain biomarkers with high specificity and sensitivity is extremely important because of the clinical course of the critically ill polytrauma patient. In this paper we wish to summarize the recent studies of biomarkers useful for the intensive care unit (ICU) physician. METHODS: For this study the available literature on specific databases such as PubMed and Scopus was thoroughly analyzed. Each article was carefully reviewed and useful information for this study extracted. The keywords used to select the relevant articles were "sepsis biomarker", "traumatic brain injury biomarker" "spinal cord injury biomarker", "inflammation biomarker", "microRNAs biomarker", "trauma biomarker", and "critically ill patients". RESULTS: For this study to be carried out 556 original type articles were analyzed, as well as case reports and reviews. For this review, 89 articles with relevant topics for the present paper were selected. The critically ill polytrauma patient, because of the clinical complexity the case presents with, needs a series of evaluations and specific monitoring. Recent studies show a series of either tissue-specific or circulating biomarkers that are useful in the clinical status evaluation of these patients. CONCLUSIONS: The biomarkers existing today, with regard to the critically ill polytrauma patient, can bring a significant contribution to increasing the survival rate, by adapting the therapy according to their expressions. Nevertheless, the necessity remains to research new non-invasive diagnostic methods that present with higher specificity and selectivity.