Reviews on Recent Clinical Trials - Volume 18, Issue 1, 2023

Patients with severe traumatic brain injury (TBI) need to be admitted to intensive care (ICU) because they require invasive mechanical ventilation (IMV) due to reduced consciousness resulting in loss of protective airway reflexes, reduced ability to cough and altered breathing control. In addition, these patients can be complicated by pneumonia and acute distress syndrome (ARDS). IMV allows these patients to be sedated, decreasing intracranial pressure and ensuring an adequate oxygen delivery and tight control of arterial carbon dioxide tension. However, IMV can also cause dangerous effects on the brain due to its interaction with intrathoracic and intracranial compartments. Moreover, when TBI is complicated by ARDS, the setting of mechanical ventilation can be very difficult as ventilator goals are often different and in conflict with each other. Consequently, close brain and respiratory monitoring is essential to reduce morbidity and mortality in mechanically ventilated patients with severe TBI and ARDS. Recently, recommendations for the setting of mechanical ventilation in patients with acute brain injury (ABI) were issued by the European Society of Intensive Care Medicine (ESICM). However, there is insufficient evidence regarding ventilation strategies for patients with ARDS associated with ABI. The purpose of this paper is to analyze in detail respiratory strategies and targets in patients with TBI associated with ARDS.

Background: Cerebral vasospasm is one of the frequent complications that can occur following subarachnoid hemorrhage (SAH). With new protocols in the management of SAH, the combined risk of death and long-term disability have been reduced by about 10% compared with the past. Objective: This work aims to report the latest updates on the vasospasm developing after the SAH in patients in the ICU department. In this short review, we reviewed the latest scientific findings on the mechanisms of vasospasm, and in addition, we considered it necessary to review the literature to report the tools for early diagnosis of vasospasm and the best treatment strategies to prevent the negative outcome in patients admitted to ICU. Aim: The aim of this narrative review is to report the main characteristics of vasospasm, new diagnostic methods, and, especially, more effective treatment of vasospasm. Materials and Methods: The peer-reviewed articles analyzed were selected from PubMed, Google scholar, Embase, and Scopus databases published in the previous 20 years using the keywords "vasospasm", "vasospasm diagnosis", "vasospasm and SAH", "vasospasm treatment", and nontraumatic brain injury. Among the 78 papers identified, 43 articles were selected; after the title - abstract examination and removing the duplicates, only 31 articles were examined. Results: Vasospasm can be classified according to clinical (asymptomatic vs. symptomatic) and diagnostic (angiographic vs. ultrasound) methods. Various procedures such as TCD and CT perfusion are used for early diagnosis and close monitoring of this condition. The treatment of vasospasm consists of both prevention (nimodipine, statitis, and magnesium sulphate) and active treatment (mainly endovascular). Conclusion: As the review shows, vasospasm is a complication of SAH, a complication that is difficult to recognize early and treat with the best outcome. However, with the equipment we have, it has been possible to improve the outcome, even if it is still not ideal, in patients who develop vasospasm. Several studies are in the final stages to improve the outcome of this unfortunately frequent condition.

Introduction: Hyponatremia is the most frequently occurring electrolyte disorder in neurocritical care and traumatic brain injury, aneurysmal subarachnoid hemorrhage (SAH), neurosurgery, and ischemic stroke are the clinical conditions more often associated with this condition. SIADH and CSWS are the main causes of hyponatremia in neurologically ill patients. Since hyponatremia is a negative prognostic factor for neurocritical patients, early diagnosis and consequent targeted therapy are of fundamental importance. The present review was carried out to provide a brief recap on the main causes and management of hyponatremia in the neurocritical patient. Methods: A methodical search of the medical literature using the online database MEDLINE was carried out and studies comprising case reports, prospective and retrospective observational studies, or randomized controlled clinical trials in which there is a diagnosis of hyponatremia in neurocritical patients were included. Results: 18 articles were analyzed, consisting of 8 case reports, 4 case series, 3 prospective trials, 1 retrospective study, and 1 multicenter trial. A total of 1371 patients from 18 studies were included. Patients’ average age was 29.28 ± 20.9, respectively. TBI was the main cause of hyponatremia in the literature reviewed; 12 studies were about the relationship between TBI and hyponatremia, 2 studies about stroke, 2 studies about SAH and 1 about hyponatremia postneurosurgical procedure. Discussion: Hyponatremia is the most common electrolyte disorder in hospitalized patients and the main scenarios of hyponatremic neurocritical patients are subarachnoid hemorrhage, ischemic stroke, traumatic brain injury and iatrogenic hyponatremia due to neurosurgical cases. Conclusion: Hyponatremia is a frequent finding in neurocritical care and is also a recognized negative prognostic factor leading to increased mortality and ICU length hospitalization. Its diagnosis and therapy are essential for correct neurocritical management. The most common cause of serum sodium abnormality is SIADH, and an early diagnosis for target treatment is paramount to prevent delayed symptoms and complications.

Background: Current evidence appraisal concepts, such as the Assessment, Development and Evaluation (GRADE) approach and Cochrane’s Risk of Bias (RoB) tool, rely on assumptions related to the classic problem of inductive reasoning and may suffer from insufficient inter-rater reliability. Discussion: The Composite Quality Score (CQS) has emerged as a possible trial appraisal tool that does not rely on inductive assumptions and has been shown to be of potentially very high inter-rater reliability. Conclusion: Although the current CQS concept is still under development, its current evidence is encouraging and justifies further study. This article presents the rationale and currently available research concerning the CQS and shows where further research is required.

Background: Since the end of 2019, SARS-CoV-2 has been responsible for the multisystemic hyper-inflammatory disease, namely, COVID-19, as a majorly impactful pandemic. Gastrointestinal (GI) symptoms occurring during and after disease are gaining increasing attention among experts. Methods: We briefly review and comment on preliminary and recent evidences on prevalence, pathophysiology, and perspective treatment options for GI disturbances during and after COVID-19. Results: Several reports from the literature show a significant portion of COVID-19 patients suffering from GI symptoms both at the early stages of the disease and after the end of it, sometimes for several months, namely “long-COVID-19” patients, irrespective of vaccination. An unsolved issue regarding COVID-19 is the association between GI symptoms and the outcome of COVID-19 patients. Several studies and metanalyses suggest a worse evolution of COVID-19 in patients presenting with GI symptoms. However, these data have not been agreed. Indeed, only one uniform observation can be found in the literature: patients with chronic liver disease have a worse outcome from COVID-19 infection. Upper and lower GI symptoms have similarities with postinfectious functional dyspepsia (FD) and irritable bowel syndrome (IBS). FD and IBS following infection are recognize as pathophysiological factor the gut microbial, which is a gut microbial quali- and quantitative unbalance, namely dysbiosis. Furthermore, several preliminary reports and ongoing clinical trials have shown gut microbiota modulation by pre-, pro- and postbiotics to be effective in changing and preventing COVID-19 natural course. Conclusion: GI symptoms characterize both long- and non-long-COVID-19 with a potentially significant impact on its natural course. Gut microbiota modulation seems to be a sensible target for disease treatment and/or prevention.

Background: The COVID-19 pandemic has significantly changed the implementation of clinical trials. A large focus has been directed on clinical trial design, timeline, and best practices. It has led clinical trial study teams to update the existing processes and perform a risk assessment to mitigate the impact of the COVID-19 pandemic according to ICH-GCP (Good Clinical Practice) requirements. Data management plays a crucial role in understanding the study team's needs and developing innovative solutions. The Clinical Data Manager (CDM) is a core clinical trial Study Team member, responsible for promptly collecting, managing, and delivering complete, highquality data. Objective: The COVID-19 pandemic required the Clinical Data Manager (CDM) to respond to changing needs by adapting data collection tools, data review strategies, and data management processes to answer new questions and address new challenges. CDMs became responsible for identifying how the COVID-19 pandemic impacted current data management processes and documentation and implementing changes to reflect new ways of working. The present article reviews the impact of the COVID-19 pandemic on clinical trials and the solutions adopted by the Clinical Data manager. Conclusion: The collection of COVID-19-related data points provides a better understanding of patient safety during the pandemic and proactively fulfills the growing regulatory interests. Strategies and innovative solutions adopted by the Clinical Data Manager serve as guidance for the clinical research team during the crisis to make the trials more robust and patient-centered.

Background: One of the most important problems associated with the treatment of Rheumatoid Arthritis (RA) is erosive-ulcerative lesions (EUL) of the gastroduodenal zone, which is associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). Aims: Our research aims to study the clinical and histo-morphological criteria for forming the EUL of the gastroduodenal zone in patients with RA. Methods: Patients were divided into 3 groups, depending on the presence of an EUL, according to Fibrogastroduodenoscopy (FGDS) data with a negative test for H. pylori. Group 1 included RA patients without EUL (n = 18), group 2 RA patients with erosive lesions of the gastroduodenal zone (n = 57), and group 3 consisted of RA patients with ulcerative lesions (n = 17). As a norm, we used data from a survey of 18 healthy donors corresponding to RA patient’s age and sex distribution, where no somatic pathology was revealed. GSRS questionnaire was used for assessment of subjective symptoms. For histomorphological studies, biopsy specimens were taken during FGDS using an Olympus Evis Exera II digital video endoscope. Results: Patients of RA with EUL in the gastro-duodenal zone were significantly different from the group of healthy donors and patients of group 1 by the severity of 5 symptoms related to the upper gastrointestinal tract according to the GSRS questionnaire, including abdominal pain, heartburn, belching acid, a feeling of sucking and burning in epigastria, nausea and vomiting. In general, there were no clinically significant differences between the frequency of occurrence and the severity of symptoms on the GSRS scale between group 2 and group 3, except for complaints of heartburn. So, RA patients of group 3 had a higher rate of heartburn feeling of 3.0 (2.0-3.0) points than patients of group 2 with 2.0 (1.0-2.0) points. Conclusion: The development of a EUL of the gastroduodenal zone in patients with RA is associated with low activity of inflammation in all studied slides, regardless of structurally destructive changes in the stomach and duodenum and compensatory hyperplastic reactions in the superficial layer of mucosa membrane, which can be determined by minimal subjective sensations or even complete absence of clinical manifestations with the formation of “silent ulcers”, complicated by bleeding and perforation.

Background: There has been a concern about the quality of clinical trials conducted in terms of data integrity, accuracy or ethical conduct. This study aimed to assess the tangible gap existing in knowledge and application of rules and guidelines among the Researcher, Research staff (RS) and Ethics Committee (EC) members - the three research stakeholders at the study sites. Methods: A validated e-questionnaire with details for demography, role, years of experience, affiliation and questions on knowledge and understanding about their clinical research functions based on the New Drugs and Clinical Trials (NDCT) Rules 2019, including: ‘Role and responsibility, Regulations, Reporting timelines, Documentation, Conflict of interest and Miscellaneous’ was circulated among the seven research sites of one organization with their fourteen Institutional ECs, as part of planned annual survey. Responses with >60% correct answers were arbitrarily considered to represent adequate knowledge. Results: Of 201 participants, there were 27.4% Researchers, 50.2% were from the EC and 22.4% RS. A greater proportion of the Researchers (43.6%) had >5 years of experience. The mean ± SD of correct answers obtained was 66.9 ± 14.77 and was statistically significant (p<0.05) among the groups, highest for the EC members (71.4 ± 11.51), those with 2-5 years of experience (68.4 ± 14.40), and least for the RS (56.8 ± 11.93). Researchers (> 90%) were aware of their role in the clinical trial agreement and the importance of the trial registration in the Clinical Trials Registry India. There were gaps in the knowledge on Informed Consent (IC) process and post-trial access. Awareness regarding the IC process was adequate among the RS (84%). Awareness that the responsibility of all delegation at the site finally lies with the Researchers was adequate (60%), but 20% incorrectly believed that the sponsor can have access to subject identification details. Deficiencies were noted regarding documentation, NDCT rules -2019 and serious adverse event (SAE) reporting process. Five percent answered that Data Clarification Forms were generated after reviewing the case report forms. The awareness that NDCT rules-2019 was not for medical devices, student projects or Investigator Initiated Studies was inadequate (56%). The EC members’ awareness of roles and responsibilities was adequate (≥ 90%). Knowledge gaps were noted in EC monitoring of the ongoing trials (32%) and SAE reporting on the SUGAM portal (8.8%), where stakeholders can access the regulator's web services using a single window interface for clinical trial related activities. Conclusion: There are gaps in the knowledge of the 3 stakeholders at the site. Identifying and rectifying the gray areas will improve the site's performance. There is a need for regular training and assessments.

Background: The hemostasis system has been extensively investigated in patients in the acute phase of coronavirus disease 2019 (COVID-19). In contrast, the post-COVID syndrome is a poorly known entity, and there is a lack of information on the mechanisms underlying the hemostasis abnormalities in the post-COVID period. Aim: To analyze the potential changes in the parameters of the hemostasis system in the post- COVID period in the plasma of donors with different titers of anti-SARS-CoV-2 IgG. Methods: The plasma from 160 donors who had recovered from COVID infection was used in the study. Based on the results of the Abbott SARS-CoV-2 IgG serological assay, all donors were divided into several groups: 5 ± 3 (n = 20); 55 ± 5 (n = 20); 65 ± 5 (n = 20); 75 ± 5 (n = 20); 85 ± 5 (n = 20); 95 ± 5 (n = 20); 125 ± 5 (n = 20); 175 ± 5 (n = 20) Index (S/C). A total of 20 healthy individuals without anti-SARS-CoV-2 IgG constituted the control group. Key laboratory parameters, such as fibrinogen concentrations, soluble fibrin monomer complex (SFMCs), and Ddimer, were investigated. In addition, the qualitative composition of the fraction of SFMCs was analyzed. Results: The slight increase in the concentration of fibrinogen, SFMCs, and D-dimers in some donor groups have been found, which could cause the development of hemostasis disorders. In the fraction of SFMCs, the increase in the number of protein fragments with a molecular weight of less than 250 kDa and an increase in the level of proteins with a molecular weight of more than 270 kDa was revealed. Conclusion: The obtained results indicated the relationship between the changes in the parameters of the hemostasis system and the titers of anti-SARS-CoV-2 IgG in donors in the post-COVID period. It can be assumed that donors with higher titers of anti-SARS-CoV-2 IgG (>55 ± 5 Index (S/C)) are more prone to hemostasis abnormalities in the post-COVID period since a pronounced imbalance in the levels of SFMCs and D-dimer characterizes them. The appearance of protein fragments of different molecular weights in the fraction of SFMC points to uncontrolled activation of biochemical processes involving molecules of fibrinogenic origin. Additional studies are required to elucidate the role of anti-SARS-CoV-2 IgG in the post-COVID period.

Background: Lower Gastrointestinal Bleeding (LGIB) is a common cause of admission to the Emergency Department (ED). Early colonoscopy is the exam of choice for evaluating LGIB, and an adequate colon cleansing is essential. High-volume solution 4L-PEG is largely used, but it has some limitations. Low-volume solution 2L-PEG may improve patient’s tolerability and compliance, reducing the time of administration and speeding up the exam. Patients and Methods: We conducted a randomized 1:1, prospective observational monocentric study in 228 patients (144M/84F) with LGIB. 121 (69M/52F) received the High-Volume, while 107 (75M/32F) received Low-Volume. They completed a “satisfaction questionnaire” (taste and smell, mood, time of taking, general experience). We collected the results of the Boston Bowel Preparation Scale (BBPS) and the final diagnosis. The study was retrospectively registered on clinicaltrial.gov with protocol number NCT0536 2227. Results: A mean value of BBPS 6,3 was achieved by both groups (p=0.57). Regarding smell, taste, mood and time of taking (1 to 5), we do not find any statistically differences. The overall satisfaction between the two preparations was 2.90 for low-volume compared to 3.17 for Highvolume (p=0.06). No side effects were reported. The proportion of patients without an evident source of bleeding was higher in High volume preparations compared to Low-volume (39% vs. 30%, respectively). Conclusion: Low volume bowel preparation showed the same efficacy and tolerability with better satisfaction compared with high volume. Low-volume could represent an effective and more desirable preparation for patients in the ED.