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The COVID-19 pandemic is one of the greatest threats to human health in the 21st century with more than 257 million cases and over 5.17 million deaths reported worldwide (as of November 23, 2021. Various agents were initially proclaimed to be effective against SARS-CoV-2, the etiological agent of COVID-19. Hydroxychloroquine, lopinavir/ritonavir, and ribavirin are all examples of therapeutic agents, whose efficacy against COVID-19 was later disproved. Meanwhile, concentrated efforts of researchers and clinicians worldwide have led to the identification of novel therapeutic options to control the disease including PAXLOVID™ (PF-07321332). Although COVID-19 cases are currently treated using a comprehensive approach of anticoagulants, oxygen, and antibiotics, the novel Pfizer agent PAXLOVID™ (PF-07321332), an investigational COVID-19 oral antiviral candidate, significantly reduced hospitalization time and death rates, based on an interim analysis of the phase 2/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness. The scheduled interim analysis demonstrated an 89 % reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset (primary endpoint). However, there still exists a great need for the development of additional treatments, as the recommended therapeutic options are insufficient in many cases. Thus far, mRNA and vector vaccines appear to be the most effective modalities to control the pandemic. In the current review, we provide an update on the progress that has been made since April 2020 in clinical trials concerning the effectiveness of therapies available to combat COVID-19. We focus on currently recommended therapeutic agents, including steroids, various monoclonal antibodies, remdesivir, baricitinib, anticoagulants and PAXLOVID™ summarizing the latest original studies and meta-analyses. Moreover, we aim to discuss other currently and previously studied agents targeting COVID-19 that either show no or only limited therapeutic activity. The results of recent studies report that hydroxychloroquine and convalescent plasma demonstrate no efficacy against SARS-CoV-2 infection. Lastly, we summarize the studies on various drugs with incoherent or insufficient data concerning their effectiveness, such as amantadine, ivermectin, or niclosamide., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Delirium is the most common manifestation of brain dysfunction in critically ill patients. In the intensive care unit (ICU), duration of delirium is independently predictive of excess death, length of stay, cost of care, and acquired dementia. There are numerous neurotransmitter/functional and/or injury-causing hypotheses rather than a unifying mechanism for delirium. Without using a validated delirium instrument, delirium can be misdiagnosed (under, but also overdiagnosed and trivialized), supporting the recommendation to use a monitoring instrument routinely. The best-validated ICU bedside instruments are CAM-ICU and ICDSC, both of which also detect subsyndromal delirium. Both tools have some inherent limitations in the neurologically injured patients, yet still provide valuable information about delirium once the sequelae of the primary injury settle into a new post-injury baseline. Now it is known that antipsychotics and other psychoactive medications do not reliably improve brain function in critically ill delirious patients. ICU teams should systematically screen for predisposing and precipitating factors. These include exacerbations of cardiac/respiratory failure or sepsis, metabolic disturbances (hypoglycemia, dysnatremia, uremia and ammonemia) receipt of psychoactive medications, and sensory deprivation through prolonged immobilization, uncorrected vision and hearing deficits, poor sleep hygiene, and isolation from loved ones so common during COVID-19 pandemic. The ABCDEF (A2F) bundle is a means to facilitate implementation of the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS) Guidelines. In over 25,000 patients across nearly 100 institutions, the A2F bundle has been shown in a dose-response fashion (i.e., greater bundle compliance) to yield improved survival, length of stay, coma and delirium duration, cost, and less ICU bounce-backs and discharge to nursing homes., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has profoundly affected the lives of millions of people. To date, there is no approved vaccine or specific drug to prevent or treat COVID-19, while the infection is globally spreading at an alarming rate. Because the development of effective vaccines or novel drugs could take several months (if not years), repurposing existing drugs is considered a more efficient strategy that could save lives now. Statins constitute a class of lipid-lowering drugs with proven safety profiles and various known beneficial pleiotropic effects. Our previous investigations showed that statins have antiviral effects and are involved in the process of wound healing in the lung. This triggered us to evaluate if statin use reduces mortality in COVID-19 patients., Results: After initial recruitment of 459 patients with COVID-19 (Shiraz province, Iran) and careful consideration of the exclusion criteria, a total of 150 patients, of which 75 received statins, were included in our retrospective study. Cox proportional-hazards regression models were used to estimate the association between statin use and rate of death. After propensity score matching, we found that statin use appeared to be associated with a lower risk of morbidity [HR = 0.85, 95% CI = (0.02, 3.93), P  = 0.762] and lower risk of death [(HR = 0.76; 95% CI = (0.16, 3.72), P  = 0.735)]; however, these associations did not reach statistical significance. Furthermore, statin use reduced the chance of being subjected to mechanical ventilation [OR = 0.96, 95% CI = (0.61-2.99), P  = 0.942] and patients on statins showed a more normal computed tomography (CT) scan result [OR = 0.41, 95% CI = (0.07-2.33), P  = 0.312]., Conclusions: Although we could not demonstrate a significant association between statin use and a reduction in mortality in patients with COVID19, we do feel that our results are promising and of clinical relevance and warrant the need for prospective randomized controlled trials and extensive retrospective studies to further evaluate and validate the potential beneficial effects of statin treatment on clinical symptoms and mortality rates associated with COVID-19., Competing Interests: Competing interestsThe authors declare that they have no conflict of interest., (© The Author(s) 2021.)

In December 2019, a novel SARS-CoV-2 coronavirus emerged, causing an outbreak of life-threatening pneumonia in the Hubei province, China, and has now spread worldwide, causing a pandemic. The urgent need to control the disease, combined with the lack of specific and effective treatment modalities, call for the use of FDA-approved agents that have shown efficacy against similar pathogens. Chloroquine, remdesivir, lopinavir/ritonavir or ribavirin have all been successful in inhibiting SARS-CoV-2 in vitro. The initial results of a number of clinical trials involving various protocols of administration of chloroquine or hydroxychloroquine mostly point towards their beneficial effect. However, they may not be effective in cases with persistently high viremia, while results on ivermectin (another antiparasitic agent) are not yet available. Interestingly, azithromycin, a macrolide antibiotic in combination with hydroxychloroquine, might yield clinical benefit as an adjunctive. The results of clinical trials point to the potential clinical efficacy of antivirals, especially remdesivir (GS-5734), lopinavir/ritonavir, and favipiravir. Other therapeutic options that are being explored involve meplazumab, tocilizumab, and interferon type 1. We discuss a number of other drugs that are currently in clinical trials, whose results are not yet available, and in various instances we enrich such efficacy analysis by invoking historic data on the treatment of SARS, MERS, influenza, or in vitro studies. Meanwhile, scientists worldwide are seeking to discover novel drugs that take advantage of the molecular structure of the virus, its intracellular life cycle that probably elucidates unfolded-protein response, as well as its mechanism of surface binding and cell invasion, like angiotensin converting enzymes-, HR1, and metalloproteinase inhibitors., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

The novel coronavirus, SARS-CoV-2-causing Coronavirus Disease 19 (COVID-19), emerged as a public health threat in December 2019 and was declared a pandemic by the World Health Organization in March 2020. Delirium, a dangerous untoward prognostic development, serves as a barometer of systemic injury in critical illness. The early reports of 25% encephalopathy from China are likely a gross underestimation, which we know occurs whenever delirium is not monitored with a valid tool. Indeed, patients with COVID-19 are at accelerated risk for delirium due to at least seven factors including (1) direct central nervous system (CNS) invasion, (2) induction of CNS inflammatory mediators, (3) secondary effect of other organ system failure, (4) effect of sedative strategies, (5) prolonged mechanical ventilation time, (6) immobilization, and (7) other needed but unfortunate environmental factors including social isolation and quarantine without family. Given early insights into the pathobiology of the virus, as well as the emerging interventions utilized to treat the critically ill patients, delirium prevention and management will prove exceedingly challenging, especially in the intensive care unit (ICU). The main focus during the COVID-19 pandemic lies within organizational issues, i.e., lack of ventilators, shortage of personal protection equipment, resource allocation, prioritization of limited mechanical ventilation options, and end-of-life care. However, the standard of care for ICU patients, including delirium management, must remain the highest quality possible with an eye towards long-term survival and minimization of issues related to post-intensive care syndrome (PICS). This article discusses how ICU professionals (e.g., physicians, nurses, physiotherapists, pharmacologists) can use our knowledge and resources to limit the burden of delirium on patients by reducing modifiable risk factors despite the imposed heavy workload and difficult clinical challenges posed by the pandemic.

Chronic obstructive pulmonary disease (COPD) has a major impact on mortality and morbidity in patients undergoing cardiac surgery. Mortality risk increases by 50% in patients who were re-intubated or required prolonged mechanical ventilation after the operation. The aim of this study was to assess the impact of COPD on the prediction of postoperative complications and outcome including intensive care unit (ICU) and hospital stay, postoperative morbidity and mortality in patients undergoing all types of cardiac surgery.We performed a retrospective cohort analysis of prospectively collected data from a tertiary cardiac surgery department of a university hospital between 2014 and 2016. We divided patients undergoing cardiac surgery into 2 sub-groups - the first - with a clinical diagnosis of COPD (n = 198) and the second comprised all other non-COPD patients (n = 2980).Among patients with COPD a longer intubation time (P = .039), longer ICU stay (P < .001) and longer hospitalization time (P = .006) was noted as compared with non-COPD patients. Patients with COPD required reintubation more often than non-COPD patients, reintubation occurring twice, 19 (9.60%) versus 144 (4.83%) P = .002, reintubation occurring 3 or more times, 7 (3.54%) versus 34 (1.14%) P = .006. Mortality within 30 days after surgery was higher in patients with pulmonary problems before surgery (P = .003). Multivariable logistic regression analysis corrected for interfering variables showed an increased risk of postoperative bronchoconstriction (odds ratio [OR] = 4.40, P = .002), respiratory failure (OR = 1.67, P = .018), atrial fibrillation (OR = 1.45, P = .023), and use of hemofiltration (OR = 1.60, P = .029) for patients with COPD.Patients with COPD undergoing all types of cardiac surgery are at increased risk of respiratory complications and mortality. The occurrence of COPD was associated with longer ICU and hospital stay. In COPD patients, undergoing cardiac surgery, treatment strategies aimed at preventing reintubation and early weaning mechanical ventilation must be employed to reduce postoperative complications.

Purpose: To investigate age-related differences in outcomes of critically ill patients with sepsis around the world., Methods: We performed a secondary analysis of data from the prospective ICON audit, in which all adult (>16 years) patients admitted to participating ICUs between May 8 and 18, 2012, were included, except admissions for routine postoperative observation. For this sub-analysis, the 10,012 patients with completed age data were included. They were divided into five age groups - ≤50, 51-60, 61-70, 71-80, >80 years. Sepsis was defined as infection plus at least one organ failure., Results: A total of 2963 patients had sepsis, with similar proportions across the age groups (≤50 = 25.2%; 51-60 = 30.3%; 61-70 = 32.8%; 71-80 = 30.7%; >80 = 30.9%). Hospital mortality increased with age and in patients >80 years was almost twice that of patients ≤50 years (49.3% vs 25.2%, p < .05). The maximum rate of increase in mortality was about 0.75% per year, occurring between the ages of 71 and 77 years. In multilevel analysis, age > 70 years was independently associated with increased risk of dying., Conclusions: The odds for death in ICU patients with sepsis increased with age with the maximal rate of increase occurring between the ages of 71 and 77 years., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Patients after cardiac surgery experience significant pain, but cannot communicate effectively due to opioid analgesia and sedation. Identification of pain with validated behavioral observation tool in patients with limited abilities to self-report pain improves quality of care and prevents suffering. Aim of this study was to validate Polish version of behavioral pain scale (BPS) in intubated, mechanically ventilated patients sedated with dexmedetomidine and morphine after cardiac surgery.Prospective observational cohort study included postoperative cardiac surgery patients, both sedated with dexmedetomidine and unsedated, observed at rest, during a nociceptive procedure (position change) and 10 minutes after intervention. Pain control was achieved using morphine infusion and nonopioid coanalgesia. Pain intensity evaluation included self-report by patient using numeric rating scale (NRS) and BPS assessments carried out by 2 blinded observers.A total of 708 assessments were performed in 59 patients (mean age 68 years), predominantly men (44/59, 75%). Results showed very good interrater correlation between raters (interrater correlation scores >0.87). Self-report NRS scores were obtained from all patients. Correlation between NRS and BPS was relatively strong during nociceptive procedures in all patients for rater A and rater B (Spearman R > 0.65, P < .001). Both mean NRS and BPS scores were significantly higher during nociceptive procedures as compared to assessments at rest, in both sedated and unsedated patients (P < .001).The results of this observational study show that the Polish translation of BPS can be regarded as a useful and validated tool for pain assessment in adult intubated patients. This instrument can be used in both unsedated and sedated cardiac surgery patients with limited communication abilities.

Introduction: Postoperative delirium is a common complication of cardiac surgery associated with increased mortality, morbidity, and long-term cognitive dysfunction. The aim of this study was to identify incidence and risk factors of delirium in elderly (≥65 years) and very elderly (≥80 years) patients undergoing major cardiac surgery., Materials and Methods: We performed a retrospective cohort analysis of prospectively collected data from a register of the cardiac surgery department of a tertiary referral university hospital between 2014 and 2016. Analysis was performed in two groups, ≥65 years and ≥80 years., Results: We analyzed 1,797 patients ≥65 years, including 230 (7.24%) patients ≥80 years. Delirium was diagnosed in 21.4% (384/1,797) of patients above 65 years, and in 33.5% (77/230) of octogenarians. Early mortality did not differ between patients with and without delirium. Intensive care unit (ICU) stay ( p <0.001), hospital stay ( p <0.001), and intubation time ( p =0.002) were significantly longer in patients undergoing cardiac surgery ≥65 years with delirium. According to multivariable analysis, <65 years, age (odds ratio [OR] 1.036, p =0.002), low ejection fraction (OR 1.634, p =0.035), diabetes (1.346, p =0.019), and extracardiac arteriopathy (OR 1.564, p =0.007) were found to be independent predictors of post-cardiac surgery delirium. Postoperative risk factors for developing delirium ≥65 years were atrial fibrillation (1.563, p =0.001), postoperative pneumonia (OR 1.896, p =0.022), elevated postoperative creatinine (OR 1.384, p =0.004), and prolonged hospitalization (OR 1.019, p =0.009)., Conclusion: Patients above 65 years of age with postoperative delirium have poorer outcome and are more likely to have prolonged hospitalization and ICU stay, and longer intubation times, but 30-day mortality is not increased. In our study, eight independent risk factors for development of post-cardiac surgery delirium were age, low ejection fraction, diabetes, extracardiac arteriopathy, postoperative atrial fibrillation, pneumonia, elevated creatinine, and prolonged hospitalization time., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: To evaluate differences in the characteristics and outcomes of intensive care unit (ICU) patients over time., Methods: We reviewed all epidemiological data, including comorbidities, types and severity of organ failure, interventions, lengths of stay and outcome, for patients from the Sepsis Occurrence in Acutely ill Patients (SOAP) study, an observational study conducted in European intensive care units in 2002, and the Intensive Care Over Nations (ICON) audit, a survey of intensive care unit patients conducted in 2012., Results: We compared the 3147 patients from the SOAP study with the 4852 patients from the ICON audit admitted to intensive care units in the same countries as those in the SOAP study. The ICON patients were older (62.5 ± 17.0 vs. 60.6 ± 17.4 years) and had higher severity scores than the SOAP patients. The proportion of patients with sepsis at any time during the intensive care unit stay was slightly higher in the ICON study (31.9 vs. 29.6%, p = 0.03). In multilevel analysis, the adjusted odds of ICU mortality were significantly lower for ICON patients than for SOAP patients, particularly in patients with sepsis [OR 0.45 (0.35-0.59), p < 0.001]., Conclusions: Over the 10-year period between 2002 and 2012, the proportion of patients with sepsis admitted to European ICUs remained relatively stable, but the severity of disease increased. In multilevel analysis, the odds of ICU mortality were lower in our 2012 cohort compared to our 2002 cohort, particularly in patients with sepsis.

Background: The increasing population of very old intensive care patients (VIPs) is a major challenge currently faced by clinicians and policymakers. Reliable indicators of VIPs' prognosis and purposefulness of their admission to the intensive care unit (ICU) are urgently needed., Methods: This is a report from the Polish sample of the VIP1 multicentre cohort study (NCT03134807). Patients ≥ 80 years of age admitted to the ICU were included in the study. Information on the type and reason for admission, demographics, utilisation of ICU procedures, ICU length of stay, organ dysfunction and the decision to apply end-of-life care was collected. The primary objective was to investigate the impact of frailty syndrome on ICU and 30-day survival of VIPs. Frailty was assessed with the Clinical Frailty Scale (≥ 5 points on a scale of 1-9)., Results: We enrolled 272 participants with a median age of 84 (81-87) years. Frailty was diagnosed in 170 (62.5%) patients. The ICU and 30-day survival rates were equal to 54.6% and 47.3% respectively. Three variables were found to significantly increase the odds of death in the ICU in a multiple logistic regression model: SOFA score (OR = 1.16; 95%CI 1.16-1.24), acute mode of admission (OR = 5.1; 95%CI 1.67-15.57) and frailty (OR = 2.25; 95%CI 1.26-4.01)., Conclusion: Measuring frailty in critically ill older adults can facilitate making more informed clinical decisions and help avoid futile interventions.

Objectives: To assess the knowledge and use of the Assessment, prevention, and management of pain; spontaneous awakening and breathing trials; Choice of analgesia and sedation; Delirium assessment; Early mobility and exercise; and Family engagement and empowerment (ABCDEF) bundle to implement the Pain, Agitation, Delirium guidelines., Design: Worldwide online survey., Setting: Intensive care., Intervention: A cross-sectional online survey using the Delphi method was administered to intensivists worldwide, to assess the knowledge and use of all aspects of the ABCDEF bundle., Measurement and Main Results: There were 1,521 respondents from 47 countries, 57% had implemented the ABCDEF bundle, with varying degrees of compliance across continents. Most of the respondents (83%) used a scale to evaluate pain. Spontaneous awakening trials and spontaneous breathing trials are performed in 66% and 67% of the responder ICUs, respectively. Sedation scale was used in 89% of ICUs. Delirium monitoring was implemented in 70% of ICUs, but only 42% used a validated delirium tool. Likewise, early mobilization was "prescribed" by most, but 69% had no mobility team and 79% used no formal mobility scale. Only 36% of the respondents assessed ICU-acquired weakness. Family members were actively involved in 67% of ICUs; however, only 33% used dedicated staff to support families and only 35% reported that their unit was open 24 hr/d for family visits., Conclusions: The current implementation of the ABCDEF bundle varies across individual components and regions. We identified specific targets for quality improvement and adoption of the ABCDEF bundle. Our data reflect a significant but incomplete shift toward patient- and family-centered ICU care in accordance with the Pain, Agitation, Delirium guidelines.

Objectives: Excessive fluid therapy in patients with sepsis may be associated with risks that outweigh any benefit. We investigated the possible influence of early fluid balance on outcome in a large international database of ICU patients with sepsis., Design: Observational cohort study., Setting: Seven hundred and thirty ICUs in 84 countries., Patients: All adult patients admitted between May 8 and May 18, 2012, except admissions for routine postoperative surveillance. For this analysis, we included only the 1,808 patients with an admission diagnosis of sepsis. Patients were stratified according to quartiles of cumulative fluid balance 24 hours and 3 days after ICU admission., Measurements and Main Results: ICU and hospital mortality rates were 27.6% and 37.3%, respectively. The cumulative fluid balance increased from 1,217 mL (-90 to 2,783 mL) in the first 24 hours after ICU admission to 1,794 mL (-951 to 5,108 mL) on day 3 and decreased thereafter. The cumulative fluid intake was similar in survivors and nonsurvivors, but fluid balance was less positive in survivors because of higher fluid output in these patients. Fluid balances became negative after the third ICU day in survivors but remained positive in nonsurvivors. After adjustment for possible confounders in multivariable analysis, the 24-hour cumulative fluid balance was not associated with an increased hazard of 28-day in-hospital death. However, there was a stepwise increase in the hazard of death with higher quartiles of 3-day cumulative fluid balance in the whole population and after stratification according to the presence of septic shock., Conclusions: In this large cohort of patients with sepsis, higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death.

Background: The question about the role of CD4+CD28- lymphocytes in the pathogenesis of atherosclerosis-related ischemic stroke is still open., Material and Methods: The study included patients, who underwent endarterectomy of internal carotid arteries. The group consisted of patients after stroke and ones without previous stroke. The histopathologic examination of obtained plaques has been performed. The percentage of CD4+CD28- lymphocytes in peripheral blood and their cytotoxicity has been assessed for each patient., Results: The global percentage of CD4+CD28- lymphocytes in blood was higher in the group of patients with plaques where connective tissue fibers consisted significantly of collagen fibers. The cytotoxicity of analysed cells related to less plaques calcification and presence of cholesterol crystals in the plaque. A multifactor regression of dependent variable presented the last relationship above as a only strong., Conclusions: CD4+CD28- cytotoxic lymphocytes seem to be involved in carotid atherosclerotic plaques development. Intraplaque cholesterol deposits may contribute to this process.

Postoperative analgesia plays a crucial role in day-case surgery. Patients expect effective pain relief after surgery, without side effects, and this may not always be possible when more complicated procedures are performed in ambulatory settings. Moreover, both surgeons and patients expect anaesthesiologists to provide an effective pain treatment service especially after ambulatory surgery, even in private practice settings. The protocols based on intravenous opioids or central neuraxial blockade are no longer appropriate, when a short, uncomplicated postoperative course is anticipated. Multimodal analgesia, combining different groups of analgesics, both opioid and non-opioid, with different mechanisms of action, and targets in central and peripheral nervous systems with minimal side effects may be an answer. In this review, we present and discuss the current status of knowledge, with special reference to the role of adjuvants to opioids in acute postoperative pain.

Postoperative analgesia should be adjusted to current needs of a patient. Non-opioid agents are recommended, wherever possible: both non-steroidal anti-inflammatory drugs (NSAIDs), metamizole or paracetamol may be useful for treatment of acute pain. The use of metamizole is associated with such complications as bone marrow damage (agranulocytosis, aplastic anaemia), chronic interstitial nephritis, gastro-intestinal disturbances, etc. Paracetamol, currently also intravenous, is likely to cause hepatocyte damage, renal necrosis, as well as vomiting, diarrhoea and skin reactions. Opinions about metamizole are controversial. In some countries, metamizole was withdrawn already in the 70ties of the previous century; in others, it is still widely used. According to the Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, the number of adverse effects registered in the years 1978-2009 (March) was 14441 for metamizol and 67581 for paracetamol. Modern multimodal analgesia should be based on a good combination of analgesics. Both metamizole and paracetamol may be used for such a purpose, yet in the lowest effective doses, within the shortest needed time and once evident contraindications have been considered. Safety of both drugs is several times higher than that of commonly used NSAIDs.