A Literature Review of Pathophysiology, Clinical Manifestations, Medications and Optimal Dosage, Outpatient, and Post-hospitalization Use of Anticoagulation in COVID-19 Patients.

Since severe acute respiratory syndrome coronavirus 2 led to a world pandemic, extensive research has been conducted to identify its characteristics and form an appropriate management plan. One recognized complication of COVID-19 is coagulation defects that can lead to thromboembolic events. We have reviewed the literature to summarize and present the latest research about the pathophysiology, clinical manifestations, anticoagulation use and appropriate dose in COVID-19 patients, as well as the effect of anticoagulation in outpatient and post-hospital settings. The pathophysiology of coagulation abnormalities in COVID-19 is not fully understood yet, but multiple mechanisms appear to be involved, such as a direct viral attack, hyperinflammation, increased immune response, blood stasis, and endothelial injury. Clinical manifestations are mainly venous thromboembolism (deep vein thrombosis and pulmonary embolism), arterial thromboembolism, ischemic stroke, central venous sinus thrombosis, and central retinal vein occlusion. Anticoagulation is widely used in hospitalized patients with COVID-19, unless it is contraindicated. Heparinoid is the main anticoagulant used. However, the appropriate dosage is still debated as research is trying to find a balance between benefits and risks. In outpatients, it appears that anticoagulation has no benefit in contrast to post-hospitalization use, where benefit could be observed in severely affected patients. We concluded that thromboprophylaxis should be used in treating hospitalized COVID-19 patients, but the dosage is still a matter of debate. More research needs to be done on outpatient and post-hospitalized patients to derive accurate conclusions.

Impact of Bacterial Infections on COVID-19 Patients: Is Timing Important?

BACKGROUND: Along with important factors that worsen the clinical outcome of COVID-19, it has been described that bacterial infections among patients positive for a SARS-CoV-2 infection can play a dramatic role in the disease process. Co-infections or community-acquired infections are recognized within the first 48 h after the admission of patients. Superinfections occur at least 48 h after admission and are considered to contribute to a worse prognosis. Microbiologic parameters differentiate infections that happen after the fifth day of hospitalization from those appearing earlier. Specifically, after the fifth day, the detection of resistant bacteria increases and difficult microorganisms emerge. OBJECTIVES: The aim of the study was to evaluate the impact of bacterial infections in patients with COVID-19 on the length of the hospital stay and mortality. METHODS: A total of 177 patients hospitalized due to COVID-19 pneumonia were consecutively sampled during the third and fourth wave of the pandemic at a University Hospital in Greece. A confirmed bacterial infection was defined as positive blood, urinary, bronchoalveolar lavage (BAL) or any other infected body fluid. Patients with confirmed infections were further divided into subgroups according to the time from admission to the positive culture result. RESULTS: When comparing the groups of patients, those with a confirmed infection had increased odds of death (odds ratio: 3.634; CI 95%: 1.795-7.358; p < 0.001) and a longer length of hospital stay (median 13 vs. 7 days). A late onset of infection was the most common finding in our cohort and was an independent risk factor for in-hospital death. Mortality and the length of hospital stay significantly differed between the subgroups. CONCLUSION: In this case series, microbial infections were an independent risk factor for a worse outcome among patients with COVID-19. Further, a correlation between the onset of infection and a negative outcome in terms of non-infected, community-acquired, early hospital-acquired and late hospital-acquired infections was identified. Late hospital-acquired infections increased the mortality of COVID-19 patients whilst superinfections were responsible for an extended length of hospital stay.

N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis.

BACKGROUND: N-acetylcysteine (NAC) is a mucolytic agents with anti-inflammatory properties that has been suggested as an adjunctive therapy in patients with COVID-19 pneumonia. OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate available evidence on the possible beneficial effects of NAC on SARS-CoV-2 infection. METHODS: In September 2022, we conducted a comprehensive search on Pubmed/Medline and Embase on randomized controlled trials (RCTs) and observational studies on NAC in patients with COVID-19 pneumonia. Study selection, data extraction and risk of bias assessment was performed by two independent authors. RCTs and observational studies were analyzed separately. RESULTS: We included 3 RCTs and 5 non-randomized studies on the efficacy of NAC in patients with COVID-19, enrolling 315 and 20826 patients respectively. Regarding in-hospital mortality, the summary effect of all RCTs was OR: 0.85 (95% CI: 0.43 to 1.67, I2=0%) and for non-randomized studies OR: 1.02 (95% CI: 0.47 to 2.23, I2=91%). Need for ICU admission was only reported by 1 RCT (OR: 0.86, 95% CI:0.44-1.69, p=0.66), while all included RCTs reported need for invasive ventilation (OR:0.91, 95% CI:0.54 to 1.53, I2=0). Risk of bias was low for all included RCTs, but certainty of evidence was very low for all outcomes due to serious imprecision and indirectness. CONCLUSION: The certainty of evidence in the included studies was very low, thus recommendations for clinical practice cannot be yet made. For all hard clinical outcomes point estimates in RCTs are close to the line of no effect, while observational studies have a high degree of heterogeneity with some of them suggesting favorable results in patients receiving NAC. More research is warranted to insure that NAC is both effective and safe in patients with COVID-19 pneumonia.

Prone Positioning Decreases Inhomogeneity and Improves Dorsal Compliance in Invasively Ventilated Spontaneously Breathing COVID-19 Patients-A Study Using Electrical Impedance Tomography.

BACKGROUND: We studied prone positioning effects on lung aeration in spontaneously breathing invasively ventilated patients with coronavirus disease 2019 (COVID-19). METHODS: changes in lung aeration were studied prospectively by electrical impedance tomography (EIT) from before to after placing the patient prone, and back to supine. Mixed effect models with a random intercept and only fixed effects were used to evaluate changes in lung aeration. RESULTS: fifteen spontaneously breathing invasively ventilated patients were enrolled, and remained prone for a median of 19 [17 to 21] hours. At 16 h the global inhomogeneity index was lower. At 2 h, there were neither changes in dorsal nor in ventral compliance; after 16 h, only dorsal compliance (ßFe +18.9 [95% Confidence interval (CI): 9.1 to 28.8]) and dorsal end-expiratory lung impedance (EELI) were increased (ßFe, +252 [95% CI: 13 to 496]); at 2 and 16 h, dorsal silent spaces was unchanged (ßFe, -4.6 [95% CI: -12.3 to +3.2]). The observed changes induced by prone positioning disappeared after turning patients back to supine. CONCLUSIONS: in this cohort of spontaneously breathing invasively ventilated COVID-19 patients, prone positioning decreased inhomogeneity, increased lung volumes, and improved dorsal compliance.

The RALE Score Versus the CT Severity Score in Invasively Ventilated COVID-19 Patients-A Retrospective Study Comparing Their Prognostic Capacities.

BACKGROUND: Quantitative radiological scores for the extent and severity of pulmonary infiltrates based on chest radiography (CXR) and computed tomography (CT) scan are increasingly used in critically ill invasively ventilated patients. This study aimed to determine and compare the prognostic capacity of the Radiographic Assessment of Lung Edema (RALE) score and the chest CT Severity Score (CTSS) in a cohort of invasively ventilated patients with acute respiratory distress syndrome (ARDS) due to COVID-19. METHODS: Two-center retrospective observational study, including consecutive invasively ventilated COVID-19 patients. Trained scorers calculated the RALE score of first available CXR and the CTSS of the first available CT scan. The primary outcome was ICU mortality; secondary outcomes were duration of ventilation in survivors, length of stay in ICU, and hospital-, 28-, and 90-day mortality. Prognostic accuracy for ICU death was expressed using odds ratios and Area Under the Receiver Operating Characteristic curves (AUROC). RESULTS: A total of 82 patients were enrolled. The median RALE score (22 [15-37] vs. 26 [20-39]; p = 0.34) and the median CTSS (18 [16-21] vs. 21 [18-23]; p = 0.022) were both lower in ICU survivors compared to ICU non-survivors, although only the difference in CTSS reached statistical significance. While no association was observed between ICU mortality and RALE score (OR 1.35 [95%CI 0.64-2.84]; p = 0.417; AUC 0.50 [0.44-0.56], this was noticed with the CTSS (OR, 2.31 [1.22-4.38]; p = 0.010) although with poor prognostic capacity (AUC 0.64 [0.57-0.69]). The correlation between the RALE score and CTSS was weak (r2 = 0.075; p = 0.012). CONCLUSIONS: Despite poor prognostic capacity, only CTSS was associated with ICU mortality in our cohort of COVID-19 patients.

The Prognostic Capacity of the Radiographic Assessment for Lung Edema Score in Patients With COVID-19 Acute Respiratory Distress Syndrome-An International Multicenter Observational Study.

Background: The radiographic assessment for lung edema (RALE) score has an association with mortality in patients with acute respiratory distress syndrome (ARDS). It is uncertain whether the RALE scores at the start of invasive ventilation or changes thereof in the next days have prognostic capacities in patients with COVID-19 ARDS. Aims and Objectives: To determine the prognostic capacity of the RALE score for mortality and duration of invasive ventilation in patients with COVID-19 ARDS. Methods: An international multicenter observational study included consecutive patients from 6 ICUs. Trained observers scored the first available chest X-ray (CXR) obtained within 48 h after the start of invasive ventilation ("baseline CXR") and each CXRs thereafter up to day 14 ("follow-up CXR"). The primary endpoint was mortality at day 90. The secondary endpoint was the number of days free from the ventilator and alive at day 28 (VFD-28). Results: A total of 350 CXRs were scored in 139 patients with COVID-19 ARDS. The RALE score of the baseline CXR was high and was not different between survivors and non-survivors (33 [24-38] vs. 30 [25-38], P = 0.602). The RALE score of the baseline CXR had no association with mortality (hazard ratio [HR], 1.24 [95% CI 0.88-1.76]; P = 0.222; area under the receiver operating characteristic curve (AUROC) 0.50 [0.40-0.60]). A change in the RALE score over the first 14 days of invasive ventilation, however, had an independent association with mortality (HR, 1.03 [95% CI 1.01-1.05]; P < 0.001). When the event of death was considered, there was no significant association between the RALE score of the baseline CXR and the probability of being liberated from the ventilator (HR 1.02 [95% CI 0.99-1.04]; P = 0.08). Conclusion: In this cohort of patients with COVID-19 ARDS, with high RALE scores of the baseline CXR, the RALE score of the baseline CXR had no prognostic capacity, but an increase in the RALE score in the next days had an association with higher mortality.

A Lower Global Lung Ultrasound Score Is Associated with Higher Likelihood of Successful Extubation in Invasively Ventilated COVID-19 Patients.

Lung ultrasound (LUS) can be used to assess loss of aeration, which is associated with outcome in patients with coronavirus disease 2019 (COVID-19) presenting to the emergency department. We hypothesized that LUS scores are associated with outcome in critically ill COVID-19 patients receiving invasive ventilation. This retrospective international multicenter study evaluated patients with COVID-19-related acute respiratory distress syndrome (ARDS) with at least one LUS study within 5 days after invasive mechanical ventilation initiation. The global LUS score was calculated by summing the 12 regional scores (range 0-36). Pleural line abnormalities and subpleural consolidations were also scored. The outcomes were successful liberation from the ventilator and intensive care mortality within 28 days, analyzed with multistate, competing risk proportional hazard models. One hundred thirty-seven patients with COVID-19-related ARDS were included in our study. The global LUS score was associated with successful liberation from mechanical ventilation (hazard ratio [HR]: 0.91 95% confidence interval [CI] 0.87-0.96; P = 0.0007) independently of the ARDS severity, but not with 28 days mortality (HR: 1.03; 95% CI 0.97-1.08; P = 0.36). Subpleural consolidation and pleural line abnormalities did not add to the prognostic value of the global LUS score. Examinations within 24 hours of intubation showed no prognostic value. To conclude, a lower global LUS score 24 hours after invasive ventilation initiation is associated with increased probability of liberation from the mechanical ventilator COVID-19 ARDS patients, independently of the ARDS severity.

Case Report: Lung Ultrasound for the Guidance of Adjunctive Therapies in Two Invasively Ventilated Patients with COVID-19.

Two patients with respiratory failure due to confirmed COVID-19 were examined using bedside lung ultrasound (LUS) shortly after intubation and start of invasive ventilation. In the first patient, LUS revealed extensive atelectatic areas. A recruitment maneuver was applied, resulting in some reaeration of areas that showed atelectasis, and some improvement in oxygenation was observed. Oxygenation improved further with the use of prone positioning. In the second patient, LUS showed diffuse abnormalities without atelectatic areas, and ventilation proceeded without a recruitment maneuver but with prone positioning. These two cases illustrate how LUS could be useful in identifying different lung morphologies early after the start of invasive ventilation and help decide on adjunctive therapies. This has possible implications for ventilator management in resource-limited settings, with limited availability of chest computed tomography and blood gas analyzers. Tailoring invasive ventilation based on LUS findings early after the start of invasive ventilation is feasible, but this should be further evaluated in future studies.