Deciding When to Intubate a COVID-19 Patient.

Background: The SARS-CoV-2 pandemic is one of the most significant challenges for healthcare providers, particularly in the critical care setting. The timing of intubation in COVID-19 patients seems to be challenging. Therefore, we aimed to investigate how it may have a survival benefit, and we determined which clinical characteristics were associated with outcomes. Methods: This cross-sectional study was conducted in the Imam Khomeini Hospital Complex. We randomly selected patients admitted to intensive care units and, based on intubation status, categorized them into three subgroups (early, late, and not intubated). Early intubation is defined as intubation within 48 hours of ICU admission, and late intubation is defined as intubation after 48 hours of ICU admission. Results: Early-intubated patients were more likely to have dyspnea than late-intubated patients, and late-intubated patients had a higher mean heart rate than early-intubated patients. The neutrophil/lymphocyte ratio was significantly (P < 0.05) lower in not-intubated patients than in other patients. There was no difference in NLR between early- and late-intubated patients. Mean serum creatine phosphokinase and troponin I levels were higher in late-intubated patients than in early- and not-intubated patients. Early-intubated patients had a lower ROX index than late-intubated patients. Patients with higher scores of APACHE 2, respiratory rates, and neutrophil to lymphocyte ratio were more likely to be intubated. Increasing APACHE and SOFA scores were associated with decreased odds of survival. Conclusions: There were no statistically significant differences in total mortality between early- and late-intubated patients. APACHE 2 scores, NLR, RR, and history of ischemic heart disease are some of the appropriate predictors of intubation. Higher respiratory rates (tachypnea) can be an indicator of early intubation. The ROX index is one of the most sensitive and capable tools for predicting intubation. Intubation status is a potent predictor of in-hospital mortality.

Does COVID-19 infection significantly affect liver transplantation? Results of liver transplantation in the COVID-19 era at a single, high-volume centre.

BACKGROUND: Liver transplantation is a proven management method for end-stage cirrhosis and is estimated to have increased life expectancy by 15 years. The COVID-19 pandemic posed a challenge to patients who were candid for a solid-organ transplant. It has been suggested that the outcomes of liver transplants could be adversely affected by the infection, as immunosuppression makes liver transplant candidates more susceptible to adverse effects while predisposing them to higher thrombotic events. MATERIAL AND METHODS: In this retrospective study, the cases who received liver transplants from January 2018 to March 2022 were assessed regarding early postoperative mortality rate and hepatic artery thrombosis (HAT) with COVID-19 infection. This study included 614 cases, of which 48 patients were infected. RESULTS: This study shows that the early COVID-19-related early postoperative mortality rates substantially increased in the elective setting (OR: 2.697), but the results for the acute liver failure were insignificant. The average model for end-stage liver disease score increased significantly during the pandemic due to new regulations. Although mortality rates increased during the pandemic, the data for the vaccination period show that mortality rates have equalised with the prepandemic era. Meanwhile, COVID-19 infection is assumed to have increased HAT by 1.6 times in the elective setting. CONCLUSION: This study shows that COVID-19 infection in an acute liver failure poses comparatively little risk; hence transplantation should be considered in such cases. Meanwhile, the hypercoagulative state induced by the infection predisposes this group of patients to higher HAT rates.

Human placenta-derived mesenchymal stem cells transplantation in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 (phase I clinical trial): safety profile assessment.

BACKGROUND: High morbidity and mortality rates of the COVID-19 pandemic have made it a global health priority. Acute respiratory distress syndrome (ARDS) is one of the most important causes of death in COVID-19 patients. Mesenchymal stem cells have been the subject of many clinical trials for the treatment of ARDS because of their immunomodulatory, anti-inflammatory, and regenerative potentials. The aim of this phase I clinical trial was the safety assessment of allogeneic placenta-derived mesenchymal stem cells (PL-MSCs) intravenous injection in patients with ARDS induced by COVID-19. METHODS: We enrolled 20 patients suffering from ARDS caused by COVID-19 who had been admitted to the intensive care unit. PL-MSCs were isolated and propagated using a xeno-free/GMP compliant protocol. Each patient in the treatment group (N = 10) received standard treatment and a single dose of 1 × 106 cells/kg PL-MSCs intravenously. The control groups (N = 10) only received the standard treatment. Clinical signs and laboratory tests were evaluated in all participants at the baseline and during 28 days follow-ups. RESULTS: No adverse events were observed in the PL-MSC group. Mean length of hospitalization, serum oxygen saturation, and other clinical and laboratory parameters were not significantly different in the two groups (p > 0.05). CONCLUSION: Our results demonstrated that intravenous administration of PL-MSCs in patients with COVID-19 related ARDS is safe and feasible. Further studies whit higher cell doses and repeated injections are needed to evaluate the efficacy of this treatment modality. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT); IRCT20200621047859N4. Registered 1 March 2021, https://en.irct.ir/trial/52947 .

Human placenta-derived mesenchymal stem cells transplantation in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 (phase I clinical trial): safety profile assessment

High morbidity and mortality rates of the COVID-19 pandemic have made it a global health priority. Acute respiratory distress syndrome (ARDS) is one of the most important causes of death in COVID-19 patients. Mesenchymal stem cells have been the subject of many clinical trials for the treatment of ARDS because of their immunomodulatory, anti-inflammatory, and regenerative potentials. The aim of this phase I clinical trial was the safety assessment of allogeneic placenta-derived mesenchymal stem cells (PL-MSCs) intravenous injection in patients with ARDS induced by COVID-19. We enrolled 20 patients suffering from ARDS caused by COVID-19 who had been admitted to the intensive care unit. PL-MSCs were isolated and propagated using a xeno-free/GMP compliant protocol. Each patient in the treatment group (N = 10) received standard treatment and a single dose of 1 × 106 cells/kg PL-MSCs intravenously. The control groups (N = 10) only received the standard treatment. Clinical signs and laboratory tests were evaluated in all participants at the baseline and during 28 days follow-ups. No adverse events were observed in the PL-MSC group. Mean length of hospitalization, serum oxygen saturation, and other clinical and laboratory parameters were not significantly different in the two groups (p > 0.05). Our results demonstrated that intravenous administration of PL-MSCs in patients with COVID-19 related ARDS is safe and feasible. Further studies whit higher cell doses and repeated injections are needed to evaluate the efficacy of this treatment modality. Trial registration: Iranian Registry of Clinical Trials (IRCT);IRCT20200621047859N4. Registered 1 March 2021, https://en.irct.ir/trial/52947 .

Safety and efficacy study of allogeneic human menstrual blood stromal cells secretome to treat severe COVID-19 patients: clinical trial phase I & II.

BACKGROUND: Cell-free Mesenchymal stromal cells (MSCs) have been considered due to their capacity to modulate the immune system and suppress cytokine storms caused by SARS-CoV-2. This prospective randomized double-blind placebo-controlled clinical trial aimed to assess the safety and efficacy of secretome derived from allogeneic menstrual blood stromal cells (MenSCs) as a treatment in patients with severe COVID-19. METHODS: Patients with severe COVID-19 were randomized (1:1) to either MenSC-derived secretome treatment or the control group. Subjects received five intravenous infusions of 5 mL secretome or the same volume of placebo for five days and were monitored for safety and efficacy for 28 days after treatment. Adverse events, laboratory parameters, duration of hospitalization, clinical symptom improvement, dynamic of O2 saturation, lymphocyte number, and serial chest imaging were analyzed. RESULTS: All safety endpoints were observed without adverse events after 72 h of secretome injection. Within 28 days after enrollment, 7 patients (50%) were intubated in the treated group versus 12 patients (80%) in the control group. Overall, 64% of patients had improved oxygen levels within 5 days of starting treatment (P < 0.0001) and there was a survival rate of 57% in the treatment group compared to 28% in the control group was (P < 0.0001). Laboratory values revealed that significant acute phase reactants declined, with mean C-reactive protein, ferritin, and D-dimer reduction of 77% (P < 0.001), 43% (P < 0.001), and 42% (P < 0.05), respectively. Significant improvement in lymphopenia was associated with an increase in mean CD4+ and CD8+ lymphocyte counts of 20% (P = 0.06) and 15% (P < 0.05), respectively. Following treatment, percentage of pulmonary involvement showed a significant improvement in the secretome group (P < 0.0001). This improvement differed significantly between survivors and those who were dying (P < 0.005). CONCLUSIONS: For the first time, this study demonstrated that in hospitalized patients with severe COVID-19, therapy with MenSCs-derived secretome leads to reversal of hypoxia, immune reconstitution, and downregulation of cytokine storm, with no adverse effects attributable to the treatment. Given these outcomes, it may be possible to use this type of treatment for serious inflammatory lung disease with a mechanism similar to COVID-19 in the future. However, it is necessary to evaluate the safety and efficacy of MenSCs-derived secretome therapy in clinical trials on a larger population of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05019287. Registered 24AGUEST 2021, retrospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT05019287 . IRCT, IRCT20180619040147N6. Registered 04/01/2021.

The outcome of using intravenous immunoglobulin (IVIG) in critically ill COVID-19 patients': a retrospective, multi-centric cohort study.

BACKGROUND: During the COVID-19 pandemic, different treatments have been used in critically ill patients. Using intravenous immunoglobulin (IVIG) has been suggested in various studies as an effective option. Our study aims to access the efficacy of IVIG in critically ill COVID-19 patients. METHODS: In this retrospective matched cohort study, records of three tertiary centers with a large number of COVID-19 admissions were evaluated and used. Based on treatment options, patients were divided into two groups, standard COVID-19 treatment (109 patients) and IVIG treatment (74 patients) patients. Also, the effect of IVIG in different dosages was evaluated. Patients with IVIG treatment were divided into three groups of low (0.25 gr/kg), medium (0.5 gr/kg), and high (1 gr/kg) dose. Data analysis was performed using an independent t test and one-way analysis of variance (ANOVA) to compare the outcomes between two groups, including duration of hospitalization, intensive care unit (ICU) length of stay, and mortality rate. RESULTS: The duration of hospitalization in the IVIG group was significantly longer than standard treatment (13.74 days vs. 11.10 days, p < 0.05). There was no significant difference between the two groups in ICU length of stay, the number of intubated patients, and duration of mechanical ventilation (p > 0.05). Also, initial outcomes in IVIG subgroups were compared separately with the standard treatment group. The results indicated that only the duration of hospitalization in the IVIG subgroup with medium dose is significantly longer than the standard treatment group (p < 0.01). CONCLUSION: Our data indicate that the use of IVIG in critically ill COVID-19 patients could not be beneficial, based on no remarkable differences in duration of hospitalization, ICU length of stay, duration of mechanical ventilation, and even mortality rate.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.