Cannabidiol Anticonvulsant Effects Against Lithium-Pilocarpine-Induced Status Epilepticus in Male Rats Are Mediated by Neuroinflammation Modulation and Cannabinoids 1 (CB1), But Not CB2 and GABAA Receptors.

Background: Status epilepticus (SE) is a series of seizures that can lead to serious neurological damages. Cannabidiol (CBD) is extracted from the cannabis plant, which has been approved as an antiseizure medication. This study aimed to determine the efficacy of various doses of CBD on lithium-pilocarpine-induced SE in rats and possible involvement of multiple pharmacological pathways. We hypothesized that cannabinoid receptors type 1 (CB1) and CB2, as well as GABAA receptors, might have important roles in the anticonvulsant effects of CBD against SE by its anti-inflammatory effects. Methods: SE was induced by intraperitoneal (i.p.) injection of lithium (127 mg/kg, i.p.) and pilocarpine (60 mg/kg, i.p., 20 h after lithium). Forty-two male rats were divided into seven groups (including control and sham groups), and the treated groups received different doses of CBD (1, 3, 5, 10, and 25 mg/kg, i.p.). SE score was recorded over the next 2 h following pilocarpine injection. Then, we measured the levels of pro-inflammatory cytokines, including interleukin (IL)-lß and tumor necrosis factor (TNF)-α, using ELISA kits. Also we analyzed the expression of CB1, CB2, and GABAA receptors using the Western blot technique. Results: CBD at 5 mg/kg significantly reduced Racine's scale and duration of seizures, and increased the onset time of seizure. Moreover, CBD 5 mg/kg caused significant reductions in the elevated levels of IL-lß and TNF-α, as well as a significant increase in the decreased level of CB1 receptor expression compared to the control group. In other word, CBD reverted the effects of SE in terms of neuroinflammation and CB1 receptor. Based on the obtained results, CBD was not able to restore the declined levels of CB2 or GABAA receptors. Conclusion: Our study found anticonvulsant effects of CBD on the SE rat model induced by lithium-pilocarpine with probable involvement of CB1 receptors and anti-inflammatory effects by reducing IL-1ß and TNF-α markers independent of CB2 and GABAA receptors.

Effects of nebulized hypertonic saline on inflammatory mediators in patients with severe COVID-19 pneumonia: A double-blinded randomized controlled trial.

INTRODUCTION: An exaggerated immune response is considered the most important aspect of COVID-19 pathogenesis. Hypertonic saline (HS) has shown promise in combating inflammation in several respiratory diseases. We investigated the effects of nebulized HS on clinical symptoms and inflammatory status in patients with severe novel coronavirus infection (COVID-19) pneumonia. MATERIALS AND METHODS: We randomly assigned 60 adults admitted to the intensive care unit (ICU) due to severe COVID-19 pneumonia to the experimental (received nebulized 5% saline) and control (received nebulized distilled water) groups. All interventions were applied 4 times daily for 5 days. The levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and other clinical factors from venous blood were evaluated before and after intervention application. Mortality rate, intubation rate, and durations of ICU and hospital stay were also compared between groups. RESULTS: The levels of TNF-α (MD: -21.35 [-32.29, -10.40], P = 0.000) and IL-6 (-9.94 [-18.86, -1.02], P = 0.003) were lower in the experimental group compared to the control group after applying the interventions. The levels of white blood cell count, PO2, and serum sodium were also statistically significant differences between groups. However, we did not observe significant differences in terms of hospitalization durations and mortality rates. CONCLUSION: Nebulization of HS in patients with severe COVID-19 pneumonia appears to be effective in reducing inflammation, but does not appear to affect intubation rates, mortality, hospitalization, or length of stay in ICU.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Safety and efficacy of pulmonary physiotherapy in hospitalized patients with severe COVID-19 pneumonia (PPTCOVID study): A prospective, randomised, single-blind, controlled trial.

BACKGROUND: Pulmonary physiotherapy (PPT) is an important treatment in the management of patients with different types of pulmonary disorders. We aimed to evaluate safety and efficacy of PPT in hospitalized patients with severe COVID-19 pneumonia. METHODS: In this randomised, single-blind, controlled trial, we enrolled hospitalized, non-intubated patients (18 to 75 years with oxygen saturation (Spo2) in free-air breathing ≤90%) with COVID-19 pneumonia at a referral hospital. Participants were randomly assigned (1:1) to receive PPT (six sessions PPT with breathing exercises and airway clearance techniques) or basic care. The primary outcomes were venous blood O2 (pO2) and CO2 (pCO2) pressures, Spo2, and three-minute walking test (3MWT) that were assessed before and end of sixth session. Secondary outcomes included level of dyspnea, venous blood PH, one-month mortality, three-month mortality and short form-36 (SF-36) after one and three months. The assessor was blinded to the assignment. This trial is registered with ClinicalTrials.gov (NCT04357340). FINDINGS: In April-May 2020, 40 participants were randomly assigned to PPT or basic care groups. While at the end of intervention, pO2 (adjusted mean difference to baseline measure (AMD) 6.43 mmHg [95%CI 2.8, 10.07], P<0.01), Spo2 (AMD 4.43% [95%CI 2.04, 6.83], P = 0.0011), and 3MTW (AMD 91.44 m [95%CI 68.88, 113.99], P<0.01) were higher in PPT group and basic care group, pCO2 was not improved (AMD -2.1 mmHg [95%CI-6.36, 2.21], P = 0.33). Based on the logistic model adjusted to baseline Spo2, the risks of mortality were reduced 81% ([95%CI: 97% reduction to 30% increase], P = .09) and 84% ([95%CI 74% reduction to 5% increase], P = .06) at one-month and three-month, respectively. There were no significant differences in most SF-36 domains scores after one and three months. No serious adverse event was observed during PPT sessions. CONCLUSION: Early PPT can be considered a safe and relatively effective therapeutic choice for patients with severe COVID-19.

Immunophenotyping characteristics of COVID-19 patients: Peripheral blood CD8+ HLA-DR+ T cells as a biomarker for mortality outcome.

INTRODUCTION: The goal of this study was to identify biomarker(s) to assign risk of mortality in COVID-19 patients to improve intensive care unit (ICU) and coronary care unit  management. A total of 100 confirmed COVID-19 patients admitted at Imam Khomeini Hospital in Tehran, were compared to 70 control subjects. Peripheral blood leukocyte was studied using staining reagents included CD3, CD4, CD8, HLA-DR, CD19, CD16, and CD56. The immunophenotyping analysis was evaluated using the FACSCalibur instrument. To investigate the cell density of lung infiltrating T cells, postmortem slides of needle necropsies taken from the lung tissue of 3 critical patients were evaluated by immunohistochemistry staining. The number of lymphocyte subpopulations was significantly lower in COVID-19 patients than in the control group. Regarding the disease severity, the absolute count of T, NK, and HLA-DR+ T cells were significantly reduced in severe patients compared to the moderate ones. The critical patients had a significantly lower count of CD8-HLA-DR+ T cells than the moderate cases. Regarding the disease mortality, based on univariate analysis, the count of HLA-DR+ T, CD8- HLA-DR+ T, and CD8+ HLA-DR+ T cells was associated with mortality in COVID-19 patients. Receiver operating characteristic curve analysis showed the count of CD8+ HLA-DR+ T cells is the best candidate as a biomarker for mortality outcome. Furthermore, pulmonary infiltration of T cells in the lung tissue showed only slight infiltrations of CD3+ T cells, with an equal percentage of CD4+ and CD8+ T cell subpopulation in the lung tissue. These findings suggest that close monitoring of the value of CD8+ HLA-DR+ T cells in COVID-19 patients may be helpful to identify high-risk patients. However, further studies with larger sample size are needed.

Gargle test for successful extubation in critically ill patients underwent head and neck surgeries: A new test.

Background: Improvement of predictive tools for recognition of airway edema is crucial for safe extubation and patient safety. This study aimed to evaluate the diagnostic accuracy of the Gargle test (GT) as a new test for assessing airway edema and predicting successful extubation in patients admitted to the intensive care unit (ICU). Method: In this prospective observational study, patients underwent head and neck surgeries and admitted to ICU included. All the patients were weaned based on the same protocol.Quantitative Cuff Leak Test (CLT) and qualitative CLTwere first applied followed by GT with normal saline 0.9%. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. Results: One hundred and eighteen (male 67, female 51) participated in this study. The agreement between GT and CLT was low (Kappa: quantitative CLT 0.07, qualitative CLT 0.21). The GT compared to CLT had higher sensitivity (33.3% vs 16.6%), specificity (96.3% vs qualitative CLT 92.8%, quantitative CLT 79.4%), PPV (33.3% vs qualitative CLT 11.11%, quantitative CLT 4.0%), NPV (96.3% vs qualitative CLT 95.4%, quantitative CLT 94.6%), and accuracy (92.92% vs qualitative CLT 88.98%, quantitative CLT 76.27%. The cut-off value for GT was estimated 16.5% (sensitivity 74.1% and specificity 60%). Conclusion: The GT is a simple accurate test and can be used as a new test in the ICU for recognition of airway edema and prediction of safe extubation in patients with head and neck surgeries.

The effect of Vitamin C and Zn supplementation on the immune system and clinical outcomes in COVID-19 patients.

SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2) is the most dangerous form of the coronavirus, which causes COVID-19. In patients with severe COVID-19, the immune system becomes markedly overactive. There is evidence that supplementation with select micronutrients may play a role in maintaining immune system function in this patient population. Throughout the COVID-19 pandemic, significant emphasis has been placed on the importance of supplementing critical micronutrients such as Vitamin C and Zinc (Zn) due to their immunomodulatory effects. Viral infections, like COVID-19, increase physiological demand for these micronutrients. Therefore, the purpose of this review was to provide comprehensive information regarding the potential effectiveness of Vitamin C and Zn supplementation during viral infection and specifically COVID-19. This review demonstrated a relation between Vitamin C and Zn deficiency and a reduction in the innate immune response, which can ultimately make patients with COVID-19 more vulnerable to viral infection. As such, adequate intake of Vitamin C and Zn, as an adjunctive therapeutic approach with any necessary pharmacological treatment(s), may be necessary to mitigate the adverse physiological effects of COVID-19. To truly clarify the role of Vitamin C and Zn supplementation in the management of COVID-19, we must wait for the results of ongoing randomized controlled trials. The toxicity of Vitamin C and Zn should also be considered to prevent over-supplementation. Over-supplementation of Vitamin C can lead to oxalate toxicity, while increased Zn intake can reduce immune system function. In summary, Vitamin C and Zn supplementation may be useful in mitigating COVID-19 symptomology.

Cultural adaptation and psychometric assessment of the Persian version of the lumbar spine instability questionnaire.

BACKGROUND: The Lumbar Spine Instability Questionnaire (LSIQ) is a self-reported measure of clinical instability of the lumbar spine. This study aimed to translate and culturally adapt the LSIQ into Persian language (LSIQ-P) and to evaluate its reliability and validity in a sample of patients with chronic non-specific low back pain (LBP). METHODS: In a cross-sectional study, the LSIQ was translated using guidelines. Participants with chronic non-specific LBP, aged ≥ 18 years old, answered an online survey consisting of LSIQ-P, the Persian Functional Rating Index (FRI), and the pain Numeric Rating Scale (NRS). Construct validity, internal consistency reliability, test-retest reliability, standard error of measurement (SEM), smallest detectable change (SDC), discriminant validity, and factor analysis were evaluated. RESULTS: The LSIQ was successfully adapted into Persian. A sample of 100 participants with LBP and 100 healthy subjects completed the survey. Floor and ceiling effects were not observed. Cronbach's alpha = 0.767 and ICCagreement = 0.78 indicated good internal consistency and test-retest reliability. The SEM and SDC were 1.53 and 4.24, respectively. Construct validity of LSIQ-P was confirmed with significant correlation with Persian FRI (r = 0.44, p < 0.001) and pain NRS (r = 0.30, p = 0.003). An evidence of discriminant validity was demonstrated by significant difference in LSIQ-P total scores between the patients with LBP and healthy subjects, and between the patients with high total score ≥ 9 and those with low total score < 9 on the LSIQ-P. The LSIQ-P was found a multidimensional instrument with eight items appeared being redundant. CONCLUSIONS: The Persian LSIQ showed satisfactory metric characteristics of reliability and validity. Further studies are required to elucidate the internal structure of the LSIQ-P.

Mortality Predictive Value of APACHE II and SOFA Scores in COVID-19 Patients in the Intensive Care Unit.

Background: COVID-19 pandemic has become a global dilemma since December 2019. Are the standard scores, such as acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) score, accurate for predicting the mortality rate of COVID-19 or the need for new scores? We aimed to evaluate the mortality predictive value of APACHE II and SOFA scores in critically ill COVID-19 patients. Methods: In a cohort study, we enrolled 204 confirmed COVID-19 patients admitted to the intensive care units at the Imam Khomeini hospital complex. APACHE II on the first day and daily SOFA scoring were performed. The primary outcome was the mortality rate in the nonsurvived and survived groups, and the secondary outcome was organ dysfunction. Two groups of survived and nonsurvived patients were compared by the chi-square test for categorical variables and an independent sample t-test for continuous variables. We used logistic regression models to estimate the mortality risk of high APACHE II and SOFA scores. Result: Among 204 severe COVID-19 patients, 114 patients (55.9%) expired and 169 patients (82.8%) had at least one comorbidity that 103 (60.9%) of them did not survive (P=0.002). Invasive mechanical ventilation and its duration were significantly different between survived and nonsurvived groups (P ≤ 0.001 and P=0.002, respectively). Mean APACHE II and mean SOFA scores were significantly higher in the nonsurvived than in the survived group (14.4 ± 5.7 vs. 9.5 ± 5.1, P ≤ 0.001, 7.3 ± 3.1 vs. 3.1 ± 1.1, P ≤ 0.001, respectively). The area under the curve was 89.5% for SOFA and 73% for the APACHE II score. Respiratory diseases and malignancy were risk factors for the mortality rate (P=0.004 and P=0.007, respectively) against diabetes and hypertension. Conclusion: The daily SOFA was a better mortality predictor than the APACHE II in critically ill COVID-19 patients. But they could not predict death with high accuracy. We need new scoring with consideration of the prognostic factors and daily evaluation of changes in clinical conditions.

Effects of Melatonin and Propolis Supplementation on Inflammation, Oxidative Stress, and Clinical Outcomes in Patients with Primary Pneumosepsis: A Randomized Controlled Clinical Trial.

BACKGROUND AND OBJECTIVE: The present study aimed to investigate the effects of propolis and melatonin supplementation on inflammation, clinical outcomes, and oxidative stress markers in patients with primary pneumosepsis. MATERIALS AND METHODS: This pilot randomized controlled trial was conducted on 55 patients with primary pneumosepsis who were randomly assigned to the intervention and control groups. In the three intervention groups, the patients received propolis alone (1,000 mg/day), propolis (1,000 mg/day) plus melatonin (20 mg/day), and melatonin alone (20 mg/day). The control group received placebo. The inflammatory and oxidative stress markers as well as clinical outcomes were evaluated before and after the intervention, and the 28-day survival rate was also recorded. RESULTS: After the intervention, the combination of propolis and melatonin significantly reduced interleukin-6 (-55.282 pg/mL) and C-reactive protein (-21.656 mg/L) levels, while increasing gavage intake (326.680 mL/day) and improving some clinical outcomes (APACHE II, SOFA, and NUTRIC scores) compared to the control group. However, no significant difference was observed between the groups in terms of oxidative stress and hematological indices. In addition, there was no significant difference in the 28-day survival rate between the groups (p = 0.07). CONCLUSION: Supplementation with propolis and melatonin may improve clinical outcomes by reducing inflammation. Further investigations are required to confirm these findings.

The role of saliva PCR assay in the diagnosis of COVID-19.

INTRODUCTION: The introduction of a self-collection sampling method with less discomfort would be of great benefit in reducing the risk of medical provider's contamination and patient's acceptance. The aim of the present study was to investigate saliva samples' diagnostic performance for the COVID-19 RT-PCR test compared to pharyngeal swabs. METHODOLOGY: From individuals referred to a medical center with presentations compatible with COVID-19 who were eligible for molecular diagnostic tests, 80 cases were selected. Nasopharyngeal and oropharyngeal swabs (placed into the same transport tube) along with self-collected saliva sample were taken from each participant for COVID-19 RT-PCR assay. The results of pharyngeal swabs and saliva sample were compared. RESULTS: Sixty-two (78%) infected cases were detected, of whom 31 (39%) cases tested positive for both pharyngeal swab and saliva samples. 24 (30%) and 7 (9%) cases tested positive only for pharyngeal or saliva samples, respectively. The overall percentage of agreement between pharyngeal swab and saliva sample was 61%, with a kappa value of 0.24 (p-value = 0.019, 95% CI: 0.04-0.44), showing a fair level of agreement. The diagnostic sensitivity of pharyngeal swabs was 88.71% (95% CI: 78.11-95.34), and the diagnostic sensitivity of saliva samples was 61.29% (95% CI: 48.07-73.40). Compared to pharyngeal swabs (oropharyngeal and nasopharyngeal swabs in the same collection tube), an important observation was that seven more positive cases were detected among saliva samples. CONCLUSIONS: The findings of the present study indicated that self-collected saliva samples cannot replace pharyngeal swabs. Still, saliva samples significantly increased the case detection rate and can be used along with pharyngeal swabs.

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.

The effect of supplementation with vitamins A, B, C, D, and E on disease severity and inflammatory responses in patients with COVID-19: a randomized clinical trial.

BACKGROUND AND OBJECTIVE: Because of the effect of vitamins on modulating the immune system function, we have evaluated the effect of supplementation with vitamins A, B, C, D, and E in ICU-admitted patients with COVID-19. METHODS: This study was a randomized and single-blinded clinical trial in which 60 subjects were randomly assigned to two groups. The intervention group (n=30) received vitamins, and the control group did not receive any vitamin or placebo. The intervention was included 25,000 IU daily of vitamins A, 600,000 IU once during the study of D, 300 IU twice daily of E, 500 mg four times daily of C, and one amp daily of B complex for 7 days. At baseline and after the 7-day intervention, the serum levels of inflammatory markers, vitamins, and the SOFA score were assessed. In addition, the mortality rate and duration of hospitalization were evaluated after the intervention (IRCT registration number: IRCT20200319046819N1/registration date: 2020-04-04, https://www.irct.ir/trial/46838 ). RESULTS: Significant changes were detected in serum levels of vitamins (p < 0.001 for all vitamins), ESR (p < 0.001), CRP (p = 0.001), IL6 (p = 0.003), TNF-a (p = 0.001), and SOFA score (p < 0.001) after intervention compared with the control group. The effect of vitamins on the mortality rate was not statistically significant (p=0.112). The prolonged hospitalization rate to more than 7 days was significantly lower in the intervention group than the control group (p=0.001). Regarding the effect size, there was a significant and inverse association between receiving the intervention and prolonged hospitalization (OR = 0.135, 95% CI 0.038-0.481; p=0.002); however, after adjusting for confounders, it was not significant (OR=0.402, 95% CI 0.086-1.883; p=0.247). CONCLUSION: Supplementation with vitamins A, B, C, D, and E could improve the inflammatory response and decrease the severity of disease in ICU-admitted patients with COVID-19.

The association between serum levels of micronutrients and the severity of disease in patients with COVID-19.

OBJECTIVES: This study aimed to compare the serum level of micronutrients with normal amounts, and assess their association with the severity of disease and inflammatory cytokines in patients with coronavirus disease 2019 (COVID-19). METHODS: The present cross-sectional study included 60 patients admitted to the intensive care unit with COVID-19. We recorded data on demographic characteristics, anthropometric information, and medical history. Serum levels of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, interferon-gamma, tumor necrosis factor-alpha, interleukin-6), vitamins (A, B9, B12, C, D, E), and minerals (magnesium, zinc, iron) were measured. A radiologist assessed the severity of lung involvement according to patient computed tomography scans. The severity of illness was evaluated with the Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) score, oxygen saturation, and body temperature. Independent associations among the serum levels of micronutrients with the severity of COVID-19 were measured. RESULTS: Median patient age was 53.50 years (interquartile range, 12.75 years). Except for vitamin A and zinc, serum levels of other micronutrients were lower than the minimum normal. Patients with APACHE score ≥25 had a higher body mass index (P = 0.044), body temperature (P = 0.003), erythrocyte sedimentation rate (P = 0.008), C-reactive protein (P = 0.003), and lower oxygen saturation (P = 0.005), serum levels of vitamin D (P = < 0.001), and zinc (P = < 0.001) compared with patients with APACHE score <25. We found that lower serum levels of vitamin D, magnesium, and zinc were significantly and independently associated with higher APACHE scores (P = 0.001, 0.028, and < 0.001, respectively) and higher lung involvement (P = 0.002, 0.045, and < 0.001, respectively). CONCLUSIONS: Lower serum levels of vitamin D, zinc, and magnesium were involved in severe COVID-19.

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.

Interpretation of Hematological, Biochemical, and Immunological Findings of COVID-19 Disease: Biomarkers Associated with Severity and Mortality.

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spread rapidly all over the world in late 2019 and caused critical illness and death in some infected patients. This study aimed at examining several laboratory factors, especially inflammatory and immunological mediators, to identify severity and mortality associated biomarkers. Ninety-three hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) were classified based on disease severity. The levels of biochemical, hematological, immunological, and inflammatory mediators were assessed, and their association with severity and mortality were evaluated. Hospitalized patients were mostly men (77.4%) with an average (standard deviation) age of 59.14 (14.81) years. The mortality rate was significantly higher in critical patients (85.7%). Increased serum levels of blood sugar, urea, creatinine, uric acid, phosphorus, total bilirubin, serum glutamic-oxaloacetic transaminase, serum glutamic-oxaloacetic transaminase, lactic dehydrogenase, C-reactive protein, ferritin, and procalcitonin were significantly prevalent (p=0.002, p<0.001, p<0.001, p=0.014, p=0.047, p=0.003, p<0.001, p<0.001, p<0.001, p<0.001, P<0.001, and p<0.001, respectively) in COVID-19 patients. Decreased red blood cell, hemoglobin, and hematocrit were significantly prevalent among COVID-19 patients than healthy control subjects (p<0.001 for all). Troponin-I, interleukin-6, neutrophil/lymphocyte ratio (NLR), procalcitonin, and D-dimer showed a significant association with the mortality of patients with specificity and sensitivity more than 60%. Age, sex, underlying diseases, blood oxygen pressure, complete blood count along with C-reactive protein, lactic dehydrogenase, procalcitonin, D-dimer, and interleukin-6 evaluation help to predict the severity and required management for COVID-19 patients. Further investigations are highly recommended in a larger cohort study for validation of the present findings.

Nutritional adequacy in critically ill patients: Result of PNSI study.

BACKGROUND & AIMS: Critically ill patients are provided with the intensive care medicine to prevent further complications, including malnutrition, disease progression, and even death. This study was intended to assess nutritional support and its' efficacy in the Intensive Care Units (ICUs) of Iran. METHODS: This cross-sectional study assessed 50 ICU's patients out of 25 hospitals in the 10 major regions of Iran's health system and was performed using the multistage cluster sampling design. The data were collected from patient's medical records, ICU nursing sheets, patients or their relatives from 2017 to 2018. Nutritional status was investigated by modified NUTRIC score and food frequency checklist. RESULTS: This study included 1321 ICU patients with the mean age of 54.8 ± 19.97 years, mean mNUTRIC score of 3.4 ± 2.14, and malnutrition rate of 32.6%. The mean time of first feeding was the second day and most of patients (66%) received nutrition support, mainly through enteral (57.2%) or oral (37%) route during ICU stay. The patients received 59.2 ± 37.78 percent of required calorie and 55.5 ± 30.04 percent of required protein. Adequate intake of energy and protein was provided for 16.2% and 10.7% of the patients, respectively. The result of regression analysis showed that the odds ratio of mNUTRIC score was 0.85 (95% confidence interval [CI] = 0.74-0.98) and APACHE II was 0.92 (95%CI = 0.89-0.95) for the prediction of energy deficiency. Nutrition intake was significantly different from patient's nutritional requirements both in terms of energy (p < 0.001) and protein (p < 0.001). Also, mean mNUTRIC score varied notably (p = 0.011) with changing in energy intake, defined as underfeeding, adequate feeding, and overfeeding. CONCLUSION: The present findings shown that, provided nutritional care for ICU patients is not adequate for their requirements and nutritional status.

Pathological Findings of Postmortem Biopsies From Lung, Heart, and Liver of 7 Deceased COVID-19 Patients.

Background. A novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been affecting almost all nations around the world. Most infected patients who have been admitted to intensive care units show SARS signs. In this study, we aimed to achieve a better understanding of pathological alterations that take place during the novel coronavirus infection in most presumed affected organs. Methods. We performed postmortem core needle biopsies from lung, heart, and liver on 7 deceased patients who had died of coronavirus disease 2019. Prepared tissue sections were observed by 2 expert pathologists. Results. Diffuse alveolar damage was the main pathologic finding in the lung tissue samples. Patients with hospitalization durations of more than 10 days showed evidence of organization. Multinucleated cells in alveolar spaces and alveolar walls, atypical enlarged cells, accumulation of macrophages in alveolar spaces, and congestion of vascular channels were the other histopathologic alteration of the lung. None of our heart biopsy samples met the criteria for myocarditis. Liver biopsies showed congestion, micro- and macro-vesicular changes, and minimal to mild portal inflammation, in the majority of cases. Conclusions. Similar to the previous coronavirus infection in 2003, the main pathologic finding in the lung was diffuse alveolar damage with a pattern of organization in prolonged cases. The SARS-CoV-2 infection does not cause myocarditis, and the ischemia of myocardium is the most probable justification of the observed pathologic changes in the heart. Liver tissue sections mostly showed nonspecific findings; however, ischemia of the liver can be identified in some cases.

Clinical Characteristics and Outcomes of 905 COVID-19 Patients Admitted to Imam Khomeini Hospital Complex in the Capital City of Tehran, Iran.

BACKGROUND: We studied the clinical characteristics and outcomes of 905 hospitalized coronavirus disease 2019 (COVID-19) patients admitted to Imam Khomeini Hospital Complex (IKHC), Tehran, Iran. METHODS: COVID-19 patients were recruited based on clinical symptoms and patterns of computed tomography (CT) imaging between February 20 and March 19. All patients were tested for the presence of COVID-19 RNA. The Poisson regression model estimated the incidence rate ratio (IRR) for different parameters. RESULTS: The average age (± standard deviation) was 56.9 (±15.7) years and 61.77% were male. The most common symptoms were fever (93.59%), dry cough (79.78%), and dyspnea (75.69%). Only 43.76% of patients were positive for the RT-PCR COVID-19 test. Prevalence of lymphopenia was 42.9% and more than 90% had elevated lactate dehydrogenase (LDH) or C-reactive protein (CRP). About 11% were severe cases, and 13.7% died in the hospital. The median length of stay (LOS) was 3 days. We found higher risks of mortality in patients who were older than 70 years (IRR = 11.77, 95% CI 3.63-38.18), underwent mechanical ventilation (IRR = 7.36, 95% CI 5.06-10.7), were admitted to the intensive care unit (ICU) (IRR = 5.47, 95% CI 4.00-8.38), tested positive on the COVID-19 test (IRR = 2.80, 95% CI 1.64-3.55), and reported a history of comorbidity (IRR = 1.76, 95% CI 1.07-2.89) compared to their corresponding reference groups. Hydroxychloroquine therapy was not associated with mortality in our study. CONCLUSION: Older age, experiencing a severe form of the disease, and having a comorbidity were the most important prognostic factors for COVID-19 infection. Larger studies are needed to perform further subgroup analyses and verify high-risk groups.

A Case Report of Progressive Liver Failure Inappropriate to Decompensated Heart Failure Following Infection With COVID-19.

This article is about a known case of heart failure presented with acute liver failure following a coronavirus disease-2019 (COVID-19) respiratory tract infection. The patient was admitted with encephalopathy and respiratory distress with a positive COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test. Elevated liver enzymes, severe coagulopathy, and hypoglycemia were apparent without any clinical or laboratory findings of sepsis, acute viral hepatitis, medicine related or drug-induced, or autoimmune-related acute liver failure. Supportive and therapeutic measures related to his cardiovascular, respiratory, and liver function were executed in the ICU. Unfortunately, the patient expired because of respiratory failure.