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.

Modulation of cold pain perception by transcranial direct current stimulation in healthy individuals.

OBJECTIVES: The aim of the current study was to evaluate the effect of transcranial direct current stimulation (tDCS) on cold pain perception in healthy individuals. METHODS: Anodal, cathodal (2 mA), or sham tDCSs were applied on the primary motor cortex of 22 healthy subjects in a random order. A cold pressor test was performed ten minutes after initiation of stimulation. Pain threshold and tolerance were defined as time latencies to the onset of pain perception and to the withdrawal from cold stimulus, respectively. Furthermore, pain intensity (on a scale from 0 to 10) was rated at tolerance. RESULTS: Time latencies to pain threshold and tolerance were altered by the type of stimulation (p < 0.05). Pairwise post hoc analysis revealed that anodal tDCS led to increment in pain threshold and tolerance compared with sham stimulation (13.3 ± 7.4 vs. 10.9 ± 6.0 sec for the comparison of pain threshold and 54.6 ± 26.0 vs. 45.3 ± 17.9 for the comparison of pain tolerance following anodal and sham stimulations, respectively, p < 0.05 for both comparisons). However, cathodal stimulation did not alter pain perception in comparison to anodal and sham stimulations (p > 0.05). Furthermore, pain intensity score at tolerance was not significantly affected by the type of stimulation (p > 0.05). CONCLUSION: Anodal stimulation of the primary motor area can be utilized to alleviate cold pain perception in healthy individuals.

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).

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.

Safety and effectiveness of enhanced external counterpulsation (EECP) in refractory angina patients: A systematic reviews and meta-analysis.

Enhanced external counterpulsation (EECP) is believed to be a non-invasive treatment for coronary artery disease and angina. The aim of this study was to determine the safety and effectiveness of EECP in refractory angina patients through a systematic reviews and meta-analysis. We conducted a comprehensive search of the literature published on PubMed, Cochrane library, Scopus, ScienceDirect, Trip Database and Google Scholar databases using appropriate keywords and specific strategy with no time limit. Having selected and screened the studies based on the defined inclusion and exclusion criteria and evaluating their quality based on the Cochrane checklist. For the meta-analysis,the Mantel-Haenszel method or the generic Inverse Variance was used. Analyses were done with Review Manager 5.2 software. A number of 299 studies were initially reviewed and finally, seventeen studies were included in the meta-analysis based on the inclusion and exclusion criteria. Also, thirteen outcomes were analyzed and the results of meta-analysis in twelve outcomes including (Systolic Blood Pressure (7 studies), Diastolic Blood Pressure (7 studies), Pulse Pressure (4 studies), Mean Arterial Pressures (4 studies), Heart Rate (6 studies), Angina episodes (7 studies), Walking distance (2 studies),Canadian Cardiovascular Society classification (6 studies), Flow-Mediated Dilation (3 studies), Daily Nitrate Usage (4 studies), Exercise Treadmill Test-Time (2 studies), ST-segment depression (2 studies)demonstrated a significant clinical advantage in the EECP treatment effectiveness in patients with angina. No significant difference was observed regarding EECP usefulness (P = 0.18) in the outcome of brachial artery diameter (2 studies). Based on the meta-analysis, the results indicate the safety and effectiveness of EECP in patients with angina pectoris and indicate the usefulness of this treatment in these patients. In general, the authors believe that the general conclusion in this regard requires some studies with a large sample size and a control group assignment.

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

BACKGROUND: Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown. METHODS: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts. CONCLUSIONS: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.

Enucleation and evisceration: indications, complications and clinicopathological correlations.

AIM: To assess main indications, postoperative complications and clinicopathological correlation of ocular enucleation-evisceration. METHODS: A total of 107 subjects who underwent enucleation and/or evisceration and received hydroxyapatite implants (Scleral wrap or mesh) were assessed. For each patient clinicopathological data was collected which included demographic information, clinical history, primary clinical diagnosis, main cause of ophthalmic surgery (traumatic, non-traumatic), type of surgical procedure (enucleation, evisceration) and pathological report. Patients' postoperative clinical visits were checked for procedure-related complications during first year after surgery. RESULTS: ONE HUNDRED AND SEVEN PATIENTS (MALE: 65.4%; mean age: 26y) underwent enucleation (n=100) or evisceration (n=7) due to traumatic (n=41) and non-traumatic (n=66) causes. Disfiguring painful blind eye was the most common indication of surgery (66.4%), followed by leukocoria (19.6%) and endophthalmitis (4.7%). The main types of injury included firecracker, traffic and work accidents, and sharp object perforating injury. In 53 (80.3%) subjects in non-traumatic group the initial clinical diagnosis matched the histopathological results. Malignant tumors (retinoblastoma: 47.5%, malignant melanoma: 27.3%) were the most common pathological diagnoses followed by phthisis bulbi (25.8%). The most common procedure-related complications were major eye discharge (39.6%), and implant exposure and discharge (20.8%). CONCLUSION: Trauma and malignant tumors are the leading causes of enucleation-evisceration. Despite developing new techniques and materials, enucleation is still associated with considerable postoperative complications.