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 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. © 2020 Elsevier Lt

National guidelines for cognitive assessment and rehabilitation of Iranian traumatic brain injury patients

Background: Individuals with moderate to severe traumatic brain injury (TBI) often have prolonged cognitive impairments, resulting in long-term problems with their real-life activities. Given the urgent need for evidence-based recommendations for neuropsychological management of Iranian TBI patients, the current work aimed to adapt eligible international guidelines for cognitive assessment and rehabilitation of the TBI patients in Iran. Methods: The project was led by an executive committee, under the supervision of the Iranian Ministry of Health and Medical Education (MOHME). Following a systematic literature search and selection process, four guidelines were included for adaptation. Clinical recommendations of the source guidelines were tabulated as possible clinical scenarios for 90 PICO clinical questions covering all relevant phases of care. After summing up the scenarios, our initial list of recommendations was drafted according to the Iranian patients� conditions. The final decision-making, with the contribution of a national interdisciplinary panel of 37 experts from across the country, was conducted in two rounds using online and offline survey forms (Round 1), and face-to-face and telephone meetings (Round 2). Results: A total of 63 recommendations in six sections were included in the final list of recommendations, among which 24 were considered as key recommendations. In addition, some of the recommendations were identified as fundamental, meaning that proper implementation of the other recommendations is largely dependent on their implementation. Conclusion: Iranian health policy makers and rehabilitation program managers are recommended to address some fundamental issues to provide the necessary infrastructure to set up an efficient cognitive rehabilitation service system. © 2020 Academy of Medical Sciences of I.R. Iran. All rights reserved

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. © 2021 American Medical Association. All rights reserved

Assessment of laboratory test requests from three hospital emergency departments

Background: Laboratory requests can be justified and trimmed to what patients necessarily need. Reducing unnecessary laboratory requests can improve patient safety and both patient and provider satisfaction. Methods: In this study, the current status of laboratory requests was assessed in emergency departments of three multidisciplinary university hospitals based on ten most expensive and most requested laboratory tests and categorised by the ordering physicians and patients� chief complaints in a 6-month period. These hospitals had annual visits to the emergency departments of between 20, 000-72.000 patients. Results: The most requested tests were as follows: complete blood count, biochemistry profile including sodium, potassium, urea, and creatinine. Moreover, the cumulating most expensive tests were coagulation profile, cardiac troponin, C-reactive protein, erythrocyte sedimentation rate, liver enzymes, alkaline phosphatase, and blood gases corresponding to the frequency of requests in the emergency department. Among the services, other than emergency medicine, requesting laboratory work in the emergency departments, internal medicine, neurology and surgery services had requested more laboratory tests comprising 44.0, 24.4, and 20.8 of all specialties respectively. Moreover, the most frequent laboratory requests were from patients complaining of abdominal pain, chest pain, and penetrating or blunttraumatic injuries. Conclusions: It should be considered to rationally request the most frequent laboratory tests as many of them can be canceled by physicians and do not change the diagnosis, treatment, prognosis, and disposition in the emergency department. © 2021 The authors

Durable functional limitation in patients with coronavirus disease-2019 admitted to intensive care and the effect of intermediate-dose vs standard-dose anticoagulation on functional outcomes

Introduction: Patients affected with severe forms of coronavirus disease 2019 (COVID-19) suffer from a wide range of sequelae, from limited airway diseases to multiple organ failure. These sequelae may create exercise limitation, impair the daily activity and thus impact the mental health and the social life. However, the extent of functional limitations and depressive symptoms are understudied especially in patients with COVID-19 after intensive care unit (ICU) hospitalization.Methods: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) was a clinical trial that randomized ICU patients with COVID-19 to intermediate-dose vs standard-dose anticoagulation. In the current study, we assessed the interval change in 30-day and 90-day functional limitations based on the post-COVID-19 functional status scale (PCFS) and depressive symptoms based on the Patient Health Questionnaire-2 (PHQ-2) in the trial participants. We also assessed the effect of intermediate-dose vs standard-dose prophylactic anticoagulation on the functional outcomes and depressive symptoms.Results: Of 600 randomized patients in INSPIRATION, 375 (age: 62 years; 42% women) participated in the functional status study. 195 patients died during the 90-day follow up (191 by day 30). Among survivors, between day 30 and day 90, the proportion of patients with moderate-to-severe functional limitation (PCSF grade 3-or-4) decreased from 20.0% to 4.8% (P = 3 decreased from 25.5% to 16.6% (P = 0.05). The proportion of patients with no functional limitations (PCFS grade 0) increased (4.2% to 15.4%, P= 3 (17.9% vs 15.3%; OR, 1.14, [95% CI, 0.79-1.65]; P = 0.14), with similar results when accounting for study center.Conclusion: In patients with COVID-19 admitted to the ICU, functional limitations and depressive symptoms were common at 30-day follow-up and had some improvement by 90-day follow-up among survivors. Intermediate-dose compared to standard-dose prophylactic anticoagulation did not improve functional outcomes

Cannabinoids and epilepsy

Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and high-light scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies