Retrospective Cohort Observational Study to compare the Effect of Mycobacterium w along with Standard of Care vs Standard of Care alone in critically ill COVID-19 Patients.

BACKGROUND: COVID-19 has created enormous health crisis in India due to limited available treatments. Majority of the physicians use sepsis as a prototype to understand the pathophysiology of COVID-19 as there are similarities. Heat-killed Mycobacterium w (Mw) (Inj. Mw®) is a known immunomodulator, which is approved for the treatment of gram-negative sepsis. This observational study was aimed to evaluate the role of Mw along with standard of care (SOC) in critically ill COVID-19 patients. METHODS: Total 448 patients' data (intervention group: 298 in Mw plus SOC vs 150 in SOC alone) with reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed critically ill COVID-19 patients who were admitted at five tertiary care centers were evaluated. They were observed for changes in laboratory [C-reactive protein (CRP), D-dimer, ferritin, lactate dehydrogenase (LDH), and interleukin-6 (IL-6)] parameters, hospital stay, intensive care unit (ICU) stay, and discharge status after giving 0.3 mL intradermal Mw for 3 consecutive days along with SOC during hospitalization. Standard of care included injectable steroids, remdesivir, and heparin. Data were analyzed using STATA 14.2 (StataCorp., College Station, Texas, USA). RESULTS: In baseline characteristics, Mw plus SOC arm had more critically ill patients as seen by higher high-resolution computed tomography (HRCT) score, higher lab values [CRP, ferritin, D-dimer, LDH, creatinine, alanine aminotransferase (ALT)], and more oxygen requirement as compared to SOC alone. Mycobacterium w arm had significantly higher mortality rate in ICU and hospital. Both hospital stay and ICU stay were longer in Mw arm. However, subgroup analysis found that early initiation of Mw (<3 days vs >3 days) was associated with significantly lesser odds of mortality and lesser odds of intubation requirement. Early initiation of Mw (<3 days vs >3 days) also resulted in significantly lesser duration of stay in the ICU along with reduction of CRP, D-dimer, and LDH. Moreover, further analysis of early initiation of Mw (<3 days vs control) resulted in significant reduction in lab values (procalcitonin, CRP, ferritin, LDH, and D-dimer). CONCLUSION: Mw when added to SOC was found to associate with significantly increased risk of mortality and increased length of hospital stay. However, time since admission to administration of Mw was a significant predictor of in-ICU deaths in multivariate analysis. Early initiation of Mw (<3 days) was observed to be a protective factor against ICU deaths from the multivariate logistic regression model. However, large randomized controlled trials are required to support the same.

Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia.

PURPOSE: We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. RESULTS: We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). CONCLUSION: Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.

Noninvasive Respiratory Assist Devices in the Management of COVID-19-related Hypoxic Respiratory Failure: Pune ISCCM COVID-19 ARDS Study Consortium (PICASo).

Objective: To determine whether high-flow nasal oxygen (HFNO) or noninvasive ventilator (NIV) can avoid invasive mechanical ventilation (IMV) in COVID-19-related acute respiratory distress syndrome (ADRS), and the outcome predictors of these modalities. Design: Multicenter retrospective study conducted in 12 ICUs in Pune, India. Patients: Patients with COVID-19 pneumonia who had PaO2/FiO2 ratio <150 and were treated with HFNO and/or NIV. Intervention: HFNO and/or NIV. Measurements: The primary outcome was to assess the need of IMV. Secondary outcomes were death at Day 28 and mortality rates in different treatment groups. Main results: Among 1,201 patients who met the inclusion criteria, 35.9% (431/1,201) were treated successfully with HFNO and/or NIV and did not require IMV. About 59.5% (714/1,201) patients needed IMV for the failure of HFNO and/or NIV. About 48.3, 61.6, and 63.6% of patients who were treated with HFNO, NIV, or both, respectively, needed IMV. The need of IMV was significantly lower in the HFNO group (p <0.001). The 28-day mortality was 44.9, 59.9, and 59.6% in the patients treated with HFNO, NIV, or both, respectively (p <0.001). On multivariate regression analysis, presence of any comorbidity, SpO2 <90%, and presence of nonrespiratory organ dysfunction were independent and significant determinants of mortality (p <0.05). Conclusions: During COVID-19 pandemic surge, HFNO and/or NIV could successfully avoid IMV in 35.5% individuals with PO2/FiO2 ratio <150. Those who needed IMV due to failure of HFNO or NIV had high (87.5%) mortality. How to cite this article: Jog S, Zirpe K, Dixit S, Godavarthy P, Shahane M, Kadapatti K, et al. Noninvasive Respiratory Assist Devices in the Management of COVID-19-related Hypoxic Respiratory Failure: Pune ISCCM COVID-19 ARDS Study Consortium (PICASo). Indian J Crit Care Med 2022;26(7):791-797.

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial.

PURPOSE: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. METHODS: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. RESULTS: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. CONCLUSION: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial.

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Anticoagulation in COVID - 19: An Update.

The novel coronavirus disease, 2019 (COVID - 19) evolved as an unprecedented pandemic. The severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2) infection has been associated with significantly deranged coagulation parameters and increased incidence of thrombotic events. Deranged coagulation parameters, such as D-dimers and fibrin degradation products, can indicate a poor prognosis, and their measurement will help stratify the patients according to the disease severity, need of intensive care unit admission, and prediction of the clinical course. Gaps in understanding the natural history of the disease cause difficulties in tailoring therapies and optimizing the management of patients. Lack of specific treatment further complicates this situation. While thrombotic events can cause significant morbidity and mortality in patients, a focused approach to the prevention and treatment of venous thromboembolism (VTE) can, to a great extent, decrease the disease burden caused by thrombotic diseases. Pharmacological prophylactic anticoagulants and mechanical therapies such as pneumatic compression devices can help prevent venous thromboembolism and other thrombotic events. Thrombotic events due to COVID-19, their prevention and management, are the focus of this paper, with the prospect of providing insights into this relatively unexplored area.

Bottle gourd (Lagenaria siceraria) toxicity: a "bitter" diagnostic dilemma.

Consumption of a glass of bottle gourd juice is thought to work as a health "tonic" and part of traditional healthy living practices in India. The juice may in certain circumstances turn bitter with increased levels of the cytotoxic compound called Cucurbitacins. If the bitter juice is consumed it causes a toxic reaction in the gut, leading to abdominal discomfort/pain, vomiting, hematemesis, and hypotension which may be rarely fatal, especially in persons with pre-existing illness. In the absence of clear cut history regarding the consumption of the bitter bottle gourd juice and the initiation of symptoms, the differential diagnosis for the above symptoms will include diseases causing gastrointestinal bleed with hypotension and/or shock. We report a case of bitter bottle gourd poisoning presenting with abdominal symptoms, hematemesis and shock and with an initial differential diagnosis of septicemia with septic shock and multi-organ involvement. We conduct a literature review and ponder the various differential diagnoses of this clinical scenario.

Dengue encephalitis.

We report a case of dengue fever with features of encephalitis. The diagnosis of dengue was confirmed by the serum antibodies to dengue and the presence of a dengue antigen in the cerebrospinal fluid. This patient had characteristic magnetic resonance imaging brain findings, mainly involving the bilateral thalami, with hemorrhage. Dengue is not primarily a neurotropic virus and encephalopathy is a common finding in Dengue. Hence various other etiological possibilities were considered before concluding this as a case of Dengue encephalitis. This case explains the importance of considering the diagnosis of dengue encephalitis in appropriate situations.