A comparison of analgesic efficacy and safety of clonidine and methylprednisolone as additives to 0.25% ropivacaine in stellate ganglion block for the treatment of complex regional pain syndrome: a prospective randomised single blind study

Background@#The role of the sympathetic nervous system appears to be central in causing pain in complex regional pain syndrome (CRPS). The stellate ganglion block (SGB) using additives with local anesthetics is an established treatment modality. However, literature is sparse in support of selective benefits of different additives for SGB.Hence, the authors aimed to compare the efficacy and safety of clonidine with methylprednisolone as additives to ropivacaine in the SGB for treatment of CRPS. @*Methods@#A prospective randomized single blinded study (the investigator blinded to the study groups) was conducted among patients with CRPS-I of the upper limb, aged 18–70 years with American Society of Anaesthesiologists physical status I–III. Clonidine (15 μg) and methylprednisolone (40 mg) were compared as additives to 0.25% ropivacaine (5 mL) for SGB. After medical treatment for two weeks, patients in each of the two groups were given seven ultrasound guided SGBs on alternate days. @*Results@#There was no significant difference between the two groups with respect to visual analogue scale score, edema, or overall patient satisfaction. After 1.5 months follow-up, however, the group that received methylprednisolone had better improvement in range of motion. No significant side effects were seen with either drug. @*Conclusions@#The use of additives, both methylprednisolone and clonidine, is safe and effective for the SGB in CRPS. The significantly better improvement in joint mobility with methylprednisolone suggests that it should be considered promising as an additive to local anaesthetics when joint mobility is the concern.

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in admitted patients at a tertiary referral centre in North India

BackgroundSeroprevalence of IgG antibodies against SARS-CoV-2 is an important tool to estimate true burden of infection in a given population. Serosurveys, though being conducted in different parts of India, are not readily published in entirety and often do not report on the different characteristics of the population studied. In this present study, we aimed to serially estimate the seroprevalence of anti-SARS-CoV-2 IgG antibody over 11 months at one of the largest government hospital in India. MethodIn this cross-sectional study which was conducted between between 9th June 2020 and 27th April 2021, consecutive patients admitted to medicine wards or intensive care units, who were negative for SARS-CoV-2 by RT-PCR or CBNAAT were included. The 2linic-demographic features of the subjects were recorded in pre-formed questionnaires. Anti-SARS-CoV2 antibody levels targeting recombinant spike receptor-binding domain (RBD) protein of SARS CoV-2 were estimated in serum sample by the ELISA method. ResultsA total of 916 patients were recruited over 11 months with mean age({+/-}SD) 39.79{+/-}14.9 of years and 55% of population being males. In total 264(28.8%) patients were found to be seropositive. Residency in Delhi and non-smoking status conferred a higher risk for seropositivity. The adjusted odds ratio for seropositivity with regards to no smoking and residence out of Delhi were .31{+/-}.09 (Odds ratio {+/-} S.E) and .65 {+/-} .1 (Odds ratio {+/-} S.E) respectively. No other factors like age, socio-economic status, contact history etc showed significant relationship with seropositivity. ConclusionThe seropositivity rate among hospitalized patients was found to increase with time (from 8.45% to 38%) over a period of 9 months. Residence in Delhi and non-smokers had higher risk for seropositivity on multivariate analysis.

Selection of appropriate reference genes for normalization of qRT-PCR based gene expression analysis in SARS-CoV-2, and Covid-associated Mucormycosis infection

Selection of reference genes in quantitative PCR is critical to determine accurate and reliable mRNA expression. Despite this knowledge, not a single study has investigated the expression stability of housekeeping genes to determine their suitability to act as reference gene in SARS-CoV-2 or Covid19 associated mucormycosis (CAM) infections. Herein, we address these gaps by investigating the expression stability of nine most commonly used housekeeping genes including TBP, CypA, B2M, 18S, PGC-1, GUSB, HPRT-1, {beta}-ACTIN and GAPDH in the patients of varying severity (asymptomatic, mild, moderate and severe). We observed significant differences in the expression of candidate genes across the disease spectrum. Next, using various statistical algorithms (delta Ct, Normfinder, Bestkeeper, RefFinder and GeNorm), we observed that CypA demonstrated the most consistent expression across the patients of varying severity and emerged as the most suitable gene in Covid19, and CAM infections. Incidentally, the most commonly used reference gene GAPDH showed maximum variations and found to be the least suitable. Lastly, comparative evaluation of expression of NRF2 is performed following normalization with GAPDH and CypA to highlight the relevance of an appropriate reference gene. Our results reinforce the idea of a selection of housekeeping genes only after validation especially during infections.

Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality

The precise molecular mechanisms behind life-threatening lung abnormalities during severe SARS-CoV-2 infections are still unclear. To address this challenge, we performed whole transcriptome sequencing of lung autopsies from 31 patients suffering from severe COVID-19 related complications and 10 uninfected controls. Using a metatranscriptome analysis of lung tissue samples we identified the existence of two distinct molecular signatures of lethal COVID-19. The dominant "classical" signature (n=23) showed upregulation of unfolded protein response, steroid biosynthesis and complement activation supported by massive metabolic reprogramming leading to characteristic lung damage. The rarer signature (n=8) potentially representing "Cytokine Release Syndrome" (CRS) showed upregulation of cytokines such IL1 and CCL19 but absence of complement activation and muted inflammation. Further, dissecting expression of individual genes within enriched pathways for patient signature suggests heterogeneity in host response to the primary infection. We found that the majority of patients cleared the SARS-CoV-2 infection, but all suffered from acute dysbiosis with characteristic enrichment of opportunistic pathogens such as Staphylococcus cohnii in "classical" patients and Pasteurella multocida in CRS patients. Our results suggest two distinct models of lung pathology in severe COVID-19 patients that can be identified through the status of the complement activation, presence of specific cytokines and characteristic microbiome. This information can be used to design personalized therapy to treat COVID-19 related complications corresponding to patient signature such as using the identified drug molecules or mitigating specific secondary infections.

Novel risk factors for Coronavirus disease-associated mucormycosis (CAM): a case control study during the outbreak in India

BackgroundThe epidemiology of the Coronavirus-disease associated mucormycosis (CAM) syndemic is poorly elucidated. We aimed to identify risk factors that may explain the burden of cases and help develop preventive strategies. MethodsWe performed a case-control study comparing cases diagnosed with CAM and those who had recovered from COVID-19 without developing mucormycosis (controls). Information on comorbidities, glycemic control, and practices related to COVID-19 prevention and treatment was recorded. Results352 patients (152 cases and 200 controls) diagnosed with COVID-19 during April-May 2021 were included. In the CAM group, symptoms of mucormycosis began a mean 18.9 (SD 9.1) days after onset of COVID-19, and predominantly rhino-sinus and orbital involvement was present. All, but one, CAM cases carried conventional risk factors of diabetes and steroid use. On multivariable regression, increased odds of CAM were associated with the presence of diabetes (adjusted OR 3.5, 95%CI 1.1-11), use of systemic steroids (aOR 7.7,95% CI 2.4-24.7), prolonged use of cloth and surgical masks (vs no mask, aOR 6.9, 95%CI 1.5-33.1), and repeated nasopharyngeal swab testing during the COVID-19 illness (aOR 1.6,95% CI 1.2-2.2). Zinc therapy, probably due to its utility in immune function, was found to be protective (aOR 0.05, 95%CI 0.01-0.19). Notably, the requirement of oxygen supplementation or hospitalization did not affect the risk of CAM. ConclusionJudicious use of steroids and stringent glycemic control are vital to preventing mucormycosis. Use of clean masks, preference for N95 masks if available, and minimizing swab testing after the diagnosis of COVID-19 may further reduce the incidence of CAM.

Use of HFNC in COVID-19 patients in non-ICU setting: Experience from a tertiary referral centre of north India and a systematic review of literature

IntroductionThe rapid surge of cases and insufficient numbers of intensive care unit (ICU) beds have forced hospitals to utilise their general wards for administration of non-invasive respiratory support including HFNC(High Flow Nasal Cannula) in severe COVID-19. However, there is a dearth of data on the success of such advanced levels of care outside the ICU setting. Therefore, we conducted an observational study at our centre, and systematically reviewed the literature, to assess the success of HFNC in managing severe COVID-19 cases outside the ICU. MethodsA retrospective cohort study was conducted in a tertiary referral centre where records of all adult COVID-19 patients ([≥]18 years) requiring HFNC support were between September and December 2020 were analysed. HFNC support was adjusted to target SpO2 [≥]90% and respiratory rate [≤]30 per min. The clinical, demographic, laboratory, and treatment details of these patients were retrieved from the medical records and entered in pre-designed proforma. Outcome parameters included duration of oxygen during hospital stay, duration of HFNC therapy, length of hospital stay and death or discharge. HFNC success was denoted when a patient did not require escalation of therapy to NIV or invasive mechanical ventilation, or shifting to the ICU, and was eventually discharged from the hospital without oxygen therapy; otherwise, the outcome was denoted as HFNC failure. Systematic review was also performed on the available literature on the experience with HFNC in COVID-19 patients outside of ICU settings using the MEDLINE, Web of Science and Embase databases. Statistical analyses were performed with the use of STATA software, version 12, OpenMeta[Analyst], and visualization of the risk of bias plot using robvis. ResultsThirty-one patients receiving HFNC in the ward setting, had a median age of 62 (50 - 69) years including 24 (77%) males. Twenty-one (68%) patients successfully tolerated HFNC and were subsequently discharged from the wards, while 10 (32%) patients had to be shifted to ICU for non-invasive or invasive ventilation, implying HFNC failure. Patients with HFNC failure had higher median D-dimer values at baseline (2.2 mcg/ml vs 0.6 mcg/ml, p=0.001) and lower initial SpO2 on room air at admission (70% vs 80%, p=0.026) as compared to those in whom HFNC was successful .A cut-off value of 1.7 mg/L carried a high specificity (90.5%) and moderate sensitivity (80%) for the occurrence of HFNC failure. Radiographic severity scoring as per the BRIXIA score was comparable in both the groups(11 vs 10.5 out of 18, p=0.78). After screening 98 articles, total of seven studies were included for synthesis in the systematic review with a total of 820 patients, with mean age of the studies ranging from 44 to 83 years and including 62% males. After excluding 2 studies from the analysis, the pooled rates of HFNC failure were 36.3% (95% CI 31.1% - 41.5%) with no significant heterogeneity (I2 =0%, p=0.55). ConclusionsOur study demonstrated successful outcomes with use of HFNC in an outside of ICU setting among two-thirds of patients with severe COVID-19 pneumonia. Lower room air SpO2 and higher D-dimer levels at presentation were associated with failure of HFNC therapy leading to ICU transfer for endotracheal intubation or death. Also, the results from the systematic review demonstrated similar rates of successful outcomes concluding that HFNC is a viable option with failure rates similar to those of ICU settings in such patients.

ReCOVer study: A Cross-sectional Observational Study to Identify the Rehabilitation Need in Post-discharge COVID-19 Survivors

IntroductionWith the increasing number of Coronavirus disease-2019 (COVID-19) cases there is simultaneous increase in recovered cases too. There are many post-covid complications where need for rehabilitation intervention is very conspicuous especially pulmonary, neurological complications. Hence data are of utmost importance to find out those rehabilitation needs among post-covid survivors. Methods and analysisReCOVer (Rehabilitation Need in Post-discharge COVID-19 Survivors), a cross-sectional observational study protocol has been planned to find out rehab-need by assessing International Classification of Functioning, Disability and Health (ICF) core data set, COVID-19 Yorkshire Rehab Screen (C19-YRS) tool, The Post-COVID-19 Functional Status (PCFS) scale, barriers to functional independence and rehab services (affordability & availability). Post-discharge (minimum 1 weeks) Covid patients (required hospitalisation) will be included in the study. Study will be conducted through Telerehabilitation facility. Study will conform to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Ethics and disseminationStudy received ethical approval from Institute Ethics Committee, All India Institute of Medical Sciences (AIIMS), New Delhi, India. Findings will be disseminated at scientific conferences/meetings, peer-reviewed journals, and to relevant stakeholders including the ministry of health (if required).

Clinical correlation of lung ultrasound profiles in patients with COVID-19 infection

BackgroundLung ultrasound is a popular point of care test that correlates well with computed tomography for lung pathologies. While previous studies have shown its ability to detect COVID-19 related lung pathology, we aimed to evaluate the utility of lung ultrasound in the triage and prognostication of COVID-19 patients by determining its ability to predict clinical severity and outcomes. MethodsThis was a prospective, cross-sectional, observational, single centre study done at JPNATC and AIIMS, New Delhi, India. Consenting eligible patients aged 18 years or more were included if hospitalised with microbiologically confirmed COVID-19 and classified as mild, moderate (respiratory rate >24/min OR SpO2<94% on room air) and severe COVID-19 (respiratory rate >30/min OR SpO2<90% on room air) at the time of enrolment. The lungs were systematically assessed with ultrasound after division into 14 zones (4 anteriorly, 4 axillary and 6 posteriorly). Clinical and laboratory parameters including arterial blood gas analysis at the time of evaluation were recorded. Patients were followed till death or discharge. The primary objective was to determine the correlation between clinical severity and lung ultrasound profiles (no. of A, B and C profiles, and the total number of areas involved). Secondary objectives included assessment of the correlation between lung ultrasound profiles and clinical outcomes and development of a statistical model incorporating ultrasound and clinical parameters to allow prediction of COVID-19 related severity and outcomes. FindingsBetween October 1, 2020, and January 31,2021, patients were screened for inclusion and total n=60 patients were evaluated and included in the final analysis. The most common abnormality seen were B lines, seen in at least one zone in n=53 (88.33%) of cases. A median of 9 (IQR: 5-12) zones of the 14 assessed had a B-profile. The total number of abnormal areas (zones with a B or C profile) correlated significantly with the PaO2/FiO2 ratio ({rho}= -0.7232, p<0.0001) and SpO2/FiO2 ratio ({rho}= -0.6866, p<0.0001), and differed significantly between mild and moderate vs severe cases (p=0.0026 mild vs moderate, p<0.0001 mild vs severe, p=0.0175 moderate vs severe). The total number of B lines were predictors of mortality (p=0.0188, OR 1.03, 95% CI 1.003-1.060). Statistical models that incorporated total number of B-lines, CRP and anticoagulation use could predict mortality (p=0.0124, pseudo R2=0.1740) with an AUC= 0.7682 (95% CI=0.6176-0.9188), and the total number of involved areas and LDH levels could distinguish severe disease from mild/moderate disease (p<0.0001, Pseudo R2=0.3822), AUC = 0.8743 (95% CI=0.7752-0.9733). A simplified cut off of [≥]6 involved areas (of the 14 assessed) was 100% sensitive and 52% specific for differentiating severe disease from mild and moderate ones. InterpretationIn patients with COVID-19, increasing involvement of the lungs as assessed by ultrasonography correlates significantly with clinical severity and outcomes. These findings may be utilized in future prospective studies to validate the use of lung ultrasound to triage and prognosticate patients with COVID-19 infection. Author ApprovalAll authors have seen and approved the manuscript Competing interestsThere are no potential competing interests Data availability StatementAll data referred to in the manuscript shall be provided when asked for. DisclaimersThe authors have nothing to disclose Funding statementNo funding source was involved.

A two-arm, randomized, controlled, multi-centric, open-label Phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19

An uncontrolled increase in cytokine production may lead to systemic hyperinflammation, vascular hypo-responsiveness, increased endothelial permeability, hypercoagulation, multi-organ dysfunction and eventually death in moderate to severely ill COVID-19 patients. Targeting T-cells, an important driver of the hyperinflammatory response, in the treatment of COVID-19, could potentially reduce mortality and improve survival rates. Itolizumab is an anti-CD6 humanized monoclonal antibody with an immunomodulating action on Teffector cells that downregulates T-cell activation, proliferation and subsequent production of various chemokines and cytokines. The efficacy and safety of Itolizumab for the treatment of cytokine release syndrome in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase 2 study. Eligible patients were randomized (2:1) to arm A (best supportive care + Itolizumab) and arm B (best supportive care). The primary outcome of interest was reduction in all-cause mortality 30 days after enrolment. Thirty-six patients were screened, 5 were treated as first dose sentinels and the rest were randomized, whilst 4 patients were considered screen failures. Two patients in the Itolizumab treatment arm discontinued prior to receiving the first dose and were replaced. At the end of 1 month, there were 3 deaths in arm B, and none in arm A (p= 0.0296). At the end of the follow-up period, more patients in Arm A had improved SpO2 without increasing FiO2 (p=0.0296), improved PaO2 (p=0.0296), and reduction in IL-6 (43 pg/ml vs 212 pg/ml; p=0.0296) and tumor necrotic factor- (9 pg/ml vs 39 pg/ml; p=0.0253) levels. Itolizumab was generally safe and well tolerated, and transient lymphopenia (11 patients in Arm A) and infusion reactions (7 patients) were the commonly reported treatment related safety events. These encouraging results indicate that larger clinical trials are warranted to establish the role of Itolizumab in controlling immune hyperactivation in COVID-19.

Clinico-pathological features in fatal Covid-19 Infection: A Preliminary Experience of a Tertiary Care Centre in North India using Post-Mortem Minimally Invasive Tissue Biopsies

BackgroundThe Covid-19 pandemic began in China in December 2019. India is the second most affected country, as of November 2020 with more than 8.5million cases. Covid-19 infection primarily involves the lung with severity of illness varying from influenza-like illness to acute respiratory distress syndrome. Other organs have also found to be variably affected. Studies evaluating the histopathological changes of Covid-19 are critical in providing a better understanding of the disease pathophysiology and guiding treatment. Minimally invasive biopsy techniques (MITS/B) provide an easy and suitable alternative to complete autopsies. In this prospective single center study we present the histopathological examination of 37 patients who died with complications of Covid-19. MethodsThis was an observational study conducted in the Intensive Care Unit of JPN Trauma Centre AIIMS. A total of 37 patients who died of Covid-19 were enrolled in the study. Post-mortem percutaneous biopsies were taken by the help of surface landmarking/ultrasonography guidance from lung, heart, liver, and kidneys; after obtaining ethical consent. The biopsy samples were then stained with haematoxylin and eosin stain. Immunohistochemistry (IHC) was performed using CD61 and CD163 in all lung cores. SARS-CoV-2 virus was detected using IHC with primary antibodies in selected samples. Details regarding demographics, clinical parameters, hospital course, treatment details, and laboratory investigations were also collected for clinical correlation. ResultsA total of 37 patients underwent post-mortem minimally invasive tissue sampling. Mean age of the patients was 48.7years and 59.5% of them were males. Respiratory failure was the most common complication seen in 97.3%. Lung histopathology showed acute lung injury and diffuse alveolar damage in 78% patients. Associated bronchopneumonia was seen in 37.5% patients and scattered microthrombi were visualised in 21% patients. Immunostaining with CD61 and CD163 highlighted megakaryocytes, and increased macrophages in all samples. Immunopositivity for SARS-CoV-2 was observed in Type II pneumocytes. Acute tubular injury with epithelial vacuolization was seen in 46% of the renal biopsies but none of them showed evidence of microvascular thrombosis. 71% of the liver tissue cores showed evidence of Kupfer cell hyperplasia. 27.5% had evidence of submassive hepatic necrosis and 14% had features of acute on chronic liver failure. All the heart biopsies showed non-specific features such as hypertrophy with nucleomegaly with no evidence of myocardial necrosis in any of the samples. ConclusionsThe most common finding in this cohort is the diffuse alveolar damage with demonstration of SARS-CoV-2 protein in the acute phase of DAD. Microvascular thrombi were rarely identified in the lung, liver and kidney. Substantial hepatocyte necrosis, hepatocyte degeneration, Kupffer cell hypertrophy, micro, and macrovesicular steatosis unrelated to microvascular thrombi suggests that liver might be a primary target of Covid-19. This study highlights the importance of MITS/B in better understanding the pathological changes associated with Covid-19.

Outcome of Conservative Therapy in COVID-19 Patients Presenting with Gastrointestinal Bleeding

Background/ObjectiveThere is a paucity of data on the management of gastrointestinal (GI) bleeding in patients with COVID-19 amid concerns about the risk of transmission during endoscopic procedures. We aimed to study the outcomes of conservative treatment for GI bleeding in patients with COVID-19. MethodsIn this retrospective analysis, 24 of 1342 (1.8%) patients with COVID-19, presenting with GI bleeding from 22 April to 22 July 2020, were included. ResultsThe mean age of patients was 45.8{+/-}12.7 years; 17 (70.8%) were males; upper GI (UGI) bleeding: lower GI (LGI) 23:1. Twenty-two (91.6%) patients had evidence of cirrhosis-21 presented with UGI bleeding while one had bleeding from hemorrhoids. Two patients without cirrhosis were presumed to have non-variceal bleeding. The medical therapy for UGI bleeding included vasoconstrictors-somatostatin in 17 (73.9%) and terlipressin in 4 (17.4%) patients. All patients with UGI bleeding received proton pump inhibitors and antibiotics. Packed red blood cells (PRBCs), fresh frozen plasma and platelets were transfused in 14 (60.9%), 3 (13.0%) and 3 (13.0%), respectively. The median PRBCs transfused was 1 (0-3) unit(s). The initial control of UGI bleeding was achieved in all 23 patients and none required an emergency endoscopy. At 5-day follow-up, none rebled or died. Two patients later rebled, one had intermittent bleed due to gastric antral vascular ectasia, while another had rebleed 19 days after discharge. Three (12.5%) cirrhosis patients succumbed to acute hypoxemic respiratory failure during hospital stay. ConclusionConservative management strategies including pharmacotherapy, restrictive transfusion strategy, and close hemodynamic monitoring can successfully manage GI bleeding in COVID-19 patients and reduce need for urgent endoscopy. The decision for proceeding with endoscopy should be taken by a multidisciplinary team after consideration of the patients condition, response to treatment, resources and the risks involved, on a case to case basis.

Clinical characteristics and management of patients with fat embolism syndrome in level I Apex Trauma Centre / 中华创伤杂志(英文版)

PURPOSE@#Fat embolism syndrome (FES) is systemic manifestation of fat emboli in the circulation seen mostly after long bone fractures. FES is considered a lethal complication of trauma. There are various case reports and series describing FES. Here we describe the clinical characteristics, management in ICU and outcome of these patients in level I trauma center in a span of 6 months.@*METHODS@#In this prospective study, analysis of all the patients with FES admitted in our polytrauma intensive care unit (ICU) of level I trauma center over a period of 6 months (from August 2017 to January 2018) was done. Demographic data, clinical features, management in ICU and outcome were analyzed.@*RESULTS@#We admitted 10 cases of FES. The mean age of patients was 31.2 years. The mean duration from time of injury to onset of symptoms was 56 h. All patients presented with hypoxemia and petechiae but central nervous system symptoms were present in 70% of patients. The mean duration of mechanical ventilation was 11.7 days and the mean length of ICU stay was 14.7 days. There was excellent recovery among patients with no neurological deficit.@*CONCLUSION@#FES is considered a lethal complication of trauma but timely management can result in favorable outcome. FES can occur even after fixation of the fracture. Hypoxia is the most common and earliest feature of FES followed by CNS manifestations. Any patient presenting with such symptoms should raise the suspicion of FES and mandate early ICU referral.