Amino Acid-Based Molecular and Membranous Chiral Tools for Enantiomeric Recognition.

Given the need, both academic and industrial, for new approaches and technologies for chiral discrimination of enantiomers, the present work demonstrates the development through rational design and integration of two new chiral platforms (molecular and membranous) for enantioselective recognition through visual as well as microscopic observation. The molecular platform (TPT) is based on the tryptophan derivative developed through the condensation of two tryptophan units with terepthaloyl chloride. While TPT based on l-tryptophan recognizes R-mandelic acid over the S-isomer, the host with reverse chirality (TPDT) recognizes S-mandelic acid over R-isomer. The role of chemical functionality in this sensitive recognition process was established experimentally by developing an analogue of TPT and by judiciously using different chiral analytes. Importantly, a detailed theoretical study at the molecular level revealed the U-shaped conformation of TPT, creating a cavity for accommodating a chiral guest with selective functional interaction resulting in the discrimination of enantiomers. Finally, a chiral polymeric mat of poly(methyl methacrylate) (PMMA)/polyacrylonitrile (PAN) (2:3) impregnated with TPT was developed via electrospinning. The resulting fibrous mat was successfully utilized for chiral recognition through microscopic and architectural observation. Hence, the present work reports simple chiral tools for enantiomeric recognition.

Brønsted acid-catalyzed enantioselective addition of 1,3-diones to in situ generated N-acyl ketimines.

A Brønsted acid-catalyzed asymmetric Mannich-type addition of 1,3-diones to cyclic N-acyl ketimines is reported for the synthesis of enantioenriched isoindolinones. Various dicarbonyl-substituted isoindolinones bearing a quaternary carbon stereocenter were synthesized with excellent yields (up to 98%) and moderate to high enantioselectivities (up to 95% ee), and most of them possess a fluorine atom at the reactive center. Furthermore, the synthetic utility of the protocol has been demonstrated by the debenzoylation of the product.

Advances in Microcirculatory Assessment: A Game Changer in Sepsis Management or the Latest Fad?

Gupta R, Ray S. Advances in Microcirculatory Assessment: A Game Changer in Sepsis Management or the Latest Fad? Indian J Crit Care Med 2022;26(3):261-263.

Cu(I)-Catalyzed asymmetric exo-selective synthesis of substituted pyrrolidines via a 1,3-dipolar cycloaddition reaction.

An (R)-DM-BINAP/Cu(CH3CN)4BF4 complex catalyzed exo-selective asymmetric 1,3-dipolar cycloaddition (1,3-DCA) reaction of imino esters with α,ß-unsaturated pyrazoleamides has been developed. A series of highly functionalized pyrrolidines with multiple stereogenic centers were obtained with good yields and diastereoselectivities and excellent enantioselectivities (up to 99% ee).

How Robust are the Evidences that Formulate Surviving Sepsis Guidelines? An Analysis of Fragility and Reverse Fragility of Randomized Controlled Trials that were Referred in these Guidelines.

OBJECTIVES: "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016" provides guidelines in regard to prompt management and resuscitation of sepsis or septic shock. The study is aimed to assess the robustness of randomized controlled trials (RCTs) that formulate these guidelines in terms of fragility index and reverse fragility index. METHOD: RCTs that contributed to these guidelines having parallel two-group design, 1:1 allocation ratio, and at least one dichotomous outcome were included in the study. The median fragility index was calculated for RCTs with significant statistical outcomes, whereas the median reverse fragility index was calculated for RCTs with nonsignificant statistical results. RESULTS: Hundred RCTs that met the inclusion criteria were analyzed. The median fragility index was 5.5 [95% confidence interval (CI) 1-30] and median reverse fragility index was 13 (95% CI 12.07-16.8) at a p value of 0.05. The median reverse fragility index was 16 (95% CI 10-26) at a p value of 0.01. Most of the RCTs included in this analysis were of good quality, having a median Jadad score of 6. CONCLUSION: This analysis found that the surviving sepsis guidelines were based on highly robust RCTs with statistically insignificant results and on some moderately robust RCTs with statistically significant results. RCTs with statistically insignificant results were more robust than RCTs with statistically significant results in regard to these guidelines. HIGHLIGHTS: The study assessed the robustness of randomized controlled trials (RCTs) that were used to formulate surviving sepsis guidelines. Most RCTs showed statistically nonsignificant results. RCTs with statistically significant results were moderately fragile whereas RCTs with nonsignificant results were more robust. HOW TO CITE THIS ARTICLE: Choupoo NS, Das SK, Saikia P, Dey S, Ray S. How Robust are the Evidences that Formulate Surviving Sepsis Guidelines? An Analysis of Fragility and Reverse Fragility of Randomized Controlled Trials that were Referred in these Guidelines. Indian J Crit Care Med 2021;25(7):773-779.

Expert Consensus Statements on the Use of Corticosteroids in Non-severe COVID-19.

INTRODUCTION: There is strong evidence for the use of corticosteroid in the management of severe coronavirus disease-2019 (COVID-19). However, there is still uncertainty about the timing of corticosteroids. We undertook a modified Delphi study to develop expert consensus statements on the early identification of a subset of patients from non-severe COVID-19 who may benefit from using corticosteroids. METHODS: A modified Delphi was conducted with two anonymous surveys between April 30, 2021, and May 3, 2021. An expert panel of 35 experts was selected and invited to participate through e-mail. The consensus was defined as >70% votes in multiple-choice questions (MCQ) on Likert-scale type statements, while strong consensus as >90% votes in MCQ or >50% votes for "very important" on Likert-scale questions in the final round. RESULTS: Twenty experts completed two rounds of the survey. There was strong consensus for the increased work of breathing (95%), a positive six-minute walk test (90%), thorax computed tomography severity score of >14/25 (85%), new-onset organ dysfunction (using clinical or biochemical criteria) (80%), and C-reactive protein >5 times the upper limit of normal (70%) as the criteria for patients' selection. The experts recommended using oral or intravenous (IV) low-dose corticosteroids (the equivalent of 6 mg/day dexamethasone) for 5-10 days and monitoring of oxygen saturation, body temperature, clinical scoring system, blood sugar, and inflammatory markers for any "red-flag" signs. CONCLUSION: The experts recommended against indiscriminate use of corticosteroids in mild to moderate COVID-19 without the signs of clinical worsening. Oral or IV low-dose corticosteroids (the equivalent of 6 mg/day dexamethasone) for 5-10 days are recommended for patients with features of disease progression based on clinical, biochemical, or radiological criteria after 5 days from symptom onset under close monitoring. HOW TO CITE THIS ARTICLE: How to cite this article: Nasa P, Chaudhry D, Govil D, Daga MK, Jain R, Chhallani AA, et al. Expert Consensus Statements on the Use of Corticosteroids in Non-severe COVID-19. Indian J Crit Care Med 2021;25(11):1280-1285.

Mottling, Lactate, and the Microcirculation in Sepsis: Are We Back to Bedside Clinical Assessment after the Honeymoon with Technology?

How to cite this article: Das S, Ray S. Mottling, Lactate, and the Microcirculation in Sepsis: Are We Back to Bedside Clinical Assessment after the Honeymoon with Technology? Indian J Crit Care Med 2020;24(8):615-616.

Evaluating the Efficacy and Safety of the Existing Repurposed Pharmacological Agents for Treating COVID-19: A Meta-analysis and Systematic Review of Clinical Trials.

PURPOSE: The present study systematically searched important medical databases, assessed the quality of available pieces of evidence, and performed a meta-analysis to test the efficacy of different therapeutic options currently available for treating COVID-19. MATERIALS AND METHODS: PubMed, CNKI, LILACS, Koreamed, WHO clinical trial registry, and medRxiv were searched since December 2019. Any observational or controlled study that tested the efficacy of any pharmacological intervention in COVID-19 patients either prospectively or retrospectively was included in the qualitative analysis. We assessed outcomes as dichotomous variables, i.e., a patient having a positive clinical outcome. Relative risks/risk ratios (RR) having a 95% confidence interval (CI) were derived. Studies conforming to inclusion criteria were pooled using the random-effect model. RESULTS: Nine trials on hydroxychloroquine (HCQ), six studies on antiviral, four studies on monoclonal antibodies, two on corticosteroids, two on convalescent plasma (CP), and one on interferon-α2b were included in the systematic review. Meta-analysis containing six scientific trials and analyzing 522 patients revealed that the relative risk of positive clinical outcomes with HCQ treatment was 1.042 (95% CI, 0.884 to 1.874) with a number needed to treat (NNT) of 12.6. A meta-analysis of two studies analyzing 285 patients showed that the relative risk of clinical resolution with lopinavir and ritonavir combination was 1.152 (95% CI 0.709 to 1.87). Out of various antiviral used, the only remdesivir showed a positive result in a case series. Monoclonal antibodies showed decreased C-reactive protein, decreased oxygen, and ventilator requirements. A corticosteroid may increase mortality with increased dose. Two small case series on CP showed some promising results. CONCLUSION: The study showed slightly favorable results with HCQ, monoclonal antibodies, remdesivir, and CP in treating COVID-19 patients. Further research is warranted in establishing the efficacy of studied interventions. PROSPERO IDENTIFIER: CRD42020180979. HOW TO CITE THIS ARTICLE: Choupoo NS, Das SK, Haldar R, Sarkar H, Tewari R, Ray S. Evaluating the Efficacy and Safety of the Existing Repurposed Pharmacological Agents for Treating COVID-19: A Meta-analysis and Systematic Review of Clinical Trials. Indian J Crit Care Med 2020;24(11):1106-1113.

A Comparative Study of the Diagnostic and Prognostic Utility of Soluble Urokinase-type Plasminogen Activator Receptor and Procalcitonin in Patients with Sepsis and Systemic Inflammation Response Syndrome.

INTRODUCTION: Differentiation between sepsis and systemic inflammation response syndrome (SIRS) remains a diagnostic challenge for clinicians as both may have similar clinical presentation. A quick and accurate diagnostic tool that can discriminate between these two conditions would aid in appropriate therapeutic decision-making. This prospective study was conducted to evaluate the diagnostic and prognostic utility of soluble urokinase-type plasminogen activator receptor (suPAR) and procalcitonin (PCT) in sepsis and SIRS patients. MATERIALS AND METHODS: Eighty-eight patients were enrolled, of which 29 were SIRS and 59 were sepsis patients. The levels of suPAR and PCT were measured on the day of admission (day 1), day 3, and day 7. RESULTS: The levels of suPAR and PCT were significantly higher (p = 0.05 and p < 0.001, respectively) in sepsis group as compared to the SIRS group. The soluble urokinase-type plasminogen activator receptor was a better diagnostic tool in predicting sepsis over PCT [area under curve (AUC) 0.89 vs 0.82] on day 1. The best cutoff for suPAR was 5.58 pg/mL [96% sensitivity and 90% negative predictive value (NPV)] and the best cut-off for PCT was 1.96 ng/mL (93.1% sensitivity and 80% NPV). However, PCT had better prognostic trends (p = 0.006) to identify nonsurvivors in sepsis group. CONCLUSION: Our findings suggest that both suPAR and PCT can be used as potential test tools to differentiate between SIRS and sepsis. Procalcitonin showed significant prognostic trends to identify nonsurvivors. The soluble urokinase-type plasminogen activator receptor showed better diagnostic potential than PCT on day 1. CLINICAL SIGNIFICANCE: Both suPAR and PCT can be used as surrogate biomarkers to distinguish sepsis from SIRS. Procalcitonin showing a significant prognostic trend to identify nonsurvivors can help the clinicians to take relevant clinical decisions. Also, the use of biomarkers like PCT and suPAR could reduce the inappropriate use of antibiotics in noninfective SIRS. HOW TO CITE THIS ARTICLE: Sharma A, Ray S, Mamidipalli R, Kakar A, Chugh P, Jain R, et al. A Comparative Study of the Diagnostic and Prognostic Utility of Soluble Urokinase-type Plasminogen Activator Receptor and Procalcitonin in Patients with Sepsis and Systemic Inflammation Response Syndrome. Indian J Crit Care Med 2020;24(4):245-251.

Indian Society of Critical Care Medicine Position Statement for Central Venous Catheterization and Management 2020.

BACKGROUND AND PURPOSE: Short-term central venous catheterization (CVC) is one of the commonly used invasive interventions in ICU and other patient-care areas. Practice and management of CVC is not standardized, varies widely, and need appropriate guidance. Purpose of this document is to provide a comprehensive, evidence-based and up-to-date, one document source for practice and management of central venous catheterization. These recommendations are intended to be used by critical care physicians and allied professionals involved in care of patients with central venous lines. METHODS: This position statement for central venous catheterization is framed by expert committee members under the aegis of Indian Society of Critical Care Medicine (ISCCM). Experts group exchanged and reviewed the relevant literature. During the final meeting of the experts held at the ISCCM Head Office, a consensus on all the topics was made and the recommendations for final document draft were prepared. The final document was reviewed and accepted by all expert committee members and after a process of peer-review this document is finally accepted as an official ISCCM position paper.Modified grade system was utilized to classify the quality of evidence and the strength of recommendations. The draft document thus formulated was reviewed by all committee members; further comments and suggestions were incorporated after discussion, and a final document was prepared. RESULTS: This document makes recommendations about various aspects of resource preparation, infection control, prevention of mechanical complication and surveillance related to short-term central venous catheterization. This document also provides four appendices for ready reference and use at institutional level. CONCLUSION: In this document, committee is able to make 54 different recommendations for various aspects of care, out of which 40 are strong and 14 weak recommendations. Among all of them, 42 recommendations are backed by any level of evidence, however due to paucity of data on 12 clinical questions, a consensus was reached by working committee and practice recommendations given on these topics are based on vast clinical experience of the members of this committee, which makes a useful practice point. Committee recognizes the fact that in event of new emerging evidences this document will require update, and that shall be provided in due time. ABBREVIATIONS LIST: ABHR: Alcohol-based hand rub; AICD: Automated implantable cardioverter defibrillator; BSI: Blood stream infection; C/SS: CHG/silver sulfadiazine; Cath Lab: Catheterization laboratory (Cardiac Cath Lab); CDC: Centers for Disease Control and Prevention; CFU: Colony forming unit; CHG: Chlorhexidine gluconate; CL: Central line; COMBUX: Comparison of Bedside Ultrasound with Chest X-ray (COMBUX study); CQI: Continuous quality improvement; CRBSI: Catheter-related blood stream infection; CUS: Chest ultrasonography; CVC: Central Venous Catheter; CXR: Chest X-ray; DTTP: Differential time to positivity; DVT: Deep venous thrombosis; ECG: Electrocardiography; ELVIS: Ethanol lock and risk of hemodialysis catheter infection in critically ill patients; ER: Emergency room; FDA: Food and Drug Administration; FV: Femoral vein; GWE: Guidewire exchange; HD catheter: Hemodialysis catheter; HTS: Hypertonic saline; ICP: Intracranial pressure; ICU: Intensive Care Unit; IDSA: Infectious Disease Society of America; IJV: Internal jugular vein; IPC: Indian penal code; IRR: Incidence rate ratio; ISCCM: Indian Society of Critical Care Medicine; IV: Intravenous; LCBI: Laboratory confirmed blood stream infection; M/R: Minocycline/rifampicin; MBI-LCBI: Mucosal barrier injury laboratory-confirmed bloodstream infection; MRSA: Methicillin-resistant Staphylococcus aureus; NHS: National Health Service (UK); NHSN: National Healthcare Safety Network (USA); OT: Operation Theater; PICC: Peripherally-inserted central catheter; PIV: Peripheral intravenous line; PL: Peripheral line; PVI: Povidone-iodine; RA: Right atrium; RCT: Randomized controlled trial; RR: Relative risk; SCV/SV: Subclavian vein; ScVO2: Central venous oxygen saturation; Sn: Sensitivity; SOP: Standard operating procedure; SVC: Superior vena cava; TEE: Transesophageal echocardiography; UPP: Useful Practice Points; USG: Ultrasonography; WHO: World Health Organization. HOW TO CITE THIS ARTICLE: Javeri Y, Jagathkar G, Dixit S, Chaudhary D, Zirpe KG, Mehta Y, et al. Indian Society of Critical Care Medicine Position Statement for Central Venous Catheterization and Management 2020. Indian J Crit Care Med 2020;24(Suppl 1):S6-S30.

BF3·OEt2-Catalyzed Vinyl Azide Addition to in Situ Generated N-Acyl Iminium Salts: Synthesis of 3-Oxoisoindoline-1-acetamides.

BF3·OEt2-catalyzed nucleophilic addition of vinyl azides to in situ generated N-acyl iminium salts obtained from 3-hydroxyisoindolinones is described in this article. The procedure is operationally simple, mild, additive, and metal-free. The reaction proceeds smoothly at ambient temperature with a wide range of 3-hydroxyisoindol-1-ones and vinyl azides to afford 3-oxoisoindoline-1-acetamides (32 examples) in high yields (up to 97%). Furthermore, the synthetic utility of this methodology is depicted by exploiting the reactivity of an amide functionality in the products.

Hemostatic Agents in Critically Ill Patients.

How to cite this article: Das SK, Reddy MM, Ray S. Hemostatic Agents in Critically Ill Patients. Indian J Crit Care Med 2019;23(Suppl 3):S226-S229.

Efficient Synthesis of Ditopic Polyamide Receptors for Cooperative Ion Pair Recognition in Solution and Solid States.

Following a late-stage functionalization strategy, a series of heteroditopic cryptand receptors were prepared in three steps only from 1,4-dioxane. As evidenced by 1 H NMR spectroscopic and solid state analyses, these polyamide-crown ether conjugates present general ion pair binding capacity towards salts of monovalent cations and linear triatomic anions.

(R)-DM-SEGPHOS-Ag(I)-Catalyzed Enantioselective Synthesis of Pyrrolidines and Pyrrolizidines via (1,3)- and Double (1,3)-Dipolar Cycloaddition Reactions.

An efficient diastereo- and enantioselective route to access a wide range of highly substituted pyrrolidine and pyrrolizidine derivatives has been described via (1,3)- and double (1,3)-dipolar cycloaddition reactions catalyzed by the (R)-DM-SEGPHOS-Ag(I) complex. The reactions proceed smoothly at ambient temperature, affording a variety of pyrrolidines and pyrrolizidines in high yields (up to 93%) with up to 99:1 dr and excellent enantioselectivities (up to 98% ee) without any additives. The newly synthesized pyrrolidine and pyrrolizidine derivatives contain four and seven contiguous stereogenic centers, respectively. Moreover, the synthetic utility of enantioenriched products has been demonstrated by transforming them into various synthetically useful advanced intermediates.

Controlled Release of Ciprofloxacin from Core-Shell Nanofibers with Monolithic or Blended Core.

Sustained controlled drug release is one of the prominent contributions for more successful treatment outcomes in the case of several diseases. However, the incorporation of hydrophilic drugs into nanofibers, a promising novel delivery system, and achieving a long-term sustained release still pose a challenging task. In this work we demonstrated a robust method of avoiding burst release of drugs and achieving a sustained drug release from 2 to 4 weeks using core-shell nanofibers with poly(methyl methacrylate) (PMMA) shell and monolithic poly(vinyl alcohol) (PVA) core or a novel type of core-shell nanofibers with blended (PVA and PMMA) core loaded with ciprofloxacin hydrochloride (CIP). It is also shown that, for core-shell nanofibers with monolithic core, drug release can be manipulated by varying flow rate of the core PVA solution, whereas for core-shell nanofibers with blended core, drug release can be manipulated by varying the ratios between PMMA and PVA in the core. During coaxial electrospinning, when the solvent from the core evaporates in concert with the solvent from the shell, the interconnected pores spanning the core and the shell are formed. The release process is found to be desorption-limited and agrees with the two-stage desorption model. Ciprofloxacin-loaded nanofiber mats developed in the present work could be potentially used as local drug delivery systems for treatment of several medical conditions, including periodontal disease and skin, bone, and joint infections.

Long-Term Sustained Ciprofloxacin Release from PMMA and Hydrophilic Polymer Blended Nanofibers.

Nanofibers represent an attractive novel drug delivery system for prolonged and controlled release. However, sustained release of hydrophilic drugs, like ciprofloxacin hydrochloride (CIP), from polymeric nanofibers is not an easy task. The present study investigates the effect of different hydrophobic polymers (PCL and PMMA) alone in monolithic nanofibers or with hydrophilic polymers (PVA, PEO, and chitosan) in blended nanofibers aiming to achieve sustained CIP release. CIP release from PCL nanofibers was 46% and from PMMA just 1.5% over 40 day period. Thus, PMMA holds great promise for modification of CIP release from blended nanofibers. PMMA blends with 10% PEO, PVA, or chitosan were used to electrospin nanofibers from solution in the mixture of acetic and formic acid. These nanofibers exhibited different drug-release profiles: PEO containing nanofiber mats demonstrated high burst effect, chitosan containing mats revealed very slow gradual release, and PVA containing mats yielded smaller burst effect with favorable sustained release. We have also shown that gradual sustain release of antibiotic like CIP can be additionally tuned over 18 days with various blend ratios of PMMA with PVA or chitosan reaching almost 100%. A mathematical model in agreement with the experimental observation revealed that the sustained CIP release from the blended nanofibers corresponded to the two-stage desorption process.

Exploration of eosinopenia as a diagnostic parameter to differentiate sepsis from systemic inflammatory response syndrome: Results from an observational study.

AIM OF THE STUDY: Initial differentiation of sepsis from systemic inflammatory response syndrome (SIRS) is of prime importance for early institution of appropriate treatment. This study aimed to compare the differential diagnostic efficacy of absolute eosinophil count (AEC - a routinely available economic marker) with total leukocyte count (TLC) and procalcitonin (PCT - a costly marker available only in specialized settings). MATERIALS AND METHODS: In this prospective observational study, 170 patients of sepsis (severe sepsis = 125; SIRS = 45) were enrolled. AEC, TLC, and PCT were measured in the blood of all patients at the time of admission and data analyzed statistically. RESULTS: Median AEC was 0 cells/mm(3) in both SIRS and sepsis. TLC and PCT levels were significantly higher (P < 0.001) in culture negative, culture positive, and overall sepsis groups in comparison to SIRS group. At a cutoff of < 50 cells/mm(3), AEC demonstrated a sensitivity and specificity of 23% and 68%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of TLC were 57%, 71%, 85%, 37% and of PCT were 82.4%, 82.2%, 93%, and 63%, respectively with area under curve of 0.455 for AEC, 0.640 for TLC, 0.908 for PCT. CONCLUSIONS: This study suggests that eosinopenia is not a reliable diagnostic tool to differentiate sepsis from SIRS. PCT and TLC are better differential diagnostic biomarkers.

Interrelationship between procalcitonin and organ failure in sepsis.

Sepsis suffers from lack of specific clinical symptoms which contribute to one of the major causes of mortality. In the present study, our aim was to evaluate the role of a recent biomarker Procalcitonin (PCT) in predicting organ dysfunction. 71 patients admitted with sepsis were included in the study. PCT levels were measured at 0, 24, 72 h and 7th day and sequential organ failure assessment score (SOFA) scores were calculated. PCT levels significantly decreased (p < 0.001) in 89.3 % of surviving patients, whereas, in 60 % non surviving patients the PCT level increased significantly (p < 0.001). A significant positive correlation between PCT and SOFA score was observed in survivors at each hour. These observations indicate that PCT concentration is significantly associated with severity of multi organ dysfunction and also helps in determining the prognosis of septic patients.