Zinc Deficiency in Critically Ill Patients: Impact on Clinical Outcome.

Background Zinc is a trace element essential for the normal functioning of many vital enzymes and organ systems. Studies examining the rates and degrees of zinc deficiency and its consequences in patients with critical illnesses remain scarce. Materials and methods This is a prospective observational study assessing zinc deficiency in critically ill adult patients admitted to a tertiary care intensive care unit (ICU) and its impact on clinical outcomes. Patients were divided into those with normal (≥ 71 µg/dl) and low (≤ 70 µg/dl) zinc levels. Zinc-deficient patients were further divided into mild, moderate, and severe zinc deficiency groups based on zinc levels of 61-70 µg/dl, 51-60 µg/dl, and below 51 µg/dl, respectively. The primary outcome assessed was ICU mortality, and the secondary outcomes were ICU length of stay (LOS), duration of invasive mechanical ventilation (IMV), acute kidney injury (AKI) at admission, need for non-invasive ventilation (NIV), renal replacement therapy (RRT), or vasopressors during the course of the ICU. Other parameters compared included APACHE (Acute Physiology and Chronic Health Evaluation) II, SOFA (Sequential Organ Failure Assessment) score on day 1, and levels of lactate, procalcitonin, calcium, magnesium, phosphate, and serum albumin. The study also compared the mean zinc levels in patients with low and high SOFA scores (scores up to 7 vs. 8 and above) and low and high APACHE II values (scores up to 15 vs. 16 and above). Results A total of 50 patients were included, of whom 43 (86%) were zinc deficient. Mortality in zinc-deficient and normal zinc-level patients was 33% and 43%, respectively (p = 0.602). Patients with zinc deficiency were also older (mean age 69 vs. 49 years, p = 0.02). There was no difference in secondary outcome parameters, except for more zinc-deficient patients needing RRT. Twenty-six of the zinc-deficient patients had severe zinc deficiency, ten moderate, and seven mild (p = 0.663). ICU mortality was approximately 42%, 10%, and 29% in the severe, moderate, and mild deficiency groups, respectively (p = 0.092). Zinc levels were similar between those with low and high APACHE II scores (mean 47.9 vs. 45.5 µg/dl, p = 0.606) as well as between low and high SOFA scores (mean 47.8 vs. 45.7 µg/dl, p = 0.054). Conclusion The present study suggests that zinc deficiency is very common in critically ill patients but does not correlate with their severity of illness, nor does it lead to a poorer outcome in these patients. However, further studies with a larger cohort of patients would be required to make definitive conclusions.

India-discovered levonadifloxacin & alalevonadifloxacin: A review on susceptibility testing methods, CLSI quality control and breakpoints along with a brief account of their emerging therapeutic profile as a novel standard-of-care.

BACKGROUND: Levonadifloxacin (intravenous) and alalevonadifloxacin (oral prodrug) are novel antibiotics based on benzoquinolizine subclass of fluoroquinolone, licensed for clinical use in India in 2019. The active moiety, levonadifloxacin, is a broad-spectrum antibiotic with a high potency against methicillin-resistant Staphylococcus. aureus, multi-drug resistant pneumococci and anaerobes. OBJECTIVE: This review, for the first time, critically analyses the antimicrobial susceptibility testing methods, Clinical Laboratory & Standards Institute (CLSI)-quality control of susceptibility testing and breakpoints of levonadifloxacin. Further, the genesis, discovery and developmental aspects as well as therapeutic profile of levonadifloxacin and alalevonadifloxacin are briefly described. CONTENTS: In order to aid the scientific and clinician communities with a single comprehensive overview on all the key aspects of levonadifloxacin and alalevonadifloxacin, the present article covers the reference MIC and disk diffusion methods for levonadifloxacin susceptibility testing that were approved by CLSI and the reference ranges for quality control strains published in the CLSI M100 document. The breakpoints of levonadifloxacin were derived in concordance to US FDA, European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI approaches. Further, the article provides a brief account of challenges encountered during the discovery stages of levonadifloxacin and alalevonadifloxacin, activity spectrum and safety benefits accruing from structural novelty-linked mechanism of action. Further, the review also covers in vitro and in vivo activities, registrational clinical studies and patient-friendly features of levonadifloxacin/alalevonadifloxacin. Cumulatively, levonadifloxacin has a potential to offer a long awaited new standard-of-care treatment for the resistant Gram-positive bacterial infections.

Ocular adverse effects of COVID-19 vaccines: A systematic review.

The COVID-19 pandemic has led to the development and rollout of several vaccines worldwide at unprecedented pace. This systematic review of published literature has been undertaken to spread awareness among general physicians and ophthalmologists about the various reported adverse effects in the eye following COVID-19 vaccination. A systematic search was performed on 25 January 2022 through PuBMed, Medline and Google scholar for publications on ocular adverse effects after COVID-19 vaccination. One brief communication, four retrospective case series, sixteen case reports, and five letters to editors were included. Ocular manifestations most commonly appear in the uvea and retina. Other manifestations are seen on the eyelid, cornea and ocular surface, and in cranial nerves innervating the eye. The incidence rate of these manifestations is quite low after COVID-19 vaccinations. Our systematic review meticulously enumerates various adverse effects of COVID -19 vaccine on the eye. Most of these adverse effects are transient and observed to resolve without any sequelae except for cases of retinal and ophthalmic vascular occlusions and corneal graft rejections. An emphasis on close follow-up and a need to delay vaccination and modified therapy to control flare up of signs and symptoms in certain sub-populations, Graves' disease (autoimmune etiology), pre-existing uveal inflammation and corneal graft cases are warranted. We need long-term, larger, multicentric studies to substantiate our findings and establish the causal relationship with certainty. Mass vaccinations to curb this pandemic after outweighing the ocular risks associated with it is warranted.

Systemic thrombolytics as rescue therapy for COVID-19 patients with acute respiratory distress syndrome: A retrospective observational study.

Background: Coronavirus disease 2019 (COVID-19) pneumonia with severe acute respiratory distress syndrome (ARDS) is often associated with a progressive respiratory failure that is refractory to maximal ventilatory support and other ARDS strategies. Studies show evidence of a hypercoagulable state in COVID-19 patients, including capillary thrombosis and alveolar fibrin deposits which impede normal gas exchange. In this context, thrombolysis is considered as a salvage therapy to rescue critically hypoxemic patients. Methods: In this retrospective observational study, the efficacy of thrombolysis on outcome of COVID-19 ARDS with respiratory failure was analyzed. Patients with severe ARDS and d-dimer levels of 5 µg/ml or above were initiated on alteplase, as a 25 mg bolus followed by a 25 mg infusion over 22 h. Primary outcome was intensive care unit (ICU) mortality and secondary outcomes were change in PaO2/FiO2 24 h after thrombolysis, avoidance of intubation, ventilator free days (VFD), and ICU and hospital length-of-stay (LOS). Results: Thirteen out of 34 patients with severe COVID ARDS underwent thrombolysis. They had lower ICU mortality than non-thrombolysed patients (23.1% vs. 71.4%, P = 0.006), greater percentage improvement in PaO2/FiO2 (116% vs. 31.5%, P = 0.002), more VFDs (13 days vs. 0 day, P = 0.004), and lesser requirement for intubation (23.1% vs. 76.2%, P = 0.004). ICU and hospital LOS were similar. Conclusion: Thrombolysis can be considered as a rescue therapy for nonintubated COVID-19 ARDS patients with severe hypoxemic respiratory failure, who show evidence of a procoagulant state. Larger studies are needed before inclusion into the regular treatment protocol for COVID-19 patients.

Meeting the Unmet Need in the Management of MDR Gram-Positive Infections with Oral Bactericidal Agent Levonadifloxacin.

Levonadifloxacin (intravenous) and its oral prodrug alalevonadifloxacin are broad-spectrum antibacterial agents developed for the treatment of difficult-to-treat infections caused by multidrug-resistant Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus, atypical bacteria, anaerobic bacteria, and biodefence pathogens as well as Gram-negative bacteria. Levonadifloxacin has a well-defined mechanism of action involving a strong affinity for DNA gyrase as well as topoisomerase IV. Alalevonadifloxacin with widely differing solubility and oral bioavailability has pharmacokinetic profile identical to levonadifloxacin. Unlike existing MRSA drugs such as vancomycin and linezolid, which cause unfavorable side effects like nephrotoxicity, bone-marrow toxicity, and muscle toxicity, levonadifloxacin/alalevonadifloxacin has demonstrated superior safety and tolerability features with no serious adverse events. Levonadifloxacin/alalevonadifloxacin could be a useful weapon in the battle against infections caused by resistant microorganisms and could be a preferred antibiotic of choice for empirical therapy in the future.

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.

Cytokine Storm and Immunomodulation in COVID-19.

COVID-19 has become a major pandemic in recent times. The exact pathophysiology and understanding of cytokine storm and immunomodulation are evolving. Various cytokines have been implicated in the pathophysiology of COVID-19. Immunosuppressant immunomodulators like steroids, canakinumab, anakinra, tocilizumab, sarilumab, baricitinib, ruxolitinib, bevacizumab, and itolizumab have been tried. Immunostimulant immunomodulators like interferons (IFNs) and Mycobacterium w (Mw) have also been repurposed. Considering the role of multiple cytokines implicated in COVID-19, molecules working on the majority of the targets, may hold a promising future prospect. HOW TO CITE THIS ARTICLE: Rangappa P. Cytokine Storm and Immunomodulation in COVID-19. Indian J Crit Care Med 2021;25(11):1288-1291.

A rare case of vaccine-induced immune thrombosis and thrombocytopenia and approach to management.

BACKGROUND: The use of the COVID-19 vaccines Vaxzevria from AstraZeneca and Covishield from Janssen has been associated with sporadic reports of thrombosis with thrombocytopenia, a complication referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT) or vaccine-induced prothrombotic immune thrombocytopenia. It presents commonly as cerebral sinus venous thrombosis (CSVT), within 4-30 days of vaccination. Females under 55 years of age are considered to be especially at high risk. Mortality up to 50% has been reported in some countries. Identification of early warning signs and symptoms with prompt medical intervention is crucial. CASE DESCRIPTION: We report here a case of VITT in a young female who presented 11 days after receiving the first dose of the Covishield vaccine, with severe headache and hemiparesis. She was diagnosed with CSVT with a large intraparenchymal bleed, requiring decompressive craniectomy and extended period on mechanical ventilation. CONCLUSION: The patient was successfully treated with intravenous immunoglobulin and discharged after 19 days in ICU. Although she was left with long-term neurological deficits, an early presentation and a multidisciplinary approach to management contributed toward a relatively short stay in hospital and avoided mortality.

Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. METHODS: Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ2) test (p < 0·05 was considered as unstable). RESULTS: Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment. CONCLUSION: Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited. TRIAL REGISTRATION: The study was registered with Clinical trials.gov Identifier: NCT04534569.

Current Approaches to COVID-19: Therapy and Prevention.

The coronavirus disease-2019 (COVID-19) pandemic has affected millions of people worldwide. As our understanding of the disease is evolving, our approach to the patient management is also changing swiftly. Available new evidence is helping us take radical decisions in COVID-19 management. We searched for inclusion of the published literature on treatment of COVID-19 from around the globe. All relevant evidences available till the time of submission of this article were briefly discussed. Once advised as blanket therapy for all patients, recent reports of hydroxychloroquine with or without azithromycin indicated no potential benefit and use of such combination may increase the risk of arrhythmias. Clinical evidence with newer antivirals such as remdesivir and favipiravir is promising that can hasten the patient recovery and reduce the mortality. With steroids, evidence is much clear in that it should be used in low dose and for short period not extending beyond 7 days in moderate to severe hospitalized patients. Low-molecular-weight heparin should be initiated in all hospitalized COVID-19 patients and dose should be based on the coagulation profile and risk of thromboembolism. Immunomodulatory drugs such tocilizumab may be considered for severe and critically ill patients to improve the outcomes. Though ulinastatin can be a potential alternative immunomodulator, there is lack of clinical evidence on its usage in COVID-19. Convalescent plasma therapy can be potentially lifesaving in critically ill patients. However, there is need to generate further evidence with various such therapies. Though availability of a potent vaccine is awaited, current treatment of COVID-19 is based on available therapies, which is guided by the evidence. In this review, we discuss the potential treatments available around the globe with current evidence on each of such treatments. How to cite this article: Dixit SB, Zirpe KG, Kulkarni AP, Chaudhry D, Govil D, Mehta Y, et al. Current Approaches to COVID-19: Therapy and Prevention. Indian J Crit Care Med 2020;24(9):838-846.

A Study of Multidrug-Resistant, Colistin-Only-Sensitive Infections in Intubated and Mechanically Ventilated Patients Over 2 Years.

BACKGROUND AND AIMS: Multidrug-resistant, Gram-negative infections are increasingly common in the intensive care unit (ICU). This study compares the occurrence and outcome of colistin-only-sensitive (COS) infections among mechanically ventilated patients at a tertiary hospital ICU. METHODS: The study included adult patients admitted over a period of 2 years, who were intubated and mechanically ventilated for more than 48 h. They were divided into two groups, those with COS infections and those without, and their GCS and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, ICU length of stay, leukocyte count, and mortality were compared. COS patients were divided into neurosurgery, neurology, respiratory, and sepsis with bacteremia groups. The COS organisms in each group, their sources, ICU length of stay, ventilator-free days, and mortality were analyzed. RESULTS: Three hundred and one patients were selected, of whom 41 (13.6%) had COS infections. COS patients had a longer ICU length of stay than non-COS patients (P = 0.001) but comparable APACHE II and GCS scores, leukocyte count, and mortality. The sepsis group accounted for 8 out of 15 (53%) deaths among COS patients (P = 0.03). Acinetobacter baumannii accounted for 61% of the COS infections, Klebsiella pneumonia: 24.4%, Pseudomonas aeruginosa: 12.2%, and Escherichia coli: 2.4%. Endotracheal secretion cultures accounted for 65.8% of COS isolates, urine cultures 17%, pus cultures 7.3%, and blood cultures 4.9%. ICU length of stay, ventilator-free days, and mortality were similar between each COS organism. CONCLUSION: Intubated patients with multidrug-resistant, COS infections have a longer stay in ICU than non-COS patients. COS infections associated with bacteremia have high mortality.

Hyperbaric oxygen therapy: Can it be a novel supportive therapy in COVID-19?

The coronavirus disease 2019 (COVID-19) is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Although 85% of infected patients remain asymptomatic, 5% show severe symptoms such as hypoxaemic respiratory failure and multiple end organ dysfunction (MODS) requiring intensive care unit (ICU) admission with a mortality rate of about 2.8%. Since a definitive treatment is yet to be identified, preventive and supportive strategies remain the mainstay of management. Supportive measures such as oxygen therapy with nasal cannula, face mask, noninvasive ventilation, mechanical ventilation and even extreme measures such as extracorporeal membrane oxygenation (ECMO) fail to improve oxygenation in some patients. Hence, hyperbaric oxygen therapy (HBOT) has been proposed as a supportive strategy to improve oxygenation in COVID-19 patients. HBOT is known to increase tissue oxygenation by increasing the amount of dissolved oxygen in plasma. HBOT also mitigates tissue inflammation thus reducing the ill effects of cytokine storm in COVID-19 patients. Though there is limited literature available on HBOT in COVID-19 patients, considering the present need for additional supportive therapy to improve oxygenation, HBOT has been proposed as a novel supportive treatment in COVID-19 patients.

Practice Guidelines for Nutrition in Critically Ill Patients: A Relook for Indian Scenario.

BACKGROUND AND AIM: Intensive-care practices and settings may differ for India in comparison to other countries. While international guidelines are available to direct the use of enteral nutrition (EN), there are no recommendations specific to Indian settings. Advisory board meetings were arranged to develop the practice guidelines specific to Indian context, for the use of EN in critically ill patients and to overcome challenges in this field. METHODS: Various existing guidelines, meta-analyses, randomized controlled trials, controlled trials, and review articles were reviewed for their contextual relevance and strength. A systematic grading of practice guidelines by advisory board was done based on strength of the supporting evidence. Wherever Indian studies were not available, references were taken from the international guidelines. RESULTS: Based on the literature review, the recommendations for developing the practice guidelines were made as per the grading criteria agreed upon by the advisory board. The recommendations were to address challenges regarding EN versus parenteral nutrition; nutrition screening and assessment; nutrition in hemodynamically unstable; route of nutrition; tube feeding and challenges; tolerance; optimum calorie-protein requirements; selection of appropriate enteral feeding formula; micronutrients and immune-nutrients; standard nutrition in hepatic, renal, and respiratory diseases and documentation of nutrition practices. CONCLUSION: This paper summarizes the optimum nutrition practices for critically ill patients. The possible solutions to overcome the challenges in this field are presented as practice guidelines at the end of each section. These guidelines are expected to provide guidance in critical care settings regarding appropriate critical-care nutrition practices and to set up Intensive Care Unit nutrition protocols.

Cerebrospinal Fluid Lactate as a Prognostic Indicator in Postneurosurgical Bacterial Meningitis and Use of Intrathecal Colistin.

Postneurosurgical bacterial meningitis (PNBM) is an emergency and requires early diagnosis and treatment with appropriate antibiotics. The cornerstone of diagnosis is microbiological analysis of the cerebrospinal fluid (CSF) cytochemical characteristics such as leucocyte count, CSF glucose, and protein concentration and CSF: Serum glucose ratio. However, this is often misleading in PNBM. The role of CSF lactate assay for diagnosis and prognosis has been debated. This case report looks into the serial measurement of CSF lactates in PNBM. It also looks into the role of intrathecal colistin. CSF lactate showed a steady decrease corresponding to improvement in clinical condition. Hence, CSF lactate could have a better prognostic value than other conventional markers in PNBM. Intrathecal colistin, in conjunction with the standard antibiotics, can contribute to a quick resolution of the condition.

Outcome of Patients Admitted to a Tertiary Referral Intensive Care Unit with Urosepsis Needing Source Control.

INTRODUCTION: Urosepsis is one of the common causes of admission to the Intensive Care Unit (ICU). It has traditionally been treated with antibiotics, but surgical management with Double J [DJ] ureteral stents is gaining popularity. This study compares patients with complicated urosepsis who underwent surgical source control by ureteral stenting with those managed medically. MATERIALS AND METHODS: The study enrolled patients admitted to a tertiary adult ICU with a diagnosis of urosepsis over a period of 2 years. The primary outcomes were renal replacement therapy (RRT) requirement and ICU mortality. The secondary outcomes were ICU and hospital length of stay, ventilator-free days, and inotrope free days. Patients were divided those with obstructive and nonobstructive urinary tract infection (UTI). RESULTS: A total of 58 patients met the criteria, of who 32 had obstructive UTI and were included in Group A, with the remaining 26 with nonobstructive UTI comprised Group B. In Group A, 27 patients underwent source control with ureteral DJ stenting, three patients recovered with medical management, and two who were advised source control did not consent to the procedure. Seventeen patients in Group A and seven patients in Group B required RRT (P = 0.044). There was no significant difference in ICU mortality, hospital mortality, and 28 days survival between the two groups. CONCLUSION: With early source control, obstructive UTI outcomes were comparable to nonobstructive UTI. However, despite undergoing ureteric stenting, more patients with obstructive UTI required RRT than those with nonobstructive UTI.