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In critically ill patients with low albumin, dose individualization of phenytoin is a challenge. The currently used Sheiner-Tozer equation does not accurately predict the free phenytoin concentration in serum and can result in incorrect dose modifications. The best measure to advocate in these patients is the direct-measurement of free phenytoin concentration.Phenytoin exhibits complex pharmacokinetics, requiring careful therapeutic drug monitoring. This study aimed to compare the accuracy of the established Sheiner-Tozer calculation method against the direct-measurement of free phenytoin concentration in serum by high performance liquid chromatography in critically ill patients with low albumin.Blood specimens for direct-measurement of both total and free phenytoin concentration were obtained from 57 patients with hypoalbuminemia monitored in the intensive care unit.The median [inter-quartile range (IQR)] for Sheiner-Tozer equation calculated total phenytoin concentration and direct-measured total was 17.14 (10.63-24.53) and 9.82 (6.02-13.85) μg mLIn patients with low albumin, free phenytoin concentration based on the Sheiner-Tozer corrected equation accurately classified patients based on their therapeutic category of free phenytoin in 73.7% of patients. Hence, for individualization of phenytoin dosage in critically ill patients with low albumin, we recommend direct-measurement of free phenytoin concentration.Wilfred PM, Mathew S, Chacko B, Prabha R, Mathew BS. Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations. Indian J Crit Care Med 2022;26(6):682-687.

Objectives The aim of this study was to inform public health policy decisions through the assessment of IgG antibody seroprevalence in the population and the risk factors for SARS-CoV-2 infection. Methods The seroprevalence of IgG antibodies among different subpopulations at the end of the first and second waves of the pandemic was estimated. Various risk factors associated with seropositivity, including sociodemography, IgG antibodies against endemic human coronavirus, and vaccination status, were also assessed. Results For all 2433 consenting participants, the overall estimated seroprevalences at the end of first and second waves were 28.5% (95% CI 22.3–33.7%) and 71.5% (95% CI 62.8–80.5%), respectively. The accrual of IgG positivity was heterogeneous, with the highest seroprevalences found in urban slum populations (75.1%). Vaccine uptake varied among the subpopulations, with low rates (< 10%) among rural and urban slum residents. The majority of seropositive individuals (75%) were asymptomatic. Residence in urban slums (OR 2.02, 95% CI 1.57–2.6; p < 0.001), middle socioeconomic status (OR 1.77, 95% CI 1.17–2.67; p = 0.007), presence of diabetes (OR 1.721, 95% CI 1.148–2.581; p = 0.009), and hypertension (OR 1.75, 95% CI 1.16–2.64; p = 0.008) were associated with seropositivity in multivariable analyses. Conclusion Although considerable population immunity has been reached, with more than two-thirds seropositive, improved vaccination strategies among unreached subpopulations and high-risk individuals are suggested for better preparedness in future.

Patients with tuberculosis (TB) developing acute respiratory distress syndrome (ARDS) may have a higher mortality when compared with ARDS of other infectious etiology.In this single-centre retrospective cohort study spanning 5-years (2012 to 2016), TB-ARDS patients were age and gender matched (1:2) with non-TB infectious ARDS and followed up until death or hospital discharge. Clinical profile, treatment and outcomes were compared using t-test and Chi-square as appropriate. Mortality predictors were explored using Conditional Poisson regression analysis and expressed as relative risk (RR) with 95% confidence interval (CI).Of the 516 ARDS patients, 74 TB-ARDS and 148 non-TB infectious ARDS patients were included. Although admission APACHE-II (21.4 ± 7.1 vs. 17.6 ± 6.8, p 0.001), incidence of shock (36.5% vs. 19.1%, p = 0.005) and mortality (59.5% vs. 29.7%, p 0.001) were significantly higher in TB-ARDS than non-TB etiology, overall ICU length of stay and nosocomial infections were similar in both groups. On regression analysis, after adjusting for confounders, TB-ARDS (RR 1.82; 95% CI 1.13-2.92) and need for inotropes (RR 3.49; 95% CI 1.44-8.46) were independently associated with death.Patients with TB-ARDS presented sicker and had higher mortality when compared with ARDS due to non-TB infectious etiology.

Aim and objective Although studies have described the clinical profile of patients admitted to the intensive care unit (ICU) with tuberculosis, it is unclear if the type of tuberculosis (pulmonary, extrapulmonary, or disseminated) impacts outcome. Matrials and methods Demographic data, microbiology, treatment, and outcomes over 5 years (2012–16) were obtained from electronic records. Patients were categorized as pulmonary, extrapulmonary, or disseminated tuberculosis. Comparisons were done using t test and Fisher's exact test as appropriate. Predictors of outcome were explored using bivariate and multivariate logistic regression analysis and expressed as odds ratio (OR) with 95% confidence intervals (CI). Results Of the 428 ICU admissions with suspected tuberculosis, 212 (121 male) patients with mean (standard deviation) age of 41.9 (16.7) years and APACHE-II score of 20.8 (6.6) were diagnosed as pulmonary (n = 55) and extrapulmonary (n = 52) or disseminated tuberculosis (n = 105). In 50.5%, the diagnosis of tuberculosis was established during the current ICU admission when they presented with organ dysfunction. Overall, microbiological confirmation was possible in 75.5%; 14 (10.3%) isolates were Rifampicin resistant. ICU admission was required primarily for ventilation (n = 176; 83%) and hemodynamic instability (n = 67; 32%). Hospital mortality was 50%. Outcomes were similar in the three groups except for longer duration of stay (p value = 0.04) in disseminated tuberculosis. On multivariate logistic regression analysis, pulmonary tuberculosis (OR 2.83; 95% CI 1.15–6.95) and vasoactive treatment (OR 15.8; 95% CI 6.4–39.2) were independently associated with death; need for ventilation predicted mortality perfectly. Conclusion In this cohort of patients admitted to ICU with tuberculosis, 50% were newly diagnosed during ICU admission. Pulmonary site of involvement and need for organ support are independent risk factors for death. How to cite this article Thomas L, Chacko B, Jupudi S, Mathuram A, George T, Gunasekaran K, et al. Clinical Profile and Outcome of Critically Ill Patients with Tuberculosis. Indian J Crit Care Med 2021;25(1):21–28.

In acute organophosphorus (OP) or carbamate poisoning, some patients require high dose atropine to counteract the effects on heart rate (HR) and blood pressure (BP). This study describes the factors associated with high dose atropine therapy and the use of adrenaline to reverse the inadequate HR response to atropine.Consecutive patients admitted to the intensive care unit (ICU) were prospectively recruited. Demographic data, treatment and outcomes of patients who failed to achieve target HR (100/min) or systolic BP90 mm Hg with either a cumulative atropine dose of 100-mg within 6-h following admission or an infusion of 30 mg/h for at least 3-h were compared with patients who achieved the targets. Factors associated with high dose atropine therapy were explored using logistic regression analysis and expressed as odds ratio (OR) with 95% confidence intervals (CIs).Of the 181 patients admitted with OP or carbamate poisoning, 155 patients fulfilled inclusion criteria. The mean (SD) age was 35.7 (15.8) years; admission APACHE-II score was 14.6 (7.5). Heart rate and/or BP target was not achieved in 13.6%. In these patients, target HR was achieved after adding adrenaline infusion at 2-4 μg/min. Ventilation duration (11.6 ± 6.3 vs. 8.4 ± 6.9 days,High dose atropine therapy is required in a subset of patients with OP and carbamate poisoning and was associated with longer ventilation duration and ICU stay. Adrenaline infusion improved hemodynamics in these patients.

ObjectiveLarge data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma.DesignSecondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease.Setting39 public and private hospitals across India during the study period from 22 April to 14 July 2020.ParticipantsOf the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed.Primary outcome measureFactors associated with all-cause mortality at 28 days after enrolment.ResultsThe mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3–7) and non-survivors (4 days; IQR 3–6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p2/FiO2 ratio 10 (9.97, 3.65–27.13, p1.0 mg/L (2.50, 1.14–5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44–4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60–5.45, p=0.001) were significantly associated with death.ConclusionIn this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death.Trial registration numberCTRI/2020/04/024775.

Purpose Stenotrophomonas maltophilia is an emerging multi-drug resistant pathogen increasingly isolated in India. This study aimed to identify patients from whom Stenotrophomonas maltophilia had been isolated and assess predictors of mortality in this population. Methods This was a retrospective cohort study of hospitalized patients with a positive culture for S. maltophilia over a 3-year period. Clinical details and laboratory results were assessed from hospital records. Bivariate and multivariate analysis was used to identify risk factors for mortality. Results One hundred and nineteen patients (mean age 48.6 years) were included in the study. Of these, 111 patients were hospitalized for at least 48 ​hours prior to culture and 98 were admitted in the intensive care unit. Bivariate analysis revealed multiple associations with mortality, including a background of renal, cardiac, autoimmune disease, recent carbapenam use and COVID-19 infection and increasing ventilatory requirement, lower PaO2/FiO2 (P/F) ratio, vasopressor use, thrombocytopenia, and hypoalbuminemia at the time of positive isolate. Multivariate analysis showed that autoimmune disease [OR 27.38; 95% CI (1.39–540)], a P/F ratio of less than 300 [OR 7.58; 95% CI (1.52–37.9)], vasopressor requirement [OR 39.50; 95% CI (5.49–284)] and thrombocytopenia [OR 11.5; 95% CI (2.04–65.0)] were statistically significantly associated with increased mortality, while recent surgery and receipt of antibiotics [OR 0.16; 95% CI (0.03–0.8)] targeted against S. maltophilia were associated with decreased mortality. Conclusion Stenotrophomonas maltophilia is primarily isolated in patients in the intensive care unit. In our study the need for vasopressors, autoimmune disease, lower P/F ratios and thrombocytopenia were associated with higher mortality. The association of targeted antibiotics with reduced mortality suggests that the pathogenic role of S. maltophilia should not be underestimated. This finding needs to be confirmed with larger, prospective studies.

Introduction The role of NIV in SARS-CoV2 (COVID-19) related acute respiratory failure (C-ARF) is unclear. Methods C-ARF patients managed on NIV were categorised as NIV success or failure (death or intubation). Factors associated with failure were explored using regression analysis and expressed as Odds ratio (OR) with 95% Confidence Interval (CI). Results Between 1st April 2020 and 15th September 2020, 286 patients, age (Mean, SD) 53.1±11.6 years and APACHE-II score 11.1±5.5 were initiated on NIV. Of the 182 patients (63.6%) successfully managed on NIV alone, 118 had moderate or severe Acute Respiratory Distress Syndrome (ARDS). When compared with NIV success, NIV failure was associated with lower admission PaO2/FiO2 ratio (p

This is the twelfth version (eleventh update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline.What is the role of drugs in the treatment of patients with covid-19?The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and under way. The emerging SARS-CoV-2 variants (such as omicron) and subvariants are also changing the role of therapeutics. This update provides updated recommendations for remdesivir, addresses the use of combination therapy with corticosteroids, interleukin-6 (IL-6) receptor blockers, and janus kinase (JAK) inhibitors in patients with severe or critical covid-19, and modifies previous recommendations for the neutralising monoclonal antibodies sotrovimab and casirivimab-imdevimab in patients with non-severe covid-19.• Remdesivir: a conditional recommendation for its use in patients with severe covid-19; and a conditional recommendation against its use in patients with critical covid-19. • Concomitant use of IL-6 receptor blockers (tocilizumab or sarilumab) and the JAK inhibitor baricitinib: these drugs may now be combined, in addition to corticosteroids, in patients with severe or critical covid-19. • Sotrovimab and casirivimab-imdevimab: strong recommendations against their use in patients with covid-19, replacing the previous conditional recommendations for their use.When moving from new evidence to updated recommendations, the Guideline Development Group (GDG) considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. For remdesivir, new trial data were added to a previous subgroup analysis and provided sufficiently trustworthy evidence to demonstrate benefits in patients with severe covid-19, but not critical covid-19. The GDG considered benefits of remdesivir to be modest and of moderate certainty for key outcomes such as mortality and mechanical ventilation, resulting in a conditional recommendation. For baricitinib, the GDG considered clinical trial evidence (RECOVERY) demonstrating reduced risk of death in patients already receiving corticosteroids and IL-6 receptor blockers. The GDG acknowledged that the clinical trials were not representative of the world population and that the risk-benefit balance may be less advantageous, particularly in patients who are immunosuppressed at higher risk of opportunistic infections (such as serious fungal, viral, or bacteria), those already deteriorating where less aggressive or stepwise addition of immunosuppressive medications may be preferred, and in areas where certain pathogens such as HIV or tuberculosis, are of concern. The panel anticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy or to combine medications in a stepwise fashion in patients who are deteriorating. The decision to combine the medications will depend on their availability, and the treating clinician's perception of the risk-benefit balance associated with combination immunosuppressive therapy, particularly in patient populations at risk of opportunistic infections who may have been under-represented in clinical trials. When making a strong recommendation against the use of monoclonal antibodies for patients with covid-19, the GDG considered in vitro neutralisation data demonstrating that sotrovimab and casirivimab-imdevimab evaluated in clinical trials have meaningfully reduced neutralisation activity of the currently circulating variants of SARS-CoV-2 and their subvariants. There was consensus among the panel that the absence of in vitro neutralisation activity strongly suggests absence of clinical effectiveness of these monoclonal antibodies. However, there was also consensus regarding the need for clinical trial evidence in order to confirm clinical efficacy of new monoclonal antibodies that reliably neutralise the circulating strains in vitro. Whether emerging new variants and subvariants might be susceptible to sotrovimab, casirivimab-imdevimab, or other anti-SARS-CoV-2 monoclonal antibodies cannot be predicted.• Recommended for patients with severe or critical covid-19—strong recommendations for systemic corticosteroids; IL-6 receptor blockers (tocilizumab or sarilumab) in combination with corticosteroids; and baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids. • Recommended for patients with non-severe covid-19 at highest risk of hospitalisation—a strong recommendation for nirmatrelvir/ritonavir; conditional recommendations for molnupiravir and remdesivir. • Not recommended for patients with non-severe covid-19—a conditional recommendation against systemic corticosteroids; a strong recommendation against convalescent plasma; a recommendation against fluvoxamine, except in the context of a clinical trial; and a strong recommendation against colchicine. • Not recommended for patients with non-severe covid-19 at low risk of hospitalisation—a conditional recommendation against nirmatrelvir/ritonavir. • Not recommended for patients with severe or critical covid-19—a recommendation against convalescent plasma except in the context of a clinical trial; and a conditional recommendation against the JAK inhibitors ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity—a strong recommendations against hydroxychloroquine and against lopinavir/ritonavir; and a recommendation against ivermectin except in the context of a clinical trial.This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact.Recommendations on anticoagulation are planned for the next update to this guideline.

Objective:Antimicrobial stewardship programs (ASPs) are effective in developed countries. In this study, we assessed the effectiveness of an infectious disease (ID) physician–driven post-prescription review and feedback as an ASP strategy in India, a low middle-income country (LMIC).Design and setting:This prospective cohort study was carried out for 18 months in 2 intensive care units of a tertiary-care hospital, consisting of 3 phases: baseline, intervention, and follow up. Each phase spanned 6 months.Participants:Patients aged ≥15 years receiving 48 hours of study antibiotics were recruited for the study.Methods:During the intervention phase, an ID physician reviewed the included cases and gave alternate recommendations if the antibiotic use was inappropriate. Acceptance of the recommendations was measured after 48 hours. The primary outcome of the study was days of therapy (DOT) per 1,000 study patient days (PD).Results:Overall, 401 patients were recruited in the baseline phase, 381 patients were recruited in the intervention phase, and 379 patients were recruited in the follow-up phase. Antimicrobial use decreased from 831.5 during the baseline phase to 717 DOT per 1,000 PD in the intervention phase (P < .0001). The effect was sustained in the follow-up phase (713.6 DOT per 1,000 PD). De-escalation according to culture susceptibility improved significantly in the intervention phase versus the baseline phase (42.7% vs 23.6%; P < .0001). Overall, 73.3% of antibiotic prescriptions were inappropriate. Recommendations by the ID team were accepted in 60.7% of the cases.Conclusion:The ID physician–driven implementation of an ASP was successful in reducing antibiotic utilization in an acute-care setting in India.

Introduction: Carbapenem resistance (CR) in Klebsiella pneumoniae is mainly mediated by bla NDM and bla OXA-48 carbapenemases. Newer Food and Drug Administration-approved antimicrobial ceftazidime/avibactam (C/A) has a potent activity against bla OXA-48-like producers. However, its activity is limited in organisms co-producing bla NDM and bla OXA-48-like. Addition of aztreonam (ATM) to C/A potentially expands the spectrum of coverage for carbapenemase co-producers. With this, we aimed to determine the synergistic activity of combination of C/A plus ATM against bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like producing CR Klebsiella pneumoniae (CRKp). Materials and Methods: A total of 12 isolates of CRKp-harbouring genes encoding bla NDM and bla OXA-48-like were tested. Minimum inhibitory concentrations (MICs) were determined for several antimicrobial agents, including C/A (0.5–8 μg/ml) by broth microdilution method. Checkerboard assay was performed for the combination of C/A plus ATM at varying concentrations. Fold differences in the MIC of C/A with and without addition of ATM were determined to infer synergistic effects. Results: MIC of C/A and ATM ranged from 0.5 to >8 μg/ml and 64 to 2048 μg/ml, respectively. Two isolates were susceptible to C/A with MIC of 0.5 and 1 μg/ml, while others were resistant with MIC of >8 μg/ml. Synergistic effects of >8-fold MIC difference in C/A MIC were noted with addition of ATM at 4 μg/ml. This was observed for all CRKp with profiles of bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like genes, which was a promising effect. Notably, all five of the colistin-resistant CRKp were inhibited with >8-fold MIC difference in the combination of C/A plus ATM at 4 μg/ml. Conclusion: With the increasing burden of CRKp, the use of C/A with ATM combination seems to be very promising, especially for bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48like carbapenemases.

There has seen an increase in anticoagulant consumption worldwide over the past few decades. With this widespread utilization of anticoagulants, clinicians are increasingly likely to encounter situations where anticoagulants would need to be withheld. This includes emergency and elective procedures or surgeries as well as major or minor bleeding as a direct result of over anticoagulation or consequent to other intercurrent illnesses such as sepsis or trauma with multiorgan failure, where the anticoagulant may contribute to coagulation abnormalities. Clinicians are required to have a thorough understanding of the indications for anticoagulant prescription, drug interactions and monitoring, indications and options of reversal of anticoagulation and management of bleeding in the situations described above. Once the acute process is managed, the ongoing need and timing of reinitiation of anticoagulation is also crucial. This article provides an overview on the indications for reversal of anticoagulation, the agents used for reversal and the timing of reinitiation of anticoagulants. How to cite this article Chacko B, Peter JV, Subramani K. Reversal of Anticoagulants in Critical Care. Indian J Crit Care Med 2019;23(Suppl 3):S221–S225.

Objective: Deliberate self-harm (DSH) is an important cause for intensive care admission in developing countries. The evaluation of incidence and risk factors for nosocomial infection development in DSH with its impact on the outcome is not clearly elucidated. Methods: Demographic, infection, and outcome data were collected in this retrospective study of 2 years. Factors associated with infection and mortality were explored using bivariate and multivariate logistic regression analyses, which were expressed as odds ratio (OR) with 95% confidence interval (CI). Results: Of the 3274 admissions, 302 (9.2%) were due to DSH, whereas the majority (n = 178, 58.9%) were due to organophosphorus (OP) compounds, with the mean (SD) APACHE-II score of 14.7 (6.0); 278 (92.1%) patients were ventilated. 55 (18.2%) patients developed a nosocomial infection, accounting for 15.6 infections per 1000 hospital days, with an overall mortality of 14.2%. Mortality was significantly (p < 0.001) higher in those who developed an infection (30.9% vs. 10.5%). Multivariate logistic regression analysis demonstrated that DSH due to OP compounds (OR 2.9; 95%CI 1.1–7.1) and ventilation duration (OR 1.1; 95%CI 1.1–1.3) were independently associated with nosocomial infection development. APACHE-II score, nosocomial infection, and the need for dialysis significantly (p < 0.001) associated with mortality. Conclusion: In the DSH setting, acquiring nosocomial infection during intensive care admission impacts mortality. DSH due to OP compounds and duration of ventilation were independent risk factors for the development of infection.

Clinical question What is the role of drugs in preventing covid-19? Why does this matter? There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. Recommendations The second version of this living guideline reiterates the previous strong recommendation against the use of hydroxychloroquine and includes a new conditional recommendation against the use of tixagevimab-cilgavimab in individuals who do not have covid-19. How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provides methodological support. A living systematic review with network analysis informs the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produces recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the recommendations The living network meta-analysis informing this guideline included 12 trials (8379 participants) comparing hydroxychloroquine to standard care/placebo, and one trial (5197 participants) comparing tixagevimab-cilgavimab to standard care/placebo. When moving from evidence to the continued strong recommendation against the use of hydroxychloroquine, the GDG emphasised additional evidence suggesting no or little effect on mortality and hospital admission, and an increased risk of adverse effects. For the new conditional recommendation against the use of tixagevimab-cilgavimab, the GDG emphasised in vitro evidence reducing the applicability of available trial data. While trial results demonstrated modest reduction in the occurrence of laboratory confirmed symptomatic covid-19, lack of in vitro neutralisation of new SARS-CoV-2 sub-lineages was considered to have rendered these results obsolete. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. Readers note This is the second version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19 and living guidance regarding covid-19 related clinical management. When citing this article, please consider adding the update number and date of access for clarity.

Background: In acute Organophosphorus (OP) or Carbamate poisoning, some patients require high dose atropine to achieve atropinisation targets. This study evaluated the incidence and factors associated with atropine refractoriness. Methods: Consecutive patients, admitted to the intensive care unit (ICU) with OP and Carbamate, were prospectively recruited. Atropine refractoriness was defined as failure to achieve target heart rate (100/min) or systolic BP >90 mm Hg with either a cumulative atropine dose of 100-mg within 6-h following admission or an infusion of 30 mg/h for at least 3-h. Demographic data, treatment and outcomes were recorded. Factors associated with atropine refractoriness were explored using logistic regression analysis and expressed as Odds ratio (OR) with 95% Confidence Intervals (CI). Findings: Of the 181 patients admitted with OP or Carbamate poisoning, 155 patients fulfilled inclusion criteria. The mean (SD) age was 35·7 (15·8) years; admission APACHE-II score was 14·6 (7·5). Atropine refractoriness occurred in 13·6%. In these patients, target heart rate was achieved after adding adrenaline infusion at 2-4 mcg/min. Ventilation duration (11·6±6·3 vs. 8·4±6·9 days, P=0·05) and ICU stay (12.3±5·8 vs. 8·9±5·8 days, P=0·01) were longer in atropine refractory patients when compared with non-refractory patients. On multivariate logistic regression analysis, shorter time to presentation to hospital (p=0·04) was associated with atropine refractoriness. Overall mortality was 9% and similar in refractory and non-refractory patients (P=0·41). Interpretation: Atropine refractoriness is not uncommon in OP and Carbamate poisoning and is associated with longer ventilation duration and ICU stay. Adrenaline infusion improves hemodynamics in these patients. Funding Statement: None. Declaration of Interests: There is no conflict of interest or any financial disclosures for all the authors listed in the submission. Ethics Approval Statement: The study was approved by the institutional review board (IRB) and ethics committees of the institution (IRB Min. No. 10100, dated 10.06.2016).

Close monitoring and management of temperature abnormalities are crucial in the critically ill to minimize the physiological and biochemical ill effects of extremes of temperature. In the intensive care unit, core temperature monitoring using either urinary, nasopharyngeal, or esophageal temperatures is recommended. One needs to be aware of the pitfalls and fallacies of other commonly used sites.

Background: Healthcare-associated infections (HAIs) are a major global threat to patient safety. Systematic surveillance is crucial for understanding HAI rates and antimicrobial resistance trends and to guide infection prevention and control (IPC) activities based on local epidemiology. In India, no standardized national HAI surveillance system was in place before 2017. Methods: Public and private hospitals from across 21 states in India were recruited to participate in an HAI surveillance network. Baseline assessments followed by trainings ensured that basic microbiology and IPC implementation capacity existed at all sites. Standardized surveillance protocols for central-line–associated bloodstream infections (CLABSIs) and catheter-associated urinary tract infections (CAUTIs) were modified from the NHSN for the Indian context. IPC nurses were trained to implement surveillance protocols. Data were reported through a locally developed web portal. Standardized external data quality checks were performed to assure data quality. Results: Between May 2017 and April 2019, 109 ICUs from 37 hospitals (29 public and 8 private) enrolled in the network, of which 33 were teaching hospitals with >500 beds. The network recorded 679,109 patient days, 212,081 central-line days, and 387,092 urinary catheter days. Overall, 4,301 bloodstream infection (BSI) events and 1,402 urinary tract infection (UTI) events were reported. The network CLABSI rate was 9.4 per 1,000 central-line days and the CAUTI rate was 3.4 per 1,000 catheter days. The central-line utilization ratio was 0.31 and the urinary catheter utilization ratio was 0.57. Moreover, 3,542 (73%) of 4,742 pathogens reported from BSIs and 868 (53%) of 1,644 pathogens reported from UTIs were gram negative. Also, 1,680 (26.3%) of all 6,386 pathogens reported were Enterobacteriaceae. Of 1,486 Enterobacteriaceae with complete antibiotic susceptibility testing data reported, 832 (57%) were carbapenem resistant. Of 951 Enterobacteriaceae subjected to colistin broth microdilution testing, 62 (7%) were colistin resistant. The surveillance platform identified 2 separate hospital-level HAI outbreaks; one caused by colistin-resistant K. pneumoniae and another due to Burkholderia cepacia. Phased expansion of surveillance to additional hospitals continues. Conclusions: HAI surveillance was successfully implemented across a national network of diverse hospitals using modified NHSN protocols. Surveillance data are being used to understand HAI burden and trends at the facility and national levels, to inform public policy, and to direct efforts to implement effective hospital IPC activities. This network approach to HAI surveillance may provide lessons to other countries or contexts with limited surveillance capacity.Funding: NoneDisclosures: None

Carbapenem resistance (CR) in Klebsiella pneumoniae is mainly mediated by bla NDM and bla OXA-48 carbapenemases. Newer Food and Drug Administration-approved antimicrobial ceftazidime/avibactam (C/A) has a potent activity against bla OXA-48-like producers. However, its activity is limited in organisms co-producing bla NDM and bla OXA-48-like. Addition of aztreonam (ATM) to C/A potentially expands the spectrum of coverage for carbapenemase co-producers. With this, we aimed to determine the synergistic activity of combination of C/A plus ATM against bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like producing CR Klebsiella pneumoniae (CRKp).A total of 12 isolates of CRKp-harbouring genes encoding bla NDM and bla OXA-48-like were tested. Minimum inhibitory concentrations (MICs) were determined for several antimicrobial agents, including C/A (0.5-8 μg/ml) by broth microdilution method. Checkerboard assay was performed for the combination of C/A plus ATM at varying concentrations. Fold differences in the MIC of C/A with and without addition of ATM were determined to infer synergistic effects.MIC of C/A and ATM ranged from 0.5 to8 μg/ml and 64 to 2048 μg/ml, respectively. Two isolates were susceptible to C/A with MIC of 0.5 and 1 μg/ml, while others were resistant with MIC of8 μg/ml. Synergistic effects of8-fold MIC difference in C/A MIC were noted with addition of ATM at 4 μg/ml. This was observed for all CRKp with profiles of bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like genes, which was a promising effect. Notably, all five of the colistin-resistant CRKp were inhibited with8-fold MIC difference in the combination of C/A plus ATM at 4 μg/ml.With the increasing burden of CRKp, the use of C/A with ATM combination seems to be very promising, especially for bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48like carbapenemases.

How to cite this article: Chacko B, Krishna B, Kulkarni AP. Poisoning—The Road Less Travelled. Indian J Crit Care Med 2019;23(Suppl 4):S233.

Secondary hemophagocytic lymphohistiocytosis (sHLH) may be responsible for some of the deaths in adult patients with severe COVID-19. We present our experience of low-volume plasma exchange (PLEX) with low-dose steroid in the treatment of adult patients with sHLH and acute liver failure caused by dengue virus and other nonviral triggers and discuss how this may be effective in the management of severe COVID-19. sHLH is poorly understood and without effective treatment. Endothelium of the capillaries of the lungs and kidneys and of liver sinusoids does not express von Willebrand factor (VWF) in health and is where most macrophages are located. Plasma VWF levels are high in sHLH and require clearance by macrophages, which when activated enlarge and likely block the lumen. Current histology studies neither appreciate microcirculatory sludge nor display endothelial–macrophage interactions. We hypothesize that low-volume PLEX and low-dose steroid may reverse sHLH and improve survival in severe COVID-19 patients with acute lung injury.

How to cite this article: Chacko B. Kidney Injury in Sepsis: Fuel to the Fire. Indian J Crit Care Med 2020;24(4):216–217.

Context: Procalcitonin is a biomarker of bacterial sepsis. It is unclear if scrub typhus, a rickettsial illness, is associated with elevated procalcitonin levels. Aim: To assess if scrub typhus infection is associated with high procalcitonin levels and whether high levels portend a poorer prognosis. Setting and Design: Retrospective study of patients with severe scrub typhus infection, admitted to the medical intensive care unit of a tertiary care university affiliated teaching hospital. Materials and Methods: Eighty-four patients with severe scrub typhus infection that also had procalcitonin levels were assessed. Statistical Analysis: Relationship between procalcitonin and mortality explored using univariate and multivariate analyses. Results: The mean (±standard deviation) age was 40.0 ± 15.5 years. Patients were symptomatic for 8.3 ± 4.3 days prior to presentation. The median admission procalcitonin level was 4.0 (interquartile range 1.8 to 8.5) ng/ml; 59 (70.2%) patients had levels >2 ng/ml. Invasive mechanical ventilation was required in 65 patients; 20 patients died. On univariate analysis, admission procalcitonin was associated with increased odds of death [odds ratio (OR) 1.09, 95% confidence interval (CI) 1.03 to 1.18]. On multivariate logistic regression analysis including procalcitonin and APACHE-II score, the APACHE-II score was significantly associated with mortality (OR 1.16, 95% CI 1.06 to 1.30, P = 0.004) while a trend was observed with procalcitonin (OR 1.05, 95%CI 1.01 to 1.13, P = 0.09). The area under the receiver operating characteristic (ROC) curve, AUC, for mortality was 0.77 for procalcitonin and 0.78 for APACHE-II. Conclusions: Procalcitonin is elevated in severe scrub typhus infection and may be associated with higher mortality.

Cardiomyopathy, cardiogenic shock or acute pulmonary oedema are well recognised complications of scorpion sting envenomation occurring in about 1-3% of patients. Current treatment recommendations include afterload reduction using prazosin and improving cardiac contractility with inotropes like dobutamine. We report the use of intra-aortic balloon pump (IABP) as rescue therapy in a patient with refractory cardiogenic shock due to Mesobuthus tamulus (Indian red scorpion) envenomation.A 32-year-old woman was referred 24 h after a scorpion sting. At presentation she was ventilated and in circulatory shock (systolic blood pressure50 mmHg). After admission, the patient had four cardiac arrests (three episodes of pulseless ventricular tachycardia/ventricular fibrillation and one episode of asystole) over the next few hours. Following resuscitation, despite a combination of dobutamine, noradrenaline, and adrenaline, blood pressure did not improve significantly. In view of persistent tachycardia (heart rate 160/min), catecholamine storm was suspected and prazosin was added. However, shock was refractory. Hence, IABP was considered as rescue therapy. Following initiation of IABP, there was improvement in cardiac function (improved ejection fraction) which translated to weaning of inotropes over 48 h and improved organ function (renal, respiratory) in the next 2-3 d. However, following extubation, on Day 8, she was noted to have features of hypoxic brain injury. This improved gradually. At discharge (Day 30) she was independent for activities of daily living and was able to mobilise without support.IABP could be generally considered as a rescue therapy in refractory cardiogenic shock in envenomations.

Influenza virus is prone to mutations that may alter the intensity of subsequent waves of infection. In this study, we evaluated whether outcomes were different in the two waves of the influenza A (H1N1) 2009 pandemic in patients admitted to the intensive-care unit. Age, gender, lag-time to presentation and APACHE-II scores were similar in both waves. Although ventilatory requirements were similar (36/37 vs. 36/39), non-significant reductions in the durations (days) of ventilation (10.3 ± 8.0 vs. 7.8 ± 9.4, p 0.11) and hospitalization (14.9 ± 10.5 vs. 12.3 ± 14.1, p 0.20) were observed in the second wave. The clinical profile and outcomes were not significantly different between the two waves among severely ill patients.

Background and Aims: When dealing with very sick patients, the speed and accuracy of tests to detect metabolic derangements is very important. We evaluated if there was agreement between whole blood electrolytes measured by a point-of-care device and serum electrolytes measured using indirect ion-selective electrodes. Materials and Methods: In this prospective study, electrolytes were analyzed in 44 paired samples drawn from critically ill patients. Whole blood electrolytes were analyzed using a point-of-care blood gas analyzer and serum electrolytes were analyzed in the central laboratory on samples transported through a rapid transit pneumatic system. Agreement was summarized by the mean difference with 95% limits of agreement (LOA) and Lin’s concordance correlation (p c). Results: There was a significant difference in the mean (±standard deviation) sodium value between whole blood and serum samples (135.8 ± 5.7 mmol/L vs. 139.9 ± 5.4 mmol/L, P < 0.001), with the agreement being modest (pc = 0.71; mean difference −4.0; 95% LOA −8.78 to 0.65). Although the agreement between whole blood and serum potassium was good (pc = 0.96), and the average difference small (−0.3; 95% LOA −0.72 to 0.13), individual differences were clinically significant, particularly at lower potassium values. For potassium values

Background: Computerized medical information systems have been popularized over the last two decades to improve quality and safety, and for decreasing medical errors. Aim: To develop a clinician-friendly computer-based support system in the intensive care unit (ICU) that incorporates recording, reminders, alerts, checklists and diagnostic differentials for common conditions encountered in critical care. Materials and Methods: This project was carried out at the Medical ICU CMC Hospital, Vellore, in collaboration with the Computer Science Department, VIT University. The first phase was to design and develop monitoring and medication sheets. Terminologies such as checklists (intervention list that pops up at defined times for all patients), reminders (intervention unique to each patient) and alerts (time-based, value-based, trend-based) were defined. The diagnostic and intervention bundles were characterized in the second phase. The accuracy and reliability of the software to generate alerts, reminders and diagnoses was tested in the third phase. The fourth phase will be to integrate this with the hospital information system and the bedside monitors. Results: Alpha testing was performed using six scenarios written by intensivists. The software generated real-time alerts and reminders and provided diagnostic differentials relevant to critical care. Predefined interventions for each diagnostic possibility appeared as pop-ups. Problems identified during alpha testing were rectified prior to beta testing. Conclusions: The use of a computer-assisted monitoring, recording and diagnostic system appears promising. It is envisaged that further software refinements following beta testing would facilitate the improvement of quality and safety in the critical care environment.

Intensive care unit (ICU) treatment costs pose special challenges in developing countries.To determine the prognostic value of the "utility" score and evaluate the relationship of willingness to pay assessment to utility score during ICU admission.We performed a prospective study spanning 12 months in a 24-bed medical ICU in India. Treatment cost was estimated by direct measurement. Global utility score was assessed daily by healthcare providers on a Likert scale (0-1 in increments of 0.1, with 0 indicating death/severe disability and 1 indicating cure/perfect health). The sensitivity, specificity, and likelihood ratios of utility in predicting ICU mortality was calculated. Receiver operating characteristic curves were generated to compare Day 2 utility with APACHE II. The caregiver's willingness to pay for treatment was assessed on alternate days using the bidding method by presenting a cost bid. Based on the response ("yes" or "no"), bids were increased or decreased in a prespecified manner until a final bid value was reached. Simultaneously, treating doctors were asked how much institutional funds they would be willing to spend for treatment.Primary diagnosis in 499 patients included infection (26%) and poisoning (21%). The mean (SD) APACHE II score was 13.9 (5.8); 86% were ventilated. ICU stay was 7.8 (5.5) days. ICU mortality was 23.9% (95% confidence interval, 20.3-27.8). Survival without disability was 8.3% (2/24) for Day 2 utility score ≤0.3 and 95.8% (53/56) for Day 5 score0.8 (P 0.001). The likelihood ratio to predict mortality increased as utility values decreased and was highest (5.85) for utility 0.2. Area under the receiver operating characteristic curves for utility and APACHE II were similar. Willingness to pay by the caregiver was 53% of treatment cost and was not influenced by utility. Willingness to pay by ICU doctors showed an inverted U-shaped relationship with utility.Utility scores help prognosticate, with Day 2 score ≤0.3 associated with poor outcome and ≥0.8 Day 5 score with survival. The caregiver's willingness to pay was inadequate to meet treatment cost. ICU doctors were willing to spend more for moderate utility scores than for very high or low utility values. Further prospective studies are needed to optimize the utilization of scarce ICU resources by identifying patients for appropriate step-down care using utility and willingness to pay.

Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) account for one-quarter of cases of acute respiratory failure in intensive care units (ICUs). A third to half of patients will die in the ICU, in hospital or during follow-up. Mechanical ventilation of people with ALI/ARDS allows time for the lungs to heal, but ventilation is invasive and can result in lung injury. It is uncertain whether ventilator-related injury would be reduced if pressure delivered by the ventilator with each breath is controlled, or whether the volume of air delivered by each breath is limited. Objectives To compare pressure-controlled ventilation (PCV) versus volume-controlled ventilation (VCV) in adults with ALI/ARDS to determine whether PCV reduces in-hospital mortality and morbidity in intubated and ventilated adults. Search methods In October 2014, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Isssue 9), MEDLINE (1950 to 1 October 2014), EMBASE (1980 to 1 October 2014), the Latin American Caribbean Health Sciences Literature (LILACS) (1994 to 1 October 2014) and Science Citation Index-Expanded (SCI-EXPANDED) at the Institute for Scientific Information (ISI) Web of Science (1990 to 1 October 2014), as well as regional databases, clinical trials registries, conference proceedings and reference lists. Selection criteria Randomized controlled trials (RCTs) and quasi-RCTs (irrespective of language or publication status) of adults with a diagnosis of acute respiratory failure or acute on chronic respiratory failure and fulfilling the criteria for ALI/ARDS as defined by the American-European Consensus Conference who were admitted to an ICU for invasive mechanical ventilation, comparing pressure-controlled or pressure-controlled inverse-ratio ventilation, or an equivalent pressure-controlled mode (PCV), versus volume-controlled ventilation, or an equivalent volume-controlled mode (VCV). Data collection and analysis Two review authors independently screened and selected trials, assessed risk of bias and extracted data. We sought clarification from trial authors when needed. We pooled risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with their 95% confidence intervals (CIs) using a random-effects model. We assessed overall evidence quality using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. Main results We included three RCTs that randomly assigned a total of 1089 participants recruited from 43 ICUs in Australia, Canada, Saudi Arabia, Spain and the USA. Risk of bias of the included studies was low. Only data for mortality and barotrauma could be combined in the meta-analysis. We downgraded the quality of evidence for the three mortality outcomes on the basis of serious imprecision around the effect estimates. For mortality in hospital, the RR with PCV compared with VCV was 0.83 (95% CI 0.67 to 1.02; three trials, 1089 participants; moderate-quality evidence), and for mortality in the ICU, the RR with PCV compared with VCV was 0.84 (95% CI 0.71 to 0.99; two trials, 1062 participants; moderate-quality evidence). One study provided no evidence of clear benefit with the ventilatory mode for mortality at 28 days (RR 0.88, 95% CI 0.73 to 1.06; 983 participants; moderate-quality evidence). The difference in effect on barotrauma between PCV and VCV was uncertain as the result of imprecision and different co-interventions used in the studies (RR 1.24, 95% CI 0.87 to 1.77; two trials, 1062 participants; low-quality evidence). Data from one trial with 983 participants for the mean duration of ventilation, and from another trial with 78 participants for the mean number of extrapulmonary organ failures that developed with PCV or VCV, were skewed. None of the trials reported on infection during ventilation or quality of life after discharge. Authors' conclusions Currently available data from RCTs are insufficient to confirm or refute whether pressure-controlled or volume-controlled ventilation offers any advantage for people with acute respiratory failure due to acute lung injury or acute respiratory distress syndrome. More studies including a larger number of people given PCV and VCV may provide reliable evidence on which more firm conclusions can be based.

AIM To study the impact of hospital-acquired infections (HAIs) on cost and outcome from intensive care units (ICU) in India. METHODS Adult patients (> 18 years) admitted over 1-year, to a 24-bed medical critical care unit in India, were enrolled prospectively. Treatment cost and outcome data were collected. This cost data was merged with HAI data collected prospectively by the Hospital Infection Control Committee. Only infections occurring during ICU stay were included. The impact of HAI on treatment cost and mortality was assessed. RESULTS The mean (± SD) age of the cohort (n = 499) was 42.3 ± 16.5 years. Acute physiology and chronic health evaluation-II score was 13.9 (95%CI: 13.3-14.5); 86% were ventilated. ICU and hospital length of stay were 7.8 ± 5.5 and 13.9 ± 10 d respectively. Hospital mortality was 27.9%. During ICU stay, 76 (15.3%) patients developed an infection (ventilator-associated pneumonia 50; bloodstream infection 35; urinary tract infections 3), translating to 19.7 infections/1000 ICU days. When compared with those who did not develop an infection, an infection occurring during ICU stay was associated with significantly higher treatment cost [median (inter-quartile range, IQR) INR 92893 (USD 1523) (IQR 57168-140286) vs INR 180469 (USD 2958) (IQR 140030-237525); P < 0.001 and longer duration of ICU (6.7 ± 4.5 d vs 13.4 ± 7.0 d; P < 0.01) and hospital stay (12.4 ± 8.2 d vs 21.8 ± 13.9 d; P < 0.001)]. However ICU acquired infections did not impact hospital mortality (31.6% vs 27.2%; P = 0.49). CONCLUSION An infection acquired during ICU stay was associated with doubling of treatment cost and prolonged hospitalization but did not significantly increase mortality.

Background: This multi-center study from India details the profile and outcomes of patients admitted to the intensive care unit (ICU) with pandemic Influenza A (H1N1) 2009 virus [P(H1N1)2009v] infection. Materials and Methods: Over 4 months, adult patients diagnosed to have P(H1N1)2009v infection by real-time RT-PCR of respiratory specimens and requiring ICU admission were followed up until death or hospital discharge. Sequential organ failure assessment (SOFA) scores were calculated daily. Results: Of the 1902 patients screened, 464 (24.4%) tested positive for P(H1N1)2009v; 106 (22.8%) patients aged 35±11.9 (mean±SD) years required ICU admission 5.8±2.7 days after onset of illness. Common symptoms were fever (96.2%), cough (88.7%), and breathlessness (85.9%). The admission APACHE-II and SOFA scores were 14.4±6.5 and 5.5±3.1, respectively. Ninety-six (90.6%) patients required ventilation for 10.1±7.5 days. Of these, 34/96 (35.4%) were non-invasively ventilated; 16/34 were weaned successfully whilst 18/34 required intubation. Sixteen patients (15.1%) needed dialysis. The duration of hospitalization was 14.0±8.0 days. Hospital mortality was 49%. Mortality in pregnant/puerperal women was 52.6% (10/19). Patients requiring invasive ventilation at admission had a higher mortality than those managed with non-invasive ventilation and those not requiring ventilation (44/62 vs. 8/44, P