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1.
Aging (Albany NY) ; 14(10): 4211-4219, 2022 May 18.
Article in English | MEDLINE | ID: covidwho-1856446

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) is spreading around the world. The COVID-19 vaccines may improve concerns about the pandemic. However, the roles of inactivated vaccines in older patients (aged ≥60 years) with infection of Delta variant were less studied. METHODS: We classified the older patients with infection of Delta variant into three groups based on the vaccination status: no vaccination (group A, n = 113), one dose of vaccination (group B, n = 46), and two doses of vaccination (group C, n = 22). Two inactivated COVID-19 vaccines (BBIBP-CorV or CoronaVac) were evaluated in this study. The demographic data, laboratory parameters, and clinical severity were recorded. RESULTS: A total of 181 older patients with infection of Delta variant were enrolled. 111 (61.3%) patients had one or more co-morbidities. The days of "turn negative" and hospital stay in Group C were lower than those in the other groups (P < 0.05). The incidences of multiple organ dysfunction syndrome (MODS), septic shock, acute respiratory distress syndrome (ARDS), acute kidney injury, and cardiac injury in Group A were higher than those in the other groups (P < 0.05). The MV-free days and ICU-free days during 28 days in Group A were also lower than those in the other groups (P < 0.05). In patients with co-morbidities, vaccinated cases had lower incidences of MODS (P = 0.015), septic shock (P = 0.015), and ARDS (P = 0.008). CONCLUSIONS: The inactivated COVID-19 vaccines were effective in improving the clinical severity of older patients with infection of Delta variant.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Shock, Septic , Aged , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , China/epidemiology , Humans , Multiple Organ Failure , SARS-CoV-2 , Vaccines, Inactivated
3.
Lancet Respir Med ; 10(3): 307-312, 2022 03.
Article in English | MEDLINE | ID: covidwho-1751527

ABSTRACT

Extracorporeal haemoadsorption is increasingly being used for the removal of endotoxin or inflammatory cytokines in patients with septic shock or other severe inflammatory states. A reduction in excessively high levels of inflammatory mediators-and mitigation of the devastating clinical impact of severe inflammation-might be a sound rationale for extracorporeal haemoadsorption in critical care, but the evidence for beneficial effects is uncertain. Few randomised controlled trials have been undertaken, and they have not provided reliable evidence for routine use in clinical practice. No study has shown a survival benefit, and only a few studies have shown a significant effect on patients' blood cytokine concentrations. Nonetheless, some clinicians have encouraged the use of haemoadsorption devices, largely on the basis of incomplete data or contentious interpretations of the available data. Further research is required, particularly well designed, prospective clinical trials assessing relevant patient-centred outcomes, including mortality, before widespread adoption of this technology can be recommended.


Subject(s)
Shock, Septic , Critical Care , Cytokines , Humans , Inflammation Mediators , Prospective Studies , Shock, Septic/therapy
4.
Clin Chim Acta ; 531: 4-11, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-1734231

ABSTRACT

BACKGROUND: COVID-19 patients experience several features of dysregulated immune system observed in sepsis. We previously showed a dysregulation of several proline-selective peptidases such as dipeptidyl peptidase 4 (DPP4), fibroblast activation protein alpha (FAP), prolyl oligopeptidase (PREP) and prolylcarboxypeptidase (PRCP) in sepsis. In this study, we investigated whether these peptidases are similarly dysregulated in hospitalized COVID-19 patients. METHODS: Fifty-six hospitalized COVID-19 patients and 32 healthy controls were included. Enzymatic activities of DPP4, FAP, PREP and PRCP were measured in samples collected shortly after hospital admission and in longitudinal follow-up samples. RESULTS: Compared to healthy controls, both DPP4 and FAP activities were significantly lower in COVID-19 patients at hospital admission and FAP activity further decreased significantly in the first week of hospitalization. While PRCP activity remained unchanged, PREP activity was significantly increased in COVID-19 patients at hospitalization and further increased during hospital stay and stayed elevated until the day of discharge. CONCLUSION: The changes in activities of proline-selective peptidases in plasma are very similar in COVID-19 and septic shock patients. The pronounced decrease in FAP activity deserves further investigation, both from a pathophysiological viewpoint and as its utility as a part of a biomarker panel.


Subject(s)
COVID-19 , Shock, Septic , Carboxypeptidases , Dipeptidyl Peptidase 4 , Endopeptidases , Gelatinases , Humans , Membrane Proteins , Peptide Hydrolases , Proline , Serine Endopeptidases
5.
N Engl J Med ; 386(9): 861-868, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1721753

ABSTRACT

Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an uncommon infection that is typically associated with exposure to soil and water in tropical and subtropical environments. It is rarely diagnosed in the continental United States. Patients with melioidosis in the United States commonly report travel to regions where melioidosis is endemic. We report a cluster of four non-travel-associated cases of melioidosis in Georgia, Kansas, Minnesota, and Texas. These cases were caused by the same strain of B. pseudomallei that was linked to an aromatherapy spray product imported from a melioidosis-endemic area.


Subject(s)
Aromatherapy/adverse effects , Burkholderia pseudomallei/isolation & purification , Disease Outbreaks , Melioidosis/epidemiology , Aerosols , Brain/microbiology , Brain/pathology , Burkholderia pseudomallei/genetics , COVID-19/complications , Child, Preschool , Fatal Outcome , Female , Genome, Bacterial , Humans , Lung/microbiology , Lung/pathology , Male , Melioidosis/complications , Middle Aged , Phylogeny , Shock, Septic/microbiology , United States/epidemiology
6.
Crit Care ; 26(1): 26, 2022 01 25.
Article in English | MEDLINE | ID: covidwho-1701731

ABSTRACT

BACKGROUND: Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C's enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock. METHODS: This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations. RESULTS: Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35-62) hours and in the placebo group was 54 (95% CI 41-62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05). CONCLUSIONS: Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence. TRIAL REGISTRATION: ACTRN12617001184369 (11/8/2017).


Subject(s)
Shock, Septic , Ascorbic Acid/therapeutic use , Double-Blind Method , Humans , Organ Dysfunction Scores , Pilot Projects , Shock, Septic/drug therapy , Vitamins
7.
Scand J Clin Lab Invest ; 82(2): 108-114, 2022 04.
Article in English | MEDLINE | ID: covidwho-1662010

ABSTRACT

In critical patients with Coronavirus Disease (COVID-19), we investigated the diagnostic value of presepsin in the early diagnosis of superinfection with sepsis, and the effect of antibiotic treatment (AT) in the levels of presepsin and procalcitonin and C-reactive protein. A total of 68 critical patients with sepsis and septic shock in the intensive care unit and 20 outpatients (control group) with COVID-19 were taken. ICU patients (n = 68) were further divided into three groups. C(-)AT(-) had negative blood or tracheal aspirate cultures (C) and not AT on admission to ICU (n = 18), C(-)AT(+) had negative C and AT on admission to intensive care unit (n = 31) and C(+) had positive C (n = 19). Presepsin, procalcitonin, C-reactive protein results were compared between the groups. There were no significant relationships between presepsin levels with sepsis, septic shock, mortality, or length of stay in ICU in patients with COVID-19. For procalcitonin and C-reactive protein levels in C(-)AT(+) and C(+) groups were significantly higher than in control and C(-)AT(-) groups (p < .001). C-reactive protein levels in C(-)AT(-) group were significantly higher than in the control group (p < .001). PCT and CRP, there was no difference between C(-)AT(+) and C(+) groups, and procalcitonin there was no difference between control and C(-)AT(-) groups. Presepsin was not found as a useful biomarker for the prediction of sepsis in COVID-19 patients. These study findings indicate that procalcitonin and C-reactive protein may be an indicator of an early diagnostic marker for superinfection in critical COVID-19 patients.


Subject(s)
COVID-19 , Sepsis , Shock, Septic , Superinfection , Biomarkers , C-Reactive Protein/analysis , COVID-19/diagnosis , Early Diagnosis , Humans , Lipopolysaccharide Receptors , Peptide Fragments , Procalcitonin , Shock, Septic/diagnosis
8.
BMJ Open Qual ; 11(1)2022 01.
Article in English | MEDLINE | ID: covidwho-1613016

ABSTRACT

INTRODUCTION: Sepsis is a common cause of emergency department (ED) presentation and hospital admission, accounting for a disproportionate number of deaths each year relative to its incidence. Sepsis outcomes have improved with increased recognition and treatment standards promoted by the Surviving Sepsis Campaign. Due to delay in recognition and other barriers, sepsis bundle compliance remains low nationally. We hypothesised that a targeted education intervention regarding use of an electronic health record (EHR) tool for identification and management of sepsis would lead to increased EHR tool utilisation and increased sepsis bundle compliance. METHODS: We created a multidisciplinary quality improvement team to provide training and feedback on EHR tool utilisation within our ED. A prospective evaluation of the rate of EHR tool utilisation was monitored from June through December 2020. Simultaneously, we conducted two retrospective cohort studies comparing overall sepsis bundle compliance for patients when EHR tool was used versus not used. The first cohort was all patients with intention-to-treat for any sepsis severity. The second cohort of patients included adult patients with time of recognition of sepsis in the ED admitted with a diagnosis of severe sepsis or septic shock. RESULTS: EHR tool utilisation increased from 23.3% baseline prior to intervention to 87.2% during the study. In the intention-to-treat cohort, there was a statistically significant difference in compliance between EHR tool utilisation versus no utilisation in overall bundle compliance (p<0.001) and for several individual components: initial lactate (p=0.009), repeat lactate (p=0.001), timely antibiotics (p=0.031), blood cultures before antibiotics (p=0.001), initial fluid bolus (p<0.001) and fluid reassessment (p<0.001). In the severe sepsis and septic shock cohort, EHR tool use increased from 71.2% pre-intervention to 85.0% post-intervention (p=0.008). CONCLUSION: With training, feedback and EHR optimisation, an EHR tool can be successfully integrated into current workflows and appears to increase sepsis bundle compliance.


Subject(s)
Sepsis , Shock, Septic , Adult , Anti-Bacterial Agents/therapeutic use , Electronic Health Records , Emergency Service, Hospital , Guideline Adherence , Humans , Lactic Acid , Retrospective Studies , Sepsis/diagnosis , Sepsis/therapy , Shock, Septic/drug therapy
10.
Clin Hemorheol Microcirc ; 79(3): 485-488, 2021.
Article in English | MEDLINE | ID: covidwho-1581405

ABSTRACT

Sepsis and septic shock result in impaired microcirculation and red blood cell rheology which lead to tissue hypoxia and multi-organ failure. Early administration of triiodothyronine prevents tissue hypoxia in experimental sepsis. In this context, a clinical trial was initiated to test the efficacy of acute triiodothyronine administration to combat tissue hypoxia in critically ill COVID19 patients. Here, we provide preliminary data from interim analysis of this study showing a novel acute effect of triiodothyronine on erythrocyte sedimentation rate which may have an important therapeutic impact on red blood cell rheology and tissue hypoxia in sepsis and particular in COVID19 critical illness.Trial registration: ClinicalTrials.gov, NCT04348513. Registered 16 April 2020, https://clinicaltrials.gov/ct2/show/NCT04348513.


Subject(s)
COVID-19 , Sepsis , Shock, Septic , Blood Sedimentation , Critical Illness , Erythrocytes , Humans , SARS-CoV-2 , Sepsis/drug therapy , Triiodothyronine
12.
Anaesthesist ; 70(8): 673-680, 2021 Aug.
Article in German | MEDLINE | ID: covidwho-1573821

ABSTRACT

BACKGROUND: The reported mortality for sepsis and septic shock varies between 15% and 59% in international comparison. For Germany, the number of studies is limited. Previous estimations of mortality in Germany are outdated or based on claims data analyses. Various authors discuss whether lacking quality initiatives and treatment standards in Germany could cause higher mortality for sepsis. This contrasts with the internationally well-recognized performance of the German intensive care infrastructure during the COVID-19 pandemic. OBJECTIVES: The objectives of this systematic review and meta-analysis were to estimate 30-day and 90-day mortality of patients with sepsis and patients with septic shock in Germany and to compare the mortality with that of other industrialized regions (Europe, North America). MATERIAL AND METHODS: A systematic literature search included interventional and observational studies published between 2009 and 2020 in PubMed and the Cochrane Library that analyzed adult patients with sepsis, severe sepsis and septic shock in Europe and North America. Studies with less than 20 patients were excluded. The 30-day and 90-day mortality for sepsis and septic shock were pooled separately for studies conducted in Germany, Europe (excluding Germany) and North America in a meta-analysis using a random effects model. Mortality over time was analyzed in a linear regression model. RESULTS: Overall, 134 studies were included. Of these, 15 studies were identified for the estimation of mortality in Germany, covering 10,434 patients, the number of patients per study ranged from 28 to 4183 patients. The 30-day mortality for sepsis was 26.50% (95% confidence interval, CI: 19.86-33.15%) in Germany, 23.85% (95% CI: 20.49-27.21%) in Europe (excluding Germany) and 19.58% (95% CI: 14.03-25.14%) in North America. The 30-day mortality for septic shock was 30.48% (95% CI: 29.30-31.67%) in Germany, 34.57% (95% CI: 33.51-35.64%) in Europe (excluding Germany) and 33.69% (95% CI: 31.51-35.86%) in North America. The 90-day mortality for septic shock was 38.78% (95% CI: 32.70-44.86%) in Germany, 41.90% (95% CI: 38.88-44.91%) in Europe (excluding Germany) and 34.41% (95% CI: 25.66-43.16%) in North America. A comparable decreasing trend in sepsis 30-day mortality was observed in all considered regions since 2009. CONCLUSION: Our analysis does not support the notion that mortality related to sepsis and septic shock in Germany is higher in international comparison. A higher mortality would not be obvious either, since intensive care, for example also during the COVID-19 pandemic, is regarded as exemplary in Germany and the structural quality, such as the number of intensive care beds per 100,000 inhabitants, is high in international comparison. Nevertheless, deficits could also exist outside intensive care medicine. A comparison of international individual studies should take greater account of the structure of healthcare systems, the severity of disease and the limitations resulting from the data sources used.


Subject(s)
Sepsis , Shock, Septic , Adult , Germany/epidemiology , Humans , Observational Studies as Topic , Sepsis/mortality , Shock, Septic/mortality
13.
Int J Mol Sci ; 22(23)2021 Nov 26.
Article in English | MEDLINE | ID: covidwho-1551605

ABSTRACT

The "normal" immune response to an insult triggers a highly regulated response determined by the interaction of various immunocompetent cells with pro- and anti-inflammatory cytokines. Under pathologic conditions, the massive elevation of cytokine levels ("cytokine storm") could not be controlled until the recent development of hemoadsorption devices that are able to extract a variety of different DAMPs, PAMPs, and metabolic products from the blood. CytoSorb® has been approved for adjunctive sepsis therapy since 2011. This review aims to summarize theoretical knowledge, in vitro results, and clinical findings to provide the clinician with pragmatic guidance for daily practice. English-language and peer-reviewed literature identified by a selective literature search in PubMed and published between January 2016 and May 2021 was included. Hemoadsorption can be used successfully as adjunct to a complex therapeutic regimen for various conditions. To the contrary, this nonspecific intervention may potentially worsen patient outcomes in complex immunological processes. CytoSorb® therapy appears to be safe and useful in various diseases (e.g., rhabdomyolysis, liver failure, or intoxications) as well as in septic shock or cytokine release syndrome, although a conclusive assessment of treatment benefit is not possible and no survival benefit has yet been demonstrated in randomized controlled trials.


Subject(s)
Cytokine Release Syndrome/therapy , Cytokines , Shock, Septic/therapy , Animals , Anti-Bacterial Agents , COVID-19 , Cytokine Release Syndrome/immunology , Cytokines/blood , Databases, Factual , Humans , Hyperbilirubinemia , Rhabdomyolysis , Sepsis/blood , Shock, Septic/immunology
14.
JAMA ; 326(18): 1807-1817, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1527380

ABSTRACT

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


Subject(s)
COVID-19/drug therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Life Support Care , Aged , COVID-19/complications , COVID-19/mortality , Dexamethasone/adverse effects , Dose-Response Relationship, Drug , Female , Glucocorticoids/adverse effects , Humans , Hypoxia/etiology , Hypoxia/therapy , Male , Middle Aged , Mycoses/etiology , Respiration, Artificial , Shock, Septic/etiology , Single-Blind Method
15.
CNS Neurol Disord Drug Targets ; 20(5): 473-477, 2021.
Article in English | MEDLINE | ID: covidwho-1526730

ABSTRACT

INTRODUCTION: Catatonia is a psychomotor syndrome that presents with severe symptoms which can lead to dangerous and lethal conditions if not diagnosed and treated properly. SARS-- CoV-2 is a positive-sense single-stranded RNA virus that can occur in severe cases with acute pneumonia, ARDS, sepsis and septic shock. In these cases, ICU admission is necessary. CASE SUMMARY: A 59-year-old Caucasian man with septic shock and bilateral interstitial pneumonia from SARS-CoV-2 and schizotypal personality disorder presented with catatonic behaviour manifested by soporous state, response to intense painful stimuli with the opening of the eyes, execution of simple verbal commands, maintenance of the same position, catalepsy, immobility, rigidity and mutism. At the same time, there were symptoms of septic shock and catatonic symptoms, causing greater difficulty in the correct formulation of the diagnosis. During the course of his hospitalization, he was treated with asenapine 20 mg/day. The catatonia responded rapidly and significantly to the asenapine. DISCUSSION: To date, the pathophysiology of catatonia is unclear, and few guidelines are available for the treatment of catatonia. In the literature, studies have reported the efficacy of benzodiazepines such as lorazepam and diazepam, GABAA agonists such as zolpidem, NMDA receptor antagonists such as memantine, antidepressant SSRIs such as fluoxetine and paroxetine, and antipsychotics such as olanzapine, clozapine and aripiprazole. We demonstrate that the antipsychotic asenapine is also effective in treating catatonic symptoms in psychiatric disorders. CONCLUSION: Asenapine produced a rapid and significant reduction in catatonic symptoms in our patient with schizotypal personality disorder.


Subject(s)
Antipsychotic Agents/therapeutic use , COVID-19/complications , Catatonia/drug therapy , Catatonia/etiology , Depressive Disorder, Major/complications , Dibenzocycloheptenes/therapeutic use , Schizotypal Personality Disorder/complications , Shock, Septic/complications , Shock, Septic/etiology , Catatonia/psychology , Humans , Male , Middle Aged , Pain/etiology , Respiratory Distress Syndrome/complications
16.
Curr Opin Infect Dis ; 34(6): 718-727, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1506882

ABSTRACT

PURPOSE OF REVIEW: The COVID-19 pandemic has caused multiple challenges to ICUs, including an increased rate of secondary infections, mostly caused by Gram-negative micro-organisms. Worrying trends of resistance acquisition complicate this picture. We provide a review of the latest evidence to guide management of patients with septic shock because of Gram-negative bacteria. RECENT FINDINGS: New laboratory techniques to detect pathogens and specific resistance patterns from the initial culture are available. Those may assist decreasing the time to adequate antimicrobial therapy and avoid unnecessary broad-spectrum antibiotic overuse. New antimicrobials, including ß-lactam/ß-lactamase inhibitor combinations, such as ceftolozane-tazobactam, imipenem-relebactam or meropenem-vaborbactam and cephalosporins, such as cefiderocol targeted to specific pathogens and resistance patterns are available for use in the clinical setting. Optimization of antibiotic dosing and delivery should follow pharmacokinetic and pharmacodynamic principles and wherever available therapeutic drug monitoring. Management of sepsis has brought capillary refill time back to the spotlight along with more reasoned fluid resuscitation and a moderate approach to timing of dialysis initiation. SUMMARY: Novel rapid diagnostic tests and antimicrobials specifically targeted to Gram-negative pathogens are available and should be used within the principles of antimicrobial stewardship including de-escalation and short duration of antimicrobial therapy.


Subject(s)
COVID-19 , Gram-Negative Bacterial Infections , Shock, Septic , Anti-Bacterial Agents/therapeutic use , Cephalosporins , Diagnostic Tests, Routine , Gram-Negative Bacteria , Gram-Negative Bacterial Infections/diagnosis , Gram-Negative Bacterial Infections/drug therapy , Humans , Microbial Sensitivity Tests , Pandemics , SARS-CoV-2 , Shock, Septic/drug therapy
17.
Semin Respir Crit Care Med ; 42(5): 672-682, 2021 10.
Article in English | MEDLINE | ID: covidwho-1493295

ABSTRACT

While the use of vitamin C as a therapeutic agent has been investigated since the 1950s, there has been substantial recent interest in the role of vitamin C supplementation in critical illness and particularly, sepsis and septic shock. Humans cannot synthesize vitamin C and rely on exogenous intake to maintain a plasma concentration of approximately 70 to 80 µmol/L. Vitamin C, in healthy humans, is involved with antioxidant function, wound healing, endothelial function, and catecholamine synthesis. Its function in the human body informs the theoretical basis for why vitamin C supplementation may be beneficial in sepsis/septic shock.Critically ill patients can be vitamin C deficient due to low dietary intake, increased metabolic demands, inefficient recycling of vitamin C metabolites, and loss due to renal replacement therapy. Intravenous supplementation is required to achieve supraphysiologic serum levels of vitamin C. While some clinical studies of intravenous vitamin C supplementation in sepsis have shown improvements in secondary outcome measures, none of the randomized clinical trials have shown differences between vitamin C supplementation and standard of care and/or placebo in the primary outcome measures of the trials. There are some ongoing studies of high-dose vitamin C administration in patients with sepsis and coronavirus disease 2019; the majority of evidence so far does not support the routine supplementation of vitamin C in patients with sepsis or septic shock.


Subject(s)
Ascorbic Acid/pharmacology , Ascorbic Acid/therapeutic use , Shock, Septic/drug therapy , Vitamins/pharmacology , Vitamins/therapeutic use , Animals , Antioxidants/pharmacology , Ascorbic Acid/administration & dosage , Ascorbic Acid/adverse effects , Ascorbic Acid Deficiency/physiopathology , Clinical Trials as Topic , Critical Illness , Dose-Response Relationship, Drug , Glucocorticoids/pharmacology , Humans , Inflammation Mediators/metabolism , Vasoconstrictor Agents/pharmacology , Vitamins/administration & dosage , Vitamins/adverse effects
19.
Int Immunopharmacol ; 101(Pt A): 108264, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1487769

ABSTRACT

Topoisomerase (TOP) inhibitors were commonly used as chemotherapeutic agents in the treatment of cancers. In our present study, we found that etoposide (ETO), a topoisomerase 2 (TOP2) inhibitor, upregulated the production of Interleukin 10 (IL-10) in lipopolysaccharide (LPS)-stimulated macrophages. Besides, other TOP2 inhibitors including doxorubicin hydrochloride (DOX) and teniposide (TEN) were also able to augment IL-10 production. Meanwhile, the expression levels of pro-inflammatory factors, for example IL-6 and TNF-α, were also decreased accordingly by the treatment of the TOP2 inhibitors. Of note, ETO facilitated IL-10 secretion, which might be regulated by transcription factor Maf via PI3K/AKT pathway, as pharmaceutic blockage of kinase PI3K or AKT attenuated ETO-induced Maf and IL-10 expression. Further, in LPS-induced mice sepsis model, the enhanced generation of IL-10 was observed in ETO-treated mice, whereas pro-inflammatory cytokines were decreased, which significantly reduced the mortality of mice from LPS-induced lethal cytokine storm. Taken together, these results indicated that ETO may exhibit an anti-inflammatory role by upregulating the alteration of transcription factor Maf and promoting subsequential IL-10 secretion via PI3K/Akt pathway in LPS-induced macrophages. Therefore, ETO may serve as a potential anti-inflammatory agent and employed to severe pro-inflammatory diseases including COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Etoposide/pharmacology , Interleukin-10/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-maf/genetics , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Cell Line , Disease Models, Animal , Down-Regulation/drug effects , Etoposide/therapeutic use , Female , Interleukin-10/genetics , Interleukin-6/genetics , Interleukin-6/metabolism , Lipopolysaccharides/toxicity , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-maf/metabolism , Shock, Septic/chemically induced , Shock, Septic/drug therapy , Topoisomerase II Inhibitors/therapeutic use , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/drug effects
20.
JAMA ; 326(18): 1807-1817, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1482066

ABSTRACT

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


Subject(s)
COVID-19/drug therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Life Support Care , Aged , COVID-19/complications , COVID-19/mortality , Dexamethasone/adverse effects , Dose-Response Relationship, Drug , Female , Glucocorticoids/adverse effects , Humans , Hypoxia/etiology , Hypoxia/therapy , Male , Middle Aged , Mycoses/etiology , Respiration, Artificial , Shock, Septic/etiology , Single-Blind Method
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