Acute respiratory distress syndrome (ARDS) is defined as a syndrome of acute onset, with bilateral opacities on chest imaging and respiratory failure not caused by cardiac failure, leading to mild, ...moderate, or severe oxygenation impairment. The syndrome is most commonly a manifestation of sepsis-induced organ dysfunction, characterized by disruption of endothelial barrier integrity and diffuse lung damage. Imbalance between coagulation and inflammation is a predominant characteristic of ARDS, leading to extreme inflammatory response and diffuse fibrin deposition in vascular capillary bed and alveoli. Activated platelets, neutrophils, endothelial cells, neutrophil extracellular traps, microparticles, and coagulation proteases, participate in the complex process of immunothrombosis, which is a key event in ARDS pathophysiology. The present review is focused on the elucidation of immunothrombosis in ARDS and the potential therapeutic implications.
Invasive fungal infections are a growing problem in critically ill patients and are associated with increased morbidity and mortality. Most of them are due to Candida species, especially Candida ...albicans. Invasive candidiasis includes candidaemia, disseminated candidiasis with deep organ involvement and chronic disseminated candidiasis. During the last decades rare pathogenic fungi, such as Aspergillus species, Zygomycetes, Fusarium species and Scedosporium have also emerged. Timely diagnosis and proper treatment are of paramount importance for a favorable outcome. Besides blood cultures, several laboratory tests have been developed in the hope of facilitating an earlier detection of infection. The antifungal armamentarium has also been expanded allowing a treatment choice tailored to individual patients' needs. The physician can choose among the old class of polyenes, the older and newer azoles and the echinocandins. Factors related to patient's clinical situation and present co-morbidities, local epidemiology data and purpose of treatment (prophylactic, pre-emptive, empiric or definitive) should be taken into account for the appropriate choice of antifungal agent.
There is increasing interest for strategies that could curtail antibiotic resistance in the critical care setting. We sought to determine the effectiveness and safety of procalcitonin-guided ...algorithms in the management of septic patients in the intensive care unit.
MEDLINE, Scopus, Cochrane Central Register of Controlled Trials (through April 2010), reference lists of retrieved publications, and queries of corresponding authors. No language restrictions were applied.
We included only randomized controlled studies reporting on antibiotic use and clinical outcomes of intensive care unit patients managed with a procalcitonin-guided algorithm or according to routine practice.
Data on study characteristics, interventions, and outcomes were retrieved by two independent reviewers. Pooled odds ratios, weighted mean differences, and 95% confidence intervals were calculated by implementing both the Mantel-Haenszel fixed effect model and the DerSimonian-Laird random effects model.
Seven randomized controlled studies involving 1131 intensive care unit patients (adults = 1010; neonates = 121) were included. In comparison with routine practice, the implementation of procalcitonin-guided algorithms decreased the duration of antibiotic therapy for the first episode of infection by approximately 2 days (weighted mean difference = -2.36 days; 95% confidence interval, -3.11 to -1.61) and the total duration of antibiotic treatment by 4 days (fixed effect model: weighted mean difference: -4.19 days; 95% confidence interval, -4.98 to -3.39). The comparison between the procalcitonin and the routine practice group was not associated with any apparent adverse clinical outcome: 28-day mortality (fixed effect model: odds ratio = 0.93; 95% confidence interval, 0.69 to 1.26), intensive care unit length of stay (fixed effect model: pooled weighted mean difference = -0.49 days, 95% confidence interval, -1.55 to 0.57), and relapsed/persistent infection rate (fixed effect model: odds ratio = 0.97; 95% confidence interval, 0.56 to 1.69).
The implementation of a procalcitonin-based algorithm may reduce antibiotic exposure in critically ill, septic patients without compromising clinical outcomes, but further research is necessary before the wide adoption of this strategy.
A subanalysis of a randomized clinical trial indicated sepsis survival benefit from interleukin (IL)-1 blockade in patients with features of the macrophage activation-like syndrome (MALS). This study ...aimed to investigate the frequency of MALS and to develop a biomarker of diagnosis and prognosis.
Patients with infections and systemic inflammatory response syndrome were assigned to one test cohort (n = 3417) and a validation cohort (n = 1704). MALS was diagnosed for patients scoring positive either for the hemophagocytic syndrome score and/or having both hepatobiliary dysfunction and disseminated intravascular coagulation. Logistic regression analysis was used to estimate the predictive value of MALS for 10-day mortality in both cohorts. Ferritin, sCD163, IL-6, IL-10, IL-18, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were measured in the blood the first 24 h; ferritin measurements were repeated in 747 patients on day 3.
The frequency of MALS was 3.7% and 4.3% in the test and the validation cohort, respectively. In both cohorts, MALS was an independent risk factor for 10-day mortality. A ferritin level above 4420 ng/ml was accompanied by 66.7% and 66% mortality after 28 days, respectively. Ferritin levels above 4420 ng/ml were associated with an increase of IL-6, IL-18, INF-γ, and sCD163 and a decreased IL-10/TNF-α ratio, indicating predominance of pro-inflammatory phenomena. Any less than 15% decrease of ferritin on day 3 was associated with more than 90% sensitivity for unfavorable outcome after 10 days. This high mortality risk was also validated in an independent Swedish cohort (n = 109).
MALS is an independent life-threatening entity in sepsis. Ferritin measurements can provide early diagnosis of MALS and may allow for specific treatment.
Sepsis is a dysregulated host response to infection related to devastating outcomes. Recently, interest has been shifted towards apoptotic and antiapoptotic pathobiology. Apoptosis is executed ...through the activation of caspases regulated by a number of antiapoptotic proteins, such as survivin. The survivin and caspases' responses to sepsis have not yet been elucidated. This is a multicenter prospective observational study concerning patients with sepsis (n = 107) compared to patients with traumatic systemic inflammatory response syndrome (SIRS) (n = 75) and to healthy controls (n = 89). The expression of survivin was quantified through real-time quantitative polymerase chain reaction for the different survivin splice variants (wild type-WT, ΔEx3, 2B, 3B) in peripheral blood leukocytes. The apoptotic or antiapoptotic tendency was specified by measuring survivin-WT, caspase-3, and -9 serum protein concentrations through enzyme-linked immunosorbent assay. The survivin-WT, -2B, -ΔΕx3 mRNA, survivin protein, and caspases showed an escalated increase in SIRS and sepsis, whereas survivin-3B was repressed in sepsis (p < 0.05). Survivin correlated with IL-8 and caspase-9 (p < 0.01). For discriminating sepsis, caspase-9 achieved the best receiver operating characteristic curve (AUROC) of 0.95. In predicting mortality, caspase-9 and survivin protein achieved an AUROC of 0.70. In conclusion, specific apoptotic and antiapoptotic pathways might represent attractive targets for future research in sepsis.
Tissue hypoxia is the main cause of multi-organ dysfunction in sepsis. However, effective pharmacological treatments to combat sepsis-induced tissue hypoxia are not available. Emerging experimental ...and clinical evidence reveals an evolutionary conserved action of thyroid hormone (TH) to adapt injured tissue to hypoxic conditions via its action on p38 MAPK, Akt signaling pathways. In addition, TH has favorable effects on the immune system and viral load in infected tissue. Non-Thyroid Illness Syndrome is common in sepsis, acute myocardial infarction and trauma and is associated with increased mortality. Thus, TH may be a novel treatment in the setting of critical illness due to viral infection in which hypoxia prevails. The present study aims to address the efficacy and safety of acute administration of triiodothyronine (T3) in critically ill COVID-19 infected patients requiring mechanical respiratory support or Extra Corporeal Membrane Oxygenation (ECMO).
This study is a phase II, parallel, 2-arm (1:1 ratio), multi-centre, prospective, randomized, double-blind, placebo controlled trial.
Male and female patients aged over 18 years old who are diagnosed with pulmonary infection due to COVID-19, admitted to Intensive Care Unit and requiring mechanical ventilation or ECMO will be enrolled in this trial. Patients will be excluded in cases of pregnancy, severe systemic disease with life expectancy less than 6 months, participation in another trial of an investigational drug or device, corticosteroid and/or sympathomimetic use before initiation of treatment. All data will be collected in electronic CRF files. Participants will start to be recruited from the ICU center of "ATTIKO" University Hospital in Greece. We aim to include two more clinical sites in the trial one from Greece and one from Germany INTERVENTION AND COMPARATOR: Intervention: T3 Solution for injection 10 μg/ml. The dose administered will be 0.8g/kg i.v. bolus and will be followed by an infusion of 0.113g. kg-1.h-1 i.v. for 48 hours (therapeutic dose). After the first 48h, a maintenance dose will be administered corresponding to 50% of the therapeutic dose (0.057g. kg-1.h-1 i.v.). Drug administration will stop after successful weaning or end of follow up (maximum 30 days). Comparator: Placebo with composition and dosage identical apart from the active substance.
The primary outcome assessed in the present study will be the percentage of patients successfully weaned after 30 days of follow-up. Successful weaning is defined as no requirement for ventilatory support after extubation (mechanical support) or support from ECMO for 48 hours.
An allocation sequence to one of the groups will be prepared by the Sponsor of the study. A 1:1 treatment allocation will be adopted. An electronic CRF will be used incorporating IWRS in order to assure proper randomization and unblinding in emergency cases. The representative of the sponsor will get a copy of randomization codes. The information of the randomization codes will then be locked in the database until the time at which an interim analysis or final analysis is performed.
Participants, caregivers, and all investigators assessing the outcomes will be blinded to group assignment.
The sample size of 60 patients (that indicates 30 subjects for each group) will have 84% power to detect the estimated difference between the two study groups. The criterion for significance (alpha) has been set at 0.05 and the test is 2-tailed.
Protocol number T3inj-02/ThySupport, version 03, May 11, 2020. The trial is not recruiting yet. The trial will start recruitment June 18
2020. Estimated recruitment will finish June 18
, 2021.
Triiodothyronine for the Treatment of Critically Ill Patients With COVID-19 Infection (Thy-Support), ClinicalTrials.gov Identifier: NCT04348513, date of trial registration: April 16, 2020, EudraCT Identifier: 2020-001623-13, date of trial registration: April 22, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
There is controversy on whether catheter-related bloodstream infections (CR-BSI) affect the mortality of critically ill patients.
Meta-analysis of comparative studies that reported on mortality of ...intensive care unit (ICU) adult patients with and without CR-BSI.
PubMed, Current Contents, and reference lists of retrieved publications were searched with no language or time restrictions. Heterogeneity was assessed by means of I-statistic and chi-square test. Publication bias was detected by the funnel plot method using Egger's test. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated by implementing both the Mantel-Haenszel fixed effect and the DerSimonian-Laird random effects model.
Eight studies, involving 2,540 ICU patients, were included. Heterogeneity was detected (I = 0.67, 95% CI 0.32-0.85, p = 0.003). Publication bias was not found (Egger's test, p = 0.28). All-cause in-hospital mortality was higher in ICU patients with CR-BSI than in those without CR-BSI (fixed effect model: OR = 1.81, 95% CI 1.44-2.28; random effects model: OR = 1.96, 95% CI 1.25-3.09). This was also the case for the subgroup analysis of the studies that were matched for severity of illness (fixed effect model: OR = 1.65, 95% CI 1.28-2.13; random effects model: OR = 1.70, 95% CI 1.00-2.90).
Presence, as opposed to absence, of CR-BSI is associated with higher mortality in critically ill adult patients. This finding seems to justify and may enhance efforts to prevent CR-BSI in such patients.
Purpose
We sought to perform a systematic review and meta-analysis of procalcitonin(PCT)-guided antibiotic therapy algorithms for critically ill adult patients.
Methods
We performed a search in ...PubMed and in the Cochrane Central Register of Controlled Trials. Seven evaluable randomised clinical trials (RCTs) were identified and analysed. Primary outcomes included the duration of antibiotic therapy for the first episode of infection and 28-day mortality. Secondary outcomes included length of ICU stay, length of hospitalisation, antibiotic-free days within the first 28 days of hospitalisation, recurrences, and superinfections.
Results
Data on the duration of antibiotic therapy for the first episode of infection were provided in five out of seven included RCTs, while data on 28-day mortality were provided in all of the included RCTs. Duration of antibiotic therapy for the first episode of infection was reduced in favour of PCT-guided treatment pooled weighted mean difference (WMD) = −3.15 days, random effects model, 95 % confidence interval (CI) −4.36 to −1.95,
P
< 0.001. There was no difference in 28-day mortality between the compared arms fixed effect model (FEM), odds ratio = 0.96, 95 % CI 0.79–1.15,
P
= 0.63). Antibiotic-free days were increased within the first 28 days of hospitalisation in favour of the PCT-guided treatment arm (pooled WMD = 3.08 days, FEM, 95 % CI 2.06–4.10,
P
< 0.001). No difference was found regarding the remaining outcomes. Sensitivity analyses including studies of higher quality and studies using the TRACE method to measure PCT yielded similar results.
Conclusions
Procalcitonin-guided antibiotic therapy algorithms could help in reducing the duration of antimicrobial administration without having a negative impact on survival.
Increasing multidrug-resistance to Gram-positive pathogens, particularly to staphylococci, enterococci and streptococci, is a major problem, resulting in significant morbidity, mortality and ...healthcare costs. In recent years, only a small number of novel antibiotics effective against Gram-positive bacteria has been approved. This review will discuss the current evidence for novel branded antibiotics that are highly effective in the treatment of multidrug-resistant infections by Gram-positive pathogens, namely ceftobiprole, ceftaroline, telavancin, oritavancin, dalbavancin, tedizolid, besifloxacin, delafloxacin, ozenoxacin, and omadacycline. The mechanism of action, pharmacokinetics, microbiological spectrum, efficacy and safety profile will be concisely presented. As for any emerging antibiotic agent, resistance is likely to develop against these highly effective antibiotics. Only through appropriate dosing, utilization and careful resistance development monitoring will these novel antibiotics continue to treat Gram-positive pathogens in the future.