Sepsis and septic shock are common in critically ill patients and, as recommended by the Surviving Sepsis Campaign (SSC), early empiric antimicrobial therapy, specifically within the first hour, is ...crucial for the successful management of these conditions. To be effective, the antimicrobial therapy must also be appropriately administered: the drugs should cover the most probable pathogens and achieve effective concentrations at the site of infection. However, pharmacokinetics are frequently altered in critically ill patients and continuously change since the clinical conditions of these patients quickly and markedly change over time, either improving or deteriorating. Accordingly, optimizing antimicrobial drug dosing is fundamental in intensive care units (ICUs). This Special Issue of
examines the epidemiology, diagnostic innovations, and strategies applied in the context of infections in critically ill patients with MDR infections.
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at ...https://www.biomedcentral.com/collections/annualupdate2020. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
Purpose
Limited data exist on the correlation between higher flow rates of high-flow nasal cannula (HFNC) and its physiologic effects in patients with acute hypoxemic respiratory failure (AHRF). We ...assessed the effects of HFNC delivered at increasing flow rate on inspiratory effort, work of breathing, minute ventilation, lung volumes, dynamic compliance and oxygenation in AHRF patients.
Methods
A prospective randomized cross-over study was performed in non-intubated patients with patients AHRF and a PaO
2
/FiO
2
(arterial partial pressure of oxygen/fraction of inspired oxygen) ratio of ≤300 mmHg. A standard non-occlusive facial mask and HFNC at different flow rates (30, 45 and 60 l/min) were randomly applied, while maintaining constant FiO
2
(20 min/step). At the end of each phase, we measured arterial blood gases, inspiratory effort, based on swings in esophageal pressure (ΔPes) and on the esophageal pressure–time product (PTP
Pes
), and lung volume, by electrical impedance tomography.
Results
Seventeen patients with AHRF were enrolled in the study. At increasing flow rate, HFNC reduced ΔPes (
p
< 0.001) and PTP
Pes
(
p
< 0.001), while end-expiratory lung volume (ΔEELV), tidal volume to ΔPes ratio (
V
T
/ΔPes, which corresponds to dynamic lung compliance) and oxygenation improved (
p
< 0.01 for all factors). Higher HFNC flow rate also progressively reduced minute ventilation (
p
< 0.05) without any change in arterial CO
2
tension (
p
= 0.909). The decrease in ΔPes, PTP
Pes
and minute ventilation at increasing flow rates was better described by exponential fitting, while ΔEELV,
V
T
/ΔPes and oxygenation improved linearly.
Conclusions
In this cohort of patients with AHRF, an increasing HFNC flow rate progressively decreased inspiratory effort and improved lung aeration, dynamic compliance and oxygenation. Most of the effect on inspiratory workload and CO
2
clearance was already obtained at the lowest flow rate.
Endometriosis is one of the most common gynaecologic diseases in women of reproductive age. It is characterized by the presence of endometrial tissue outside the uterine cavity. The women affected ...suffer from pelvic pain and infertility. The complex etiology is still unclear and it is based on three main theories: retrograde menstruation, coelomic metaplasia, and induction theory. Genetics and epigenetics also play a role in the development of endometriosis. Recent studies have put the attention on the role of oxidative stress, defined as an imbalance between reactive oxygen species (ROS) and antioxidants, which may be implicated in the pathophysiology of endometriosis causing a general inflammatory response in the peritoneal cavity. Reactive oxygen species are intermediaries produced by normal oxygen metabolism and are inflammatory mediators known to modulate cell proliferation and to have deleterious effects. A systematic review was performed in order to clarify the different roles of oxidative stress and its role in the development of endometriosis. Several issues have been investigated: iron metabolism, oxidative stress markers (in the serum, peritoneal fluid, follicular fluid, peritoneal environment, ovarian cortex, and eutopic and ectopic endometrial tissue), genes involved in oxidative stress, endometriosis-associated infertility, and cancer development.
Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in ...the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611--620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for "lumping and splitting" are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147--155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939). Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-related genes in sepsis-induced and influenza-induced ARDS, but whole blood expression does not give a robust diagnostic test for ARDS. Despite improvements in management of ARDS on the critical care unit, this complex disease continues to be a major life-threatening event. Clinical trials of β
-agonists, statins, surfactants and keratinocyte growth factor (KGF) have been disappointing. In addition, monoclonal antibodies (anti-TNF) and TNFR fusion protein have also been unconvincing. However, there have been major advances in methods of mechanical ventilation, a neuromuscular blocker (cisatracurium besilate) has shown some benefit, and stem cell therapy is being developed. In the future, by understanding the role of biomarkers in the pathophysiology of ARDS and lung injury, it is hoped that this will provide rational therapeutic targets and ultimately improve clinical care (Seymour CW, Gomez H, Chang CH, Clermont G, Kellum JA, Kennedy J, Yende S, Angus DC, Crit Care 2017, 21:257).
Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular ...cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS.
This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS.
In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001).
COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.
BACKGROUND:The amount of extracorporeal carbon dioxide removal may influence respiratory drive in acute respiratory distress syndrome (ARDS) patients undergoing extracorporeal membrane oxygenation ...(ECMO). The authors evaluated the effects of different levels of extracorporeal carbon dioxide removal in patients recovering from severe ARDS undergoing pressure support ventilation (PSV) and neurally adjusted ventilatory assist (NAVA).
METHODS:The authors conducted a prospective, randomized, crossover study on eight spontaneously breathing ARDS patients undergoing venovenous ECMO since 28 ± 20 days. To modulate carbon dioxide extraction, ECMO gas flow (GF) was decreased from baseline resting protective conditions (i.e., GF100%, set to obtain pressure generated in the first 100 ms of inspiration against an occluded airway less than 2 cm H2O, respiratory rate less than or equal to 25 bpm, tidal volume less than 6 ml/kg, and peak airway pressure less than 25 cm H2O) to GF50%-GF25%-GF0% during both PSV and NAVA (random order for ventilation mode). Continuous recordings of airway pressure and flow and esophageal pressure were obtained and analyzed during all study phases.
RESULTS:At higher levels of extracorporeal carbon dioxide extraction, pressure generated in the first 100 ms of inspiration against an occluded airway decreased from 2.8 ± 2.7 cm H2O (PSV, GF0%) and 3.0 ± 2.1 cm H2O (NAVA, GF0%) to 0.9 ± 0.5 cm H2O (PSV, GF100%) and 1.0 ± 0.8 cm H2O (NAVA, GF100%; P < 0.001) and patients’ inspiratory muscle pressure passed from 8.5 ± 6.3 and 6.5 ± 5.5 cm H2O to 4.5 ± 3.1 and 4.2 ± 3.7 cm H2O (P < 0.001). In time, decreased inspiratory drive and effort determined by higher carbon dioxide extraction led to reduction of tidal volume from 6.6 ± 0.9 and 7.5 ± 1.2 ml/kg to 4.9 ± 0.8 and 5.3 ± 1.3 ml/kg (P < 0.001) and of peak airway pressure from 21 ± 3 and 25 ± 4 cm H2O to 21 ± 3 and 21 ± 5 cm H2O (P < 0.001). Finally, transpulmonary pressure linearly decreased when the amount of carbon dioxide extracted by ECMO increased (R = 0.823, P < 0.001).
CONCLUSIONS:In patients recovering from ARDS undergoing ECMO, the amount of carbon dioxide removed by the artificial lung may influence spontaneous breathing. The effects of carbon dioxide removal on spontaneous breathing during the earlier acute phases of ARDS remain to be elucidated.
Monitoring with electrical impedance tomography (EIT) during a decremental PEEP trial has been used to identify the PEEP that yields the optimal balance of pulmonary overdistension and collapse. This ...method is based on pixel-level changes in respiratory system compliance and depends on fixed or measured airway driving pressure. We developed a novel approach to quantify overdistension and collapse during pressure support ventilation (PSV) by integrating transpulmonary pressure and EIT monitoring and performed pilot tests in three hypoxemic patients. We report that our experimental approach is feasible and capable of identifying a PEEP that balances overdistension and collapse in intubated hypoxemic patients undergoing PSV.
The physiological effects of high-flow nasal cannula O
therapy (HFNC) have been evaluated mainly in patients with hypoxemic respiratory failure. In this study, we compared the effects of HFNC and ...conventional low-flow O
therapy on the neuroventilatory drive and work of breathing postextubation in patients with a background of chronic obstructive pulmonary disease (COPD) who had received mechanical ventilation for hypercapnic respiratory failure.
This was a single center, unblinded, cross-over study on 14 postextubation COPD patients who were recovering from an episode of acute hypercapnic respiratory failure of various etiologies. After extubation, each patient received two 1-h periods of HFNC (HFNC1 and HFNC2) alternated with 1 h of conventional low-flow O
therapy via a face mask. The inspiratory fraction of oxygen was titrated to achieve an arterial O
saturation target of 88-92%. Gas exchange, breathing pattern, neuroventilatory drive (electrical diaphragmatic activity (EAdi)) and work of breathing (inspiratory trans-diaphragmatic pressure-time product per minute (PTP
)) were recorded.
EAdi peak increased from a mean (±SD) of 15.4 ± 6.4 to 23.6 ± 10.5 μV switching from HFNC1 to conventional O
, and then returned to 15.2 ± 6.4 μV during HFNC2 (conventional O
: p < 0.05 versus HFNC1 and HFNC2). Similarly, the PTP
increased from 135 ± 60 to 211 ± 70 cmH
O/s/min, and then decreased again during HFNC2 to 132 ± 56 (conventional O
: p < 0.05 versus HFNC1 and HFNC2).
In patients with COPD, the application of HFNC postextubation significantly decreased the neuroventilatory drive and work of breathing compared with conventional O
therapy.
Assessing alveolar recruitment at different positive end-expiratory pressure (PEEP) levels is a major clinical and research interest because protective ventilation implies opening the lung without ...inducing overdistention. The pressure-volume (P-V) curve is a validated method of assessing recruitment but reflects global characteristics, and changes at the regional level may remain undetected. The aim of the present study was to compare, in intubated patients with acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS), lung recruitment measured by P-V curve analysis, with dynamic changes in poorly ventilated units of the dorsal lung (dependent silent spaces DSSs) assessed by electrical impedance tomography (EIT). We hypothesized that DSSs might represent a dynamic bedside measure of recruitment.
We carried out a prospective interventional study of 14 patients with AHRF and ARDS admitted to the intensive care unit undergoing mechanical ventilation. Each patient underwent an incremental/decremental PEEP trial that included five consecutive phases: PEEP 5 and 10 cmH
O, recruitment maneuver + PEEP 15 cmH
O, then PEEP 10 and 5 cmH
O again. We measured, at the end of each phase, recruitment from previous PEEP using the P-V curve method, and changes in DSS were continuously monitored by EIT.
PEEP changes induced alveolar recruitment as assessed by the P-V curve method and changes in the amount of DSS (p < 0.001). Recruited volume measured by the P-V curves significantly correlated with the change in DSS (r
= 0.734, p < 0.001). Regional compliance of the dependent lung increased significantly with rising PEEP (median PEEP 5 cmH
O = 11.9 IQR 10.4-16.7 ml/cmH
O, PEEP 15 cmH
O = 19.1 14.2-21.3 ml/cmH
O; p < 0.001), whereas regional compliance of the nondependent lung decreased from PEEP 5 cmH
O to PEEP 15 cmH
O (PEEP 5 cmH
O = 25.3 21.3-30.4 ml/cmH
O, PEEP 15 cmH
O = 20.0 16.6-22.8 ml/cmH
O; p <0.001). By increasing the PEEP level, the center of ventilation moved toward the dependent lung, returning to the nondependent lung during the decremental PEEP steps.
The variation of DSSs dynamically measured by EIT correlates well with lung recruitment measured using the P-V curve technique. EIT might provide useful information to titrate personalized PEEP.
ClinicalTrials.gov, NCT02907840 . Registered on 20 September 2016.
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