Preserving spontaneous breathing during mechanical ventilatory support: an old yet fascinating story

Facilitation of early spontaneous breathing activity is the most important measure to shorten weaning and avoid ventilator-induced lung injury and diaphragmatic injury in mechanically ventilated patients. However, the optimal degree of spontaneous muscle activity and ventilator support remains to be determined. Furthermore, effectiveness in relation to the pathophysiology of respiratory failure is unclear. In this regard the experimental study by Saddy and colleagues reveals interesting insights into the pathophysiology of ventilator-induced injury. More important, their results raise important questions that should be evaluated in further studies.In a recent issue of Critical Care, Saddy and colleagues [1] present an important article on the impact of partial ventilatory support on lung tissue inflammation and diaphragm dysfunction in mechanically ventilated rats. Their data reveal surprising results, in particular showing that the degree of diaphragmatic injury may depend not only on the amount of spontaneous respiratory activity preserved by applying specific settings of mechanical support, but also on the etiology of acute lung injury; that is, pulmonary versus extrapulmonary acute respiratory distress syndrome (ARDS). The present article reminds us that the question posed by Milic-Emili in a commentary published nearly 30 years ago as to whether weaning is an art or a science [2] is still valid, albeit a substantial body of available evidence now clearly explains several pathophysiological details of respiratory muscle failure in ICU patients [3,4].Of course, the relevance of animal models in translational research may always be questioned. This is particularly the case for rodent models, as the validity of the inflammatory response in these species as a model for human diseases has been challenged very recently [5]. Furthermore, respiratory mechanics widely differs between humans and rodents, as suggested, for example, by the different physiological respiratory rates that are relatively higher in the latter species and may, therefore, influence gas transport and exchange [6]. Nevertheless, the present study has the major merits of, firstly, having included diaphragm function and morphology (a relevant topic that still deserves fundamental research), and, secondly, having quantified diaphragmatic activity under different experimental conditions by means of the pressure–time product. This variable is calculated by tracing the esophageal pressure and is therefore particularly challenging to measure in small animals, but it is close to clinical reality as it is fairly well accessible in humans and may therefore support translating experimental results into clinical conditions [7].Taken together, the present data confirm, in principle, the well accepted notions that passive mechanical ventilation quickly damages the diaphragm [8] and promotes lung injury by atelectasis formation [9]. However, they also reveal that the impact of mechanical ventilation may be more difficult to explain, especially in extrapulmonary ARDS. In fact, under partial spontaneous breathing combined with low degree of ventilator support the authors observed an unexpected increase in diaphragmatic injury whereas atelectasis formation decreased comparable to pulmonary ARDS.These fairly surprising results may remind us that the impact of mechanical ventilation on lung tissue and the diaphragm is still far from being completely understood and merit intensive study in the future. In particular, some effort should be spent reproducing in the experimental conditions factors that potentially influence the response to mechanical ventilation in clinical settings. For example, most ICU patients are affected by co-existing diseases, especially cardiovascular diseases, diabetes, and chronic obstructive pulmonary disease, which, independent of the acute condition, also influence the muscular and diaphragmatic function and may even accentuate the impact of mechanical ventilation.Animal models mimicking conditions of co-existing chronic diseases should therefore be recommended to improve translation of experimental data into clinical situations and may be considered as the next step in studying the impact of mechanical ventilation and partial spontaneous breathing on diaphragm and lung tissue. Furthermore, most patients requiring mechanical ventilator support are affected by septic conditions leading to organ dysfunction and metabolic disorders. The utility of partial spontaneous breathing for maintaining diaphragmatic function has been well demonstrated in several experiments and nicely confirmed in the present study, but the effects of spontaneous breathing under septic conditions still need to be investigated. Finally, it is well known that not only restriction of passive movement but also muscular overload due to increased work of breathing may cause structural diaphragmatic damage that is characteristic for weaning failure. Thus, another important task of further studies is to find the perfect balance between diaphragmatic loading and unloading with regard to diaphragmatic and pulmonary function. In this context it will be interesting to see if modern spontaneous breathing modes may find their role in future concepts of lung and diaphragmatic protective ventilation strategies.In summary, the present article improves our knowledge in a fundamental topic of critical care and should encourage us to further study the influence of mechanical ventilatory support on lung tissue and diaphragm function, which is likely to be an important key to improving patient outcome in the ICU.     

Rule out of acute aortic dissection with plasma matrix metalloproteinase 8 in the emergency department

Introduction

Matrix metalloproteinases (MMPs) are involved in aortic pathophysiology. Preliminary studies have detected increased plasma levels of MMP8 and MMP9 in patients with acute aortic dissection (AAD). However, the performance of plasma MMP8 and MMP9 for the diagnosis of AAD in the emergency department is at present unknown.

Methods

The levels of MMP8 and MMP9 were measured by ELISA on plasma samples obtained from 126 consecutive patients evaluated in the emergency department for suspected AAD. All patients were subjected to urgent computed tomography (CT) scan for final diagnosis.

Results

In the study cohort (N = 126), AAD was diagnosed in 52 patients and ruled out in 74 patients. Median plasma MMP8 levels were 36.4 (interquartile range 24.8 to 69.3) ng/ml in patients with AAD and 13.2 (8.1 to 31.8) ng/ml in patients receiving an alternative final diagnosis (P <0.0001). Median plasma MMP9 levels were 169.2 (93.0 to 261.8) ng/ml in patients with AAD and 80.5 (41.8 to 140.6) ng/ml in patients receiving an alternative final diagnosis (P = 0.001). The area under the curve (AUC) on receiver-operating characteristic (ROC) analysis of MMP8 and MMP9 for the diagnosis of AAD was respectively 0.75 and 0.70, as compared to 0.87 of D-dimer. At the cutoff of 3.6 ng/ml, plasma MMP8 had a sensitivity of 100.0% (95% CI, 93.2% to 100.0%) and a specificity of 9.5% (95% CI, 3.9% to 18.5%) and ruled out AAD in 5.6% of patients. Combination of plasma MMP8 with D-dimer increased the AUC on ROC analysis to 0.89. Presence of MMP8 <11.0 ng/ml and D-dimer <1.0 or <2.0 µg/ml provided a negative predictive value of 100% and ruled out AAD in 13.6% and 21.4% of patients respectively.

Conclusions

Low levels of plasma MMP8 can rule out AAD in a minority of patients. Combination of plasma MMP8 and D-dimer at individually suboptimal cutoffs could safely rule out AAD in a substantial proportion of patients evaluated in the emergency department.     

Millisecond spatiotemporal dynamics of FRET biosensors by the pair correlation function and the phasor approach to FLIM

Here we present a fluctuation-based approach to biosensor Förster resonance energy transfer (FRET) detection that can measure the molecular flow and signaling activity of proteins in live cells. By simultaneous use of the phasor approach to fluorescence lifetime imaging microscopy (FLIM) and cross–pair correlation function (pCF) analysis along a line scanned in milliseconds, we detect the spatial localization of Rho GTPase activity (biosensor FRET signal) as well as the diffusive route adopted by this active population. In particular we find, for Rac1 and RhoA, distinct gradients of activation (FLIM-FRET) and a molecular flow pattern (pCF analysis) that explains the observed polarized GTPase activity. This multiplexed approach to biosensor FRET detection serves as a unique tool for dissection of the mechanism(s) by which key signaling proteins are spatially and temporally coordinated.     

From the Cover: Feature Article: Identification of an essential endogenous regulator of blood–brain barrier integrity,and its pathological and therapeutic implications

The blood–brain barrier (BBB), a critical guardian of communication between the periphery and the brain, is frequently compromised in neurological diseases such as multiple sclerosis (MS), resulting in the inappropriate passage of molecules and leukocytes into the brain. Here we show that the glucocorticoid anti-inflammatory messenger annexin A1 (ANXA1) is expressed in brain microvascular endothelial cells, where it regulates BBB integrity. In particular, ANXA1^−/− mice exhibit significantly increased BBB permeability as a result of disrupted interendothelial cell tight junctions, essentially related to changes in the actin cytoskeleton, which stabilizes tight and adherens junctions. This situation is reminiscent of early MS pathology, a relationship confirmed by our detection of a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of patients with MS. Importantly, this loss is swiftly restored by i.v. administration of human recombinant ANXA1. Analysis in vitro confirms that treatment of cerebrovascular endothelial cells with recombinant ANXA1 restores cell polarity, cytoskeleton integrity, and paracellular permeability through inhibition of the small G protein RhoA. We thus propose ANXA1 as a critical physiological regulator of BBB integrity and suggest it may have utility in the treatment of MS, correcting BBB function and hence ameliorating disease.The presence of narrow and dense tight junctions between adjacent endothelial cells is peculiar to the cerebral vasculature, and their integrity is essential for the maintenance of correct blood–brain barrier (BBB) function as the primary regulator of cross-talk between the brain and the rest of the body (1). Increasing evidence indicates that the integrity of this structural and functional barrier is compromised in neurological conditions such as multiple sclerosis (MS), Alzheimer’s, and Parkinson diseases, leading to the failure of the normal mechanisms controlling passage of substances into the brain (2) and to the sensitization and/or worsening of pathologic conditions. Pharmacological intervention to prevent or correct BBB alteration in such diseases is a difficult task, but potential therapeutic leads can be gained from the study of endogenous mediators regulating barrier integrity.Annexin A1 (ANXA1) is an important anti-inflammatory protein, principally known as a regulator of peripheral leukocyte migration and a promoter of macrophage phagocytosis (3). ANXA1 is expressed in several cell types within the brain, including ependyma and microglia, but in particular in the endothelium of the brain microvasculature (4), although its role in these cells remains obscure. We have previously shown glucocorticoids to up-regulate expression of ANXA1 in the cerebral endothelium (5), and, given that glucocorticoids enhance BBB tightness (6), we hypothesized that ANXA1 may play a role in the regulation of BBB permeability. Through combined in vitro and in vivo approaches, we have identified a dual role for ANXA1 in organizing the interendothelial cell tight and adherens junctions: (i) endogenously through its interactions with the actin cytoskeleton, and (ii) exogenously in an autocrine/paracrine via formyl peptide receptor 2 (FPR2), leading to the down-regulation of RhoA GTPase activity. Together, these two actions of ANXA1 regulate paracellular permeability in the BBB, and provide a major contribution to BBB integrity and function. Moreover, we describe a selective down-regulation of ANXA1 expression in the plasma and cerebral microvascular endothelia of patients with MS, strongly suggesting an explanation for the BBB dysfunction that is a typical early sign of this disease. All these findings pinpoint ANXA1 as a critical component of the BBB endothelium contributing to barrier integrity. Its autoparacrine role and the loss in patients with MS highlight the potential utility of the protein or its peptidomimetics as a therapeutic target for pathologic processes characterized by compromised BBB function, such as MS.     

Idiopathic Thrombocytopenic purpura and Helicobacter pylori Infection

Abstract

Objective. As a minimally invasive modality, radiofrequency ablation (RFA) has been increasingly applied not only for the treatment of hepatocellular carcinoma, but also for that of colorectal liver metastasis (CLM). However, RFA for CLM has been shown to be associated with a high local recurrence rate, and no optimal treatment for RFA failure has been established yet. The aim of this study was to evaluate the feasibility and outcome of surgical resection for local recurrence after RFA. Material and methods. A retrospective study of 17 patients, who underwent surgery for local recurrence after RFA for resectable CLM, was carried out. The surgical procedures involved in the actual surgery were compared with those envisioned for the primary resection if RFA had not been selected. Results. Surgical resection for RFA recurrence was more invasive than the envisioned surgical procedure in 10 cases (58%). In addition, the proportions of cases that required technically demanding procedures among the patients receiving surgery for RFA recurrence were higher than those in envisioned operations; major hepatectomy, eight cases [47%] versus two cases [12%] (p < 0.0205); excision and/or reconstruction of the major hepatic veins, three cases [18%] versus zero case [0%] (p = 0.035); excision of diaphragm: three cases [18%] versus zero case [0%] (p = 0.035). The 1-, 3- and 5-year overall survival rates were 92%, 45% and 45%, respectively. Conclusions. Surgical resection for RFA recurrence for CLM required more invasive and technically demanding procedures. Thus, RFA for CLM should be limited to unresectable cases, and patients with resectable CLM should be thoroughly advised not to undergo RFA, but rather surgical resection.     

The relationship between the severity of hemolysis,clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe

The intensity of hemolytic anemia has been proposed as an independent risk factor for the development of certain clinical complications of sickle cell disease, such as pulmonary hypertension, hypoxemia and cutaneous leg ulceration. A composite variable derived from several individual markers of hemolysis could facilitate studies of the underlying mechanisms of hemolysis. In this study, we assessed the association of hemolysis with outcomes in sickle cell anemia. A hemolytic component was calculated by principal component analysis from reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and total bilirubin concentrations in 415 hemoglobin SS patients. Association of this component with direct markers of hemolysis and clinical outcomes was assessed. As primary validation, both plasma red blood cell microparticles and cell-free hemoglobin concentration were higher in the highest hemolytic component quartile compared to the lowest quartile (P≤0.0001 for both analyses). The hemolytic component was lower with hydroxyurea therapy, higher hemoglobin F, and alpha-thalassemia (P≤0.0005); it was higher with higher systemic pulse pressure, lower oxygen saturation, and greater values for tricuspid regurgitation velocity, left ventricular diastolic dimension and left ventricular mass (all P<0.0001). Two-year follow-up analysis showed that a high hemolytic component was associated with an increased risk of death (hazard ratio, HR 3.44; 95% confidence interval, CI: 1.2–9.5; P=0.02). The hemolytic component reflects direct markers of intravascular hemolysis in patients with sickle cell disease and allows for adjusted analysis of associations between hemolytic severity and clinical outcomes. These results confirm associations between hemolytic rate and pulse pressure, oxygen saturation, increases in Doppler-estimated pulmonary systolic pressures and mortality (Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00492531","term_id":"NCT00492531"}}NCT00492531).     

Effectiveness of prevention of SARS-CoV-2 transmission among unvaccinated Italian healthcare workers

Background:We aimed to investigate the association between personal protective equipment (PPE) use and SARS-CoV-2 infection among healthcare workers (HCWs).Methods:We analyzed occupational surveillance contact forms followed by a PCR test notified between March and September 2020 by Italian HCWs. The odds ratios (ORs) and 95% Confidence Intervals (CIs) for positive PCR based on HCWs and contacts characteristics were calculated through multivariable logistic regression models. When multiple contacts were potentially effective for a PCR test, they were weighted by the inverse of their number.Results:Overall, 4,883 contacts reported by 2,952 HCWs were analyzed, and 224 contacts among 144 HCWs had positive PCR. No difference was found according to sex, age, employment, or job title, except for an OR of 0.30 (95%CI 0.11-0.78) for resident physicians, compared to administrative staff. The ORs for use of surgical mask were 0.59 (95%CI=0.40-0.86) for use only by HCW, 0.49 (95%CI=0.22-1.07) only by the infected person, and 0.40 (95%CI=0.27-0.60) by both, compared to use by neither. Use of other PPEs was not associated with infection, while the OR for hand sanitation was 0.61 (95%CI=0.40-0.93). HCWs reporting fever, cough, and asthenia had a higher risk of infection.Conclusions:Use of surgical masks was associated with a 40-60% lower risk of infection, especially when both HCWs and infected individuals used them. Our results quantify the role played by mask use and hand sanitation in preventing SARS-CoV-2 transmission in high-risk circumstances.