An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome

BACKGROUND: This document provides evidence-based clinical practice guidelines on the use of mechanical ventilation in adult patients with acute respiratory distress syndrome (ARDS). METHODS: A multidisciplinary panel conducted systematic reviews and metaanalyses of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations. RESULTS: For all patients with ARDS, the recommendation is strong for mechanical ventilation using lower tidal volumes (4-8 ml/kg predicted body weight) and lower inspiratory pressures (plateau pressure < 30 cm H2O) (moderate confidence in effect estimates). For patients with severe ARDS, the recommendation is strong for prone positioning for more than 12 h/d (moderate confidence in effect estimates). For patients with moderate or severe ARDS, the recommendation is strong against routine use of high-frequency oscillatory ventilation (high confidence in effect estimates) and conditional for higher positive end-expiratory pressure (moderate confidence in effect estimates) and recruitment maneuvers (low confidence in effect estimates). Additional evidence is necessary to make a definitive recommendation for or against the use of extracorporeal membrane oxygenation in patients with severe ARDS. CONCLUSIONS: The panel formulated and provided the rationale for recommendations on selected ventilatory interventions for adult patients with ARDS. Clinicians managing patients with ARDS should personalize decisions for their patients, particularly regarding the conditional recommendations in this guideline.

Setting mechanical ventilation in ARDS patients during VV-ECMO: where are we?

Currently, many centers use venovenous extracorporeal membrane oxygenation (VV-ECMO) as an adjunctive means of gas exchange to mechanical ventilation (MV) in patients with severe ARDS and refractory hypoxemia. One of the most interesting and controversial issues in the management of these patients is how to set the ventilatory strategy. The support provided by VV-ECMO makes the balance between risks and benefits of MV remarkably different from the conventional setting, since the need for MV to facilitate oxygenation and carbon dioxide clearance is greatly reduced or abolished during VV-ECMO. Therefore, the risks of causing ventilator-induced lung injury are of foremost importance; however, the issue of the optimum ventilatory strategy during VV-ECMO has not received sufficient consideration. This paper will describe the diverse MV strategies applied during VV-ECMO in clinical practice and will highlight specific pathophysiological considerations that are crucial in the process of defining optimal ventilation settings in patients with ARDS supported with VV-ECMO.

Increasing the number of lungs available for transplantation.

Lung transplantation has become a standard treatment for patients with a broad spectrum of end stage lung diseases. Despite this success, many patients die on the waiting list while waiting for appropriate lungs to become available. This review describes the current strategies aimed at addressing this shortage of lungs, as well as summarizing potential future directions in the field. They include efforts to: 1) increase the number of organ donors by legislative action, and education of the public; 2) optimize the management of deceased, potential organ donors; 3) implement optimal criteria to determine organs suitable for transplantation; 4) use ex vivo reconditioning of lungs; and 5) develop xenotransplantation.

Recommendations for anesthesia and perioperative management of patients with neuromuscular disorders.

Patients with neuromuscular disorders are at high risk of intraoperative and postoperative complications. General anesthesia in these patients may exacerbate respiratory and cardiovascular failure due to a marked sensitivity to several anesthetic drugs. Moreover, succinylcholine and halogenated agents can trigger life-threatening reactions, such as malignant hyperthermia, rhabdomyolysis and severe hyperkalemia. Therefore, regional anesthesia should be used whenever possible. If general anesthesia is unavoidable, special precautions must be taken. In particular, for patients at increased risk of respiratory complications (i.e., postoperative atelectasis, acute respiratory failure, nosocomial infections), noninvasive ventilation associated with aggressive airway clearance techniques can successfully treat upper airway obstruction, hypoventilation and airway secretion retention, avoiding prolonged intubation and tracheotomy. Anesthesia and perioperative management of patients with neuromuscular disorders are described in this article. To grade the strength of recommendations and the quality of evidence we adopted the GRADE approach. In case of low-quality evidence, these recommendations represent the collective opinion of the expert panel.

Bridging to lung transplantation by extracorporeal support.

Ideally, bridging patients with end stage severe respiratory failure to lung transplantation should significantly extend the pretransplant life expectancy to increase the chances to receive a suitable organ, as well as efficiently preserve the post-transplant long-term life expectancy by maintaining physiological homeostasis and avoiding multi-organ dysfunction. Various advanced strategies of extracorporeal circulation can replace at least in part the respiratory function of the lung and can potentially provide the appropriate mode and level of cardiopulmonary support for each patient's physiologic requirements. Therefore, patients on the lung transplant waiting list developing severe hypoxemic and/or hypercapnic respiratory failure can be supported for a prolonged period of time before the transplant, preserving a satisfactory post-transplant life expectancy. However, a more systematic clinical study on this issue is warranted in order to define the actual efficacy of these treatments in reducing the mortality rate on the waiting transplant list, and eventually improve the outcome of patients with end stage respiratory failure.

Invasive and non-invasive long-term mechanical ventilation in Italian children.

BACKGROUND: To date, few studies have been published regarding the number of children in Italy who require long-term mechanical ventilation (LTV) and their underlying diagnoses, ventilatory needs and hospital discharge rate. METHODS: A preliminary national postal survey was conducted and identified 535 children from 57 centers. Detailed data were then obtained for 378 children from 30 centers. RESULTS: The estimated prevalence in Italy of this population was 4.3/100000. The majority of children (72.2%) were followed in pediatric units. The primary physicians who cared for these patients were either pediatric intensivists or pediatric pulmonologists. Neurological patients (78.2% of cases) represented the principal disorder category. 57.2% of the patients were non-invasively ventilated, with a nasal mask being the most common interface (85% of cases). The presence of clinical symptoms that were associated with abnormal findings on diagnostic testing was the primary indication for ventilatory support, whereas weaning failure was the primary indication for tracheotomy. Invasive ventilation was significantly related to younger age, longer daily hours on ventilation and cerebral palsy. Ventilatory modes with guaranteed minimal tidal volume were more often used in patients with tracheotomy. Despite their age, illness severity and need for technological care, 98% of the study population were successfully home discharged. CONCLUSION: Managing pediatric home LTV requires tremendous effort on the part of the patient's family and places a significant strain on community financial resources. In particular, neurological patients require more health care than patients in other categories. To further improve the quality of care for these patients, it is essential to establish a dedicated national database.

Are guidelines for non-invasive ventilation during weaning still valid?

Noninvasive ventilation (NIV) has gained increasing acceptance over the years to reduce endotracheal intubation, pneumonia and to prevent or treat respiratory failure in patients with different diagnoses. The international consensus conference, and the British society guidelines on NIV ventilation have analyzed its use during the weaning phase concluding that there were still conflicting results of its use. However, recent clinical trials have shown clear clinical benefits on the use of NIV in several patient populations during the weaning period. Acute respiratory failure (ARF) during the weaning process is the main object of recently published studies. The latest published randomized trials on the application of NIV for acute respiratory failure following extubation failed to demonstrate any favorable outcome. Even so, the use of NIV during the process of weaning in patients experiencing multiple weaning failure or as a preventive therapy in patients at higher risk of respiratory deterioration showed improved clinical outcomes only in chronic obstructive pulmonary disease and in particular in hypercapnic patients. Reduced invasive mechanical ventilation, tracheostomy and lower mortality rate at 90 days were the major advantages.

The use of CO2 removal devices in patients awaiting lung transplantation: an initial experience.

BACKGROUND: Lung transplantation is the treatment of choice for patients with end-stage lung failure. Limitations are presented by the shortage of donors and the long waiting list periods. New techniques, such as extracorporeal membrane ventilator devices with or without pump support, have been developed as bridges to transplantation for patients with severe, unresponsive respiratory insufficiency. METHODS: Between November 2005 and September 2009, 12 patients (7 males and 5 females), of overall mean age of 43.3 +/- 15.5 years underwent decapneization with extracorporeal devices. In 6 cases, a NovaLung system was used; in the remaining 6 patients, it was a Decap device. Causes of respiratory failure that led to implantation of such devices were cystic fibrosis (n = 6), pulmonary emphysema (n = 5), and chronic rejection of a previous double lung transplant (n = 1). RESULTS: Mean time on extracorporeal decapneization was 13.5 +/- 14.2 days. Eight patients died on the device. Three patients were bridged to lung transplantation; 1 recovered and was weaned from the device after 11 days. Mean PaCO(2) on the extracorporeal gas exchanger was significantly lower for both the devices at 24, 48, and 72 hours after implantation (P < .05). No significant difference was observed for the 2 systems. CONCLUSION: In our initial experience, decapneization devices have been simple, efficient methods to support patients with mild hypoxia and severe hypercapnia that is refractory to mechanical ventilation. This could represent a valid bridge to lung transplantation in these patients.

Respiratory management of acute respiratory failure in neuromuscular diseases.

Neuromuscular diseases (NMD) can affect all major respiratory muscles, leading to the development of respiratory failure, which is the most common cause of morbidity and mortality in patients affected by those conditions. Based on the clinical onset of acute respiratory failure (ARF), NMD can be classified into two main categories: 1) slowly progressive NMD with acute exacerbations of chronic respiratory failure, and 2) rapidly progressive NMD with acute episodes of respiratory failure. The most common slowly progressive NMDs, such as motor neuron diseases and inherited myopathies, account for the majority of NMD patients developing chronic neuromuscular respiratory failure at risk of acute exacerbations. Conversely, rapidly progressive NMDs, such as Guillain-Barré syndrome and myasthenic crises, are characterized by a sudden onset of ARF, usually in patients with previously normal respiratory function. The patho-physiological mechanisms responsible for ARF in NMD and the variety and complexity of specific challenges presented by the two main categories of NMD will be analyzed in this review, with the aim of providing clinically relevant suggestions for adequate respiratory management of these patients.

Tat-induced platelet-activating factor synthesis contributes to the angiogenic effect of HIV-1 Tat.

This study shows that human umbilical cord vein-derived endothelial cells (HUVEC) stimulated with HIV-1 Tat synthesized platelet-activating factor (PAF), a phospholipid mediator of inflammation that possesses angiogenic properties. The synthesis of PAF by HUVEC stimulated with Tat was dose and time dependent. Moreover, in vitro experiments were performed to evaluate whether migration of HUVEC induced by Tat was dependent on the synthesis of PAF. It was found that the cell motility induced by Tat was inhibited by WEB 2170, a specific PAF receptor antagonist. In vivo, the neoangiogenesis induced by Tat was also inhibited by WEB 2170 in a murine model, in which matrigel subcutaneously injected was used as substratum for angiogenesis. These results suggest that the synthesis of PAF by endothelial cells mediates, at least in part, the angiogenic activity of Tat by promoting the endothelial cell migration.

Role of platelet-activating factor in functional alterations induced by xenoreactive antibodies in porcine endothelial cells.

BACKGROUND: Platelet-activating factor (PAF) is a phospholipid mediator of inflammation which has been implicated in rejection. The interaction of anti-alpha-galactosyl natural antibodies (anti-alpha gal Abs) with endothelial cells is the initial step for the development of xenograft rejection. In our study, we stimulated porcine aortic endothelial cells (PAEC) with anti-alpha gal IgG to investigate the synthesis of PAF from PAEC and its biological consequences. METHODS AND RESULTS: PAF was extracted and chromatographically purified from cultured PAEC stimulated with baboon anti-alpha gal Abs. The Abs induced a dose-dependent synthesis of PAF peaking after 30 min of incubation, and decreasing thereafter. Concomitant cell shape change, motility, and cytoskeleton redistribution were observed. These events were prevented by addition of a panel of PAF-receptor antagonists. An SV40 T-large antigen-immortalized PAEC line was engineered to express PAF acetyl-hydrolase (PAF-AH) cDNA, the major PAF-inactivating enzyme. These transfected cells exposed to anti-alpha gal Abs showed reduced cell contraction and motility compared with empty vector-transfected cells. Moreover, in PAEC stimulated with anti-alpha gal Abs, the synthesis of PAF promoted the adhesion of a monocytic cell line as shown by the inhibitory effect of PAF-receptor antagonists and of PAF-AH expression. Finally, studies on cell monolayer demonstrated an enhanced permeability 48 hr after exposure to anti-alpha gal Abs, and this increase was prevented by PAF-inactivation and by PAF-receptor blockade. CONCLUSIONS: These results demonstrate that on stimulation with anti-alpha gal Abs, PAEC synthetize PAF which can contribute to several vascular events involved in xenograft rejection.

Platelet-activating factor enhances vascular endothelial growth factor-induced endothelial cell motility and neoangiogenesis in a murine matrigel model.

We previously reported that platelet-activating factor (PAF) enhances the angiogenic activity of certain polypeptide mediators such as tumor necrosis factor and hepatocyte growth factor by promoting endothelial cell motility. The purpose of the present study was to evaluate whether the synthesis of PAF induced by vascular endothelial growth factor (VEGF) might affect endothelial cell motility, microvascular permeability, and angiogenesis. The neoangiogenesis and synthesis of PAF induced by VEGF were studied in vivo in a murine Matrigel model. Dermal permeability was studied in mice by injection of (125)I-albumin. The synthesis of PAF, cell motility, and the increased (125)I-albumin transfer across endothelial monolayers were studied in vitro by using cultures of human umbilical cord vein-derived endothelial cells (HUVECs). The results obtained demonstrate that the neoangiogenesis induced by VEGF in vivo was associated with a local synthesis of PAF and was inhibited by WEB2170 and CV3988, 2 chemically unrelated, specific PAF-receptor antagonists. In contrast, WEB2170 did not inhibit VEGF-enhanced dermal permeability, suggesting that the latter was independent of the synthesis of PAF. In vitro, it was found that VEGF induced the synthesis of PAF by HUVECs in a dose- and time-dependent manner. The cell motility induced by VEGF was inhibited by PAF-receptor antagonists. In contrast, VEGF-induced proliferation of HUVECs and albumin transfer through HUVEC monolayer were unaffected by PAF-receptor antagonists. These results suggest that the synthesis of PAF induced by VEGF enhances endothelial cell migration and contributes to the angiogenic effect of VEGF in the in vivo Matrigel model.

Motility induced by human immunodeficiency virus-1 Tat on Kaposi's sarcoma cells requires platelet-activating factor synthesis.

In the present study, we evaluated whether motility of Kaposi's sarcoma (KS) spindle cells induced by HIV-1 Tat protein is dependent on the synthesis of platelet-activating factor (PAF). The results obtained indicate that Tat induced a dose-dependent synthesis of PAF from KS cells at a concentration as low as 0.1 ng/ml. PAF production started rapidly after Tat stimulation, peaking at 30 minutes and declining thereafter. Tat-induced cell migration was also a rapid event starting at 30 minutes. The motility was abrogated by addition of a panel of chemically unrelated PAF receptor antagonists (WEB 2170, CV 3988, CV 6209, and BN 52021), suggesting that the synthesized PAF mediates the motogenic effect of Tat. This effect was also present on cells plated on a type-I collagen-, fibronectin-, or basement membrane extract-coated surface. Expression of PAF receptor-specific mRNA was detected in KS cells. In addition, examination of the cytoskeletal organization showed that Tat-mediated KS cell redistribution of actin filaments and shape change was also inhibited by a PAF receptor antagonist. Moreover, PAF receptor blockade prevented the up-regulation of beta1 integrin and the down-regulation of alphavbeta3 observed after stimulation of KS cells with Tat. In conclusion, the results of the present study indicate that Tat-induced PAF synthesis plays a critical role in triggering the events involved in motility of KS cells.

Activation of CD40 favors the growth and vascularization of Kaposi's sarcoma.

Although CD40 is expressed by several tumor lines and is up-regulated in tumor vascular endothelium, its role in tumor biology is still unclear. In the present study, we investigated the role of CD40 in the growth and vascularization of Kaposi's sarcoma (KS). In vitro, stimulation of CD40 induced migration of KS cells and inhibited vincristine-induced apoptosis. Similarly, the CD40 engagement on endothelial cells resulted in cell contraction, migration, and prevention of serum withdrawal-apoptosis. To understand the biological relevance of CD40 in vivo, KS cells were engineered to express and release a soluble form of CD40 (KS-sCD40) able to disrupt CD40-CD154 interaction. SCID mice s.c. injected with KS-sCD40 cells developed tumors that were significantly smaller than those induced by control cells (KS-neo). In addition, KS-sCD40 tumors showed several areas of necrosis, diffuse presence of apoptotic cells, and poor vascularization. In contrast, KS-neo tumors showed few or absent areas of necrosis and apoptosis and intense vascularization. Moreover, anti-CD40 Abs stimulated neo-angiogenesis in a murine model in which s.c. implantation of Matrigel was used as a vehicle for the delivery of mediators. These observations provide demonstration that CD40 supports tumor cell survival, growth, and neo-vascularization of KS.

Human IL-3 stimulates endothelial cell motility and promotes in vivo new vessel formation.

Angiogenesis is a critical process for growth of new capillary blood vessels from preexisting capillaries and postcapillary venules, both in physiological and pathological conditions. Endothelial cell proliferation is a major component of angiogenesis and it is regulated by several growth factors. It has been previously shown that the human hemopoietic growth factor IL-3 (hIL-3), predominantly produced by activated T lymphocytes, stimulates both endothelial cell proliferation and functional activation. In the present study, we report that hIL-3 is able to induce directional migration and tube formation of HUVEC. The in vivo neoangiogenetic effect of hIL-3 was also demonstrated in a murine model in which Matrigel was used for the delivery of the cytokine, suggesting a role of hIL-3 in sustaining neoangiogenesis. Challenge of HUVEC with hIL-3 lead to the synthesis of platelet-activating factor (PAF), which was found to act as secondary mediator for hIL-3-mediated endothelial cell motility but not for endothelial cell proliferation. Consistent with the role of STAT5 proteins in regulating IL-3-mediated mitogenic signals, we herein report that, in hIL-3-stimulated HUVEC, the recruitment of STAT5A and STAT5B, by the beta common (betac) subunit of the IL-3R, was not affected by PAF receptor blockade.

The synthesis of platelet-activating factor modulates chemotaxis of monocytes induced by HIV-1 Tat.

HIV-1 Tat protein has been shown to induce chemotaxis and recruitment of monocytes. In the present study, we evaluated whether HIV-1 Tat protein was able to induce the synthesis of platelet-activating factor (PAF), which is a potent mediator of cell motility, and whether the synthesis of PAF was instrumental in triggering Tat-induced monocyte chemotaxis. The results obtained indicate that Tat, but not gp120 and gp41, induced a time-dependent synthesis of PAF from monocytes at concentration as low as 0.1 ng/ml. As inferred by the inhibitory effect of anti-Flt-1 antibody and by the desensitization of monocytes following preincubation with vascular endothelial growth factor, the synthesis of PAF by monocytes stimulated with Tat was induced by activation of vascular endothelial growth factor receptor 1. Moreover, the Tat-induced chemotaxis of monocytes was abrogated both by WEB 2170 and by CV 3988, two chemically unrelated PAF receptor antagonists, suggesting that the synthesized PAF modulates the chemotactic response of monocytes to Tat. In conclusion, the results of the present study indicate that Tat-induced PAF synthesis plays a critical role in triggering the events involved in the migratory response of monocytes.

Thrombopoietin stimulates endothelial cell motility and neoangiogenesis by a platelet-activating factor-dependent mechanism.

In this study, we demonstrate that human umbilical cord vein-derived endothelial cells (HUVECs) expressed c-Mpl, the thrombopoietin (TPO) receptor, and that TPO activates HUVECs in vitro, as indicated by directional migration, synthesis of 1-alkyl-/1-acyl-platelet-activating factor (PAF) and interleukin-8 (IL-8), and phosphorylation of the signal transducers and activators of transcription (STAT) STAT1 and STAT5B. The observation that WEB 2170 and CV3988, 2 structurally unrelated PAF receptor antagonists, prevented the motility of HUVECs induced by TPO suggests a role of PAF as secondary mediator. Moreover, kinetic analysis of TPO-induced tyrosine phosphorylation of STAT demonstrated that STAT5B activation temporally correlated with the synthesis of PAF. PAF, in turn, induced a rapid tyrosine phosphorylation of STAT5B and PAF receptor blockade, by WEB 2170, preventing both TPO- and PAF-mediated STAT5B activation. The in vivo angiogenic effect of TPO, studied in a mouse model of Matrigel implantation, demonstrated that TPO induced a dose-dependent angiogenic response that required the presence of heparin. Moreover, the in vivo angiogenic effect of TPO was inhibited by the PAF receptor antagonist WEB 2170 but not by the anti-basic fibroblast growth factor neutralizing antibody. These results indicate that the effects of TPO are not restricted to cells of hematopoietic lineages, because TPO is able to activate endothelial cells and to induce an angiogenic response in which the recruitment of endothelial cells is mediated by the synthesis of PAF. Moreover, biochemical analysis supports the hypothesis that STAT5B may be involved in the signaling pathway leading to PAF-dependent angiogenesis.