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This manuscript describes how the permeability of pulmonary artery microvascular endothelial cell (RPMEC) monolayer is elevated by hypoxia and the role played by HSP27 phosphorylation. p38 MAP kinase activation leading to HSP27 phosphorylation was previously shown by our laboratory to alter the actin cytoskeleton and tethering properties of RPMEC. This effect was independent of hypoxia-induced contractility which was ROCK-dependent rather than HSP27-dependent. Results described here show that increased HSP27 phosphorylation not only does not underlie hypoxia-induced permeability, but may actually augment the endothelial barrier. Hypoxia causes gap formation between RPMEC and increases MLC2 phosphorylation. The phosphorylation of MYPT1, which inhibits MLC2 phosphatase, is also increased in hypoxia. In addition, FAK phosphorylation, which alters focal adhesion signaling, is increased in hypoxia. Overexpressing phosphomimicking HSP27 (pmHSP27), which induces significant actin stress fiber formation, surprisingly renders RPMEC resistant to hypoxia- or TGFbeta-induced permeability. siRNA against pmHSP27 reverses the increased actin stress fiber formation in pmHSP27-overexpressing cells, and disrupting actin stress fibers in pmHSP27-overexpressing RPMEC renders them more susceptible to hypoxia. Finally, hypoxia-induced gap formation, as well as phosphorylation of MLC2, MYPT1 and FAK are almost abolished by overexpressing pmHSP27 in RPMEC. These effects of pmHSP27 overexpression might represent decreased cytoskeletal plasticity and increased tethering which counteracts permeability-inducing contractility. Thus hypoxia activates two pathways one leading to contractility and increased permeability, the other leading to actin stress fibers, stronger adhesion, and reduced permeability. Altering HSP27 phosphorylation, which tips the balance towards decreased permeability, might be targeted in managing endothelial barrier dysfunction.

Background: Failure to wean from prolonged mechanical ventilation (MV) is common in long-term acute care hospitals (LTACHs), but the process of terminal withdrawal of MV in LTACHs is not well described. We compared terminal withdrawal of MV at an LTACH with that in a medical ICU (MICU)., Methods: A retrospective medical chart review was done of all patients undergoing terminal withdrawal of MV in an LTACH (n = 30) and in a MICU (n = 74) over a 2-year period., Results: The decision to withdraw MV was more likely initiated by patient or family in the LTACH and by medical staff in the MICU (p < 0.0001). Social workers, pastoral care, and hospital administration were more likely to participate in the withdrawal process at the LTACH compared with the MICU (p < 0.05). Time from initiation of MV to orders for do not resuscitate, comfort measures only, or withdrawal of MV was significantly greater in the LTACH (weeks) compared with the MICU (days) (p < 0.05). The dose of benzodiazepines given during the final 24 h of life was greater in the MICU as compared with the LTACH (p < 0.05). Narcotic and benzodiazepine use in the hour before or after withdrawal of MV did not differ between the two groups. COPD and pneumonia were the most common causes of death among patients undergoing withdrawal of MV at the LTACH, as opposed to septic shock in the MICU (p < 0.05)., Conclusions: Terminal withdrawal of MV in the LTACH differs from that in the MICU with regard to decision making, benzodiazepine use, and cause of death.

Background: Noninvasive positive-pressure ventilation (NPPV) modes are currently available on bilevel and ICU ventilators. However, little data comparing the performance of the NPPV modes on these ventilators are available., Methods: In an experimental bench study, the ability of nine ICU ventilators to function in the presence of leaks was compared with a bilevel ventilator using the IngMar ASL5000 lung simulator (IngMar Medical; Pittsburgh, PA) set at a compliance of 60 mL/cm H(2)O, an inspiratory resistance of 10 cm H(2)O/L/s, an expiratory resistance of 20 cm H(2)O/ L/s, and a respiratory rate of 15 breaths/min. All of the ventilators were set at 12 cm H(2)O pressure support and 5 cm H(2)O positive end-expiratory pressure. The data were collected at baseline and at three customized leaks., Main Results: At baseline, all of the ventilators were able to deliver adequate tidal volumes, to maintain airway pressure, and to synchronize with the simulator, without missed efforts or auto-triggering. As the leak was increased, all of the ventilators (except the Vision [Respironics; Murrysville, PA] and Servo I [Maquet; Solna, Sweden]) needed adjustment of sensitivity or cycling criteria to maintain adequate ventilation, and some transitioned to backup ventilation. Significant differences in triggering and cycling were observed between the Servo I and the Vision ventilators., Conclusions: The Vision and Servo I were the only ventilators that required no adjustments as they adapted to increasing leaks. There were differences in performance between these two ventilators, although the clinical significance of these differences is unclear. Clinicians should be aware that in the presence of leaks, most ICU ventilators require adjustments to maintain an adequate tidal volume.

Postoperative pulmonary hypertension is a challenging and feared complication of many types of surgery, including lung and heart transplantation, pulmonary thromboendarterectomy, congenital-heart-disease repair, and others. The most severe manifestation is acute right heart syndrome, characterized by right heart failure and cardiovascular collapse-a daunting therapeutic challenge associated with a high mortality. Patients with postoperative pulmonary hypertension must be carefully evaluated to identify reversible contributing factors such as fluid and metabolic imbalance, hypoxemia, and right heart ischemia. A pulmonary arterial catheter and echocardiogram are recommended for evaluation, although their value has not been established in carefully designed trials. Basic principles of management include maintenance of systemic perfusion pressure, optimization of cardiac inotropy, use of lung-protective ventilator strategies, and attempting to reduce right-ventricular afterload using pulmonary vasodilators. Unfortunately, controlled trials upon which to base therapy are lacking, and most approaches are supported only by uncontrolled or anecdotal evidence. Better understanding of the pathophysiology of right heart failure and controlled trials testing therapeutic approaches are needed if we are to make progress in treating this heretofore highly mortal condition.

Background: We examined the process of decannulation following tracheostomy in patients transferred to a long-term acute care (LTAC) hospital for weaning from prolonged mechanical ventilation (PMV)., Methods: A retrospective chart review of 135 patients., Results: Decannulation was successful in 35% of patients a median of 45 days (IQR, 32-76) following tracheostomy. Patients who failed decannulation had a tracheostomy tube placed earlier (14 days; IQR 11-18 vs. 18 days; IQR 14-30, P=.04) and had a shorter length of stay at the acute facility (20 days; IQR, 16-23 vs. 31 days; IQR 24-45, P=.003) compared with patients who were decannulated. Length of stay and cost of care at the LTAC did not differ with decannulation status. At 3.5 years, 35% (47/135) of all patients and 62% (29/47) of decannulated patients were alive., Conclusions: Decannulation was achieved in 35% of patients transferred to an LTAC for weaning from prolonged mechanical ventilation.

Noninvasive ventilation (NIV) has assumed an important role in the management of certain types of respiratory failure in acute-care hospitals. However, the optimal location for NIV has been a matter of debate. Some have argued that all patients begun on NIV in the acute-care setting should go to an intensive care unit (ICU), but this is impractical because ICU beds are often unavailable, and it may not be a sensible use of resources. Also, relatively few studies have examined the question of location for NIV. One problem is that various units' capabilities to deliver NIV differ substantially, even in the same hospital. Choosing the appropriate environment for NIV requires consideration of the patient's need for monitoring, the monitoring capabilities of the unit, including both technical and personnel resources (nursing and respiratory therapy), and the staff's skill and experience. In some hospitals NIV is begun most often in the emergency department, but is most often managed in an ICU. Step-down units are often good locations for NIV, but many institutions do not have step-down units. With ICU beds at a premium, many hospitals are forced to manage some NIV patients on general wards, which can be safely done with more stable patients if the ward is suitably monitored and experienced. When deciding where to locate the patient, clinicians must be familiar with the capabilities of the units in their facility and try to match the patient's need for monitoring and the unit's capabilities.

Results from clinical trials serve as the basis for approval of therapies by regulatory agencies as well as for treatment decisions by clinicians. But these findings are relevant only to patients who are similar to the ones enrolled into the trials. This is germane to clinical trials on pulmonary arterial hypertension (PAH) because the disease is uncommon but highly heterogeneous and results can easily be misapplied. The characteristics of patients entering the trials are largely determined by inclusion/exclusion criteria, with the result that most participants have idiopathic, connective tissue disease- and congenital heart disease-related PAH. Earlier trials enrolled patients mainly with New York Heart Association functional class III and IV disease and with severe pulmonary hemodynamic abnormalities. Because it has been the major outcome variable in most of the trials, eligibility is also dependent on six-minute-walk distance, ensuring that patients are moderately but not too severely functionally impaired, thereby maximizing the likelihood of detecting a favorable response to therapy. More recent trials have enrolled less ill patients, with more patients with New York Heart Association functional class II disease, less severe hemodynamic abnormalities, and more stability over time. This reflects, in part, ethical concerns about enrolling sicker patients into placebo-controlled trials. Trials have mainly enrolled white females in their 40s and 50s and have consistently excluded non-WHO group 1 forms of pulmonary hypertension. These characteristics must be carefully considered when applying the findings of pulmonary hypertension trials in clinical practice.

Critically ill patients have severe sleep disruption and typically encounter loss of circadian sleep pattern, steep fragmentation, increasing proportions of transitional stages of sleep, and loss of slow wave and rapid eye movement sleep. Mechanical ventilation is associated with these same sleep abnormalities, but what is attributable to the intensive care unit environment versus mechanical ventilation itself may be difficult to discern. Recent studies have shown that the ventilator mode and inappropriate settings can contribute to sleep fragmentation, and it is important to avoid overventilation that can induce central apneas when using spontaneous breathing modes. Noninvasive ventilation in the acute setting seems to be associated with the same sleep abnormalities as invasive ventilation. Long-term noninvasive positive pressure ventilation assists ventilation nocturnally and improves for patients with chronic respiratory failure caused by restrictive thoracic disorders.

Nocturnal noninvasive ventilation (NNV), the provision of ventilatory assistance via a noninvasive interface mainly during sleep, has assumed an important role in the management of chronic hypoventilatory syndromes. This review focuses on recent developments related to the use of NNV to treat various forms of chronic respiratory failure or insufficiency. In the past, NNV has been used mainly to treat respiratory insufficiency in patients with neuromuscular disease (NMD) or chest wall deformity; it should be instituted when these patients have orthopnea or daytime symptoms associated with nocturnal hypoventilation. An emerging application is to treat obesity-hypoventilation syndrome, particularly in continuous positive airway pressure (CPAP) failures. Additionally, it has a role in managing some patients with obstructive sleep apnea who are hypoventilating or find the lower expiratory pressure with bilevel positive pressure ventilators more tolerable than with CPAP alone. NNV to treat severe, stable COPD remains controversial, although a subgroup of patients with hypercapnea and sleep-disordered breathing (SDB) seems most likely to respond favorably. NNV to treat central SDB in patients with congestive heart failure continues to be investigated. Recent findings from a Canadian CPAP trial were disappointing, but preliminary results on a novel adaptive NNV mode are promising.

Rationale: For patients with acute respiratory failure who have declined intubation and resuscitation or have chosen comfort measures only, noninvasive ventilation (NIV) may help them achieve important health or personal goals, or merely prolong the dying process., Objective: To determine clinicians' attitudes to and stated use of NIV for these patients., Methods: We developed an instrument to assess the attitudes of intensivists, pulmonologists, and respiratory therapists (RTs) toward the use of NIV for patients with acute respiratory failure near or at the end of life. After assessing its psychometric properties, we mailed the survey to these clinicians at 18 Canadian and two U.S. hospitals. We analyzed factors associated with stated use of NIV for do-not-resuscitate and comfort-measures-only patients., Results: Overall, 104 of 183 (57%) physicians and 290 of 473 (61%) RTs participated. Two thirds of physicians include NIV during life support discussions with do-not-resuscitate patients at least sometimes, and 87% of RTs stated that NIV should be included in such discussions. For patients choosing comfort measures only, almost half of physicians reported including NIV as an option in their discussions at least sometimes, while fewer than half of RTs stated that these discussions should be conducted. Most (>80%) physicians use NIV and most (>80%) RTs are asked to initiate NIV for do-not-resuscitate patients with chronic obstructive pulmonary disease or cardiogenic pulmonary edema. Fewer clinicians report using NIV for do-not-resuscitate patients with underlying malignancy (59% of physicians, 69% of RTs) or for patients choosing comfort measures only (40% of physicians, 51% of RTs; p < .001)., Conclusions: For patients with do-not-resuscitate orders, many physicians use NIV, and many RTs are asked to initiate NIV, most often to treat chronic obstructive pulmonary disease and cardiogenic pulmonary edema. Further study is needed on the goals of NIV near the end of life, whether these goals are understood by all stakeholders, and how well they are achieved in practice.

Objective: Pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD) is difficult to manage, and has a poor prognosis. The phosphodiesterase-5 inhibitor sildenafil citrate enhances vasodilatation, has antiproliferative effects, and is effective in the treatment of PAH. We examined the efficacy and safety of oral sildenafil in patients with PAH-CTD., Methods: In a 12-week, double-blind study (SUPER-1), 278 patients with PAH were randomized to oral placebo, sildenafil 20 mg, sildenafil 40 mg, or sildenafil 80 mg 3 times daily (tid). In a post-hoc subgroup analysis of 84 patients with PAH-CTD, exercise capacity, hemodynamic measures, World Health Organization functional class, and tolerability were assessed., Results: Forty-five percent of the patients had scleroderma, 23% had systemic lupus erythematosus, and the rest (32%) were categorized as other. Patients were predominantly functional class II (38%) or III (61%) at baseline. Sildenafil-treated patients exhibited mean increases in 6-minute walk distance at Week 12 of 42 m (95% CI 20, 64) for 20 mg, 36 m (95% CI 14, 58) for 40 mg, and 15 m (95% CI -24, 54) for 80 mg, while placebo-treated patients exhibited a mean decrease of 13 m (95% CI -36, 10). Improvement of at least 1 functional class occurred in 29%-42% of sildenafil-treated patients, compared to 5% for placebo. Significant improvements in mean pulmonary arterial pressure and pulmonary vascular resistance were observed with sildenafil 20 mg, and sildenafil was generally well tolerated., Conclusion: In patients with PAH-CTD, sildenafil improves exercise capacity, hemodynamic measures (at the 20 mg dose), and functional class after 12 weeks of treatment.

Objective: We recently reported a high success rate using noninvasive positive pressure ventilation (NPPV) to treat COPD exacerbations with hypercapnic encephalopathy. This study compared the hospital outcomes of NPPV vs. conventional mechanical ventilation (CMV) in COPD exacerbations with moderate to severe hypercapnic encephalopathy, defined by a Kelly score of 3 or higher., Design and Setting: A 3-year prospective matched case-control study in a respiratory semi-intensive care unit (RSICU) and intensive care unit (ICU)., Patients and Participants: From 103 consecutive patients the study included 20 undergoing NPPV and 20 CMV, matched for age, simplified acute physiology score II, and baseline arterial blood gases., Measurements and Results: ABG significantly improved in both groups after 2 h. The rate of complications was lower in the NPPV group than in the CMV group due to fewer cases of nosocomial pneumonia and sepsis. In-hospital mortality, 1-year mortality, and tracheostomy rates were similar in the two groups. Fewer patients remained on ventilation after 30 days in NPPV group. The NPPV group showed a shorter duration of ventilation., Conclusions: In COPD exacerbations with moderate to severe hypercapnic encephalopathy, the use of NPPV performed by an experienced team compared to CMV leads to similar short and long-term survivals with a reduced nosocomial infection rate and duration of ventilation.

Fibroblasts play a major role in tissue repair and remodeling. Their differentiation into myofibroblasts, marked by increased expression of smooth muscle-specific alpha-actin (alpha-SMA), is believed to be important in wound healing and fibrosis. We have recently described a role for MK2 in this phenotypic differentiation in culture. In this article, we demonstrate that MK2 also regulates myofibroblasts in vivo. Disruption of MK2 in mice prevented myofibroblast formation in a model of pulmonary fibrosis. However, MK2 disruption and consequent lack of myofibroblast formation exacerbated fibrosis rather than ameliorated it as previously postulated. When mice lacking MK2 (MK2-/-) were exposed to bleomycin, more collagen accumulated and more fibroblasts populated fibrotic regions in their lungs than in similarly treated wild-type mice. While there were many vimentin-positive cells in the bleomycin-treated MK2-/- mouse lungs, few alpha-SMA-positive cells were observed in these lungs compared with wild-type mouse lungs. siRNA against MK2 reduced alpha-SMA expression in wild-type mouse embryonic fibroblasts (MEF), consistent with its suppression in MK2-/- MEF. On the other hand expressing constitutively active MK2 in MK2-/- MEF significantly increased alpha-SMA expression. MK2-/-MEF proliferated at a faster rate and produced more collagen; however, they migrated at a slower rate than wild-type MEF. Overexpressing phosphomimicking HSP27, a target of MK2, did not reverse the effect of MK2 disruption on fibroblast migration. MK2 disruption did not affect Smad2 activation by transforming growth factor-beta. Thus, MK2 appears to mediate myofibroblast differentiation, and inhibiting that differentiation might contribute to fibrosis rather than protect against it.

Introduction: Endothelin receptor antagonism has become an important component in the treatment of pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). The purpose of this study was to analyse the safety and effectiveness of sitaxsentan, a selective antagonist of the ET(A) receptor, in a cohort of patients with PAH and CTD. Short-term clinical and haemodynamic effects and longer-term follow-up data are presented., Methods: A post hoc subgroup analysis was performed on 42 patients who had PAH associated with CTD, out of a group of 178 patients enrolled in a 12-week, double-blind, randomised clinical trial of sitaxsentan versus placebo. Data from 33 patients assigned to sitaxsentan 100 mg or 300 mg daily were pooled and compared with nine placebo-treated patients. There were 41 patients entered into the blinded extension study, in which all patients received either 100 mg or 300 mg sitaxsentan once daily., Results: Patients treated with sitaxsentan had a mean (SD) increase in 6 minute walk distance of 20 (5) m from baseline to week 12 (p = 0.037), whereas the placebo group had a decrease of 38 (84) m, resulting in a placebo-subtracted treatment effect of 58 m (p = 0.027). Parallel improvements in quality of life and haemodynamics were also observed. No patient discontinued their drug during the 12-week trial. In the blinded extension study (median treatment duration 26 weeks), more patients were in functional class I-II than in III-IV (p<0.001) at the end of the study compared with the start of active therapy. Elevation of hepatic transaminase levels occurred in two patients., Conclusions: Sitaxsentan appears to be efficacious in patients with PAH associated with CTD.

Objectives: Noninvasive positive-pressure ventilation (NPPV) is increasingly used in patients with acute respiratory failure, but few data exist regarding current sedation practices during NPPV. We sought to characterize current practices and attitudes regarding sedation during NPPV., Design: Cross-sectional Web-based survey., Setting: Medical institutions., Participants: Physician members of the American College of Chest Physician's Critical Care Network (n = 2,656) and the European Respiratory Society's Assembly of Critical Care (n = 339)., Interventions: Survey., Measurements and Main Results: Of the 790 of 2,985 (27%) of physicians who responded, 15%, 6%, and 28% never used sedation, analgesia, or hand restraints any of the time for NPPV patients, respectively, and the large majority reported using these interventions in < or =25% of patients. Sedation, analgesia, and hand restraints were more commonly used by North Americans than Europeans (41% vs. 24% for sedation, 48% vs. 35% for analgesia, and 27% vs. 16% for hand restraints, all p < .01) and critical care vs. noncritical care physicians (42% vs. 24% for sedation and 50% vs. 34% for analgesia, all p < .01). A benzodiazepine alone was the most preferred (33%), followed by an opioid alone (29%). Europeans were less likely to use a benzodiazepine alone (25% vs. 39%, p < .001) but more likely to use an opioid alone (37% vs. 26%, p < .009). Sedation was usually administered as an intermittent intravenous bolus, outside of a protocol, and was assessed by nurses using clinical end points rather than a sedation scale., Conclusions: Most physicians infrequently use sedation and analgesic therapy for NPPV to treat acute respiratory failure, but practices vary widely within and between specialties and geographic regions.

Background: Noninvasive ventilation has assumed an important role in the management of respiratory failure in critical care units, but it must be used selectively depending on the patient's diagnosis and clinical characteristics., Data: We review the strong evidence supporting the use of noninvasive ventilation for acute respiratory failure to prevent intubation in patients with chronic obstructive pulmonary disease exacerbations or acute cardiogenic pulmonary edema, and in immunocompromised patients, as well as to facilitate extubation in patients with chronic obstructive pulmonary disease who require initial intubation. Weaker evidence supports consideration of noninvasive ventilation for chronic obstructive pulmonary disease patients with postoperative or postextubation respiratory failure; patients with acute respiratory failure due to asthma exacerbations, pneumonia, acute lung injury, or acute respiratory distress syndrome; during bronchoscopy; or as a means of preoxygenation before intubation in critically ill patients with severe hypoxemia., Conclusion: Noninvasive ventilation has assumed an important role in managing patients with acute respiratory failure. Patients should be monitored closely for signs of noninvasive ventilation failure and promptly intubated before a crisis develops. The application of noninvasive ventilation by a trained and experienced intensive care unit team, with careful patient selection, should optimize patient outcomes.

Serotonin (5-HT) stimulates smooth muscle cell growth through 5-HT receptors and the 5-HT transporter (5-HTT), and has been associated with pulmonary hypertension (PH). Platelet-derived growth factor receptors (PDGFR) have also been associated with PH. We present evidence for the first time that 5-HT transactivates PDGFRbeta through the 5-HTT in pulmonary artery (PA) SMCs. Inhibition of PDGFR kinase with imatinib or AG1296 blocks 5-HT-stimulated PDGFRbeta phosphorylation. 5-HTT inhibitors and the Na+/K+-ATPase inhibitor ouabain, but not 5-HT2 and 5-HT1B/1D receptor inhibitors, block PDGFRbeta activation by 5-HT. Notably, 5-HTT binds the PDGFRbeta upon 5-HT stimulation and the 5-HTT inhibitor fluoxetine blocks both the binding and PDGDRbeta activation. Activation of PDGFRbeta may occur through oxidation of a catalytic cysteine of tyrosine phosphatase. 5-HT-activated PDGFRbeta phosphorylation is blocked by the antioxidant N-acetyl-L-cysteine and the NADPH oxidase inhibitor, DPI. Inhibition of PDGFR kinase with imatinib or AG1296 significantly inhibits SMC proliferation and migration induced by 5-HT in vitro. Infusion of 5-HT by miniosmotic pumps enhances PDGFRbeta activation in mouse lung in vivo. In summary, these results demonstrate that 5-HT transactivates PDGFRbeta in PASMCs leading to SMC proliferation and migration, and may be an important signaling pathway in the production of PH in vivo.

Noninvasive ventilation (NIV), the provision of ventilatory assistance without an artificial airway, has emerged as an important ventilatory modality in critical care. This has been fueled by evidence demonstrating improved outcomes in patients with respiratory failure due to COPD exacerbations, acute cardiogenic pulmonary edema, or immunocompromised states, and when NIV is used to facilitate extubation in COPD patients with failed spontaneous breathing trials. Numerous other applications are supported by weaker evidence. A trial of NIV is justified in patients with acute respiratory failure due to asthma exacerbations and postoperative states, extubation failure, hypoxemic respiratory failure, or a do-not-intubate status. Patients must be carefully selected according to available guidelines and clinical judgment, taking into account risk factors for NIV failure. Patients begun on NIV should be monitored closely in an ICU or other suitable setting until adequately stabilized, paying attention not only to vital signs and gas exchange, but also to comfort and tolerance. Patients not having a favorable initial response to NIV should be considered for intubation without delay. NIV is currently used in only a select minority of patients with acute respiratory failure, but with technical advances and new evidence on its proper application, this role is likely to further expand.

Nutrient availability is one of the strongest determinants of cell size. When grown in rich media, single-celled organisms such as yeast and bacteria can be up to twice the size of their slow-growing counterparts. The ability to modulate size in a nutrient-dependent manner requires cells to: (1) detect when they have reached the appropriate mass for a given growth rate and (2) transmit this information to the division apparatus. We report the identification of a metabolic sensor that couples nutritional availability to division in Bacillus subtilis. A key component of this sensor is an effector, UgtP, which localizes to the division site in a nutrient-dependent manner and inhibits assembly of the tubulin-like cell division protein FtsZ. This sensor serves to maintain a constant ratio of FtsZ rings to cell length regardless of growth rate and ensures that cells reach the appropriate mass and complete chromosome segregation prior to cytokinesis.

Background: To assess the factors associated with reintubation in patients who had successfully passed a spontaneous breathing trial., Methods: We used logistic regression and recursive partitioning analyses of prospectively collected clinical data from adults admitted to ICUs of 37 hospitals in eight countries, who had undergone invasive mechanical ventilation for > 48 h and were deemed ready for extubation., Results: Extubation failure occurred in 121 of the 900 patients (13.4%). The logistic regression analysis identified the following associations with reintubation: rapid shallow breathing index (RSBI) [odds ratio (OR), 1.009 per unit; 95% confidence interval (CI), 1.003 to 1.015]; positive fluid balance (OR, 1.70; 95% CI, 1.15 to 2.53); and pneumonia as the reason for initiating mechanical ventilation (OR, 1.77; 95% CI, 1.10 to 2.84). The recursive partitioning analysis allowed the separation of patients into different risk groups for extubation failure: (1) RSBI of > 57 breaths/L/min and positive fluid balance (OR, 3.0; 95% CI, 1.8 to 4.8); (2) RSBI of < 57 breaths/L/min and pneumonia as reason for mechanical ventilation (OR, 2.0; 95% CI, 1.1 to 3.6); (3) RSBI of > 57 breaths/L/min and negative fluid balance (OR, 1.4; 95% CI, 0.8 to 2.5); and (4) RSBI of < 57 breaths/L/min (OR, 1 [reference value])., Conclusions: Among routinely measured clinical variables, RSBI, positive fluid balance 24 h prior to extubation, and pneumonia at the initiation of ventilation were the best predictors of extubation failure. However, the combined predictive ability of these variables was weak.

Study Objectives: We assessed the efficacy of bosentan in transitioning from prostacyclin infusions in patients with pulmonary arterial hypertension (PAH)., Methods: Twenty-two PAH patients were recruited from five PAH centers if they had been clinically stable while receiving therapy with IV epoprostenol or subcutaneous treprostinil for at least 3 months. Patients were observed in an open-label prospective trial while bosentan was added to therapy, and then epoprostenol or treprostinil were tapered after 2 months., Results: Ten of the 22 patients were transitioned off prostacyclin infusion therapy after a mean (+/- SEM) duration of 6.1 +/- 1.2 months. Of those patients, seven patients have continued not receiving prostacyclin infusion therapy for a mean duration of 17.7 +/- 5.3 months, with no significant changes in pulmonary artery (PA) pressure estimated by echocardiography, World Health Organization (WHO)/New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD), or Borg dyspnea score. The conditions of three patients deteriorated, necessitating the resumption of prostacyclin therapy, and two patients subsequently died. Twelve patients failed to transition or even lower the prostacylin infusion rate and had worsening of their WHO/NYHA functional class and estimated systolic PA pressures, and had a trend toward deterioration in their mean 6MWD (294 +/- 41 to 198 +/- 34 m, respectively; p = 0.2). Of these, two patients subsequently died. The baseline characteristics of those who transitioned successfully vs those who transitioned unsuccessfully were a lower prostacyclin infusion rate, and less severe elevations in the mean and estimated systolic PA pressures., Conclusion: Transitioning from therapy with prostacyclin to bosentan is possible in some PAH patients, mainly in those receiving lower prostacyclin doses and having less pulmonary hypertension at baseline. Careful patient selection and close interim monitoring is needed because the conditions of patients can deteriorate, and they may not respond to the resumption of therapy with prostacyclin.

Purposes: Little information is available on the utilization of noninvasive positive-pressure ventilation (NPPV) in the United States. Accordingly, we performed a survey on the use of NPPV at acute care hospitals in a region of the United States to determine variations in utilization and between hospitals, the reasons for lower rates of utilization, and the techniques used for application., Methods: Using survey methodology, we developed a questionnaire consisting of 19 questions and distributed it by mail to directors of respiratory care at all 82 acute care hospitals in Massachusetts and Rhode Island. Nonresponders were contacted by phone to complete the survey. Responses were analyzed using standard statistics, including t tests and Mann-Whitney U tests where appropriate., Results: We obtained responses from 71 of the 82 hospitals (88%). The overall utilization rate for NPPV was 20% of ventilator starts, but we found enormous variation in the estimated utilization rates among different hospitals, from none to > 50%. The top two reasons given for lower utilization rates were a lack of physician knowledge and inadequate equipment. In the 19 hospitals that provided detailed information, COPD and congestive heart failure constituted 82% of the diagnoses of patients receiving NPPV, but NPPV was still used in only 33% of patients with these diagnoses receiving any form of mechanical ventilation., Conclusions: The utilization rates for NPPV vary enormously among different acute care hospitals within the same region. The perceived reasons for lower utilization rates include lack of physician knowledge, insufficient respiratory therapist training, and inadequate equipment. Educational programs directed at individual institutions may be useful to enhance utilization rates.

Study Objectives: Brain natriuretic peptide (BNP) blunts hypoxic pulmonary hypertension in animal models, but its acute hemodynamic effects in patients with pulmonary arterial hypertension (PAH) are not known. The aim of this study was to determine if human B-type natriuretic peptide is a safe and efficacious pulmonary vasodilator in patients with PAH and if the pulmonary hemodynamic effects are potentiated by phosphodiesterase inhibition., Design: Open-label study., Setting: Medical ICUs of three tertiary care hospitals in New England., Patients: Thirteen consecutive adult patients undergoing right-heart catheterization and a pulmonary vasodilator trial for the initial evaluation of PAH., Interventions: Patients were administered inhaled nitric oxide (iNO), i.v. epoprostenol, and a 3-h infusion of BNP alone and 1 h after an oral dose of the phosphodiesterase-5 inhibitor sildenafil., Results: iNO and sildenafil alone decreased mean pulmonary artery pressure (mPAP) without a significant fall in pulmonary vascular resistance (PVR). Epoprostenol decreased both mPAP and PVR. BNP alone had no significant effect on pulmonary hemodynamics, but the combination of sildenafil plus BNP decreased mPAP and PVR for up to 6 h after stopping BNP. The decrease in mPAP with sildenafil plus BNP (+/- SE) was greater than after 1 h of sildenafil alone (44.6 +/- 3.8 to 40.6 +/- 3.9 mm Hg, p = 0.027). An acute vasodilator response, defined as a decrease in mPAP > 10 mm Hg and end mPAP < 40 mm Hg, was seen in 0 of 8 patients with iNO, 1 of 13 patients with epoprostenol, 0 of 13 patients with BNP, and 4 of 12 patients with sildenafil plus BNP. BNP decreased mean systemic arterial pressure (5.6 +/- 2.8 mm Hg) but had no effect on cardiac output or systemic vascular resistance., Conclusions: A 3-h BNP infusion does not significantly improve pulmonary hemodynamics in most patients with PAH but is well tolerated and augments the acute pulmonary vasodilator effect of sildenafil.

The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previously studied. We sought evidence for a role of 12-LO and 12(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small-size pulmonary arteries and in alveolar walls of hypoxic lungs. 12-LO protein expression was increased in hypoxic cultured rat pulmonary artery SMCs. 12(S)-HETE at concentrations as low as 10(-5) microM stimulated proliferation of pulmonary artery SMCs. 12(S)-HETE induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 12(S)-HETE-stimulated SMC proliferation was blocked by the MEK inhibitor PD-98059, but not by the p38 MAPK inhibitor SB-202190. Hypoxia (3%)-stimulated pulmonary artery SMC proliferation was blocked by both U0126, a MEK inhibitor, and baicalein, an inhibitor of 12-LO. We conclude that 12-LO and its product, 12(S)-HETE, are important intermediates in hypoxia-induced pulmonary artery SMC proliferation and may participate in hypoxia-induced pulmonary hypertension.

The selection of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) to receive noninvasive ventilation (NIV) is challenging, partly because there are few reliable selection criteria. The study by Rana and colleagues in the previous issue of Critical Care identifies metabolic acidosis and a lower oxygenation index as predictors of NIV failure, although it is unable to identify threshold values. It also demonstrates that treating patients with NIV for ALI/ARDS and shock is an exercise in futility. Future studies need to focus on criteria that will enable selection of patients for whom NIV will have a high likelihood of success.

Pulmonary rehabilitation programs use multidisciplinary teams to optimize physical and social functioning of patients with chronic respiratory impairment. These programs provide rehabilitation in inpatient, outpatient, or home settings, using at least three sessions weekly (one may be unsupervised) for at least 6 wk. The programs usually consist of exercise training, education, and psychosocial/behavioral components. Upper extremity exercises and instruction on breathing technique are included in most rehabilitation programs and reduce dyspnea, but the contribution of these to improved functional capacity remains unproven. Decreases in the sensation of dyspnea, increased functional exercise capacity, and enhanced quality of life of patients with chronic obstructive pulmonary disease (COPD) are established benefits of pulmonary rehabilitation. Evidence is lacking for the efficacy of rehabilitation for patients with non-COPD causes of pulmonary impairment, but many of these patients probably benefit. Despite the availability of strong evidence to support the efficacy of pulmonary rehabilitation programs in patients with severe COPD, third-party reimbursement policies have been inconsistent. Nonetheless, enrollment in a pulmonary rehabilitation program is encouraged for all appropriate candidates with chronic respiratory impairment, particularly for those with severe COPD.

Sildenafil and inhaled nitric oxide (iNO) relax smooth muscle by inhibiting the degradation and stimulating the production of cyclic guanosine monophosphate, respectively. We compared the acute pulmonary vasodilator effects of sildenafil, iNO, and epoprostenol and asked whether the combination of iNO with sildenafil had additive pulmonary vasodilator effects. We assessed the effects of extended use of sildenafil in a small cohort of patients. Twenty patients with pulmonary arterial hypertension underwent an acute vasodilator trial with sildenafil (all patients), iNO and iNO plus sildenafil (11), and epoprostenol (19). We also provided sildenafil to patients who were ineligible for, or had clinical deterioration on epoprostenol, treprostinil, or bosentan. Mean+/-se pulmonary artery pressure dropped by 13+/-3%, 19+/-4%, 14+/-3%, and 26+/-4% with epoprostenol, iNO, sildenafil, and iNO+sildenafil, respectively. Cardiac index increased with epoprostenol and sildenafil. A correlation was found between the effects of iNO and epoprostenol. Nine out of ten patients who were started on long-term sildenafil treatment alone or in combination with other vasodilators had symptomatic improvement. Three died of right heart failure. In conclusion, sildenafil is a potent acute pulmonary vasodilator, an effect that is potentiated by combination with iNO. Long-term therapy of pulmonary hypertension with sildenafil alone or in combination with other agents appears to be safe and well tolerated.

Phosphodiesterase-5 (PDE5) inhibitors and other agents that modulate intracellular cGMP are now emerging as promising, safe, and easy to administer therapies for pulmonary hypertension, with relatively few side effects. Recent studies have shown that PDE5 inhibitors are potent acute pulmonary vasodilators in experimental models that partially reverse established pulmonary arterial hypertension and blunt chronic pulmonary hypertension. In addition, studies on animals reveal that PDE5 inhibitors work in concert with nitric oxide and/or natriuretic peptide levels by enhancing intracellular cGMP and cGMP-mediated vasodilator effects. Further, the combination of PDE5 inhibitors and agents that increase cGMP or cAMP also yields additive beneficial effects on pulmonary hemodynamics in patients with pulmonary arterial hypertension.

Introduction: Hypercapnic coma secondary to acute respiratory failure (ARF) is considered to be a contraindication to the use of treatment with noninvasive positive-pressure ventilation (NPPV). However, intubation exposes these patients to the risk of complications such as nosocomial pneumonia, sepsis, and even death., Patients and Methods: We performed a prospective, open, noncontrolled study to assess the outcomes of NPPV therapy in patients with a Glasgow coma scale (GCS) score of 8 responded to therapy (70%; p = 0.04). A total of 25 coma patients died in the hospital (26.3%), and 287 noncoma patients died in the hospital (33.2%; p = 0.17). The variables related to the success of NPPV therapy were GCS score 1 h posttherapy (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.53 to 3.53) and higher levels of multiorgan dysfunction, as measured by the maximum sequential organ failure assessment index score reached during NPPV therapy (OR, 0.72; 95% CI, 0.55 to 0.92)., Conclusions: We concluded that selected patients with hypercapnic coma secondary to ARF can be treated as successfully with NPPV as awake patients with ARF.

Background: Retinoic acid has antimitogenic effects on smooth muscle cells. Studies on the systemic circulation suggest that it may reduce vascular thickening. Relationships between retinoids and pulmonary hypertension/pulmonary vascular remodeling, however, have not been explored. Thus, the present study examined retinoid levels in plasma of patients with idiopathic pulmonary arterial hypertension and the effects of retinoic acid on human pulmonary artery smooth muscle cell growth., Methods and Results: We measured retinoid levels by gas chromatograph-mass spectrometer technique in plasma of idiopathic pulmonary arterial hypertension patients and in age- and sex-matched healthy control subjects. Patients had significantly lower levels of all-trans retinoic acid and 13-cis retinoic acid than control subjects but similar 9-cis retinoic acid and retinol levels. In cultured human pulmonary artery smooth muscle cells, all-trans retinoic acid suppressed serotonin-induced cell growth. These cells were found to express the retinoid acid receptors RARalpha, RARbeta, RARgamma, RXRalpha, and RXRbeta. Gene array analysis showed that retinoic acid induces the expression of GADD45A, a known cell growth suppressor. Contrary to expectations, plasma from pulmonary hypertension patients suppressed cell growth, likely influenced by factors other than retinoids., Conclusions: Idiopathic pulmonary arterial hypertension patients have reduced retinoic acid levels, and retinoic acid treatment can elicit growth-inhibitory signals in pulmonary artery smooth muscle cells in vitro. Thus, retinoic acid may influence pulmonary vascular remodeling in humans.

Purpose of Review: This review critically examines recent literature related to applications of noninvasive ventilation in the acute setting., Recent Findings: Recent articles have strengthened the evidence supporting the use of noninvasive ventilation for patients with cardiogenic pulmonary edema and exacerbation of severe chronic pulmonary obstructive disease. In the former, however, it remains unclear whether noninvasive ventilation offers any significant advantages over continuous positive airway pressure. The rate of myocardial infarction seems to be no higher when patients with cardiogenic pulmonary edema are treated with noninvasive ventilation rather than continuous positive airway pressure, although caution is still advised in patients with acute coronary syndromes. Noninvasive ventilation also does not seem to increase the risk of dissemination of severe acute respiratory syndrome to health care workers as long as strict isolation procedures are used. Noninvasive ventilation facilitates weaning in patients with chronic obstructive pulmonary disease but should not be used routinely to treat extubation failure, and necessary intubation should not be delayed. Guidelines for the use of noninvasive ventilation can alter caregivers' behavior but have not been clearly shown to improve outcomes. Outcomes do seem to improve, however, as caregivers acquire experience with the technique., Summary: The recent literature has refined some of the current indications for noninvasive ventilation in the acute-care setting, including chronic pulmonary obstructive disease and cardiogenic pulmonary edema. Guidelines for use are now being developed, and outcomes seem to be improving, partly as a consequence of greater caregiver experience and possibly related to technologic advances.

Thoracic restrictive disorders (i.e., chest wall deformities or neuromuscular diseases), may predispose to sleep-disordered breathing, poor sleep quality, and nocturnal hypoventilation. These disorders intensify the effects of reductions in both respiratory center output and central chemosensitivity and increases in upper airway resistance that occur with the onset of sleep. Normally, rapid eye movement (REM) sleep suppresses the activity of nondiaphragmatic breathing muscles, further reducing ventilation. Diaphragmatic or upper airway muscle weakness and reduced chest wall compliance in patients with thoracic restrictive disorders enhance the severity of sleep-disordered breathing during REM sleep, worsening gas exchange abnormalities and sleep fragmentation and impairing daytime functioning. Although daytime respiratory function and nocturnal oxygen saturation are not well correlated, some markers may be useful for identifying patients with thoracic restriction at risk for sleep-disordered breathing. Although some patients may respond to continuous positive airway pressure (CPAP) alone, noninvasive positive pressure ventilation (NPPV) is a more important part of disease management for patients with restrictive thoracic disorders. This technique improves nocturnal ventilation and sleep quality but may also contribute to sleep fragmentation in some patients. If the patient is an unsuitable candidate for or fails NPPV, tracheostomy mechanical ventilation should be considered.

Fourteen Hereford steers were used to compare carcass traits, meat quality, and fatty acid composition of beef from cattle grazing tall fescue infected with either wild-type (E+; n = 6) or novel, nil ergot alkaloid (AR542; n = 8) endophyte for 209 d. Average daily gain, live weight, and HCW were greater (P < 0.05) for AR542 cattle than for E+. No differences in LM color or pH were observed between AR542 and E+. Steaks from E+ cattle tended (P = 0.10) to have higher L* and b* than those from AR542 cattle at 0 d of display. Ground beef from E+ cattle also had higher (P < 0.05) L* than AR542 cattle, with no differences in a* or b* at 0 d of display. Color changes during display did not differ for both steaks and ground beef from E+ and AR542. Lipid oxidation levels increased (P < 0.05) during simulated retail display, but they did not differ between endophyte treatments. Adipose tissues from E+ cattle had a higher (P < 0.05) percentage of SFA, and a lower (P < 0.05) percentage of MUFA than adipose from AR542 cattle. Ground beef and i.m. fat had higher (P < 0.05) concentrations of SFA, MUFA, and cis-9, trans-11 isomer of conjugated linoleic acid, and lower (P < 0.05) concentrations of PUFA and PUFA:SFA ratio than s.c. fat. The n-6:n-3 fatty acid ratio did not differ among fat depots. Ergot-alkaloids were detected in s.c. adipose tissues, and alkaloid concentration was greater (P < 0.05) for E+ than AR542. Warner-Bratzler shear force values did not differ between endophyte types, but it decreased (P < 0.01) across the postmortem aging period. Conversely, sensory panel evaluation detected greater (P < 0.01) chewiness and lower (P < 0.05) juiciness for AR542 than for E+ steaks aged for 14 d. Although grazing cattle on tall fescue pastures infected with nil ergot alkaloid endophyte improved cattle performance, these results suggest that endophyte type has minor effects on carcass traits and meat quality of pasture-fed beef. Moreover, finishing cattle on tall fescue pastures showed the potential to enhance the fatty acid profile of beef from a human health perspective. Alkaloid concentration was greater (P < 0.05) in s.c. fat from E+ than AR542 (2.81 vs. 0.92 ppb; fresh-tissue basis). This is the first published report demonstrating the presence of alkaloids in beef tissues.

Context: The results of studies on noninvasive positive pressure ventilation (NPPV) for acute hypoxemic respiratory failure unrelated to cardiogenic pulmonary edema have been inconsistent., Objective: To assess the effect of NPPV on the rate of endotracheal intubation, intensive care unit and hospital length of stay, and mortality for patients with acute hypoxemic respiratory failure not due to cardiogenic pulmonary edema., Data Source: We searched the databases of MEDLINE (1980 to October 2003) and EMBASE (1990 to October 2003). Additional data sources included the Cochrane Library, personal files, abstract proceedings, reference lists of selected articles, and expert contact., Study Selection: We included studies if a) the design was a randomized controlled trial; b) patients had acute hypoxemic respiratory failure not due to cardiogenic pulmonary edema; c) the interventions compared noninvasive ventilation and standard therapy with standard therapy alone; and d) outcomes included need for endotracheal intubation, length of intensive care unit or hospital stay, or intensive care unit or hospital survival., Data Extraction: In duplicate and independently, we abstracted data to evaluate methodological quality and results., Data Synthesis: The addition of NPPV to standard care in the setting of acute hypoxemic respiratory failure reduced the rate of endotracheal intubation (absolute risk reduction 23%, 95% confidence interval 10-35%), ICU length of stay (absolute reduction 2 days, 95% confidence interval 1-3 days), and ICU mortality (absolute risk reduction 17%, 95% confidence interval 8-26%). However, trial results were significantly heterogeneous., Conclusion: Randomized trials suggest that patients with acute hypoxemic respiratory failure are less likely to require endotracheal intubation when NPPV is added to standard therapy. However, the effect on mortality is less clear, and the heterogeneity found among studies suggests that effectiveness varies among different populations. As a result, the literature does not support the routine use of NPPV in all patients with acute hypoxemic respiratory failure.

We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase stimulator, atrial natriuretic peptide (ANP), would act synergistically to increase cGMP levels and blunt hypoxic pulmonary hypertension in rats, because these compounds act via different mechanisms to increase the intracellular second messenger. Acute hypoxia: Adult Sprague-Dawley rats were gavaged with sildenafil (1 mg/ kg) or vehicle and exposed to acute hypoxia with and without ANP (10(-8)-10(-5) M ). Sildenafil decreased systemic blood pressure (103 +/- 10 vs. 87 +/- 6 mm Hg, P < 0.001) and blunted the hypoxia-induced increase in right ventricular systolic pressure (RVSP; percent increase 73.7% +/- 9.4% in sildenafil-treated rats vs. 117.2% +/- 21.1% in vehicle-treated rats, P = 0.03). Also, ANP and sildenafil had synergistic effects on blunting the hypoxia-induced increase in RVSP (P < 0.001) and on rising plasma cGMP levels (P < 0.05). Chronic hypoxia: Other rats were exposed to prolonged hypoxia (3 weeks, 0.5 atm) after subcutaneous implantation of a sustained-release pellet containing lower (2.5 mg), or higher (25 mg) doses of sildenafil, or placebo. Higher-dose, but not lower-dose sildenafil blunted the chronic hypoxia-induced increase in RVSP (P = 0.006). RVSP and plasma sildenafil levels were inversely correlated in hypoxic rats (r(2) = 0.68, P = 0.044). Lung cGMP levels were increased by both chronic hypoxia and sildenafil, with the greatest increase achieved by the combination. Plasma and right ventricular (RV) cGMP levels were increased by hypoxia, but sildenafil had no effect. RV hypertrophy and pulmonary artery muscularization were also unaffected by sildenafil. In conclusion, sildenafil and ANP have synergistic effects on the blunting of hypoxia-induced pulmonary vasoconstriction. During chronic hypoxia, sildenafil normalizes RVSP, but in the doses used, sildenafil has no effect on RV hypertrophy or pulmonary vascular remodeling.

Objective: To determine whether diagnosis and bedside observations predict outcomes of patients who have declined intubation but accept noninvasive positive pressure ventilation (NPPV) to treat their respiratory failure., Design: Prospective multiple-center cohort trial., Setting: Two teaching hospitals and two community-based hospitals in southeastern New England from January through October 1999., Patients: All patients receiving NPPV for acute respiratory failure were screened and enrolled if they had a written do-not-intubate (DNI) order., Interventions: Patients were begun on NPPV with mean inspiratory and expiratory pressures of 13.4 +/- 0.3 and 5.0 +/- 1 cm H2O, respectively. Respiratory therapists recorded demographic information, blood gases, and ventilator type and settings, and they made bedside assessments of cough strength, presence of airway secretions, awake state, and agitation. Patients were followed until discharge for duration of NPPV, survival status, and disposition., Measurements and Main Results: Of 1,211 screened patients, 114 had a DNI status and were enrolled into the study. Of these, 49 (43%) survived to discharge. Age, gender, location in a community vs. teaching hospital, and initial pH and PaO2 did not affect survival, but a higher baseline PaCO2 was associated with a favorable odds ratios for survival to discharge. Diagnosis was an important determinant of survival, with congestive heart failure patients having significantly better survival rates than those with chronic obstructive pulmonary disease, cancer, pneumonia, or other diagnoses. A stronger cough and being awake were also associated with increased probability of survival., Conclusion: Patients with respiratory failure and a DNI status have a high overall mortality rate when treated with NPPV, but those with diagnoses such as congestive heart failure or chronic obstructive pulmonary disease, who have a strong cough, or who are awake have better prognoses. These data should be useful when counseling DNI patients and their families on use of NPPV.

Consumption of wild-type (toxic) endophyte-infected tall fescue (E+) by horses during late gestation is known to adversely affect pregnancy outcome; however, little is known of the potential disruptive consequences of E+ consumption by mares during the critical phases of placentation and fetal development in early pregnancy. The objective of this study was to evaluate the detrimental effects of feeding E+ to mares during early gestation. Mares (n = 12) paired by stage of gestation (d 65 to 100) were assigned to diets (six per diet) consisting of endophyte-free (E-) or E+ tall fescue seed (50% E- or E+ tall fescue seed, 45% sweet feed, and 10% molasses fed at 1.0% of BW/d). Mares also had ad libitum access to E+ or E- annual ryegrass hay, and were fed diets for 10 d. Following removal from the tall fescue diet on d 11, mares were placed on common bermudagrass pasture and monitored until d 21. Morning and evening rectal temperatures were recorded and daily blood samples were collected for progesterone and prolactin (PRL) analyses, whereas samples for 3,4-dihydroxyphenyl acetic acid (a catecholamine metabolite) analysis were collected on alternate days. For clinical chemistry analysis, blood samples were collected on d 0, 5, 10 and 21. Daily urine samples were collected for ergot alkaloid analysis, and ultrasonography was performed for presence of echogenic material in fetal fluids. Rectal temperatures (E+ 37.76+/-0.03; E- 37.84+/-0.03 degrees C) and serum PRL concentrations (E+ 14.06< or =0.76; E- 12.11+/-0.76 ng/mL) did not differ (P = 0.96) between treatments. Measuring the change in basal serum concentration from d 0 over time, progesterone concentrations did not differ (-0.64 +/-1.49 and -0.55+/-1.47 ng/mL for E+ and E- mares, respectively). There was no negative pregnancy outcome, and ultrasonography indicated no increase in echogenic material in fetal fluids. Plasma 3,4-dihydroxyphenyl acetic acid concentrations decreased (P < 0.05) in E+ compared with E- mares (2.1+/-0.14 and 4.4+/0.43 ng/mL, respectively). Urinary ergot alkaloid concentration was greater (P < 0.01) in mares consuming E+ compared with E- (532.12+/- 52.51 and 13.36+/-2.67 ng/mg of creatinine, respectively). Although no fetal loss was observed during the current study, elevated concentrations of urinary ergot alkaloid were consistent with depressed endogenous catecholamine activity, suggestive of an endocrine disruptive effect of hypothalamic origin.

Objective: The purpose of the conference was to provide clinical practice guidance in end-of-life care in the ICU via answers to previously identified questions relating to variability in practice, inadequate predictive models for death, elusive knowledge of patient preferences, poor communication between staff and surrogates, insufficient or absent training of healthcare providers, the use of imprecise and insensitive terminology and incomplete documentation in the medical record., Participants: Presenters and jury were selected by the sponsoring organizations (American Thoracic Society, European Respiratory Society, European Society of Intensive Care Medicine, Society of Critical Care Medicine, Société de Réanimation de Langue Française). Presenters were experts on the question they addressed. Jury members were general intensivists without special expertise in the areas considered. Experts presented in an open session to jurors and other healthcare professionals., Evidence: Experts prepared review papers on their specific topics in advance of the conference for the jury's reference in developing the consensus statement., Consensus Process: Jurors heard experts' presentations over 2 days and asked questions of the experts during the open sessions. Jury deliberation with access to the review papers occurred for 2 days following the conference. A writing committee drafted the consensus statement for review by the entire jury. The 5 sponsoring organizations reviewed the document and suggested revisions to be incorporated into the final statement., Conclusions: Strong recommendations for research to improve end-of-life care were made. The jury advocates a shared approach to end-of-life decision-making involving the caregiver team and patient surrogates. Respect for patient autonomy and the intention to honor decisions to decline unwanted treatments should be conveyed to the family. The process is one of negotiation, and the outcome will be determined by the personalities and beliefs of the participants. Ultimately, it is the attending physician's responsibility, as leader of the team, to decide on the reasonableness of the planned action. If a conflict cannot be resolved, an ethics consultation may be helpful. The patient must be assured of a pain-free death. The jury subscribes to the moral and legal principles that prohibit administering treatments specifically designed to hasten death. The patient must be given sufficient analgesia to alleviate pain and distress; if such analgesia hastens death, this "double-effect" should not detract from the primary aim to ensure comfort.