Matthew R. Lammi

Response to Fluid Boluses in the Fluid and Catheter Treatment Trial

BACKGROUND Recent emphasis has been placed on methods to predict fluid responsiveness, but the usefulness of using fluid boluses to increase cardiac index in critically ill patients with ineffective circulation or oliguria remains unclear. METHODS This retrospective analysis investigated hemodynamic responses of critically ill patients in the ARDS Network Fluid and Catheter Treatment Trial (FACTT) who were given protocol-based fluid boluses. Fluid responsiveness was defined as ≥ 15% increase in cardiac index after a 15 mL/kg fluid bolus. RESULTS A convenience sample of 127 critically ill patients enrolled in FACTT was analyzed for physiologic responses to 569 protocolized crystalloid or albumin boluses given for shock, low urine output (UOP), or low pulmonary artery occlusion pressure (PAOP). There were significant increases in mean central venous pressure (9.9 ± 4.5 to 11.1 ± 4.8 mm Hg, P < .0001) and mean PAOP (11.6 ± 3.6 to 13.3 ± 4.3 mm Hg, P < .0001) following fluid boluses. However, there were no significant changes in UOP, and there were clinically small changes in heart rate, mean arterial pressure, and cardiac index. Only 23% of fluid boluses led to a ≥ 15% change in cardiac index. There was no significant difference in the frequency of fluid responsiveness between boluses given for shock or oliguria vs boluses given only for low PAOP (24.0% vs 21.8%, P = .59). There were no significant differences in 90-day survival, need for hemodialysis, or return to unassisted breathing between patients defined as fluid responders and fluid nonresponders. CONCLUSIONS In this cohort of critically ill patients with ARDS who were previously resuscitated, the rate of fluid responsiveness was low, and fluid boluses only led to small hemodynamic changes.

Increased oxygen pulse after lung volume reduction surgery is associated with reduced dynamic hyperinflation

Stroke volume augmentation during exercise is limited in chronic obstructive pulmonary disease patients because of decreased preload from dynamic hyperinflation (DH). We hypothesised that oxygen pulse and pulse pressure (PP) improve following lung volume reduction surgery (LVRS), and the magnitude of improvement correlates with reduction in DH. We compared 16 emphysema patients undergoing LVRS with six emphysema patients not undergoing LVRS. Oxygen pulse and PP were calculated from maximal cardiopulmonary exercise tests at baseline and 6 months. End-expiratory lung volume (EELV)/total lung capacity (TLC) represented DH. Comparisons were made between baseline and 6 months at metabolic isotimes (per cent maximal carbon dioxide production (V′CO2,max)). At baseline, the LVRS group was older with higher forced expiratory volume in 1 s, but had similar hyperinflation to the non-LVRS group. At 6 months, oxygen pulse (50%, 75%, and 100% V′CO2,max) and PP (50% and 75% V′CO2,max) increased in the LVRS, but not in the non-LVRS group. Baseline functional residual capacity/TLC inversely correlated with resting oxygen pulse (r= -0.449, p=0.04). Decreased EELV/TLC correlated with increased oxygen pulse at 75% (r= -0.487, p=0.02) and 100% V′CO2,max (r= -0.548, p=0.008). LVRS led to increased oxygen pulse and PP during exercise at metabolic isotimes 6 months following surgery. Reductions in DH correlated with increases in oxygen pulse during exercise. Reducing lung volume may improve stroke volume response to exercise by decreasing DH.

DNA-dependent protein kinase inhibition blocks asthma in mice and modulates human endothelial and CD4+ T-cell function without causing severe combined immunodeficiency

BACKGROUND We reported that DNA-dependent protein kinase (DNA-PK) is critical for the expression of nuclear factor κB-dependent genes in TNF-α-treated glioblastoma cells, suggesting an involvement in inflammatory diseases. OBJECTIVE We sought to investigate the role of DNA-PK in asthma. METHODS Cell culture and ovalbumin (OVA)- or house dust mite-based murine asthma models were used in this study. RESULTS DNA-PK was essential for monocyte adhesion to TNF-α-treated endothelial cells. Administration of the DNA-PK inhibitor NU7441 reduced airway eosinophilia, mucus hypersecretion, airway hyperresponsiveness, and OVA-specific IgE production in mice prechallenged with OVA. Such effects correlated with a marked reduction in lung vascular cell adhesion molecule 1 expression and production of several cytokines, including IL-4, IL-5, IL-13, eotaxin, IL-2, and IL-12 and the chemokines monocyte chemoattractant protein 1 and keratinocyte-derived chemokine, with a negligible effect on IL-10/IFN-γ production. DNA-PK inhibition by gene heterozygosity of the 450-kDa catalytic subunit of the kinase (DNA-PKcs(+/-)) also prevented manifestation of asthma-like traits. These results were confirmed in a chronic model of asthma by using house dust mite, a human allergen. Remarkably, such protection occurred without causing severe combined immunodeficiency. Adoptive transfer of TH2-skewed OT-II wild-type CD4(+) T cells reversed IgE and TH2 cytokine production but not airway hyperresponsiveness in OVA-challenged DNA-PKcs(+/-) mice. DNA-PK inhibition reduced IL-4, IL-5, IL-13, eotaxin, IL-8, and monocyte chemoattractant protein 1 production without affecting IL-2, IL-12, IFN-γ, and interferon-inducible protein 10 production in CD3/CD28-stimulated human CD4(+) T cells, potentially by blocking expression of Gata3. These effects occurred without significant reductions in T-cell proliferation. In mouse CD4(+) T cells in vitro DNA-PK inhibition severely blocked CD3/CD28-induced Gata3 and T-bet expression in CD4(+) T cells and prevented differentiation of TH1 and TH2 cells under respective TH1- and TH2-skewing conditions. CONCLUSION Our results suggest DNA-PK as a novel determinant of asthma and a potential target for the treatment of the disease.

Pulmonary Tumor Embolism

A 36-year-old woman with breast cancer was admitted with shortness of breath. A computed tomography angiogram was obtained and was negative for pulmonary embolism. She quickly developed hypoxemic respiratory failure and was transferred to the intensive care unit. She appeared to be improving when she suffered sudden cardiac death. Autopsy showed extensive lymphatic and vascular tumor emboli, which were the immediate cause of death. Tumor emboli are rarely diagnosed before death but seem to be more common than realized. It is important to recognize this entity, because there have been some case reports of cure. The usual mechanism of death is progressive right heart failure; sudden death from tumor embolism has rarely been described.

Treatment with intranasal iloprost reduces disease manifestations in a murine model of previously established COPD

Pulmonary endothelial prostacyclin appears to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The effect of treatment with a prostacyclin analog in animal models of previously established COPD is unknown. We evaluated the short- and long-term effect of iloprost on inflammation and airway hyperresponsiveness (AHR) in a murine model of COPD. Nineteen mice were exposed to LPS/elastase, followed by either three doses of intranasal iloprost or saline. In the long-term treatment experiment, 18 mice were exposed to LPS/elastase and then received 6 wk of iloprost or were left untreated as controls. In the short-term experiment, iloprost did not change AHR but significantly reduced serum IL-5 and IFN-γ. Long-term treatment with iloprost for both 2 and 6 wk significantly improved AHR. After 6 wk of iloprost, there was a reduction in bronchoalveolar lavage (BALF) neutrophils, serum IL-1β (30.0 ± 9.2 vs. 64.8 ± 7.4 pg/ml, P = 0.045), IL-2 (36.5 ± 10.6 vs. 83.8 ± 0.4 pg/ml, P = 0.01), IL-10 (75.7 ± 9.3 vs. 96.5 ± 3.5 pg/ml, P = 0.02), and nitrite (15.1 ± 5.4 vs. 30.5 ± 10.7 μmol, P = 0.01). Smooth muscle actin (SMA) in the lung homogenate was also significantly reduced after iloprost treatment (P = 0.02), and SMA thickness was reduced in the small and medium blood vessels after iloprost (P < 0.001). In summary, short- and long-term treatment with intranasal iloprost significantly reduced systemic inflammation in an LPS/elastase COPD model. Long-term iloprost treatment also reduced AHR, serum nitrite, SMA, and BALF neutrophilia. These data encourage future investigations of prostanoid therapy as a novel treatment for COPD patients.

Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity

Although expression of inducible NO synthase (iNOS) in the lungs of asthmatics and associated nitrosative damage are established, iNOS failed as a therapeutic target for blocking airway hyperresponsiveness (AHR) and inflammation in asthmatics. This dichotomy calls for better strategies with which the enzyme is adequately targeted. Here, we confirm iNOS expression in the asthmatic lung with concomitant protein nitration and poly(ADP-ribose) polymerase (PARP) activation. We show, for the first time, that iNOS is highly expressed in peripheral blood mononuclear cells (PBMCs) of asthmatics with uncontrolled disease, which did not correspond to protein nitration. Selective iNOS inhibition with L-NIL protected against AHR upon acute, but not chronic, exposure to ovalbumin or house dust mite (HDM) in mice. Supplementation of NO by nitrite administration significantly blocked AHR in chronically HDM-exposed mice that were treated with L-NIL. Protection against chronic HDM exposure-induced AHR by olaparib-mediated PARP inhibition may be associated with the partial but not the complete blockade of iNOS expression. Indeed, L-NIL administration prevented olaparib-mediated protection against AHR in chronically HDM-exposed mice. Our study suggests that the amount of iNOS and NO are critical determinants in the modulation of AHR by selective iNOS inhibitors and renews the potential of iNOS as a therapeutic target for asthma.

SAT0442 Mycophenolate Mofetil (MMF) Use in Scleroderma Patients with Pulmonary Hypertension: FVC, Outcomes and Survival- Observations from the Pulmonary Hypertension Recognition and Outcomes in Scleroderma (Pharos) Cohort

Background Systemic sclerosis (SSc) related pulmonary hypertension (PH) carries a high mortality and patients with SSc-PH related to restrictive lung disease (RLD) having an even worse prognosis. Speculation regarding the potential of MMF to exert anti-fibrotic and anti-remodeling effects on parenchymal lung and vascular intimal fibrosis, led us to query the possible differences in outcomes and survival between 4 groups based on forced vital capacity (FVC) and MMF use in SSc PH. Methods PHAROS is a prospective registry designed to provide substantive data to recognize aspects of PH unique to SSc. For this analysis patients were stratified by an FVC of >70% or ≤70% predicted on spirometry at the time of PH diagnosis by right heart catheterization (RHC) and then by MMF duration of ≥6 months from PH diagnosis. MMF<6 months or cyclophosphamide use was exclusionary to all groups. Calculations are derived from one-way ANOVA with Tukeys post test or Kruskal Wallis with Dunns post-test. Categorical variables were compared with Chi square. These analyses were followed by Cox and stepwise backward regression analysis to assess baseline characteristics associated with risk of death (variables with p<0.1 included) and Kaplan-Meyer analysis. Results 256 cases from the PHAROS database matched criteria and had baseline spirometry results coincident with diagnostic RHC, of those 173 had a baseline FVC>70% with 23 on MMF and 150 without; and 83 had a baseline FVC≤70% with 26 on MMF and 57 without. Across groups, no differences were found in age, disease duration, race nor surprisingly in skin score, 6 minute walk test (6MWD) or NYHA Class. WHO Group I, female sex and lcSSc classification were higher in the FVC>70 MMF- group; with FVC≤70%/RLD groups having significantly more lung fibrosis, lower FVC:DLCO ratio, and more WHO Group III classifications supporting our RLD definition. There was no significant interval change in baseline FVC and follow-up FVC 6-18 month later. Of interest, baseline mPAP and PVR were lower in both MMF+ groups regardless of FVC. Survival was statistically worse with FVC≤70 without MMF at 3 years (p=0.04). Male sex, mPAP, DLCO were significant independent predictors of death in all groups (p=0.001, p<0.0001, p<0.0001) especially when FVC was ≤70% (p=0.007, p=0.003, p=0.005). Conclusions Statistically significant improved survival in patients with PH with FVC≤70 treated with MMF even in the absence of improvement of FVC is intriguing. MMF effects on pulmonary artery remodeling should be considered. These findings warrant prospective controlled investigations and examination of larger combined international databases of MMF in SScPH particularly in those with restrictive lung disease. Acknowledgements PHAROS is supported by an investigator initiated grant from Gilead Science. Disclosure of Interest L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee; Gilead, M. Lammi: None declared, A. Fischer: None declared, J. Molitor: None declared, V. Steen Grant/research support from: Actelion Pharmaceuticals US Bayer CSL Berhing Intermune Roche Pharmaceuticals Sanofi-Aventis Pharmaceutical UCB United Therapeutics

Association Between Initial Oral Therapy and Outcomes in Systemic Sclerosis-Related Pulmonary Arterial Hypertension.

To compare time to clinical worsening (TTCW) based on initial oral therapy for pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc)–related PAH.

Heterogeneity of Lung Volume Reduction Surgery Outcomes in Patients Selected by Use of Evidence-Based Criteria

BACKGROUND Despite its benefit, lung volume reduction surgery (LVRS) is underused, partially because of the heterogeneous responses and lack of recent outcomes data. METHODS Data from 59 consecutive emphysema patients who underwent LVRS were analyzed. The proportion of patients responding based on 6-minute walk distance (6-MWD), exercise capacity (watts), and forced expiratory volume in 1 second (FEV1) were calculated. Baseline variables were correlated with improvements in 6-MWD, maximal watts, and FEV1. RESULTS Eighty-eight percent of patients responded to LVRS, with a higher proportion of FEV1 and 6-MWD responders in our cohort compared with similar patients from the National Emphysema Treatment Trial. Significant associations existed between lower baseline 6-MWD and increased 6-MWD after operation (r = -0.423), more extensive emphysema and increased FEV1 (r = 0.491), and hyperinflation and increased maximal watts (r = 0.438). The probability of survival was 0.93 at 90 days, 0.90 at 1 year, and 0.80 (3 years). The lowest exercise group (<20 watts on baseline testing) had an increased risk for death (RR 13.3, p = 0.001). CONCLUSIONS There were durable improvements in FEV1 and exercise capacity in patients meeting the National Emphysema Treatment Trial criteria. Survival was comparable to that in similar patients from the National Emphysema Treatment Trial; response rates were higher in our cohort for FEV1 and 6-MWD. Those with lower 6-MWD, more emphysema, and more hyperinflation at baseline were most likely to respond to LVRS. Those with lowest exercise capacity at baseline may have a higher risk of death after LVRS.

Clinical Differences in COPD Patients with Variable Patterns of Hypoxemia

Background: Chronic obstructive pulmonary disease (COPD) patients enrolled into the Long-term Oxygen Treatment Trial had hypoxemia at rest, hypoxemia on exertion, or hypoxemia both at rest and on exertion. We hypothesized that patients with different patterns of hypoxemia may have significant differences in clinical features. Methods: All patients had COPD and oxygen saturation measured by pulse oximetry (blood oxygenation [SpO2]) at rest and during the 6-minute walk test (6MWT). Hypoxemia at rest was defined as resting SpO2 between 89-93%. SpO2 < 90% for at least 10 seconds and ³ 80% for at least 5 minutes during ambulation characterized hypoxemia on exertion. Severe exercise hypoxemia (< 80% for > 1 minute) was exclusionary. Results: Of 738 patients studied, 133 (18.0%) had mild-moderate hypoxemia at rest only, 319 (43.2%) had hypoxemia on exertion only, and 286 (38.8%) had hypoxemia at both rest and exertion. Patients with hypoxemia at rest only were more likely to be current smokers, had higher body mass index (BMI) and a higher incidence of self-reported diabetes. Patients with hypoxemia on exertion only were more severely obstructed compared to the other groups. General and disease-specific quality of life scores were similarly impaired in all groups. Quality of well-being scores were more impaired in those with hypoxemia at rest only. Conclusions: COPD patients with mild-moderate hypoxemia have distinct clinical characteristics based on the pattern of oxygen desaturation at rest and with exertion.