Brian Casserly

The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients.

Like the systemic inflammatory response syndrome (SIRS), the compensatory anti-inflammatory response syndrome (CARS) is a complex pattern of immunologic responses to severe infection or injury. The difference is that while SIRS is a proinflammatory response tasked with killing infectious organisms through activation of the immune system, CARS is a global deactivation of the immune system tasked with restoring homeostasis. Much research now suggests that the timing and relative magnitude of this response have a profound impact on patient outcomes.

Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent

B-type natriuretic peptide (BNP) is a member of the natriuretic peptide family, a group of widely distributed, but evolutionarily conserved, polypeptide mediators that exert myriad cardiovascular effects. BNP is a potent vasodilator with mitogenic, hypertrophic and pro-inflammatory properties that is upregulated in pulmonary hypertensive diseases. Circulating levels of BNP correlate with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH). Elevated plasma BNP levels are associated with increased mortality in patients with PAH and a fall in BNP levels after therapy is associated with improved survival. These findings have important clinical implications in that a noninvasive blood test may be used to identify PAH patients at high-risk of decompensation and to guide pulmonary vasodilator therapy. BNP also has several biologic effects that could be beneficial to patients with PAH. However, lack of a convenient method for achieving sustained increases in circulating BNP levels has impeded the development of BNP as a therapy for treating pulmonary hypertension. New technologies that allow transdermal or oral administration of the natriuretic peptides have the potential to greatly accelerate research into therapeutic use of BNP for cor pulmonale and pulmonary vascular diseases. This review will examine the basic science and clinical research that has led to our understanding of the role of BNP in cardiovascular physiology, its use as a biomarker of right ventricular function and its therapeutic potential for managing patients with pulmonary vascular disease.

Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign

ObjectiveThe Surviving Sepsis Campaign (SSC) developed guidelines and treatment bundles for the administration of steroids in adult septic shock. However, it is not clear how this has affected clinical practice or patient outcome.Design and settingThe SSC has developed an extensive database to assess the overall effect of its guidelines on clinical practice and patient outcome. This analysis focuses on one particular element of the SSC’s management bundle, namely, the administration of low-dose steroids in adult septic shock. This analysis was conducted on data submitted from January 2005 through March 2010 including 27,836 subjects at 218 sites.Main resultsA total of 17,847 (of the total 27,836) patients in the database required vasopressor therapy despite fluid resuscitation and therefore met the eligibility criteria for receiving low-dose steroids. A total of 8,992 patients (50.4xa0%) received low-dose steroids for their septic shock. Patients in Europe (59.4xa0%) and South America (51.9xa0%) were more likely to be prescribed low-dose steroids compared to their counterparts in North America (46.2xa0%, pxa0<xa00.001). The adjusted hospital mortality was significantly higher (OR 1.18, 95xa0% CI 1.09–1.23, pxa0<xa00.001) in patients who received low-dose steroids compared to those who did not. There was still an association with increased adjusted hospital mortality with low-dose steroids even if they were prescribed within 8xa0h (OR 1.23, 95xa0% CI 1.13–1.34, pxa0<xa00.001).ConclusionsSteroids were commonly administered in the treatment of septic shock in this subset analysis of the Surviving Sepsis Campaign database. However, this was associated with an increase in adjusted hospital mortality.

Role of protein tyrosine phosphatase SHP2 in barrier function of pulmonary endothelium

Pulmonary edema is mediated in part by disruption of interendothelial cell contacts. Protein tyrosine phosphatases (PTP) have been shown to affect both cell-extracellular matrix and cell-cell junctions. The SH2 domain-containing nonreceptor PTP, SHP2, is involved in intercellular signaling through direct interaction with adherens junction proteins. In this study, we examined the role of SHP2 in pulmonary endothelial barrier function. Inhibition of SHP2 promoted edema formation in rat lungs and increased monolayer permeability in cultured lung endothelial cells. In addition, pulmonary endothelial cells demonstrated a decreased level of p190RhoGAP activity following inhibition of SHP2, events that were accompanied by a concomitant increase in RhoA activity. Furthermore, immunofluorescence microscopy confirmed enhanced actin stress fiber formation and diminished interendothelial staining of adherens junction complex-associated proteins upon SHP2 inhibition. Finally, immunoprecipitation and immunoblot analyses demonstrated increased tyrosine phosphorylation of VE-cadherin, beta-catenin, and p190RhoGAP proteins, as well as decreased association between p120-catenin and VE-cadherin proteins. Our findings suggest that SHP2 supports basal pulmonary endothelial barrier function by coordinating the tyrosine phosphorylation profile of VE-cadherin, beta-catenin, and p190RhoGAP and the activity of RhoA, signaling molecules important in adherens junction complex integrity.

Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement

We have previously demonstrated that adenosine plus homocysteine enhanced endothelial basal barrier function and protected against agonist-induced barrier dysfunction in vitro through attenuation of RhoA activation by inhibition of isoprenylcysteine-O-carboxyl methyltransferase. In the current study, we tested the effect of elevated adenosine on pulmonary endothelial barrier function in vitro and in vivo. We noted that adenosine alone dose dependently enhanced endothelial barrier function. While adenosine receptor A(1) or A(3) antagonists were ineffective, an adenosine transporter inhibitor, NBTI, or a combination of DPMX and MRS1754, antagonists for adenosine receptors A(2A) and A(2B), respectively, partially attenuated the barrier-enhancing effect of adenosine. Similarly, inhibition of both A(2A) and A(2B) receptors with siRNA also blunted the effect of adenosine on barrier function. Interestingly, inhibition of both transporters and A(2A)/A(2B) receptors completely abolished adenosine-induced endothelial barrier enhancement. The adenosine receptor A(2A) and A(2B) agonist, NECA, also significantly enhanced endothelial barrier function. These data suggest that both adenosine transporters and A(2A) and A(2B) receptors are necessary for exerting maximal effect of adenosine on barrier enhancement. We also found that adenosine enhanced Rac1 GTPase activity and overexpression of dominant negative Rac1 attenuated adenosine-induced increases in focal adhesion complexes. We further demonstrated that elevation of cellular adenosine by inhibition of adenosine deaminase with Pentostatin significantly enhanced endothelial basal barrier function, an effect that was also associated with enhanced Rac1 GTPase activity and with increased focal adhesion complexes and adherens junctions. Finally, using a non-inflammatory acute lung injury (ALI) model induced by alpha-naphthylthiourea, we found that administration of Pentostatin, which elevated lung adenosine level by 10-fold, not only attenuated the development of edema before ALI but also partially reversed edema after ALI. The data suggest that adenosine deaminase inhibition may be useful in treatment of pulmonary edema in settings of ALI.

Activation of endothelial BKCa channels causes pulmonary vasodilation.

BACKGROUNDnLarge-conductance Ca(2+)-activated K(+) (BK(Ca)) channels cause hyperpolarization and can regulate vascular tone. In this study, we evaluated the effect of endothelial BK(Ca) activation on pulmonary vascular tone.nnnMETHODSnThe presence of BK(Ca) channels in lung microvascular endothelial cells (LMVEC) and rat lung tissue was confirmed by RT-PCR, immunoblotting and immunohistochemistry. Isolated pulmonary artery (PA) rings and isolated ventilated-perfused rat lungs were used to assay the effects of BK(Ca) channel activation on endothelium-dependent vasodilation.nnnRESULTSnImmunoblotting and RT-PCR revealed the presence of BK(Ca) channel alpha- and beta(4)-subunits in LMVEC. Immunohistochemical staining showed BK(Ca) channel alpha-subunit expression in vascular endothelium in rat lungs. In arterial ring studies, BK(Ca) channel activation by NS1619 enhanced endothelium-dependent vasodilation that was attenuated by tetraethylammonium and iberiotoxin. In addition, activation of BK(Ca) channels by C-type natriuretic peptide caused endothelial-dependent vasodilation that was blocked by iberiotoxin, L-NAME, and lanthanum. Furthermore, BK(Ca) activation by NS1619 caused a dose-dependent reduction in PA pressures that was attenuated by L-NAME. In vitro, BK(Ca) channel activation in LMVEC caused hyperpolarization and increased NO production.nnnCONCLUSIONSnPulmonary endothelium expresses BK(Ca) channels. Activation of endothelial BK(Ca) channels causes hyperpolarization and NO mediated endothelium-dependent vasodilation in micro- and macrovasculature in the lung.

Association of change in depression and anxiety symptoms with functional outcomes in pulmonary rehabilitation patients

OBJECTIVEnPulmonary rehabilitation (PR) has emerged over the last decade as an essential component of an integrated approach to managing patients with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). We sought to examine how depression and anxiety symptom changes relate to disease-specific quality of life outcomes following PR.nnnMETHODSnWe performed a cohort study of 81 patients with COPD who completed PR at a Veterans Administration Medical Center. Pulmonary rehabilitation consisted of supervised exercise training and education twice weekly for 8 weeks. Beck Depression and Anxiety Inventories (BDI and BAI) assessed symptom burden at baseline and completion of PR. We measured change in disease-specific quality of life using the dyspnea, mastery, emotion and fatigue domains of the Chronic Respiratory Questionnaire Self-Reported (CRQ-SR) from baseline to completion of PR.nnnRESULTSnParticipants were 69.8±9.1 years old and all male. Forced expiratory volume in 1 s (FEV1) was 1.23±0.39 L. The CRQ-SR scores improved significantly: dyspnea (P<.0001), mastery (P=.015) and fatigue (P=.017). The BDI scores improved significantly (13.1±10.5 to 10.8±9.9, P=.003; BAI: 13.1±10.1 to 12.1±11.7). Multivariate regression models controlling for age, FEV1, depression treatment and anxiety treatment showed that improvement in depressive symptoms were associated with improvement in fatigue (P=.003), emotion (P=.003) and mastery (P=.01). Anxiety symptom change was not significantly associated with change in disease-specific quality of life domains.nnnCONCLUSIONnAddressing anxiety symptoms in PR patients may be indicated because disease-specific quality of life improvement appears to be associated with mood.

Echocardiographic evidence of pulmonary hypertension is associated with increased 1-year mortality in patients admitted with chronic obstructive pulmonary disease.

Pulmonary hypertension (PH) is associated with decreased overall survival in patients with chronic lung disease. The purpose of this study was to determine the effect of echocardiographic evidence of PH on 1-year survival in patients hospitalized with acute exacerbations of chronic obstructive pulmonary disease (COPD). This is a retrospective study of patients admitted to a respiratory intermediate care unit with COPD exacerbation between October 1, 2002 and September 30, 2004. All patients who had 2D echocardiograms and pulmonary function tests done within 12xa0months prior to hospital admission or during the admission were examined. Charts were reviewed for the following outcomes: length of hospital stay, need for mechanical ventilation, survival at discharge, and mortality over the next year. Data were analyzed using multiple logistic regression and p values calculated using Fisher’s exact test. Forty-three patients met study entry criteria, and PH, defined as systolic right ventricular pressure greater than 45xa0mmHg, was found in 23 (53%). Sixteen of the 23 patients (70%) with PH died during the 1-year follow-up period compared to 5 of 20 (25%) patients with no PH (pxa0=xa00.0058). The effect of PH on survival was independent of age, forced expiratory volume in 1xa0s (FEV1), arterial pH, pCO2, or pO2 (pxa0<xa00.01). Echocardiographic evidence of PH is associated with increased 1-year mortality in patients admitted with COPD exacerbation. Further studies are needed to determine if PH is a cause of increased mortality in this population or an indicator of other cardiovascular disease.

Implementing a Collaborative Protocol in a Sepsis Intervention Program: Lessons Learned

The objective of this prospective cohort study was to see the effect of the implementation of a Sepsis Intervention Program on the standard processes of patient care using a collaborative approach between the Emergency Department (ED) and Medical Intensive Care Unit (MICU). This was performed in a large urban tertiary-care hospital, with no previous experience utilizing a specific intervention program as routine care for septic shock and which has services and resources commonly available in most hospitals. The study included 106 patients who presented to the ED with severe sepsis or septic shock. Eighty-seven of those patients met the inclusion criteria for complete data analysis. The ED and MICU staff underwent a 3-month training period followed by implementation of a protocol for sepsis intervention program over 6xa0months. In the first 6xa0months of the program’s implementation, 106 patients were admitted to the ED with severe sepsis and septic shock. During this time, the ED attempted to initiate the sepsis intervention protocol in 76% of the 87 septic patients who met the inclusion criteria. This was assessed by documentation of a central venous catheter insertion for continuous SvO2 monitoring in a patient with sepsis or septic shock. However, only 48% of the eligible patients completed the early goal-directed therapy (EGDT) protocol. Our data showed that the in-hospital mortality rate was 30.5% for the 87 septic shock patients with a mean APACHE II score of 29. This was very similar to a landmark study of EGDT (30.5% mortality with mean APACHE II of 21.5). Data collected on processes of care showed improvements in time to fluid administration, central venous access insertion, antibiotic administration, vasopressor administration, and time to MICU transfer from ED arrival in our patients enrolled in the protocol versus those who were not. Further review of our performance data showed that processes of care improved steadily the longer the protocol was in effect, although this was not statistically significant. There was no improvement in secondary outcomes, including total length of hospital stay, MICU days, and mortality. Implementation of a sepsis intervention program as a standard of care in a typical hospital protocol leads to improvements in processes of care. However, despite a collaborative approach, the sepsis intervention program was underutilized with only 48% of the patients completing the sepsis intervention protocol.

Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury

The pathogenesis of acute lung injury and acute respiratory distress syndrome is characterized by sequestration of leukocytes in lung tissue, disruption of capillary integrity, and pulmonary edema. PKCδ plays a critical role in RhoA-mediated endothelial barrier function and inflammatory responses. We used mice with genetic deletion of PKCδ (PKCδ(-/-)) to assess the role of PKCδ in susceptibility to LPS-induced lung injury and pulmonary edema. Under baseline conditions or in settings of increased capillary hydrostatic pressures, no differences were noted in the filtration coefficients (k(f)) or wet-to-dry weight ratios between PKCδ(+/+) and PKCδ(-/-) mice. However, at 24 h after exposure to LPS, the k(f) values were significantly higher in lungs isolated from PKCδ(+/+) than PKCδ(-/-) mice. In addition, bronchoalveolar lavage fluid obtained from LPS-exposed PKCδ(+/+) mice displayed increased protein and cell content compared with LPS-exposed PKCδ(-/-) mice, but similar changes in inflammatory cytokines were measured. Histology indicated elevated LPS-induced cellularity and inflammation within PKCδ(+/+) mouse lung parenchyma relative to PKCδ(-/-) mouse lungs. Transient overexpression of catalytically inactive PKCδ cDNA in the endothelium significantly attenuated LPS-induced endothelial barrier dysfunction in vitro and increased k(f) lung values in PKCδ(+/+) mice. However, transient overexpression of wild-type PKCδ cDNA in PKCδ(-/-) mouse lung vasculature did not alter the protective effects of PKCδ deficiency against LPS-induced acute lung injury. We conclude that PKCδ plays a role in the pathological progression of endotoxin-induced lung injury, likely mediated through modulation of inflammatory signaling and pulmonary vascular barrier function.