Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis

Microvascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis

Behavioral issues in asthma management

Despite advances in drug treatment, outcomes in asthma remain unsatisfactory. Often overlooked in developing treatment strategies are important factors that affect outcomes in asthma, namely behavioral issues such as the low rate of patient adherence to the prescribed treatment regimen, inadequate physician-patient communication, and inconsistent implementation of evidenc-based treatment guidelines. The low adherence rates among asthma patients may be improved by education programs that emphasize both the potentially serious risks of this disease and a team approach to treatment that includes patients and their families in developing a treatment plan. Interactive physician education programs have been shown to improve guideline implementation and physician communication skills. Indeed, effective physician-patient communication may be the key to improving guideline implementation and patient adherence to treatment, resulting in meaningful decreases in asthma-related morbidity and mortality. Pediatr Pulmonol. 2001; Supplement 21:26–30. © 2001 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35319/1/2003_ftp.pd

How much do health care providers value a community-based asthma care program? – a survey to collect their opinions on the utilities of and barriers to its uptake

<p>Abstract</p> <p>Background</p> <p>A comprehensive asthma care program (ACP) based on Canadian Asthma Consensus Guidelines was implemented in 8 primary care sites in Ontario, Canada. A survey was distributed to health care providers' (HCPs) to collect their opinions on the utilities of and barriers to the uptake of the ACP.</p> <p>Methods</p> <p>A 39-item self-administered survey was mailed to 184 HCPs and support staff involved in delivering the ACP at the end of implementation. The items were presented in mixed formats with most items requiring responses on a five-point Likert scale. Distributions of responses were analyzed and compared across types of HCPs and sites.</p> <p>Results</p> <p>Of the 184 surveys distributed, 108 (59%) were returned, and of that, 83 were completed by HCPs who had clinical contact with the patients. Overall, 95% of the HCPs considered the ACP useful for improving asthma care management. Most HCPs favored using the asthma care map (72%), believed it decreased uncertainties and variations in patient management (91%), and considered it a convenient and reliable source of information (86%). The most commonly reported barrier was time required to complete the asthma care map. Over half of the HCPs reported challenges to using spirometry, while almost 40% identified barriers to using the asthma action plan.</p> <p>Conclusion</p> <p>Contrary to the notion that physicians believe that guidelines foster cookbook medicine, our study showed that HCPs believed that the ACP offered an effective and reliable approach for enhancing asthma care and management in primary care.</p

Impact of increased mean arterial pressure on skin microcirculatory oxygenation in vasopressor-requiring septic patients : an interventional study

Background: Heterogeneity of microvascular blood flow leading to tissue hypoxia is a common finding in patients with septic shock. It may be related to suboptimal systemic perfusion pressure and lead to organ failure. Mapping of skin microcirculatory oxygen saturation and relative hemoglobin concentration using hyperspectral imaging allows to identify heterogeneity of perfusion and perform targeted measurement of oxygenation. We hypothesized that increasing mean arterial pressure would result in improved oxygenation in areas of the skin with most microvascular blood pooling. Methods: We included adult patients admitted to the intensive care unit within the previous 24 h with sepsis and receiving a noradrenaline infusion. Skin oxygen saturation was measured using hyperspectral imaging-based method at baseline and after the increase in mean arterial pressure by 20 mm Hg by titration of noradrenaline doses. The primary outcome was an increase in skin oxygen saturation depending upon disease severity. Results: We studied 30 patients with septic shock. Median skin oxygen saturation changed from 26.0 (24.5–27.0) % at baseline to 30.0 (29.0–31.0) % after increase in mean arterial pressure (p=0.04). After adjustment for baseline saturation, patients with higher SOFA scores achieved higher oxygen saturation after the intervention (r2=0.21; p=0.02). Skin oxygen saturation measured at higher pressure was found to be marginally predictive of mortality (OR: 1.10; 95% CI 1.00–1.23; p=0.053). Conclusions: Improvement of microcirculatory oxygenation can be achieved with an increase in mean arterial pressure in most patients. Response to study intervention is proportional to disease severity.publishersversionPeer reviewe

Physicians' Preferences for Asthma Guidelines Implementation

Purpose: Patient care based on asthma guidelines is cost-effective and leads to improved treatment outcomes. However, ineffective implementation strategies interfere with the use of these recommendations in clinical practice. This study investigated physicians` preferences for asthma guidelines, including content, supporting evidence, learning strategies, format, and placement in the clinical workplace. Methods: We obtained information through a questionnaire survey. The questionnaire was distributed to physicians attending continuing medical education courses and sent to other physicians by airmail, e-mail, and facsimile. Results: A total of 183 physicians responded (male to female ratio, 2.3:1; mean age, 40.4 +/- 9.9 years); 89.9% of respondents were internists or pediatricians, and 51.7% were primary care physicians. Physicians preferred information that described asthma medications, classified the disease according to severity and level of control, and provided methods of evaluation/treatment/monitoring and management of acute exacerbation. The most effective strategies for encouraging the use of the guidelines were through continuing medical education and discussions with colleagues. Physicians required supporting evidence in the form of randomized controlled trials and expert consensus. They preferred that the guidelines be presented as algorithms or flow charts/flow diagrams on plastic sheets, pocket cards, or in electronic medical records. Conclusions: This study identified the items of the asthma guidelines preferred by physicians in Korea. Asthma guidelines with physicians` preferences would encourage their implementation in clinical practice.This study was supported by grants from the Ministry for Health, Welfare and Family Affairs, R.O.K. (A040153).*GLOB IN ASTHM, 2009, GLOB STRAT ASTHM MANGILDENHUYS J, 2009, INT J EMERG MED, V2, P33YOO KH, 2007, J ASTHMA ALLERGY CLI, V27, P226Barosi G, 2006, NEUROL SCI, V27, pS231, DOI 10.1007/s10072-006-0624-9Cho SH, 2006, J KOREAN MED SCI, V21, P181Burr ML, 2006, THORAX, V61, P296, DOI 10.1136/thx.2005.045682CHO SH, 2006, KOREAN J MED, V70, P69KIM YS, 2006, TUBERCULOSIS RESP DI, V61, P121YOO KH, 2006, J ASTHMA ALLERGY CLI, V26, P282STONE TT, 2005, QUAL MANAG HLTH CARE, V14, P177Lai CKW, 2003, J ALLERGY CLIN IMMUN, V111, P263, DOI 10.1067/mai.2003.30LEE EK, 2003, TUBERC RESP DIS, V55, P165Kim YK, 2002, CLIN EXP ALLERGY, V32, P1706Ting S, 2002, ANN ALLERG ASTHMA IM, V88, P326*KOR I HLTH SOC AF, 2002, ASTHM MED US EVGROSS PA, 2001, MED CARE, V39, P85Crim C, 2000, CHEST, V118, p62SHartert TV, 2000, J AM GERIATR SOC, V48, P651Stone TT, 1999, AM J MED QUAL, V14, P170Doerschug KC, 1999, AM J RESP CRIT CARE, V159, P1735Beasley R, 1998, LANCET, V351, P1225*KOR AC ASTHM ALL, KOR GUID AD ASTHM TR

Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial.

PURPOSE: Bone marrow-derived, allogeneic, multipotent adult progenitor cells demonstrated safety and efficacy in preclinical models of acute respiratory distress syndrome (ARDS). METHODS: This phase 1/2 trial evaluated the safety and tolerability of intravenous multipotent adult progenitor cells in patients with moderate-to-severe ARDS in 12 UK and USA centres. Cohorts 1 and 2 were open-label, evaluating acute safety in three subjects receiving 300 or 900 million cells, respectively. Cohort 3 was a randomised, double-blind, placebo-controlled parallel trial infusing 900 million cells (n = 20) or placebo (n = 10) within 96 h of ARDS diagnosis. Primary outcomes were safety and tolerability. Secondary endpoints included clinical outcomes, quality of life (QoL) and plasma biomarkers. RESULTS: No allergic or serious adverse reactions were associated with cell therapy in any cohort. At baseline, the cohort 3 cell group had less severe hypoxia. For cohort 3, 28-day mortality was 25% for cell vs. 45% for placebo recipients. Median 28-day free from intensive care unit (ICU) and ventilator-free days in the cell vs. placebo group were 12.5 (IQR 0,18.5) vs. 4.5 (IQR 0,16.8) and 18.5 (IQR 0,22) vs. 6.5 (IQR 0,18.3), respectively. A prospectively defined severe ARDS subpopulation (PaO2/FiO2 < 150 mmHg (20 kPa); n = 16) showed similar trends in mortality, ICU-free days and ventilator-free days favouring cell therapy. Cell recipients showed greater recovery of QoL through Day 365. CONCLUSIONS: Multipotent adult progenitor cells were safe and well tolerated in ARDS. The clinical outcomes warrant larger trials to evaluate the therapeutic efficacy and optimal patient population.National Institutes of Health, Innovate UK, and Athersys, In

NF-κB targeting by way of IKK inhibition sensitizes lung cancer cells to adenovirus delivery of TRAIL

<p>Abstract</p> <p>Background</p> <p>Lung cancer causes the highest rate of cancer-related deaths both in men and women. As many current treatment modalities are inadequate in increasing patient survival, new therapeutic strategies are required. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells but not in normal cells, prompting its current evaluation in a number of clinical trials. The successful therapeutic employment of TRAIL is restricted by the fact that many tumor cells are resistant to TRAIL. The goal of the present study was to test a novel combinatorial gene therapy modality involving adenoviral delivery of TRAIL (Ad5hTRAIL) and IKK inhibition (AdIKKβKA) to overcome TRAIL resistance in lung cancer cells.</p> <p>Methods</p> <p>Fluorescent microscopy and flow cytometry were used to detect optimum doses of adenovirus vectors to transduce lung cancer cells. Cell viability was assessed via a live/dead cell viability assay. Luciferase assays were employed to monitor cellular NF-κB activity. Apoptosis was confirmed using Annexin V binding.</p> <p>Results</p> <p>Neither Ad5hTRAIL nor AdIKKβKA infection alone induced apoptosis in A549 lung cancer cells, but the combined use of Ad5hTRAIL and AdIKKβKA significantly increased the amount of A549 apoptosis. Luciferase assays demonstrated that both endogenous and TRAIL-induced NF-κB activity was down-regulated by AdIKKβKA expression.</p> <p>Conclusions</p> <p>Combination treatment with Ad5hTRAIL and AdIKKβKA induced significant apoptosis of TRAIL-resistant A549 cells, suggesting that dual gene therapy strategy involving exogenous TRAIL gene expression with concurrent IKK inhibition may be a promising novel gene therapy modality to treat lung cancer.</p

Microcirculatory alterations: potential mechanisms and implications for therapy

Multiple experimental and human trials have shown that microcirculatory alterations are frequent in sepsis. In this review, we discuss the characteristics of these alterations, the various mechanisms potentially involved, and the implications for therapy. Sepsis-induced microvascular alterations are characterized by a decrease in capillary density with an increased number of stopped-flow and intermittent-flow capillaries, in close vicinity to well-perfused capillaries. Accordingly, the surface available for exchange is decreased but also is highly heterogeneous. Multiple mechanisms may contribute to these alterations, including endothelial dysfunction, impaired inter-cell communication, altered glycocalyx, adhesion and rolling of white blood cells and platelets, and altered red blood cell deformability. Given the heterogeneous nature of these alterations and the mechanisms potentially involved, classical hemodynamic interventions, such as fluids, red blood cell transfusions, vasopressors, and inotropic agents, have only a limited impact, and the microcirculatory changes often persist after resuscitation. Nevertheless, fluids seem to improve the microcirculation in the early phase of sepsis and dobutamine also can improve the microcirculation, although the magnitude of this effect varies considerably among patients. Finally, maintaining a sufficient perfusion pressure seems to positively influence the microcirculation; however, which mean arterial pressure levels should be targeted remains controversial. Some trials using vasodilating agents, especially nitroglycerin, showed promising initial results but they were challenged in other trials, so it is difficult to recommend the use of these agents in current practice. Other agents can markedly improve the microcirculation, including activated protein C and antithrombin, vitamin C, or steroids. In conclusion, microcirculatory alterations may play an important role in the development of sepsis-related organ dysfunction. At this stage, therapies to target microcirculation specifically are still being investigated

Nursing considerations to complement the Surviving Sepsis Campaign guidelines

Objectives: To provide a series of recommendations based on the best available evidence to guide clinicians providing nursing care to patients with severe sepsis. Design: Modified Delphi method involving international experts and key individuals in subgroup work and electronic-based discussion among the entire group to achieve consensus. Methods: We used the Surviving Sepsis Campaign guidelines as a framework to inform the structure and content of these guidelines. We used the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system to rate the quality of evidence from high (A) to very low (D) and to determine the strength of recommendations, with grade 1 indicating clear benefit in the septic population and grade 2 indicating less confidence in the benefits in the septic population. In areas without complete agreement between all authors, a process of electronic discussion of all evidence was undertaken until consensus was reached. This process was conducted independently of any funding. Results: Sixty-three recommendations relating to the nursing care of severe sepsis patients are made. Prevention recommendations relate to education, accountability, surveillance of nosocomial infections, hand hygiene, and prevention of respiratory, central line-related, surgical site, and urinary tract infections, whereas infection management recommendations related to both control of the infection source and transmission-based precautions. Recommendations related to initial resuscitation include improved recognition of the deteriorating patient, diagnosis of severe sepsis, seeking further assistance, and initiating early resuscitation measures. Important elements of hemodynamic support relate to improving both tissue oxygenation and macrocirculation. Recommendations related to supportive nursing care incorporate aspects of nutrition, mouth and eye care, and pressure ulcer prevention and management. Pediatric recommendations relate to the use of antibiotics, steroids, vasopressors and inotropes, fluid resuscitation, sedation and analgesia, and the role of therapeutic end points. Conclusion: Consensus was reached regarding many aspects of nursing care of the severe sepsis patient. Despite this, there is an urgent need for further evidence to better inform this area of critical care