A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes.</p> <p>Methods/Design</p> <p>A multi-national, pilot randomized controlled trial (RCT) of once daily enteral rosuvastatin versus matched placebo administered for 14 days for the treatment of critically ill patients with suspected, probable or confirmed H1N1 infection. We propose to randomize 80 critically ill adults with a moderate to high index of suspicion for H1N1 infection who require mechanical ventilation and have received antiviral therapy for ≤ 72 hours. Site investigators, research coordinators and clinical pharmacists will be blinded to treatment assignment. Only research pharmacy staff will be aware of treatment assignment. We propose several approaches to informed consent including a priori consent from the substitute decision maker (SDM), waived and deferred consent. The primary outcome of the CHAT trial is the proportion of eligible patients enrolled in the study. Secondary outcomes will evaluate adherence to medication administration regimens, the proportion of primary and secondary endpoints collected, the number of patients receiving open-label statins, consent withdrawals and the effect of approved consent models on recruitment rates.</p> <p>Discussion</p> <p>Several aspects of study design including the need to include central randomization, preserve allocation concealment, ensure study blinding compare to a matched placebo and the use novel consent models pose challenges to investigators conducting pandemic research. Moreover, study implementation requires that trial design be pragmatic and initiated in a short time period amidst uncertainty regarding the scope and duration of the pandemic.</p> <p>Trial Registration Number</p> <p><a href="http://www.controlled-trials.com/ISRCTN45190901">ISRCTN45190901</a></p

Being hospitalized might be a dangerous adventure

Tema del mesLos hospitales son instituciones complejas y constituyen un eslabón importante en el sistema de salud. Su objetivo es mejorar la calidad de vida; resolver o controlar las enfermedades de la población, y ser centros de enseñanza y generación de conocimiento científico. Sin embargo, el tránsito de los pacientes en estas instituciones no está exento de riesgos o complicaciones. La seguridad del paciente se reconoce como una prioridad en términos de salud pública a nivel internacional, que requiere vigilancia y medición de manera constante. La participación en conjunto con una visión global, podría ayudar a reducir los riesgos para los pacientes en las instituciones.Hospitals are complex institutions and are an essential pillar for the health system. Their main objective is to preserve the quality of life, to solve or control diseases, to be a teaching centre and generate new scientific knowledge. However, patients are at risk of complications while they are hospitalized. Patient’s security is a public-health priority, therefore health’s systems need to improve and maintain active surveillance systems. It is essential a global health vision, to reduce the risk that face the patients

Resource-poor settings: infrastructure and capacity building: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement

BACKGROUND: Planning for mass critical care (MCC) in resource-poor or constrained settings has been largely ignored, despite their large populations that are prone to suffer disproportionately from natural disasters. Addressing MCC in these settings has the potential to help vast numbers of people and also to inform planning for better-resourced areas. METHODS: The Resource-Poor Settings panel developed five key question domains; defining the term resource poor and using the traditional phases of disaster (mitigation/preparedness/response/recovery), literature searches were conducted to identify evidence on which to answer the key questions in these areas. Given a lack of data upon which to develop evidence-based recommendations, expert-opinion suggestions were developed, and consensus was achieved using a modified Delphi process. RESULTS: The five key questions were then separated as follows: definition, infrastructure and capacity building, resources, response, and reconstitution/recovery of host nation critical care capabilities and research. Addressing these questions led the panel to offer 33 suggestions. Because of the large number of suggestions, the results have been separated into two sections: part 1, Infrastructure/Capacity in this article, and part 2, Response/Recovery/Research in the accompanying article. CONCLUSIONS: Lack of, or presence of, rudimentary ICU resources and limited capacity to enhance services further challenge resource-poor and constrained settings. Hence, capacity building entails preventative strategies and strengthening of primary health services. Assistance from other countries and organizations is needed to mount a surge response. Moreover, planning should include when to disengage and how the host nation can provide capacity beyond the mass casualty care event

Bedeutung und Anwendung

Title Page, Table of Contents, Motivation iv Concepts v Introduction vii 1 Fundamentals 1 1.1 Meaning of isostasy and rigidity 1 1.1.1 Isostasy according to Pratt 1 1.1.2 Isostasy according to Airy 2 1.1.3 Isostasy according to Vening-Meinesz 2 1.1.4 Elastic thickness and flexural rigidity 4 1.2 Methods for estimation of flexural parameters 5 1.2.1 Spectral methods 5 1.2.2 Advantage and disadvantage of spectral methods 10 1.2.3 Convolution method 11 1.2.4 Advantage and disadvantage of the convolution method 12 1.2.5 Conclusion 12 1.3 Gravity inversion according to Parker algorithm 13 1.3.1 Introduction 13 1.3.2 Method 13 1.3.3 Synthetic example 14 1.4 Internal loads 16 1.4.1 Calculation of gravity effect of sediments with slice program 16 1.4.2 Pseudo topography 17 2 Theoretical basics and development of the analytical solution 19 2.1 Differential equation 19 2.1.1 Plate theory according to Kirchhoff 19 2.1.2 Beam on elastic foundation 20 2.1.3 Application in geological sciences 23 2.2 Formula according to Hertz 25 2.2.1 Investigation of the Logarithm function 27 2.2.2 Investigation of the Sine function 29 2.2.3 Summary of the behavior of the functions 30 2.3 New analytical solution 31 2.3.1 Introduction 31 2.3.2 Modification and substitution 31 2.3.3 Investigation of the graph 33 2.3.4 Unification of the analytical solution 35 2.4 Transfer function 38 2.4.1 Introduction 38 2.4.2 Transfer function 39 2.4.3 Verification of the analytical solution 41 2.4.4 Conclusion. 42 2.5 Comparison with FFT solution 43 2.5.1 Comparison with flexure curves 43 2.5.2 Investigation of dependence from grid parameters 44 2.5.3 Boundary cases for elastic thickness 47 2.5.4 Comparison with Vening-Meinesz solution 49 2.5.5 Conclusion 50 2.6 Software concept 51 2.6.1 Introduction 51 2.6.2 Flexure curves and CMI 52 2.6.3 Radius of convolution 52 2.6.4 Iterative estimation of elastic thickness 54 2.6.5 Elastic thickness distribution 56 2.6.6 Reference depth 57 2.7 Comparison with Finite Element modeling 59 2.7.1 Influence of input parameters 61 2.7.2 Conclusion 69 3\. Application of the analytical solution 70 3.1 Pacific Ocean 71 3.1.1 Input data 71 3.1.2 Preliminary investigations 72 3.1.3 Estimation of gravity CMI 73 3.1.4 Estimation of rigidity And elastic thickness 76 3.1.5 Discussion and conclusion. 77 3.2 Central Andes 80 3.2.1 Input data 80 3.2.2 Preliminary investigation 82 3.2.3 Estimation of rigidity and elastic thickness 83 3.2.4 Discussion and conclusion. 86 3.3 Southern Andes 91 3.3.1 Input data 91 3.3.2 Estimation of rigidity and elastic thickness 92 3.3.3 Discussion and conclusion. 93 4 Discussion of results 98 4.1 Thick plate theory 98 4.2 Influence of temperature 99 4.2.1 Introduction 99 4.2.2 Synthetic example 99 4.2.3 Application in geological sciences 101 4.3 Significance of input parameters 105 4.3.1 Deviation of height 106 4.3.2 Deviation of gravity 107 4.3.3 Deviation of Young's modulus 107 4.3.4 Deviation of Poisson ratio 108 4.3.5 Deviation of density of crust 109 4.3.6 Deviation of density of mantle 109 4.3.7 Deviation of elastic thickness 110 4.3.8 Conclusion 111 4.4 Variation of Young's modulus 112 4.5 Visco-elastic behavior 116 4.6 Final comments and future directions 122 5 Appendix I 5.1 Density-porosity formula I 5.2 Comparison of flexure curves III 5.2.1. FFT solution compared with Logarithm and Sine function III 5.2.2. Comparison of output from computer program with FFT IV 5.3 FE models V 5.3.1. Calculation input parameters and results VI 5.3.2. Settings of the FE models IX Acknowledgement, References X Notation XI Abbreviations XIV Index of Tables XV Index of Figures XVI ReferencesIn 1939 a new concept was introduced by Vening-Meinesz proposing that the flexural strength of the lithosphere must be considered for isostatic models. A 4th order differential equation describing the flexure of a thin plate was developed. In the past the equation has been solved in frequency space using spectral methods (coherence and admittance). However, the admittance and coherence techniques have been questioned when applied to continental lithosphere. Both methods require an averaging process; therefore the variation in rigidity may be retrieved only to a limited extent. A large spatial window with a side length of at least 375 km is required over the study area. And, in where the input topography is characterized by low topographic variation, the method becomes unstable. These problems can be overcome by calculating the flexural rigidity with the convolution approach and furthermore with the use of a newly derived analytical solution of the differential equation mentioned above. This solution was developed out of three solutions from Hertz and has been made applicable to geological science. The analytical solution has been applied to both oceanic lithosphere (Nazca plate) and continental lithosphere (Central and Patagonian Andes). The resulting flexural rigidity values and their variations have been compared with the ideas and concepts developed by the members of the SFB267 community, and correlate well with tectonic units and fault systems. In the past the elastic thickness has been used synonymously for the flexural rigidity. However, the analytical solution leads to a new interpretation and meaning of the elastic thickness. It is shown that it is sufficient to operate with a constant value for both gravity and Poisson's ratio, as the variation of either parameter does not lead to a significant change in the distribution of flexural rigidity. Young's modulus is shown to be the driving factor for the flexural deformation. A temperature moment must also be taken into account in flexural investigations. Thus, the variation of the elastic thickness can be explained by temperature distribution and a change of the Young's modulus. A new definition of elastic thickness can be obtained: the value of the calculated elastic thickness is equivalent to the value of thickness of a corresponding plate described by a constant Young's modulus. Computations using the differential equation are valid for the crust/mantle interface (Moho) as well as the lithosphere/ asthenosphere boundary. The calculated boundary surface can be shifted at the position of the boundary at which a significant change of Young's modulus takes place.Im Jahre 1939 wurde von Vening-Meinesz eine Theorie entwickelt, welche die Rigidität der Lithosphärenplatte innerhalb isostatischer Betrachtungen berücksichtigte. Dazu wurde eine Differentialgleichung 4. Ordnung verwendet, welche die Deformation einer dünnen Platte beschreibt. In der Vergangenheit wurde die Gleichung mittels der Spektralmethoden im Frequenz-Bereich gelöst. Aber bezüglich der Anwendung der Kohärenz- und Admittanzmethode auf die Kontinente wurde ihre Nützlichkeit aufgrund der Nachteile, welche durch den Spektralansatz entstehen, in Frage gestellt. Dieser Ansatz bedingt eine Durchschnittsbildung, welche im Falle einer sich räumlich stark variierenden Rigidität dazu führen kann, dass jene Variation nur bis zu einem begrenzten Mabe aufgelöst wird. Für das Untersuchungsgebiet ist eine Seitenlänge von mindestens erforderlich. Ein weiteres Problem tritt im Falle niedriger Topographie auf, da kleinere Spektralwerte zu Instabilitaeten innerhalb der Anwendung führen können. Durch die Verwendung der Konvolutionsmethode und der neu entwickelten analytischen Lösung der obig eingeführten Differentialgleichung werden diese Nachteile überwunden. Diese analytische Lösung wurde aus drei verschiedenen Lösungen nach Hertz entwickelt und für die geologischen Wissenschaften anwendbar gemacht. Die analytische Lösung wurde auf die ozeanische Lithosphäre im Bereich des Pazifik (Nazca-Platte) und auf die kontinentale Lithosphäre im Bereich der Zentral - und der Patagonischen Anden angewendet. Die resultierende Rigiditätsverteilung wird mit den von den Mitgliedern der SFB267 Gemeinschaft entwickelten Ideen und Konzepten verglichen, und ist durch eine gute Korrelation mit den tektonischen Einheiten und Störungssystemen charakterisiert. Bisher wurde die elastische Dicke und die flexurelle Rigidität synonym verwendet. Aber die analytische Lösung führte zu einem neuen Verständnis und Interpretation der elastischen Dicke. In Anbetracht der Untersuchungen zur Signifikanz der Inputparameter ist es zulässig mit einem konstanten Wert für die Schwere und dem Poisson-Verhältnis zu arbeiten, denn dies wird nicht zu signifikanten Unterschieden im Ergebnis führen. Dies gilt nicht für das Elastizitätsmodul, denn dieser Parameter ist ein entscheidender Faktor für das Deformationsverhalten. Daher kann die elastische Dicke auch als äquivalente Plattendicke für eine Platte konstanten Elastizitätsmoduls definiert werden. Zudem wurde herausgefunden, daß das Temperaturmoment in den weiteren Untersuchungen mit berücksichtigt werden muss. Damit kann die beobachtete Variation der elastischen Dicke durch die Temperaturverteilung und die Veränderung des Elastizitätsmoduls erklärt werden. Zusätzlich wurde gezeigt, daß die Berechnungen mittels der Differentialgleichung und der analytischen Lösung sowohl für die Krusten/Mantel Grenze als auch die Lithosphären/Asthenosphären Grenze gültig sind. Dabei ist entscheidend, an welcher Grenzfläche sich das Elastizitätsmodul ändert

Drotrecogin alfa (Activated) in adults with septic shock

There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock.In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization.At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81).DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.)