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At this juncture, preclinical and clinical evidence support the adoption of a more restrictive transfusion strategy in most critically ill patients. However, there remain divergent views regarding the risks and benefits of treating anaemia in patients with cardiovascular disease. Laboratory-based studies [68, 69] sugge... |
Few clinical studies have attempted to elucidate the risk : benefit ratio of anaemia and transfusion in cardiac patients. Two small RCTs [62, 72] examined transfusion practice in patients undergoing coronary artery bypass grafting, and concluded that a conservative approach to the administration of RBCs may be safe. Ho... |
In a study of Jehovah's Witnesses (a group that refuses RBC transfusion on religious grounds) undergoing surgical procedures [74] , it was noted that mortality was significantly increased in patients with cardiac disease after a decrease in haemoglobin levels from 100-110 g/l to 60-69 g/l. In that study, patients with ... |
Kaplan-Meier estimates of survival in the 30 days after admission to the ICU in the restrictive and liberal transfusion strategy groups (all patients). Data from Hébert et al [10] . |
Kaplan-Meier estimates of survival in the 30 days after admission to the ICU in the restrictive and liberal transfusion strategy groups (patients with APACHE II score ≤20). Data from Hébert et al [10] . |
anaemia and mortality rates was observed. Those investigators also found that the risk of anaemia appeared to decrease with RBC transfusion in patients with cardiac disease. In patients with cardiac disease, mortality increased when haemoglobin concentrations were below 95 g/l, as compared with anaemic patients with ot... |
Hébert et al. [73] sought to examine further whether a restrictive transfusion strategy was at least as effective as a liberal strategy in critically ill patients with cardiac disease. In the subgroup of patients with cardiovascular disease from the TRICC trial, those investigators suggested that most haemodynamically ... |
Combined measures of morbidity and mortality, or composite outcomes, were also examined. When all patients who died were given a score of 24, the total MOD score between groups was not different (P = 0.39), or were the changes in MOD scores significantly different from baseline (2.7 ± 6.9 versus 4.0 ± 7.3; P = 0.08). A... |
In conclusion, a restrictive RBC transfusion strategy generally appears to be safe in most critically ill patients with cardiovascular disease, with the possible exception of patients experiencing acute myocardial infarction or unstable angina. |
Survival over 30 days in patients with ischemic heart disease in the restrictive and liberal allogeneic RBC transfusion strategy groups. This graph illustrates Kaplan-Meier survival curves for all patients with ischemic heart disease in both study groups. There is no difference in mortality in patients in the restricti... |
The need to reduce the amount of allogeneic blood transfusions in order to reduce the associated risks has been firmly established. RBCs are associated with clinically important immune suppression, and stored RBCs have been shown to cause adverse microcirculatory effects that result in increased organ failure. |
The question for some time has been whether critically ill patients are able to tolerate lower levels of haemoglobin without deleterious effects, thus reducing the amount of exposure to allogeneic transfusions. In the only large RCT, Hébert et al [10] established that there was no difference in mortality rates between ... |
In contrast, the eagerly awaited results from Italy of the prone positioning trial in ARDS were disheartening. The epidemiology of both sepsis and ARDS, and their impact on clinical studies and the future provision of critical care were also hot topics. The era of extracorporeal liver replacement therapy is upon us, wi... |
This report summarizes and discusses the presentations on the above topics. |
Angus (Pittsburgh, PA, USA) presented his group's work on the epidemiology of sepsis in the USA (accepted for publication in Critical Care Medicine). They developed a method for identifying hospitalized patients with sepsis based on ICD9 criteria, the most widely recorded coding system used in US hospitals. Prospective... |
The long-standing debate between the two schools of sepsis theory -microcirculatory dys-autoregulation versus cellular dysfunction -shows signs of resolution. New techniques for studying tissue oxygen tension, presented by Ince (Amsterdam, The Netherlands), provide more evidence that microcirculatory dys-autoregulation... |
The cellular dysfunction camp, although still somewhat doubtful as to the importance of these microcirculatory findings, have now clearly established that their championed mechanism of mitochondrial failure is a late but crucial event in the evolution of sepsis. Fink (Pittsburgh, PA, USA) presented evidence that mitoch... |
The round-table conference preceding this year's symposium concentrated on distilling current knowledge on the microscopic events in critically ill patients into an explanation of the macroscopic multiorgan failure that is so commonly encountered. The conclusions of the conference appeared to relate mostly to future di... |
The natural anticoagulants antithrombin III (AT III), tissue factor pathway inhibitor (TFPI) and activated protein C (APC), and the cytokine tumour necrosis factor (TNF)-α are the latest inflammatory mediators to be targeted in large multicentre clinical trials in an attempt to improve the current dismal outcome for pa... |
The KyberSept AT III study recruited over 2300 patients from 200 centres, with high Simplified Acute Physiology Scale scores (median 50), and a mortality of nearly 40% [2] . Unfortunately, no overall benefit was shown between AT III and placebo, although results were more encouraging in an analysis of the subgroup of p... |
Phase II clinical trial results using TFPI (TFPI n = 141, placebo n = 69; unpublished data) show a mortality benefit in the sicker sepsis patients who already have coagulation problems. Results of the phase III multicentre study are expected to be presented at the 22nd International Symposium on Intensive Care and Emer... |
Human trials of various anti-TNF-α formulations have been variable to date, and include North American sepsis trial (NORASEPT) I [3] , International sepsis trial (INTERSEPT) [4] and NORASEPT II [5] . Possible reasons have included a lack of biological activity of the anti-TNF-α formulation studied, inappropriate timing... |
The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study is hot off the press [6] , and presentation of the results at the congress allowed those of us who still carry the unopened New England Journal of Medicine issue in our briefcases to catch up! A total of 164 sites from 11 co... |
Two opposing epidemiological views of ARDS were presented by Lemaire (Créteil, France) and Evans (London, UK). Broad agreement does seem to exist as to the incidence of this condition, which is in the order of 10/100,000, although there is significant variation between countries. It was argued that this variation resul... |
Early results from the Acute Lung Injury Verification of European Epidemiology (ALIVE) study (unpublished data), sponsored by the European Society of Intensive Care Medicine, are at odds with recent trial findings. The ALIVE study, which included over 6000 patients surveyed in 1998, found a 50-60% 28-day mortality, whi... |
A diverse range of views were presented from the Third International Consensus Conference on ARDS (unpublished data), held in Barcelona late last year. The decision as to how to change the defining criteria for this condition remains unresolved. The debates surrounding chest X-ray criteria, the use of the ratio of arte... |
In addition, a debate has arisen as to whether ARDS can be a unilateral process, and whether it can coexist with cardiac failure. There appears to be increasing recognition that ARDS represents only a small subset of patients with acute lung failure (approximately 30%). Surprisingly little is known about the remainder ... |
Rouby (Paris, France) put forward a new classification for ARDS based on computed tomography findings. He observed that patients can be split into three groups, depending on the appearance of the upper lobes. In group 1 the upper lobes are normal, and positive end-expiratory pressure (PEEP) is of little benefit and res... |
Gattinoni (Milan, Italy) presented the results of the longawaited Italian multicentre randomized controlled trial of prone positioning in ARDS (unpublished data). This trial was terminated after 3 years despite having only recruited 304 patients; enrollment of 750 patients was originally planned, in order to achieve su... |
The opening session reported that we are making progress in supporting the failing liver (Wendon, London, UK). Current optimism should probably be limited to extracorporeal methods, because the molecular adsorbent recirculating system (essentially extracorporeal albumin dialysis) has been shown to have beneficial clini... |
The slide of a patient reading the newspaper through a transparent helmet, while receiving noninvasive ventilation (NIV) resembled pictures of a NASA astronaut! However, it was reported to be well tolerated for prolonged periods, and significantly reduces the complications associated with NIV (pressure areas, tolerance... |
This was a well-attended session, which, according to Levy (Providence, RI, USA), was in complete contrast to the interest shown in the USA for the subject. Although there were few new data in the session, the emphasis on a strategy for lawsuits was welcome. Suggestions included statements from scientific societies at ... |
The last day of this year's symposium was sadly abandoned by many due to the Belgian rail strike. Despite this, the usual convivial atmosphere, both in and around the congress, was as abundant as ever. Overall, the 'state of the art' lectures, pro/con debates, seminars and tutorials were of the usual high standard, alt... |
Until now, relatively few studies have addressed the role of HO-1/CO in pulmonary medicine. Several investigators have focused on the diagnostic application of the HO-1/CO system, by measuring exhaled CO (E-CO) in various pathological pulmonary conditions, such as asthma or chronic obstructive pulmonary disease (COPD) ... |
In addition to the physiological substrate heme, HO-1 responds to induction by a wide variety of stimuli associated with oxidative stress. Such inducing agents include hypoxia, hyperoxia, cytokines, nitric oxide (NO), heavy metals, ultraviolet-A (320-380 nm) radiation, heat shock, shear stress, hydrogen peroxide, and t... |
HO-1 expression is primarily regulated at the transcriptional level. Genetic analyses have revealed two enhancer sequences (E1, E2) in the murine HO-1 gene located at -4 kb (E1) and -10 kbp (E2) of the transcriptional start site [37, 38] . These enhancers mediate the induction of HO-1 by many agents, including heavy me... |
The toxic properties of CO are well known in the field of pulmonary medicine. This invisible, odorless gas still claims many victims each year by accidental exposure. CO evolves from the combustion of organic materials and is present in smoke and automobile exhaust. The toxic actions of CO relate to its high affinity f... |
Only recently has it become known that, at very low concentrations, CO participates in many physiological reactions. Where a CO exposure of 10,000 parts per million (ppm) (1% by volume CO in air) is toxic, 100-250 ppm (one hundredth to one fortieth as much) will stimulate the physiological effects without apparent toxi... |
The exact mechanisms by which CO acts at the molecular level remain incompletely understood. CO potentially exerts its physiological effects by influencing at least three known pathways (Fig. 2 ). By complexation with the heme moiety of the enzyme, CO activates soluble guanylate cyclase (sGC), stimulating the productio... |
Anti-Platelet Aggregation Anti-Proliferation |
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Inhibition of pro-inflammatory cytokine production |
Modulation of hemoprotein function of CO action [32, 34, 55, 56 ]. An anti-apoptotic effect of CO and its relation to MAPK has recently been described. The overexpression of HO-1 or the exogenous administration of CO prevented tumor necrosis factor α (TNF-α)induced apoptosis in murine fibroblasts [57] . In endothelial ... |
Oxidative stress arising from an imbalance between oxidants and antioxidants plays a central role in the pathogenesis of airway disease [59] . In lung tissue, HO-1 expression may occur in respiratory epithelial cells, fibroblasts, endothelial cells, and to a large extent in alveolar macrophages [41, 60, 61] . HO-1 indu... |
E-CO in humans originates primarily from both systemic heme metabolism, which produces CO in various tissues, and localized (lung) heme metabolism, as a result of the combined action of inducible HO-1 and constitutive HO-2 enzymatic activity. Endogenously produced or inspired CO is eliminated exclusively by respiration... |
The diagnostic value of measuring E-CO remains controversial due to many conflicting reports (i.e. some reports indicate differences in E-CO measurements between disease activity and controls, and some reports do not). The possible explanations for these discrepancies include large differences in patient populations an... |
Asthma, a form of allergic lung disease, features an accumulation of inflammatory cells and mucus in the airways, associated with bronchoconstriction and a generalized airflow limitation. Inflammation, a key component of asthma, involves multiple cells and mediators where an imbalance in oxidants/antioxidants contribut... |
In light of the potential protective effects of HO-1/CO on inflammatory processes, the study of HO-1 in asthma has gained popularity. In a mouse model of asthma, HO-1 expression increased in lung tissue in response to ovalbumin aerosol challenge, indicating a role for HO-1 in asthma [70] . In a similar model of aeroall... |
Recent human studies have revealed higher HO-1 expression in the alveolar macrophages and higher E-CO in untreated asthmatic patients than in healthy nonsmoking controls [71, 72] . Patients with exacerbations of asthma and patients who were withdrawn from inhaled steroids showed higher E-CO levels than steroid-treated ... |
Airway inflammation plays an important role in the development of COPD, characterized by the presence of macrophages, neutrophils, and inflammatory mediators such as proteinases, oxidants, and cytokines. Further-more, the inflammatory consequences of chronic microbiological infections may contribute to the progression ... |
Exposure to reactive oxygen species (from cigarette smoke or chronic infections) and an imbalance in oxidant/antioxidant status are the main risk factors for the development of COPD. To defend against oxidative stress, cells and tissues contain endogenous antioxidant defense systems, which include millimolar concentrat... |
Cystic fibrosis (CF) involves a deposition of hyperviscous mucus in the airways associated with pulmonary dysfunc-tion and pancreatic insufficiency, which may be accompanied by chronic microbiological infections. E-CO readings were higher in untreated versus oral-steroidtreated CF patients [92] . Furthermore, E-CO incr... |
In patients with pneumonia, higher Hb-CO levels can be measured at the onset of illness, with values decreasing to control levels after antibiotic treatment [62] . E-CO levels were reported to be higher in lower-respiratory-tract infections and bronchiectasis, with normalization after antibiotic treatment [96, 97] . Fu... |
The role of HO-1 in the development of interstitial lung disease remains undetermined. Comparative immunohistochemical analysis has revealed that lung tissue of control subjects, patients with sarcoidosis, usual interstitial pneumonia, and desquamative interstitial pneumonia, all showed a high expression of HO-1 in the... |
A recent report clearly shows the suppression of bleomycin-induced pulmonary fibrosis by adenovirus-mediated HO-1 gene transfer and overexpression in C57BL/6 mice, involving the inhibition of apoptotic cell death [101] . |
Overall, more research is needed to elucidate the mechanisms of HO-1 in interstitial lung disease and its possible therapeutic implications. |
HO-1 action may be of great importance in solid tumors, an environment that fosters hypoxia, oxidative stress, and neovascularization. HO-1 may have both pro-and antagonistic effects on tumor growth and survival. HO-1 and CO cause growth arrest in cell-culture systems and thus may represent a potential therapeutic moda... |
CO may represent a critical mediator of the body's adaptive response to hypoxia, a common feature in pulmonary vascular disease [104] . Since CO can modulate vascular tone by inducing cGMP and large, calcium-dependent potassium channels, HO-1 and CO probably play important roles in pulmonary vascular diseases [54] . A ... |
Supplemental oxygen therapy is often used clinically in the treatment of respiratory failure. Exposure to high oxygen tension (hyperoxia) may cause acute and chronic lung injury, by inducing an extensive inflammatory response in the lung that degrades the alveolar-capillary barrier, leading to impaired gas exchange and... |
Hyperoxia induced HO-1 expression in adult rats but apparently not in neonatal rats, in which the expression and activities of HO-1 and HO-2 are developmentally upregulated during the prenatal and early postnatal period [113] . |
Both HO-1 and HO-2 potentially influence pulmonary adaptation to high O 2 levels. In one example, the adenoviral-mediated gene transfer of HO-1 into rat lungs protected against the development of lung apoptosis and inflammation during hyperoxia [114] . In vitro studies showed that the overexpression of HO-1 in lung epi... |
In vivo studies with gene-deleted mouse strains have provided much information on the roles of HO-1 and HO-2 in oxygen tolerance. Dennery et al. demonstrated that heme oxygenase-2 knockout mice (ho-2 -/-) were more sensitive to the lethal effects of hyperoxia than wild-type mice [116] . In addition to the absence of HO... |
Otterbein et al. have shown that exogenous CO, through anti-inflammatory action, may protect the lung in a rat model of hyperoxia-induced lung injury. The presence of CO (250 ppm) prolonged the survival of rats in a hyperoxic (>95% O 2 ) environment, and inhibited the appearance of markers of hyperoxia-induced lung inj... |
In direct contrast to these studies, the group of Piantadosi and colleagues reported no significant difference in the hyperoxia tolerance of rats at CO doses between 50 and 500 ppm [120] . In their model, CO did not alter the accumulation of fluid in the airway. Furthermore, CO, when applied in combination with hyperox... |
Lung transplantation is the ultimate and often last therapeutic option for several end-stage lung diseases. After lung transplantation, there remains an ongoing hazardous situation in which both acute and chronic graft failure, as well as complications of the toxic immunosuppressive regimen used (i.e. severe bacterial,... |
So far, only very limited research data are available on the possible role for HO-1 in allograft rejection after lung transplantation. Higher HO-1 expression has been detected in alveolar macrophages from lung tissue in lung transplant recipients with either acute or chronic graft failure than in stable recipients [128... |
Beneficial effects of HO-1 modulation have also been described in xenotransplantation models, in which HO-1 gene expression appears functionally associated with xenograft survival [135] . In a mouse-to-rat heart trans-plant model, the effects of HO-1 upregulation could be mimicked by CO administration, suggesting that ... |
HO-1 may also contribute to ischemic preconditioning, a process of acquired cellular protection against ischemia/ reperfusion injury, as observed in guinea pig transplanted lungs [137] . HO-1 overexpression provided potent protection against cold ischemia/reperfusion injury in a rat model through an anti-apoptotic path... |
The evolution of CO in exhaled breath may serve as a general marker and diagnostic indicator of inflammatory disease states of the lung, though more research will be required to verify its reliability. Increases in exhaled CO presumably reflect changes in systemic and airway heme metabolic activity from the action of H... |
Ultimately, the challenge remains in applying the therapeutic potentials of HO-1 to the treatment of human diseases. In vivo models of transplantation have shown that HO-1 gene therapy protects against allograft rejection [129, 134] . Given the toxic therapy that every transplant patient receives, especially after lung... |
Sufficiently early detection of a biological attack may be accomplished through surveillance schemes that can detect infected individuals earlier in the disease process. For completeness, we note that biosensors are being developed (and deployed) that detect organisms in the air and that this type of detection, if feas... |
Surveillance methods that can detect disease at an earlier stage are an important research direction for public health surveillance. These methods are generally referred to as syndromic surveillance because they have the goal of recognition of outbreaks based on the symptoms and signs of infection and even its effects ... |
One recent example of a form of syndromic surveillance is drop-in surveillance-the stationing of public health workers in emergency departments (EDs) and special clinics during high-profile events such as the Super Bowl to capture data on patients presenting with symptoms potentially indicative of bioterrorism. The maj... |
A less expensive approach-and the one taken in the Realtime Outbreak and Disease Surveillance (RODS) system-is detection based on data collected routinely for other purposes. Examples of such data include absenteeism data, sales of over-the-counter (OTC) health care products, and chief complaints from EDs. 9 The expens... |
The role of public health surveillance is to collect, analyze, and interpret data about biological agents, diseases, risk factors, and other health events and to provide timely dissemination of collected information to decision makers. 17 Conventionally, public health surveillance relies on manual operations and off-li... |
Existing syndromic surveillance systems include the CDC's drop-in surveillance systems, 8 Early Notification of Community-based Epidemics (ESSENCE), 10,18 the Lightweight Epidemiology Advanced Detection and Emergency Response System (LEADERS), 19 the Rapid Syndrome Validation Project (RSVP), 20 and the eight systems di... |
Some systems required manual data input (e.g., CDC's dropin surveillance systems, RSVP, 20 and LEADERS 19 ), which is labor-intensive and, in the worst case, requires round-theclock staffing. Manual data input is not a feasible mid-or long-term solution even if the approach is to add items to existing encounter forms (... |
A third limitation for existing surveillance systems is that the systems may not exploit existing standards or communication protocols like Heath Level 7 (HL7) even when they are available. |
The data type most commonly used among surveillance systems is symptoms or diagnoses of patients from ED and/or physician office visits. Other types of data identified in that study include emergency call center and nurse advice lines. Other types of data being used include sales of over-thecounter health care products... |
The overall design objective for RODS is similar to that of an early warning system for missile defense; namely, to collect whatever data are required to achieve early detection from as wide an area as necessary and to analyze the data in a way that they can be used effectively by decision makers. It is required that t... |
This report describes RODS 1.5, which was completely rewritten as a Java 2 Enterprise Edition (J2EE) application since the previous publication describing it. RODS 1.5 is multidata type enabled, which means that any time series data can be incorporated into the databases and user interfaces. The deployed RODS system cu... |
Overview RODS uses clinical data that are already being collected by health care providers and systems during the registration process. When a patient arrives at an ED (or an InstaCare in Utah), the registration clerk or triage nurse elicits the patient's reason for visit (i.e., the chief complaint), age, gender, home ... |
Data about sales of OTC health care products are processed separately by the National Retail Data Monitor, which is discussed in detail in another article in this issue of JAMIA. 23 The processing was kept separate intentionally because, in the future, the servers for the National Retail Data Monitor may operate in dif... |
Prior to September 2001, RODS received data only from hospitals associated with the UPMC Health System, and efforts to recruit other hospitals met with resistance. After the terrorist attacks (including anthrax) in the Fall of 2001, other hospitals agreed to participate. Although data in this project are de-identified,... |
Health care facilities send admission, discharge, and transfer (ADT) HL7 messages to RODS for patient visits in EDs and walk-in clinics. A minimal data set is sent, as shown in Figure 2 , which qualifies as a HIPAA Limited Data Set. 24 Currently the data elements are age (without date of birth), gender, home zip code,... |
The HL7 listener receives HL7 messages from the message routers located in each health system. The HL7 listener then passes the received HL7 message to the HL7 parser bean, an Enterprise JavaBean (EJB) in the RODS business logic tier. The HL7 parser bean uses regular expressions to parse the fields in an HL7 message. T... |
Although nearly all health systems utilize the HL7 messaging standard, the location of individual data elements in an HL7 message may differ from health system to health system. For example, some care providers' systems record free-text chief complaint in the DG1 segment instead of the PV2 segment of an HL7 message. To... |
We also use this configuration file to define the database table and field in which the HL7 parser bean should store each data element. This approach is useful because it allows the HL7 data to be stored to an external database. We anticipate that health departments with existing NEDSS or other public health surveillan... |
For hospitals that do not have HL7 message routers (two of approximately 60 in our experience to date), RODS accepts ED registration data files through either a secure Web-based data upload interface or a secure file transfer protocol. In general, these types of data transfers are technically trivial and for that reaso... |
RODS checks the integrity of the data in the HL7 messages that it receives. This processing is necessary because hospital data flows may have undesirable characteristics such as duplicates. RODS identifies and deletes duplicates by using a database trigger that creates a composite primary key before inserting the data.... |
RODS monitors all data feeds to ensure continuous connections with health systems. If RODS does not receive data for six hours, it sends an alert to the RODS administrator and the sending health system's administrator. Because the commercial message routers that hospitals use queue up HL7 messages when encountering net... |
RODS uses an Oracle8i database to store ED registration data. |
(Oracle, Redwood Shores, CA). To ensure fast response for an online query (e.g., the daily counts of respiratory syndrome in a county for the past six months), we developed a cache |
For connectivity with the HL7 message routers, we utilize hardware-based routers. The VPN router is a Cisco PIX 501 and the leased-line routers are a pair of Cisco 2600s (Cisco Systems, Inc., San Jose, CA). |
All of the RODS processes can be run on a single computer, but in our current implementation-serving Pennsylvania F i g u r e 2. Sample HL7 admission, discharge, and transfer (ADT) message from an emergency department. The circled fields are age, gender, home zip code, admitted date and time, and free-text chief compla... |
and Utah as an application service provider-we use five dedicated servers: firewall, database, Web server, a geographic information system (GIS) server, and computation. The processes are written in Java code and can run on most platforms, but here we describe the specific platforms we use to indicate approximate sizin... |
We developed RODS applications using the Java 2 Enterprise Edition Software Toolkit (J2EE SDK) from Sun Microsystems for cross-platform Java application development and deployment. 26 We followed contemporary application programming practices-a multitiered application consisting of a client tier (custom applications su... |
Business logic such as the HL7 parser bean was implemented as Enterprise JavaBeans (EJBs). NEDSS specifies EJB as the standard for application logic. RODS uses Jboss, an opensource J2EE application server, to run all EJBs. 10 The Web tier comprises the graphical user-interface to RODS and uses Java Server Pages (JSP), ... |
RODS uses a naive Bayesian classifier called Complaint Coder (CoCo) to classify free-text chief complaints into one of the following syndromic categories: constitutional, respiratory, gastrointestinal, neurological, botulinic, rash, hemorrhagic, and other. CoCo computes the probability of each category, conditioned on ... |
Over the course of the project, RODS has used two detection algorithms. These algorithms have not been formally field tested because the emphasis of the project to date has been on developing the data collection infrastructure more than field testing of algorithms. |
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