Debra Foster

Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia.

Critically ill patients in the intensive care unit (ICU) are at high risk for infections associated with increased morbidity, mortality, and health care costs (1-3). The overall infection rate in critically ill patients approaches 40% and may be as high as 50% or 60% in patients who remain in the ICU for more than 5 days (4, 5). Respiratory tract infections account for 30% to 60% of all such infections. The incidence of pneumonia acquired in the ICU ranges from 10% to 65% (6-11). Among patients at high risk for ventilator-associated pneumonia (VAP) are those who have chronic obstructive pulmonary disease, burns, neurosurgical conditions, the acute respiratory distress syndrome, and witnessed aspiration; those who are reintubated; and those who receive paralytic agents or enteral nutrition (12, 13). The attributable morbidity and mortality of VAP are clinically important. In a prospective, matched cohort study, patients with VAP remained in the ICU 4.3 days (95% CI, 1.5 to 7.0 days) longer than patients who did not have VAP and had a trend toward an increased risk for death (absolute risk increase, 5.8% [CI, 2.4% to 14.0%]) (14). Six other studies using a matching strategy found a prolonged length of ICU stay associated with VAP (range, 5 to 13 days) and attributable mortality ranging from an absolute risk increase of 0% to 50% (15-20). Therefore, strategies to decrease the incidence of VAP could decrease morbidity, mortality, and health care costs and improve patient safety. A survey of the use of VAP prevention strategies identified differences across countries (21). For example, changing the ventilator circuit for each new patient was reported more frequently by French ICU directors than those in Canada (21). This survey also showed that some effective strategies were used infrequently, suggesting inadequate translation of randomized trial results into practice. One potential catalyst for knowledge translation is an evidence-based clinical practice guideline. Therefore, a Joint Planning Group of the Canadian Critical Care Society and Canadian Critical Care Trials Group commissioned the development of an evidence-based clinical practice guideline for the prevention of VAP. In this paper, we describe the methods used to create the guideline and the recommendations generated. Methods The Joint Planning Group selected an 11-member VAP Prevention Guideline Panel made up of 9 intensivists from university-affiliated and community hospitals, an ICU nurse, and an ICU respiratory therapist. Panel members were experts in critical care medicine (n= 9), VAP (n= 4), evidence-based medicine (n= 4), and guideline development (n= 3). The context was mechanically ventilated adult patients cared for in the ICU. The target audience was ICU clinicians in university-affiliated and community hospitals. To identify potentially relevant evidence, we searched 3 bibliographic databases (MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews) to 1 April 2003 for randomized trials that evaluated interventions influencing VAP (Appendix). We had no language restrictions. We also reviewed personal files and practice guidelines on this subject previously published by the Centers for Disease Control and Prevention (22) and the American Thoracic Society (23). We included randomized trials and systematic reviews of randomized trials that 1) studied adult critically ill patients; 2) had VAP as an outcome; and 3) evaluated any of the following interventions: physical strategies (route of endotracheal intubation, systematic search for maxillary sinusitis, frequency of ventilator circuit changes, type of airway humidification, frequency of humidifier changes, endotracheal suctioning system, subglottic secretion drainage, chest physiotherapy, and tracheostomy timing), positional strategies (kinetic beds, semi-recumbent positioning, and prone positioning), and pharmacologic strategies (stress ulcer prophylaxis and prophylactic antibiotics, including selective decontamination of the digestive tract). Since study authors used various definitions of VAP, we used the definitions they provided. The most common definition was a new or persistent radiographic infiltrate plus fever, leukocytosis, change in the volume or color of sputum, or isolation of a pathogen. If available, histologic evidence of pneumonia was also used. A priori, we decided to review only systematic reviews of randomized clinical trials for antibiotic prophylaxis and only randomized clinical trials for all other topics. We excluded crossover and beforeafter studies. We also excluded randomized trials of ventilator weaning, including noninvasive mechanical ventilation, and nutritional interventions evaluating VAP because guidelines addressing these topics have recently been published (24, 25). In duplicate and independently, 3 pairs of panel members critically appraised each trial (26, 27) and systematic review (28). Each member of a pair compared his or her independent appraisal of a given trial or systematic review with that of the other member of the pair. For each randomized trial, we abstracted sample, allocation, intervention, co-interventions, exclusions after randomization, blinding of outcome assessment, definition of VAP, crude VAP events, relative risk for VAP, and other outcomes. For each intervention, we summarized the risk differences and calculated a pooled risk difference. For each systematic review, we abstracted number of trials, population, intervention, selection criteria, search strategy, validity assessment, method of pooling results, homogeneity assessment, VAP definition, pooled event rates, and other outcomes. Before the panel meeting, each pair of appraisers achieved consensus on the validity and results of the trials they reviewed. One month before the panel meeting, panel members received the evidence tables for review prepared by the 3 pairs of appraisers. A priori, panel members agreed to read all circulated documents and evidence tables in advance, to use levels of evidence to generate a status statement for each item, and to abide by the group process and consensus methods. The Canadian Critical Care Society appointed a chair to ensure that the panel achieved its objectives through group process (29). At the panel meeting, each member recorded any potential conflicts of interest (30). The pair of panel members responsible for critical appraisal of each intervention provided a structured written and oral presentation of the evidence. After the panel discussion, the initial evidence summary was revised if necessary. The panel members assigned levels of evidence, semi-quantitative scores to summarize the evidence and describe the intervention, and a status statement. We classified trials as level 1 if they had all of the following: concealed randomization, blinded outcome adjudication, an intention-to-treat analysis, and an explicit definition of VAP. Trials were classified as level 2 if any one of these characteristics was unfulfilled and as level 3 if allocation was not strictly randomized. We used a semi-quantitative score (0, 1, 2, or 3) to evaluate each intervention with respect to the validity of the randomized trials; the effect size of each intervention; the confidence intervals around the estimate of effect; the homogeneity of the trial results; and the safety, feasibility, and economic consequences of the intervention. The language of the status statement for each item was keyed to the levels of evidence and the semi-quantitative scores. We used the term recommended if there were no reservations about endorsing an intervention and the term considered if the evidence supported an intervention but there were minor uncertainties about the benefits, harms, or costs. No recommendation was made if evidence regarding an intervention was inadequate or if there were major uncertainties about the benefits, harms, or costs. After the panel meeting, the chair compiled the summaries and status statements and sent them to all panel members to check accuracy and clarity. In addition, the pairs of evidence appraisers wrote background documents for the interventions they appraised, including the rationale for each intervention, appraisal of randomized trials and systematic reviews, and harms and costs of the interventions. The chair and the writing committee organized the background documents, the evidence summaries, a table of the semi-quantitative scores, and the status statement for each item. We formatted the document with a structured abstract (31), a summary of the evidentiary basis for each recommendation, and a status statement for each item. We also created a quick reference guide. The draft guideline document was submitted for structured external review by the executives of the Canadian Critical Care Society and the Canadian Critical Care Trials Group and the respective executives of the Canadian Association of Critical Care Nurses, Canadian Society of Respiratory Therapists, Canadian Infectious Disease Society, and Canadian Thoracic Society. External reviewers were asked to critique whether the guideline was logical, clear, and practical and to critique the guideline development process. The panel revised the document on the basis of this feedback. The final guideline was returned to the external reviewers for further comments and official endorsement by their respective organizations. The final guideline was then piloted in 2 institutions. To record the agreement of each panel member with the final status statement for each item, we sent the final document to all panel members. Independently, blinded to each others ratings, panel members used a Likert scale from 1 to 9 that was anchored by disagree completely at the low end and agree completely at the high end. The panel will formally review and update this guideline every 2 years (32). The funding source played no role in study selection for this guideline and had no role in its development

Diagnostic and Prognostic Implications of Endotoxemia in Critical Illness: Results of the MEDIC Study

A novel assay for endotoxin, based on the ability of antigen-antibody complexes to prime neutrophils for an augmented respiratory burst response, was studied in a cohort study of 857 patients admitted to an intensive-care unit (ICU). On the day of ICU admission, 57.2% of patients had either intermediate (>or=0.40 endotoxin activity [EA] units) or high (>or=0.60 units) EA levels. Gram-negative infection was present in 1.4% of patients with low EA levels, 4.9% with intermediate levels, and 6.9% with high levels; EA had a sensitivity of 85.3% and a specificity of 44.0% for the diagnosis of gram-negative infection. Rates of severe sepsis were 4.9%, 9.2%, and 13.2%, and ICU mortality was 10.9%, 13.2%, and 16.8% for patients with low, intermediate, and high EA levels, respectively. Stepwise logistic regression analysis showed that elevated Acute Physiology and Chronic Health Evaluation II score, gram-negative infection, and emergency admission status were independent predictors of EA.

Measures, markers, and mediators: Toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis Roundtable, Toronto, Ontario, Canada, October 25-26, 2000

BackgroundSepsis is not a single disease but a complex and heterogeneous process. Its expression is variable, and its severity is influenced by the nature of the infection, the genetic background of the patient, the time to clinical intervention, the supportive care provided by the clinician, and a number of factors as yet unknown. The evaluation of effective therapies has been hampered by limitations in our ability to characterize the process and to stratify patients into more homogeneous groups with respect to pathogenesis. ObjectivesTo develop a taxonomy of markers relevant to clinical research in sepsis and to propose a testable candidate system for stratifying patients into more therapeutically homogeneous groups. Data SourceAn expert roundtable discussion and a MEDLINE review using search terms “marker” and “sepsis.” ResultsMarkers provide information in one or more of three domains: diagnosis, prognosis, and response to therapy. More than 80 putative markers of sepsis have been described. All correlate with the risk of mortality (prognosis), yet none has shown utility in stratifying patients with respect to therapy (diagnosis) or in titrating that therapy (response). Their limitations arise from the challenges of establishing causality in a complex disease process such as sepsis and of stratifying patients into more homogeneous populations. The former limitation may be addressed through a modification of Koch’s postulates to differentiate causality from simple association. The latter suggests the need for a staging system analogous to those used in other complex disease processes such as cancer. A candidate framework for such a system, based on the infection, the host response, and the extent of organ dysfunction (the IRO system) is described. ConclusionsAdvances in the understanding and management of patients with sepsis will necessitate more rigorous approaches to disease description and stratification. Models should be developed, tested, and modified through clinical studies rather than through consensus.

A rapid assay of endotoxin in whole blood using autologous neutrophil dependent chemiluminescence.

A rapid (30 min) whole blood assay for the detection of lipopolysaccharide (LPS) is described. This chemiluminescent (CL) assay utilizes the CR1 and CR3 receptor-induced oxidant production of polymorphonuclear leucocytes as a detection platform. The differential priming of neutrophils in whole blood by LPS-antibody complexes allows the specificity of the assay to be achieved. Oxidant released in response to complement opsonized zymosan results in luminol oxidation and subsequent light emission. This is dependent on heat labile putative complement proteins in the plasma. The assay consists of a control which measures baseline whole blood neutrophil oxidant production. The test assay contains murine monoclonal IgM antibody against the Lipid A epitope of LPS and measures the enhanced chemiluminescent response of the neutrophils in the presence of LPS-antibody complexes. Maximal sensitivity of the CL assay is dependent upon optimal antigen-antibody equivalence and duration of pre-incubation with the whole blood sample. The quantification of LPS is possible by inclusion of a positive control containing a maximally reactive LPS dose (800 pg/ml Escherichia coli 055:B5 LPS at an antibody concentration of 0.8 microg/assay). The CL assay is insensitive to variations in patient neutrophil concentration over a minimum range of 0.5 to 20 x 10(9) cells/l. The CL assay is widely reactive with the LPS of many strains of gram negative bacteria but not with the cell wall products of gram positive bacteria or Candida and Aspergillus. In comparison to acid extraction chromogenic LAL, the CL assay demonstrates superior recovery precision and accuracy in in vitro studies. This was reproducible over a wide range of LPS concentrations (0.017-1.6 EU/ml or 20-2000 pg/ml). This assay may be a clinically useful tool for the diagnosis of infection or endotoxin in patients.

Daily variation in endotoxin levels is associated with increased organ failure in critically ill patients.

ABSTRACT High blood levels of endotoxin on admission to the intensive care unit are predictive of adverse outcomes, including organ failure and death. However, the significance of changes in endotoxin levels over time has not been evaluated. We examined whether dynamic daily changes in endotoxin levels resulted in the development of greater organ dysfunction over time in critically ill patients. The study was a retrospective analysis of data from the longitudinal phase of a prospective observational multicenter cohort study of endotoxin levels in patients admitted to the intensive care unit. We analyzed 345 patients. Daily variation in endotoxin levels was assessed by calculating the number of inflections in the curve generated by plotting endotoxin levels against time. The degree of organ dysfunction over time was analyzed using a calculation of the total area under the curve generated by plotting the Multi Organ Dysfunction Score against time. From 1,301 endotoxin activity assay results, patients with dynamic daily variation in endotoxin levels as measured by a greater number of inflections had a greater degree of total organ dysfunction as measured by Multi Organ Dysfunction Score against time (P < 0.05). The arithmetic mean standard deviation of endotoxin activity assay results increased stepwise in the zero, one, and two inflection groups supporting the association between inflections and variability. Endotoxin activity assay variability was found to be independent of infection status (P = 0.52). Daily dynamic variation in endotoxin levels is a marker of increased severity of illness as measured by burden of total organ dysfunction over time. Further studies are warranted to assess the role of daily variation in endotoxin levels in the pathogenesis and potential therapy of organ failure in the critically ill.

LET THE CELLS SPEAK : NEUTROPHILS AS BIOLOGIC MARKERS OF THE INFLAMMATORY RESPONSE

These questions are inherently complex, since the septic process involves the concerted interplay of multiple dynamic biochemical and physiological cascades that manifest in an unpredictable and highly variable manner. Simpli~ed models of the host immune response in critical illness have been proposed [1–4], but not tested or validated in a manner that permits them to be of use in clinical decision-making. The value of any proposed model is to provide mechanistic insights and to identify targets for intervention that can be manipulated in a predictable manner to achieve clinical bene~t. Trauma has been a popular model of the in_ammatory response since the onset of injury is well-de~ned, and the inciting insult readily identi~able. Patrick et al. [1] have described a two hit model of an initial dysfunctional in_ammatory response following major trauma, which contributes to the development of multiple organ dysfunction (Figure 1). Sequential neutrophil priming plays a pivotal role in the genesis of remote organ injury. Faist et al. [2] have proposed a model relating monocyte/macrophage and T-cell interactions to the development of an anergic state following trauma; disruption of the normal balance between TH1 and TH2 lymphocyte subsets which serves as both a marker, and a potential mechanism for developing anergy (Figure 2). Both models describe early and late phases of the immune response: an early phase of systemic in_ammation that can be exacerbated by a secondary insult, with resultant progression to a later and potentially lethal immunosuppressed or anergic state. An important assumption of these models is that the exaggerated or prolonged early pro-in_ammatory phase triggers a compensatory anti-in_ammatory response which may shift the immune balance to a suppressed phenotype [5]. This anergic state not only predisposes the host to nosocomial infection, but previously immunocompetent effector cells such as granulocytes become injurious due to super activation [6–8], uncoordinated function [9–11] and/or delayed apoptosis [12]. Models of trauma which delineate the course of immune competence, provide useful parallels in other clinical scenarios such as ischemia-reperfusion, or systemic infection. A logical prediction from these models is that anti-in_ammatory therapies which blunt the hysteresis of the pro-in_ammatory cytokinemic phase would be bene~cial at an early stage, but potentially lethal during the anergic phase. Similarly, interventions designed to augment the immune response in the anergic phase could exacerbate the cytokinemic proin_ammatory state and contribute to a deleterious outcome for the patient. De~ning the immune status prior to therapeutic intervention may therefore be of critical importance to selection of therapy. There is a recognized need for markers which can rapidly identify: 1) the inciting insults, 2) the immunological staging of the patient and 3) the immune response to therapy. Circulating levels of in_ammatory mediators of acute in_ammation such as interleukin 6 [13], procalcitonin [14], or C reactive protein [15] may provide clinically useful information about the state of activation of the host septic response. Previous studies have shown that the measurement of sustained plasma pro-in_ammatory cytokines such as TNF-a and IL-6 rather than their peak concentrations identify those patients who develop multiple organ dysfunction and death [16]. An alternative apporach to the use of levels of in_ammatory mediators as diagnostic markers is to analyze the responses of the cellular effectors of an in_ammatory response—to let the cells speak for themselves. As the foot soldiers of acute in_ammation, neutrophils are ideally suited to ful~ll this role.

Use of a screen log to audit patient recruitment into multiple randomized trials in the intensive care unit

Objective: To develop and evaluate a screen log for monitoring enrollment in multiple randomized clinical trials conducted in a single center. Setting: University‐affiliated 20‐bed tertiary care medical‐surgical intensive care unit (ICU). Patients: Consecutive ICU patients admitted between April 1995 and March 1997. Methods: We developed a screen log for multicentered studies conducted in our ICU. Using a multiple‐project, unicenter perspective, we evaluated the screen log as a tool for monitoring eligibility and enrollment of patients in four multicentered randomized trials focused on stress ulcer prophylaxis, blood transfusion thresholds, immunotherapy for sepsis and mechanical ventilation strategies. Results: The screen log was used as an instrument to monitor trial execution. We recorded all aspects of study enrollment and created a taxonomy of reasons for nonenrollment into each trial. We calculated enrollment efficiency rates and used these data to develop strategies to maximize accrual. The screen log became a communication tool that fostered research‐oriented continuous quality improvement initiatives for the management of concurrently conducted randomized trials in our ICU. Conclusions: Intensivists participating in several clinical trials may be interested in monitoring and maximizing enrollment when conducting multiple studies and understanding the influence of each trial on enrollment into the others. The unicenter, multiple‐project screen log is one tool that may help to achieve these goals.

Endotoxin Removal: How Far from the Evidence? From EUPHAS to EUPHRATES

There is a large amount of support for the safety of polymyxin-B (PMX-B) hemoperfusion in the treatment of septic shock from Japan and Europe. There is also support for potential efficacy, although randomized controlled trials are few and conflicting. PMX-B hemoperfusion represents a promising new treatment that could significantly improve survival. Previous clinical trials of PMX-B have been criticized for methodological issues, such as the absence of blinding, the use of surrogate outcomes and lack of longer term mortality outcomes. The variability in the number of treatment cartridges used, the selection of subjects based on likelihood of endotoxin presence without endotoxin measurement, and small sample sizes in mainly single-center trials have also been cited. The newly designed EUPHRATES trial (Evaluating Use of Polymyxin Hemoperfusion in a Randomized Controlled Trial of Adults treated for Endotoxemia and Septic Shock) addresses many of the methodological issues and represents a significant opportunity to test for clinical efficacy of endotoxin removal in the critically ill septic patient.

Endotoxemia is common following abdominal organ transplantation and is associated with reperfusion and rejection

Objective. Patients undergoing orthotopic liver transplantation (OLT) and multi-visceral transplantation (MVT) may have an increased incidence of endotoxemia due to translocation of endotoxin from the intestine, in combination with impaired hepatic clearance. We sought to evaluate the presence of endotoxemia in the perioperative period, using the Endotoxin Activity Assay™ (EAA) to understand the association of endotoxin activity (EA) with clinical course and outcome. Material and methods. In this prospective observational pilot study we measured EA in 40 patients undergoing OLT or MVT during the perioperative period. As a control, the EAA was performed on 10 healthy adult volunteers. We analyzed the relationships between EA and graft function, episodes of rejection, infection and outcome. Results. Mean EA in the control group was 0.21±0.05 u (range 0.16–0.27 u). For patients, baseline pre-transplant EA was significantly greater than that in controls at 0.50±0.17 u (range 0.10–0.80 u) (p=0.001) and further...

Endotoxin Removal: Bringing the Mission to North America

The EUPHRATES trial (Evaluating Use of Polymyxin B Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock) is the first biomarker-driven trial in sepsis. This unique trial is being run in a blinded manner, further contributing to the robustness of its design. This paper will describe the implementation of the EUPHRATES trial focusing on 3 pertinent features: (1) managing (and maintaining) the blinding of a medical device trial; (2) impact of the use of a diagnostic test where eligible subjects with septic shock must also have high levels of endotoxin (≥0.60 EAA units), and (3) managing enrolment in a complicated trial design where two medical teams are involved (the intensivist as the blinded caregiver and nephrologists as the unblinded performers of the intervention). The study is nearing the halfway mark and is currently experiencing excellent recruitment success.