John C. Marshall

The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis.

Objective: The Surviving Sepsis Campaign (SSC or “the Campaign”) developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations. Design and Setting: A multifaceted intervention to facilitate compliance with selected guideline recommendations in the intensive care unit, emergency department, and wards of individual hospitals and regional hospital networks was implemented voluntarily in the United States, Europe, and South America. Elements of the guidelines were “bundled” into two sets of targets to be completed within 6 hrs and within 24 hrs. An analysis was conducted on data submitted from January 2005 through March 2008. Subjects: A total of 15,022 subjects. Measurements and Main Results: Data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality. Compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 yrs (p < .0001). Compliance with the entire management bundle started at 18.4% in the first quarter and increased to 36.1% by the end of 2 yrs (p = .008). Compliance with all bundle elements increased significantly, except for inspiratory plateau pressure, which was high at baseline. Unadjusted hospital mortality decreased from 37% to 30.8% over 2 yrs (p = .001). The adjusted odds ratio for mortality improved the longer a site was in the Campaign, resulting in an adjusted absolute drop of 0.8% per quarter and 5.4% over 2 yrs (95% confidence interval, 2.5–8.4). Conclusions: The Campaign was associated with sustained, continuous quality improvement in sepsis care. Although not necessarily cause and effect, a reduction in reported hospital mortality rates was associated with participation. The implications of this study may serve as an impetus for similar improvement efforts.

No surgical innovation without evaluation: the IDEAL recommendations

Surgery and other invasive therapies are complex interventions, the assessment of which is challenged by factors that depend on operator, team, and setting, such as learning curves, quality variations, and perception of equipoise. We propose recommendations for the assessment of surgery based on a five-stage description of the surgical development process. We also encourage the widespread use of prospective databases and registries. Reports of new techniques should be registered as a professional duty, anonymously if necessary when outcomes are adverse. Case series studies should be replaced by prospective development studies for early technical modifications and by prospective research databases for later pre-trial evaluation. Protocols for these studies should be registered publicly. Statistical process control techniques can be useful in both early and late assessment. Randomised trials should be used whenever possible to investigate efficacy, but adequate pre-trial data are essential to allow power calculations, clarify the definition and indications of the intervention, and develop quality measures. Difficulties in doing randomised clinical trials should be addressed by measures to evaluate learning curves and alleviate equipoise problems. Alternative prospective designs, such as interrupted time series studies, should be used when randomised trials are not feasible. Established procedures should be monitored with prospective databases to analyse outcome variations and to identify late and rare events. Achievement of improved design, conduct, and reporting of surgical research will need concerted action by editors, funders of health care and research, regulatory bodies, and professional societies.

Evaluation and stages of surgical innovations

Surgical innovation is an important part of surgical practice. Its assessment is complex because of idiosyncrasies related to surgical practice, but necessary so that introduction and adoption of surgical innovations can derive from evidence-based principles rather than trial and error. A regulatory framework is also desirable to protect patients against the potential harms of any novel procedure. In this first of three Series papers on surgical innovation and evaluation, we propose a five-stage paradigm to describe the development of innovative surgical procedures.

Sepsis definitions: time for change

For the Ancient Greeks, sepsis referred to rot, decay, or putrefaction. Galen and Celsus described the signs of inflammation as peripheral vasodilatation (rubor), fever (calor), pain (dolor), increased capillary permeability (tumor), and organ dysfunction (functio laesa). The modern concept of sepsis has focused on the human response to invading organisms. In 1991, a North American consensus conference introduced the idea that sepsis is the hosts inflammatory response to in fection.1 For simplicity, the systemic inflammatory response syndrome (SIRS) was defined by four variables: temperature, heart rate, respiratory rate, and white blood cell count. Only minor abnormalities in these variables are needed for a patient to meet the SIRS criteria. These simple clinical criteria allowed researchers to identify patients to enrol in sepsis trials and were rapidly adopted. However, the SIRS approach has three major problems. First, the SIRS criteria are so sensitive that up to 90% of patients admitted to an intensive care unit (ICU) meet the criteria.2,3 SIRS can be caused by many non-infectious clinical processes, such as severe trauma, burns, pancreatitis, and ischaemic reperfusion events. If sepsis is defined by the presence of SIRS criteria plus an infection, and almost every acutely ill patient meets the SIRS criteria, then sepsis effectively equals infection. But, although all patients with sepsis have an infection, the reverse is not necessarily true—ie, not all patients with an infection have sepsis. Second, some degree of host response is actually inherent to the infection; indeed, this is an important component of the difference between infection and mere colonisation. Almost any infection—even a minor viral illness—is typically associated with fever and accompanying changes, including tachycardia, some hyperventilation, and an increased white cell count. This host response has beneficial aspects, and a reduced or absent reaction could suggest that the individual is immunocompromised. Third, deciphering the role of infection in the pathogenesis of SIRS has been difficult because sterile inflammation (present in, for example, severe trauma, burns, and pancreatitis) and infection can both elicit similar clinical signs of acute systemic inflammation. Moreover, several such stressors might be present simultaneously in any patient. A second consensus conference in 20014 attempted to revisit the SIRS criteria but failed to come up with an easy-to-use list of variables to define sepsis. By expanding the list of potential clinical criteria, the delegates risked making the definition less specific. The delegates attempted to list major and minor criteria, as for endocarditis, but could not identify any meaningful criteria. Hence, the 1991 criteria for sepsis continue to be used. To reach a more precise definition of sepsis than the SIRS criteria provide, we need to establish whether sepsis is the same as sterile inflammation. Several non-infectious processes that are associated with acute tissue injury and innate immune activation can induce a clinical syndrome analogous to sepsis (figure), including multiple trauma, pancreatitis, transplant rejection, and autoimmune diseases.5 Whether this syndrome is mediated by endogenous endotoxin or by non-infectious stimuli can be very difficult to define. However, we know that sepsis arises through activation of an innate immune response to a stimulus that represents a danger to the host.6 From a molecular perspective, the initial host response to infection does not differ appreciably from the host response to sterile inflammation from severe trauma, burns, ischaemic reperfusion injury, or other forms of tissue injury that are accompanied by cell necrosis.5 Figure Infectious and non-infectious stimuli that activate innate immunity and cytokine release and can cause sepsis Work over the past few decades has shown that pattern recognition receptors, such as those of the Toll-like receptor (TLR) and the nucleotide-binding oligomerisation domain (NOD) protein families, initiate the distinct cellular responses.6 Together these responses produce the phenotypic changes of sepsis. The receptors are activated by conserved microbial molecular structures, such as endotoxin or lipoteichoic acid. But the pattern recognition receptors used by the innate immune system to engage microbial ligands are the same receptors that recognise alarmins derived by host tissue and that are pathologically present in the extracellular environment.5,6 For example, high mobility group box 1 (HMGB1) is released during sterile injury and signals through TLR4 to mediate organ damage, even in the absence of infection.5 Both invasive infection and sterile tissue necrosis thus cause immediate activation of inflammatory, coagulation, microbial clearance, and tissue repair pathways to stabilise and defend the host from further injury. Clinical signs alone fail to distinguish this sterile inflammatory response from one initiated by infection. This effect explains why the phenotype of SIRS is clinically indistinguishable in patients with severe infection and those with major injury without concomitant infection. The combined actions of both the innate and adaptive immune defences are then used to eradicate microbial invaders (sepsis) or to repair tissue (sepsis and sterile tissue injury), or both.6 In a comparative transcriptome analysis, Xiao and colleagues7 showed high fidelity concordance in the mitochondrial RNA signatures in leucocytes from patients immediately after severe trauma or burns, and in people given intravenous bacterial endotoxin. These observations suggest that similar and overlapping signalling networks are activated in sterile inflammation and in invasive infection. So where does this leave our definitions? Sepsis is not simply the host response to an infection, nor is it the same as sterile inflammation. Rather, sepsis is the hosts deleterious, non-resolving inflammatory response to infection that leads to organ dysfunction. Most clinicians do not refer to patients as septic when they develop an uncomplicated mild upper-respiratory viral infection with slight fever and tachycardia. The term sepsis is usually reserved for patients with an infection who “look bad” and whose condition is severe enough that they need to be admitted to the ICU or monitored more carefully. At a Merinoff Symposium, the International Sepsis Forum wrote “sepsis is a life-threatening condition that arises when the bodys response to an infection injures its own tissues and organs”8—this is the very latest perception of sepsis. Importantly, pro-inflammatory and anti-inflammatory responses coexist in sepsis and can lead to immunosuppression. The response that predominates in the clinical phenotype varies across patients and over time in each patient. How can such a dysregulated host response be defined with clinical criteria? What we actually mean when we say a patient “looks bad” is that some degree of associated organ dysfunction is already present—eg, some degree of arterial hypotension is present, the blood lactate is slightly raised, gas exchange is impaired, or the patient is obtunded or confused. A systematic review of organ function in the infected patient includes six organ systems: cardiovascular, respiratory, renal, neurological, hepatic, and coagulation.9 Other organs, like the gut or the endocrine system, are more difficult to assess objectively. Any type of associated organ dysfunction indicates that an acute and potentially life-threatening disorder is present, which must be treated rapidly and appropriately to prevent the development of multiorgan failure and to optimise clinical outcomes. Sepsis differs from sterile inflammation, not by the nature of the activated host response pathways or by the types of organ dysfunction, but by the presence of an underlying infectious process. The first diagnostic priority in managing a patient with sepsis is, therefore, to identify any focus of invasive infection. The range of infections that can induce sepsis is broad, and the clinical phenotype is at least partly shaped by the infecting organism. Bacterial infection can typically be diagnosed with conventional methods of culture and sensitivity, and the site of infection can be identified on the basis of clinical findings supplemented by radiographic investigations. Fungal and parasitic infections are suggested by the clinical context. Viral infections can be challenging to diagnose outside of an epidemiologically defined epidemic or pandemic, but emerging nucleic acid based assays are permitting more rapid and accurate diagnosis of viral infection. Rapid treatment with antibiotics and source control measures can assist the host in clearing the pathogen, and the therapeutic focus should be on initiation of these treatments and on maintenance of perfusion. After the host has cleared the pathogen, the clinical outcome will probably be a result of how well the complications of the residual infectious or sterile systemic inflammatory response are managed. The terms severe sepsis and sepsis have often been used interchangeably. To clarify this situation, we believe evidence of organ dysfunction should be included in the criteria for sepsis—ie, sepsis should be defined as a systemic response to infection with the presence of some degree of organ dysfunction.

Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity

Pre‐B cell colony‐enhancing factor (PBEF), also known as visfatin, is a highly conserved, 52‐kDa protein found in living species from bacteria to humans. Originally a curiosity identified serendipitously in microarray studies but having no obvious functional importance, PBEF has now been shown to exert three distinct activities of central importance to cellular energetics and innate immunity. Within the cell, PBEF functions as a nicotinamide phosphoribosyl transferase, the rate‐limiting step in a salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. By virtue of this role, it can regulate cellular levels of NAD and so impact not only cellular energetics but also NAD‐dependent enzymes such as sirtuins. Although it lacks a signal peptide, PBEF is released by a variety of cells, and elevated levels can be found in the systemic circulation of patients with a variety of inflammatory diseases. As an extracellular cytokine, PBEF can induce the cellular expression of inflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6. Finally, PBEF has been shown to be an adipokine expressed by fat cells that exerts a number of insulin mimetic and antagonistic effects. PBEF expression is up‐regulated in a variety of acute and chronic inflammatory diseases including sepsis, acute lung injury, rheumatoid arthritis, inflammatory bowel disease, and myocardial infarction and plays a key role in the persistence of inflammation through its capacity to inhibit neutrophil apoptosis. This review summarizes the admittedly incomplete body of emerging knowledge about a remarkable new mediator of innate immunity.

Interhemispheric integration of visual processing during task-driven lateralization.

The mechanisms underlying interhemispheric integration (IHI) remain poorly understood, particularly for lateralized cognitive processes. To test competing theories of IHI, we constructed and fitted dynamic causal models to functional magnetic resonance data from two visual tasks that operated on identical stimuli but showed opposite hemispheric dominance. Using a systematic Bayesian model selection procedure, we found that, in the ventral visual stream, which was activated by letter judgments, interhemispheric connections mediated asymmetric information transfer from the nonspecialized right to the specialized left hemisphere when the latter did not have direct access to stimulus information. Notably, this form of IHI did not engage all areas activated by the task but was specific for areas in the lingual and fusiform gyri. In the dorsal stream, activated by spatial judgments, it did not matter which hemisphere received the stimulus: interhemispheric coupling increased bidirectionally, reflecting recruitment of the nonspecialized left hemisphere. Again, not all areas activated by the task were involved in this form of IHI; instead, it was restricted to interactions between areas in the superior parietal gyrus. Overall, our results provide direct neurophysiological evidence, in terms of effective connectivity, for the existence of context-dependent mechanisms of IHI that are implemented by specific visual areas during task-driven lateralization.

Neurophysiological correlates of relatively enhanced local visual search in autistic adolescents

Previous studies found normal or even superior performance of autistic patients on visuospatial tasks requiring local search, like the Embedded Figures Task (EFT). A well-known interpretation of this is “weak central coherence”, i.e. autistic patients may show a reduced general ability to process information in its context and may therefore have a tendency to favour local over global aspects of information processing. An alternative view is that the local processing advantage in the EFT may result from a relative amplification of early perceptual processes which boosts processing of local stimulus properties but does not affect processing of global context. This study used functional magnetic resonance imaging (fMRI) in 12 autistic adolescents (9 Asperger and 3 high-functioning autistic patients) and 12 matched controls to help distinguish, on neurophysiological grounds, between these two accounts of EFT performance in autistic patients. Behaviourally, we found autistic individuals to be unimpaired during the EFT while they were significantly worse at performing a closely matched control task with minimal local search requirements. The fMRI results showed that activations specific for the local search aspects of the EFT were left-lateralised in parietal and premotor areas for the control group (as previously demonstrated for adults), whereas for the patients these activations were found in right primary visual cortex and bilateral extrastriate areas. These results suggest that enhanced local processing in early visual areas, as opposed to impaired processing of global context, is characteristic for performance of the EFT by autistic patients.

Sepsis: rethinking the approach to clinical research

The clinical syndrome of sepsis encompasses a highly heterogeneous group of clinical disorders, varying with respect to the site, bacteriology, and even presence of infection and with the clinical syndrome evolving in the host. Clinical trials of strategies to modulate the host response that mediates sepsis were first initiated 25 years ago. A continuing record of disappointment has characterized subsequent work, and only a single new therapy has been licensed for clinical use. Yet, these commercial disappointments obscure a vibrant body of new knowledge that has clarified the biology of the innate immune response whose deranged expression is responsible for sepsis and that has provided important new insights into the failings of the traditional model of clinical research in sepsis. This review highlights advances in basic biology and underlines insights from clinical research that may point to new and more effective ways of translating an understanding of innate immunity into effective treatments for a leading cause of global morbidity and mortality.

Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock.

The role of drotrecogin alfa (activated) (DAA) in severe sepsis remains controversial and clinicians are unsure whether or not to treat their patients with DAA. In response to a request from the European Medicines Agency, Eli Lilly will sponsor a new placebo-controlled trial and history suggests the results will be subject to great scrutiny. An academic steering committee will oversee the conduct of the study and will write the study manuscripts. The steering committee intends that the study will be conducted with the maximum possible transparency; this includes publication of the study protocol and a memorandum of understanding which delineates the role of the sponsor. The trial has the potential to provide clinicians with valuable data but patients will only benefit if clinicians have confidence in the conduct, analysis and reporting of the trial. This special article describes the process by which the trial was developed, major decisions regarding trial design, and plans for independent analysis, interpretation and reporting of the data.

Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation : a multicenter observational study.

IntroductionThe intent of this study was to determine whether serum procalcitonin (PCT) levels are associated with prognosis, measured as organ dysfunctions and 28-day mortality, in patients with severe pneumonia.MethodsThis was a multicenter, observational study of critically ill adult patients with pneumonia requiring mechanical ventilation conducted in 10 academic hospitals in Canada, the United States, and Central Europe. PCT was measured daily for 14 days using an immuno-luminometric assay.ResultsWe included 175 patients, 57 with community acquired pneumonia (CAP), 61 with ventilator associated pneumonia (VAP) and 57 with hospital acquired pneumonia (HAP). Initial PCT levels were higher in CAP than VAP patients (median (interquartile range: IQR); 2.4 (0.95 to 15.8) vs. 0.7 (0.3 to 2.15), ng/ml, P < 0.001) but not significantly different to HAP (2.2 (0.4 to 8.0) ng/ml). The 28-day ICU mortality rate for all patients was 18.3% with a median ICU length of stay of 16 days (range 1 to 142 days). PCT levels were higher in non-survivors than in survivors. Initial and maximum PCT levels correlated with maximum Sequential Organ Failure Assessment (SOFA) score r2 = 0.50 (95% CI: 0.38 to 0.61) and r2 = 0.57 (0.46 to 0.66), respectively. Receiver operating curve (ROC) analysis on discrimination of 28-day mortality showed areas under the curve (AUC) of 0.74, 0.70, and 0.69 for maximum PCT, initial PCT, and Acute Physiology and Chronic Health Evaluation (APACHE) II score, respectively. The optimal cut-off to predict mortality for initial PCT was 1.1 ng/ml (odds ratio: OD 7.0 (95% CI 2.6 to 25.2)) and that for maximum PCT was 7.8 ng/ml (odds ratio 5.7 (95% CI 2.5 to 13.1)).ConclusionsPCT is associated with the severity of illness in patients with severe pneumonia and appears to be a prognostic marker of morbidity and mortality comparable to the APACHE II score.