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Handbook of Critical Care, Revised Edition
Duncan Wyncoll
Critical Care , 2005, DOI: 10.1186/cc3889
Abstract: The chapters are written in a didactic fashion, and there is very little discussion as to why a particular therapy or course of treatment is recommended. Consequently, it is no surprise that there are no references in the book to any of the major papers that form the critical care evidence base. No reference is made to the various national society guidelines on, for example, the management of trauma, head injury, or nosocomial infection. There is one reference to the Advanced Cardiac Life Support guidelines from the American Heart Association.The handbook clearly has a very North American predisposition, and given its instructive nature this could prove confusing for trainees from Europe. Examples of the potential conflicts include the recommendation for the management of oliguria to 'insert a pulmonary artery flotation catheter, and then confirm filling with a transthoracic echo'. In the section on asthma, the two first-line recommended drugs are albuterol and methylprednisolone – drugs that are rarely used for asthma in Europe. In the section on measuring cardiac output, neither the PiCCO (Pulsion Medical Systems, Munich, Germany) or LiDCO (LiDCO Ltd., Cambridge, UK) device is mentioned, both of which are frequently used in Europe. The section on infection and inflammation is weak, which is surprising given the focus on this topic in the critical care literature over the past 5 years.This book has many positives, including the general clarity, layout and the good overviews of most of the subjects covered. However, I suspect that for some European trainees the advantages would be outweighed by the frustrations that may result from the differences in specific treatment protocols used between North America and Europe.The author(s) declare that they have no competing interests.
Number needed to treat and cost-effectiveness in the prevention of ventilator-associated pneumonia
Duncan Wyncoll, Luigi Camporota
Critical Care , 2012, DOI: 10.1186/cc11346
Abstract: To answer the first question, one needs data from clinical trials and the knowledge of the baseline VAP rate with the likely RRR of the local case mix. We have calculated (Table 1) the NNT required to prevent one additional VAP for patients who require intubation and mechanical ventilation (MV) for more than 72 hours and an average time of MV of 10 days. The NNTs are based on an RRR ranging from 5% to 50% and a control event rate for VAP ranging from 1% to 20%, given a uniform distribution of NNTs across the range of RRRs. For example, with a VAP rate of approximately 8% and an intervention that reduces VAP by 45%, the NNT is 28 - a scenario that is realistic given a recent meta-analysis of one particular intervention [3].To establish whether the intervention is cost-effective, further knowledge of the cost of the intervention and the cost to treat an episode of VAP is required. A recent US study estimated the cost of VAP to be nearly $40,000 (£25,000 or €30,000) [4]. If costs are assumed to be lower in Europe, then a conservative estimate of the cost per episode of VAP would still be around £10,000, which is equivalent to an extra 7 days of intensive care unit (ICU) stay. What should we consider when assessing the cost-effectiveness of VAP prevention?We have calculated (Table 2) the additional money (in pounds) that can be spent to prevent an episode of VAP (per 10 days of MV) to achieve cost-neutrality. If we assume a hypothetical VAP cost of £10,000, then with a VAP rate of 8% and an RRR of 45%, it is cost-effective to spend up to £360. Furthermore, even for an ICU with a VAP rate of only 4% and an intervention that reduces VAP by just 25%, it is still cost-effective to spend up to £100 per 10 days of MV. It should be noted that some VAP prevention interventions (for example, a modified tracheal tube cuff) require just a 'one-off' initial cost whereas other interventions (for example, SDD) require an 'ongoing' daily cost.We think that this analysis might help cli
Practical aspects of treatment with drotrecogin alfa (activated)
Luigi Camporota, Duncan Wyncoll
Critical Care , 2007, DOI: 10.1186/cc6158
Abstract: Severe sepsis and septic shock respectively account for about 37% and 15% of patients admitted to intensive care units (ICUs) in Europe [1]. They are also the leading causes of death [2], with 27% and 47% ICU mortality, and 36% and 57% hospital mortality, respectively [1]. Data from the Intensive Care National Audit and Research Centre in England, Wales, and Northern Ireland show that the number of patients with severe sepsis admitted to the ICU is increasing over time [3], which is responsible for an increase in the absolute number of deaths, despite an improved standard of care and reduced hospital mortality.The mechanisms that lead to organ dysfunction in severe sepsis are complex. Deranged procoagulant and proinflammatory host responses to infection can lead to endothelial damage, impairment of the microcirculation and tissue hypoperfusion [4,5]. In this intricate system, activated protein C plays a key role in preserving and restoring tissue perfusion through its potent antithrombotic, profibrinolytic, and anti-inflammatory properties [6-8].During systemic sepsis, however, inflammation and endothelial dysfunction impair the conversion of protein C (PC) to its activated protein C form. Hence, almost 88% of patients with sepsis have low levels of PC (<80% of normal), and 40% have levels of PC that are severely reduced (<40% of normal) [9]. This can lead to excessive inflammation, formation of microthrombi and multiple organ failure, with an associated poor outcome [6,7,10,11].In 2001 the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial was reported [9]. It found that a 96-hour intravenous infusion (24 μg/kg per hour) of drotrecogin alfa (activated; DrotAA), a recombinant human activated protein C (Xigris?; Eli Lilly and Company, Indianapolis, IN, USA), caused a relative risk reduction (RRR) for mortality at 28 days of 19.4% (95% confidence interval [CI] 6.6% to 30.5%). The absolute risk reduction (ARR) for mortality was
New versus old blood - the debate continues
John Laurie, Duncan Wyncoll, Claire Harrison
Critical Care , 2010, DOI: 10.1186/cc8878
Abstract: The current standard red blood cell (RBC) storage time of up to 42 days is not based upon a demonstrable therapeutic benefit, but instead on the observed return of 70% of the viable transfused RBCs at 24 hours after storage for 42 days or less. The structural, biochemical and immunological changes that RBCs undergo during storage are well described, but what remains controversial is the evidence that this storage lesion translates into adverse clinical outcomes for patients receiving older blood. In a previous issue of Critical Care, Ranucci and colleagues report an adverse outcome in infants receiving older blood during cardiopulmonary bypass (CPB) [1].The effects of storage on RBCs include changes in potassium (increased levels), 2,3-diphosphoglycate (decreased levels), lactate (increased levels), pH (decreased values), glucose (decreased levels), adenosine triphosphate (decreased levels), methaemoglobin (increased levels), red cell structure (from biconcave disc, to echinocytes and then to spherocytes), and therefore red cell deformability. Storage effects also include changes to the microenvironment with reduced levels of S-nitrosohaemoglobin and nitric oxide. Prolonged storage prior to transfusion also results in an immunomodulatory effect, first described by Opelz and colleagues who demonstrated reduced transplant rejection after stored red cell administration [2]. This effect theoretically increases infection risk, by accumulation of proinflammatory lipids and neutrophil priming, resulting in severely reduced neutrophil function.The evidence that prolonged storage of RBCs contributes to demonstrable adverse outcomes remains controversial, however, and is hampered by many small retrospective studies with potential selection bias; most evidence is also confounded by relatively recent changes in practice such as leucodepletion of RBCs. Moreover, there is still no consensus on what constitutes old blood, with studies using variable definitions of 5, 12, 14 or 21
Activated protein C in severe acute pancreatitis without sepsis? Not just yet ...
Manu Shankar-Hari, Duncan Wyncoll
Critical Care , 2010, DOI: 10.1186/cc9190
Abstract: In the present issue of Critical Care, Pettila and colleagues report the first single-centred pilot randomized controlled trial of activated protein C (APC) in alcoholinduced acute pancreatitis of moderate severity but without infection [1]. After screening 215 patients, 32 patients satisfied the trial inclusion criteria and were randomized to either placebo or APC at 24 μg/kg/hour for 96 hours, in addition to standard therapy for acute pancreatitis. The study - powered to evaluate the effect of APC on the change in organ dysfunction, measured using the Sequential Organ Failure Assessment score as the primary outcome - failed to show any benefit.In acute pancreatitis, severity is defined by the occurrence of organ failure and/or peri-pancreatic complications. Severe acute pancreatitis (SAP) is characterized by the presence of an overwhelming inflammatory response, with unregulated activation of the coagulation system. Evaluation of the coagulation and the endogenous protein C/antithrombin III (AT III) system shows that nonsurvivors in SAP have significantly lower levels of protein C and AT III activity, and higher levels of D-dimer and plasminogen activator inhibitor-1, than survivors [2]. These changes mirror the patterns seen in severe bacterial sepsis that suggest exhaustion of fibrinolysis and coagulation inhibitors, thereby identifying a possible role for APC in SAP independent of the need to diagnose severe sepsis. Prior to the study by Pettila and colleagues [1], the literature was limited to animal studies [3,4] and to subgroup data from the PROWESS trial of 62 patients with acute pancreatitis and severe sepsis, where there was a trend to reduced mortality in those treated with APC (24% vs. 15%) [5]. The Consensus Guidelines thus recom mended that careful consideration is given to APC therapy in those patients with SAP and infection, given the theoretical but unproven concern of retroperitoneal haemorrhage [5].SAP is a devastating disease with an attributabl
The tracheal tube: gateway to ventilator-associated pneumonia
Parjam S Zolfaghari, Duncan LA Wyncoll
Critical Care , 2011, DOI: 10.1186/cc10352
Abstract: Ventilator-associated pneumonia (VAP) is defined as pneumonia occurring in a mechanically ventilated patient after 48 hours of endotracheal intubation [1]. Despite significant advances in managing intubated patients, VAP remains a common and occasionally fatal complication in the ICU [2]. A systematic review of published data since 1990 showed the incidence of VAP to be 10 to 20%, with a possible two-fold increase in mortality attributable to VAP [3]. The ICU length of stay was also significantly increased by a mean of 6.1 days with an attributable cost of $10,019 per case [3]. A recent Canadian study estimated an additional 4.3 ICU days attributable to VAP, occupying 2% of all ICU days and an estimated national cost of CAN$43 million per year [4]. Similar findings were reported by a North American study with increased unadjusted ICU length of stay and mortality in patients with VAP (50% mortality in VAP patients versus 34% in non-VAP) with an estimated $11,897 attributable cost [5]. Furthermore, the burden of VAP takes up a significant portion of antibiotic dispensing in the ICU [6] and may well be a contributor to the development of multi-resistant bacteria [7].Importantly, many units are recently reporting a reduction in VAP incidence following implementation of various prevention measures, as well as programs that increase compliance with such care bundles [8-10].The pathogenesis of VAP mainly stems from the introduction of microbial pathogens by microaspiration past the tracheal tube cuff and into the lower respiratory tract (Figure 1). Subsequent colonization and overwhelming of the host mechanical, humoral and cellular defence mechanisms lead to the development of VAP [11]. The tracheal tube forms the essential first part of this mechanistic pathway by breeching the anatomic barriers formed by the glottis and larynx. Suppression of the cough reflex as a result of sedation further hampers natural reflexes [2]. The oropharynx, nasal sinuses and the stomach have
Quantifying Type-Specific Reproduction Numbers for Nosocomial Pathogens: Evidence for Heightened Transmission of an Asian Sequence Type 239 MRSA Clone
Ben S. Cooper ,Theodore Kypraios,Rahul Batra,Duncan Wyncoll,Olga Tosas,Jonathan D. Edgeworth
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002454
Abstract: An important determinant of a pathogen's success is the rate at which it is transmitted from infected to susceptible hosts. Although there are anecdotal reports that methicillin-resistant Staphylococcus aureus (MRSA) clones vary in their transmissibility in hospital settings, attempts to quantify such variation are lacking for common subtypes, as are methods for addressing this question using routinely-collected MRSA screening data in endemic settings. Here we present a method to quantify the time-varying transmissibility of different subtypes of common bacterial nosocomial pathogens using routine surveillance data. The method adapts approaches for estimating reproduction numbers based on the probabilistic reconstruction of epidemic trees, but uses relative hazards rather than serial intervals to assign probabilities to different sources for observed transmission events. The method is applied to data collected as part of a retrospective observational study of a concurrent MRSA outbreak in the United Kingdom with dominant endemic MRSA clones (ST22 and ST36) and an Asian ST239 MRSA strain (ST239-TW) in two linked adult intensive care units, and compared with an approach based on a fully parametric transmission model. The results provide support for the hypothesis that the clones responded differently to an infection control measure based on the use of topical antiseptics, which was more effective at reducing transmission of endemic clones. They also suggest that in one of the two ICUs patients colonized or infected with the ST239-TW MRSA clone had consistently higher risks of transmitting MRSA to patients free of MRSA. These findings represent some of the first quantitative evidence of enhanced transmissibility of a pandemic MRSA lineage, and highlight the potential value of tailoring hospital infection control measures to specific pathogen subtypes.
The protein C pathway: implications for the design of the RESPOND study
Burkhard Vangerow, Andrew F Shorr, Duncan Wyncoll, Jonathan Janes, David R Nelson, Konrad Reinhart
Critical Care , 2007, DOI: 10.1186/cc6155
Abstract: That there is an association between sepsis and activation of the coagulation system has been known for nearly 40 years [1]. Microbial toxins and inflammatory cytokines released into the systemic circulation initiate a cascade of events that results in widespread inflammation, endothelial injury and microvascular thrombosis [2,3]. Endogenous protein C, a vitamin K dependent glycoprotein that is synthesized by the liver, plays an important role in the maintenance of haemostasis and modulation of inflammation under normal conditions [4,5]. Protein C circulates in the blood in zymogen form (inactivated form) at a concentration of approximately 4 μg/ml. Currently, various methods, reagents and equipment exist to measure protein C in the laboratory or even at the bedside in the intensive care unit (ICU). In general, these methods can be subdivided into those that are based on measuring the functional activity of the protein (%) and antigenic methods, which measure the amount of protein available (μg/ml).Protein C is converted to activated protein C (APC) by thrombin-thrombomodulin complexes. APC inactivates coagulation factors Va and VIIIa, thereby inhibiting further thrombin generation. Moreover, by inhibiting plasminogen activator inhibitor-1, APC is indirectly profibrinolytic. In addition to its role as an anticoagulant, a number of anti-inflammatory effects and anti-apoptotic properties have been described [6]. Recent research indicates that inhibition of neutrophil chemotaxis and a role in maintaining endothelial integrity are other important effects of APC. Direct cytoprotective effects of APC have been reported to be mediated by intracellular signalling, initiated by binding of APC to its receptor (the endothelial protein C receptor), which appears to be mediated by interaction with an adjacent protease-activated receptor or by indirect activation of the sphingosine 1-phosphate pathway [7,8].Protein C is rapidly depleted in severe sepsis because of consumption, de
Filter survival time and requirement of blood products in patients with severe sepsis receiving drotrecogin alfa (activated) and requiring renal replacement therapy
Luigi Camporota, Eleonora Corno, Eleonora Menaldo, John Smith, Katie Lei, Richard Beale, Duncan Wyncoll
Critical Care , 2008, DOI: 10.1186/cc7163
Abstract: This was a single-centre, retrospective observational study conducted in an adult intensive care unit (ICU). Thirty-five patients with severe sepsis who had received both RRT and DrotAA were identified, and all relevant clinical and laboratory data were retrieved from the departmental electronic patient record. We compared haemofilter parameters, requirement of blood products and haemodynamic data recorded during RRT and the infusion of DrotAA with those recorded on RRT with standard anticoagulation after the DrotAA infusion had been completed (post-DrotAA).The proportion of filter changes due to filter clotting was similar during DrotAA infusion and with conventional anticoagulation post-DrotAA infusion. There was no difference in the FST and filter parameters during DrotAA in the presence or absence of additional anticoagulation with heparin or epoprostenol. A similar proportion of patients required red cell transfusion, although a greater proportion of patients received platelet and fresh frozen plasma during DrotAA infusion compared with the post-DrotAA period with no difference between medical and surgical patients.Additional anticoagulation during DrotAA infusion does not appear to improve FST. The use of DrotAA in patients with severe sepsis requiring RRT is safe and is not associated with an increased need for PRC transfusion or major bleeding events.Drotrecogin alfa (activated) (DrotAA; Xigris, Eli Lilly & Co., Indianapolis, USA), a recombinant human activated protein C, can reduce mortality in patients with severe sepsis [1]. Data from long-term follow-up studies [2] and from international and national registries have also confirmed that the effects of DrotAA on survival seen in clinical practice are consistent with those seen in randomised trials [1,3-8]. However, despite the beneficial outcome data and acceptable safety profile, intensivists are often reluctant to prescribe DrotAA in certain groups of patients (e.g., patients who have undergone surgery,
Improved Outcome of Severe Acute Pancreatitis in the Intensive Care Unit
Polychronis Pavlidis,Siobhan Crichton,Joanna Lemmich Smith,David Morrison,Simon Atkinson,Duncan Wyncoll,Marlies Ostermann
Critical Care Research and Practice , 2013, DOI: 10.1155/2013/897107
Abstract: Background. Severe acute pancreatitis (SAP) is associated with serious morbidity and mortality. Our objective was to describe the case mix, management, and outcome of patients with SAP receiving modern critical care in the Intensive Care Unit (ICU). Methods. Retrospective analysis of patients with SAP admitted to the ICU in a single tertiary care centre in the UK between January 2005 and December 2010. Results. Fifty SAP patients were admitted to ICU (62% male, mean age 51.7 (SD 14.8)). The most common aetiologies were alcohol (40%) and gallstones (30%). On admission to ICU, the median Acute Physiology and Chronic Health Evaluation (APACHE) II score was 17, the pancreatitis outcome prediction score was 8, and the median Computed Tomography Severity Index (CTSI) was 4. Forty patients (80%) tolerated enteral nutrition, and 46% received antibiotics for non-SAP reasons. Acute kidney injury was significantly more common among hospital nonsurvivors compared to survivors (100% versus 42%, ). ICU mortality and hospital mortality were 16% and 20%, respectively, and median lengths of stay in ICU and hospital were 13.5 and 30 days, respectively. Among hospital survivors, 27.5% developed diabetes mellitus and 5% needed long-term renal replacement therapy. Conclusions. The outcome of patients with SAP in ICU was better than previously reported but associated with a resource demanding hospital stay and long-term morbidity. 1. Introduction Acute pancreatitis affects 22.4 people per 100?000 of the general UK population per annum [1]. The incidence has risen by 46% over the last three decades with an epidemiological trend towards younger, female patients and alcohol as the main aetiology. Approximately 25% of patients with acute pancreatitis develop severe disease with associated organ dysfunction and require admission to the Intensive Care Unit (ICU) [2]. Although the mortality rate for the mild form of the disease is as low as 1%, severe acute pancreatitis (SAP) is still associated with high mortality and a prolonged stay in the ICU [3]. According to the Intensive Care National Audit & Research Centre (ICNARC), between 1995 and 2003 in the UK, 2677 patients with SAP were admitted to an ICU, and ICU mortality and hospital mortality were 31% and 42%, respectively [4]. There are several different scoring systems aimed at identifying patients with a high risk of a more complicated course. The Ranson and Glasgow (Imrie) criteria are the most commonly used [5, 6]. The Computed Tomography Severity Index (CTSI) is another score that has been shown to have good predictive
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