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Despite interesting and unique pharmacological properties, levosimendan has not proven a clear superiority to placebo in the patient populations that have been enrolled in the various recent multicenter randomized controlled trials. However, the pharmacodynamic effects of levosimendan are still considered potentially very useful in a number of specific situations.Patients with decompensated heart failure requiring inotropic support and receiving beta-blockers represent the most widely accepted indication. Repeated infusions of levosimendan are increasingly used to facilitate weaning from dobutamine and avoid prolonged hospitalizations in patients with end-stage heart failure, awaiting heart transplantation or left ventricular assist device implantation. New trials are under way to confirm or refute the potential usefulness of levosimendan to facilitate weaning from veno-arterial ECMO, to treat cardiogenic shock due to left or right ventricular failure because the current evidence is mostly retrospective and requires confirmation with better-designed studies. Takotsubo syndrome may represent an ideal target for this non-adrenergic inotrope, but this statement also relies on expert opinion. There is no benefit from levosimendan in patients with septic shock. The two large trials evaluating the prophylactic administration of levosimendan (pharmacological preconditioning) in cardiac surgical patients with poor left ventricular ejection fraction could not show a significant reduction in their composite endpoints reflecting low cardiac output syndrome with respect to placebo. However, the subgroup of those who underwent isolated CABG appeared to have a reduction in mortality. A new study will be required to confirm this exploratory finding.Levosimendan remains a potentially useful inodilator agent in a number of specific situations due to its unique pharmacological properties. More studies are needed to provide a higher level of proof regarding these indications.

The purpose of this study was to compare a computer protocol against a paper protocol in managing three domains of glucose control. Hyperglycemia is common in critically ill patients, and their risk of death is associated with hyperglycemia, hypoglycemia, and glucose variability. A safe and effective insulin protocol must minimize hyperglycemia and glucose variability while also avoiding hypoglycemia. Computer-based insulin protocols promise better performance by adjusting to each individual's sensitivity to insulin.

We compared a computer-driven weaning protocol (SmartCare on Evita XL; Drager, Lubeck, Germany) with our paper-based nurse-driven weaning protocol.

When faced with the management of the patient on intensive care with acute kidney injury, the clinician has various choices to consider. The conventional therapy, where appropriate, is renal replacement therapy. This technique used to be relatively straightforward but now a relative feast of alternatives is available, not least in choice of buffer and anticoagulant. Two recent studies add to the growing body of literature concerning alternative anticoagulant regimes, and one in particular should lead to a change in practice for many of us. We also review some new studies on biomarkers in the diagnosis of acute kidney injury as well as add yet another nail in the coffin for loop diuretics in the therapy of acute kidney injury.

The burden of chronic obstructive pulmonary disease on intensive care is heavy, but newer modalities of treatment are now available to improve outcomes. Cardiac-based research continues to generate new drugs and tests to better outcome and aid in early diagnosis. And how do various intensive care interventions compare in improving clinical and functional outcomes?

Ventilator-associated pneumonia is a familiar foe in intensive care units, but those associated with Pseudomonas aeruginosa have a particularly adverse impact on outcome. Correct antibiotic therapy and a novel endotracheal tube may reduce this burden. Does activated protein C improve outcome from acute lung injury and what is the role played by hyperventilation therapy in traumatic brain injury? Recent research has attempted to answer these questions. Further novel approaches have been evaluated in the management of ischaemic heart disease, and more light has been shed on acute bowel injury.

The choice of inotropic agent, particularly in catecholamine-resistant septic shock, remains an area of debate. Here we discuss a recent trial examining the use of vasopressin in a carefully controlled trial setting. Yet more data on the use of drotrecogin alfa (activated) in septic shock are described, as are novel but as yet experimental approaches to the treatment of sepsis. Finally, it is important not to forget to read the latest surviving sepsis guidelines.

Many studies have demonstrated that prompt appropriate treatment for the critically ill patient improves outcome. Moving patients to the best place for instituting care, however, is not always associated with improved outcome. Recent studies on delivering patients to the best place for treatment as well as further work on the effects of volume are discussed. Finally, a large retrospective cohort study comparing outcomes of patients treated with continuous venovenous haemofiltration or intermittent haemodialysis is outlined.

The role of neutrophil and lymphocyte counts in blood as prognosis predictors in Community Acquired Pneumonia (CAP) has not been adequately studied. This was a derivation-validation retrospective study in hospitalized patients with CAP and no prior immunosuppression. We evaluated by multivariate analysis the association between neutrophil and lymphocyte counts and mortality risk at 30-days post hospital admission in these patients. The derivation cohort (n = 1550 patients) was recruited in a multi-site study. The validation cohort (n = 2846 patients) was recruited in a single-site study. In the derivation cohort, a sub-group of lymphopenic patients, those with, Highlights • Lymphopenia is a frequent finding in hospitalized patients with CAP, affecting approximately 50% of the patients. • Lymphopenic CAP (L-CAP) with

This commentary reflects on the paper reports published in the Critical Care Forum between 11 September 2001 and 5 November 2001

BackgroundDrowning is a cause of significant global mortality. The mechanism of injury involves inhalation of water, lung injury and hypoxia. This systematic review addressed the following question: In drowning patients with lung injury, what is the evidence from primary studies regarding treatment strategies and subsequent patient outcomes?MethodsThe search strategy utilised PRISMA guidelines. Databases searched were MEDLINE, EMBASE, CINAHL, Web of Science and SCOPUS. There were no restrictions on publication date or age of participants. Quality of evidence was evaluated using GRADE methodology.ResultsForty-one papers were included. The quality of evidence was very low. Seventeen papers addressed the lung injury of drowning in their research question and 24 had less specific research questions, however included relevant outcome data. There were 21 studies regarding extra-corporeal life support, 14 papers covering the theme of ventilation strategies, 14 addressed antibiotic use, seven papers addressed steroid use and five studies investigating diuretic use. There were no clinical trials. One retrospective comparison of therapeutic strategies was found. There was insufficient evidence to make recommendations as to best practice when supplemental oxygen alone is insufficient. Mechanical ventilation is associated with barotrauma in drowning patients, but the evidence predates the practice of lung protective ventilation. There was insufficient evidence to make recommendations regarding adjuvant therapies.ConclusionsTreating the lung injury of drowning has a limited evidentiary basis. There is an urgent need for comparative studies of therapeutic strategies in drowning.

BackgroundIntensive care units (ICUs) face financial, bed management, and staffing constraints. Detailed data covering all aspects of patients’ journeys into and through intensive care are now collected and stored in electronic health records: machine learning has been used to analyse such data in order to provide decision support to clinicians.MethodsSystematic review of the applications of machine learning to routinely collected ICU data. Web of Science and MEDLINE databases were searched to identify candidate articles: those on image processing were excluded. The study aim, the type of machine learning used, the size of dataset analysed, whether and how the model was validated, and measures of predictive accuracy were extracted.ResultsOf 2450 papers identified, 258 fulfilled eligibility criteria. The most common study aims were predicting complications (77 papers [29.8% of studies]), predicting mortality (70 [27.1%]), improving prognostic models (43 [16.7%]), and classifying sub-populations (29 [11.2%]). Median sample size was 488 (IQR 108–4099): 41 studies analysed data on > 10,000 patients. Analyses focused on 169 (65.5%) papers that used machine learning to predict complications, mortality, length of stay, or improvement of health. Predictions were validated in 161 (95.2%) of these studies: the area under the ROC curve (AUC) was reported by 97 (60.2%) but only 10 (6.2%) validated predictions using independent data. The median AUC was 0.83 in studies of 1000–10,000 patients, rising to 0.94 in studies of > 100,000 patients. The most common machine learning methods were neural networks (72 studies [42.6%]), support vector machines (40 [23.7%]), and classification/decision trees (34 [20.1%]). Since 2015 (125 studies [48.4%]), the most common methods were support vector machines (37 studies [29.6%]) and random forests (29 [23.2%]).ConclusionsThe rate of publication of studies using machine learning to analyse routinely collected ICU data is increasing rapidly. The sample sizes used in many published studies are too small to exploit the potential of these methods. Methodological and reporting guidelines are needed, particularly with regard to the choice of method and validation of predictions, to increase confidence in reported findings and aid in translating findings towards routine use in clinical practice.

Mitchell P. Fink, MD (Fig. 1), one of the most inspiring and influential leaders in the field of intensive care medicine, died at 66 years of age on 17 November 2015 after being diagnosed this summer with an aggressive sarcoma. This devastating news has left many of us with a huge sense of loss and sadness. Fig. 1 Mitchell P. Fink Mitch graduated from the Washington University School of Medicine in St. Louis, MO, in 1976 and completed general surgery training at the National Naval Medical Center in Bethesda, MD, in 1981. Thereafter, he held faculty positions at the Bethesda Naval Center and the University of Massachusetts, where he worked as surgeon and intensivist. In 1992 he moved to the Harvard Medical School, eventually becoming the Johnson and Johnson Professor in Surgery and surgeon-in-chief at the Beth Israel Deaconess Medical Center. He moved to the University of Pittsburgh in 1999, where he subsequently became the inaugural chair of the Department of Critical Care Medicine. He founded several companies based on discoveries from his laboratory and, in 2007, left the university to oversee the formation of one of these ventures. In 2009 Mitch returned to academia, joining the faculty at University of California Los Angeles where he held the title of Professor of Surgery and Vice Chair for Critical Care. During his career, Mitch cared for thousands of patients with skill and compassion, amassed a great body of experimental and clinical research, trained and mentored hundreds of physicians and scientists, demonstrated wonderful entrepreneurship, and carved a vision of modern multidisciplinary critical care with lasting benefits for our entire field. For decades, academic medicine has praised the rare individual who excels as the so-called triple threat: teacher, clinician, and scientist. Mitch was all three and more, adding to these triple roles the rare gift of visionary leader in both academia and industry. I have never known anyone quite like Mitch. His extraordinary career began early with a first author paper in Nature while still in medical school. While working in Bethesda, he forged close relationships with the National Institutes of Health critical care group, conducting a number of seminal experimental studies that both helped to establish the utility of animal models to probe the host response to sepsis, trauma, and shock and to inform our current understanding of these syndromes. Later, Mitch would conduct pioneering work using cell-based models of organ dysfunction to tease out the cellular response to stress from hypoxia and endogenous and exogenous danger signals, exploring key concepts of mitochondrial dysfunction and dysoxia. In addition to his passion for experimental research, Mitch also conducted many highly cited clinical studies, co-wrote the Textbook of Critical Care, and served on the editorial boards of numerous journals including Critical Care, Critical Care Medicine, and Intensive Care Medicine. To all of his work, Mitch brought four enduring characteristics: knowledge, logic, creativity, and focus. He maintained an encyclopedic knowledge of the world, able to quote relevant papers, data, and information off the top of his head from a dizzyingly wide range of art, science, politics, and history. He also exercised crystal-clear logic, distilling the most complex problem into a series of simple steps, whether this was a complicated piece of basic science or a tough business decision facing a start-up biotechnology company. Having concisely summarized any problem, he then brought great creativity and inventiveness to probe and tackle its solution. Finally, he always kept a clear sense of purpose, making sure neither he nor his colleagues ever lost sight of the larger goals of advancing medical knowledge and saving lives. I came to know Mitch during his tenure in Pittsburgh when he oversaw one of the most prolific and successful eras in our history, serving as a wonderful mentor and colleague, and launching the first multidisciplinary department of critical care medicine in a US medical school. In our daily contact with Mitch, we saw not only his intellect and drive, but also his warmth, compassion, wit, and grace. His door was always open, ready to listen to everyone from senior colleagues to junior residents and new staff. He had words of kindness and advice to coach us through every disappointment and words of praise and respect for every accomplishment. For me, as for many, Mitch was unquestionably one of the most supportive and influential people we have ever known. Through both his words and actions, he taught us not just about medicine and science, but about life, relationships, honor, duty, and service. We have lost an immense presence. Mitch is survived by his wife, Judy, and children, Matt and Emily. We extend our deepest condolences to them. He will be deeply missed.

The Fluids in Resuscitation of Severe Trauma (FIRST) study meets all of the criteria for assessment as a low risk of bias study, contrary to the unsupported allegations by Bayer and Reinhardt. We dispute the letter from Bayer and Reinhart together with the response from He et al. [1]. Bayer and Reinhart claim that the FIRST study [2] has a high risk of bias and cite two non-peer-reviewed letters from themselves and Finfer to support this claim. However, these authors fail to cite the extensive responses that more than adequately cover their queries [3]. Bayer and Reinhart claim that there was selective outcome reporting, but all of the outcomes listed in the methods of the FIRST trial have been reported. As with all published work, space constraints imposed by the journal limit the amount of detail that can be included. In our paper all statistically significant results were reported in detail and other outcomes that were not significant were only reported briefly as is the norm. These non-significant outcomes were more than adequately addressed in the subsequent correspondence. There is therefore no basis for the claim that this study shows a high risk of bias. Indeed, in the initial letter from Bayer and Reinhart, their own bias is clearly illustrated in their attempts to draw inferences from non-significant data. In our view, the FIRST study meets all of the criteria for assessment as a low risk of bias study and we dispute the concession made by He et al. [4] regarding the risk of bias of this study. Our view is that the original analysis in the published paper reflects the correct scientific position and that the modified Jadad score of 6 allocated to this study is appropriate.

Critical illness is a continuum, but patient care is often fragmented. Value-based critical care focuses on the overall health of the patient, not on an episode of care. The “ICU without borders” model incorporates a concept where members of the critical care team are involved in the management of patients from the onset of critical illness until recovery and beyond. In this paper, we summarise the potential benefits and challenges to patients, families, staff and the wider healthcare system and list some essential requirements, including a tight governance framework, advanced technologies, investment and trust. We also argue that “ICU without borders” should be viewed as a bi-directional model, allowing extended visiting hours, giving patients and families direct access to experienced critical care staff and offering mutual aid when needed.

Use of extracorporeal membrane oxygenation (ECMO) in cardiopulmonary resuscitation, termed eCPR, offers the prospect of improving survival with good neurological function after cardiac arrest. After death, ECMO can also be used for enhanced preservation of abdominal and thoracic organs, designated normothermic regional perfusion (NRP), before organ recovery for transplantation. To optimize resuscitation and transplantation outcomes, healthcare networks in Portugal and Italy have developed cardiac arrest protocols that integrate use of eCPR with NRP. Similar dissemination of eCPR and its integration with NRP in the USA raise novel ethical issues due to a non-nationalized health system and an opt-in framework for organ donation, as well as other legal and cultural factors. Nonetheless, eCPR investigations are ongoing, and both eCPR and NRP are selectively employed in clinical practice. This paper delineates the most pressing relevant ethical considerations and proposes recommendations for implementation of protocols that aim to promote public trust and reduce conflicts of interest. Transparent policies should rely on protocols that separate lifesaving from organ preservation considerations; robust, centralized eCPR data to inform equitable and evidence-based allocations; uniform practices concerning clinical decision-making and resource utilization; and partnership with community stakeholders, allowing patients to make decisions about emergency care that align with their values. Proactively addressing these ethical and logistical challenges could enable eCPR dissemination and integration with NRP protocols in the USA, with the potential to maximize lives saved through both improved resuscitation with good neurological outcomes and increased organ donation opportunities when resuscitation is unsuccessful or not in accordance with individuals’ wishes.

This paper discusses the use of Artificial Intelligence Chatbot in scientific writing. ChatGPT is a type of chatbot, developed by OpenAI, that uses the Generative Pre-trained Transformer (GPT) language model to understand and respond to natural language inputs. AI chatbot and ChatGPT in particular appear to be useful tools in scientific writing, assisting researchers and scientists in organizing material, generating an initial draft and/or in proofreading. There is no publication in the field of critical care medicine prepared using this approach; however, this will be a possibility in the next future. ChatGPT work should not be used as a replacement for human judgment and the output should always be reviewed by experts before being used in any critical decision-making or application. Moreover, several ethical issues arise about using these tools, such as the risk of plagiarism and inaccuracies, as well as a potential imbalance in its accessibility between high- and low-income countries, if the software becomes paying. For this reason, a consensus on how to regulate the use of chatbots in scientific writing will soon be required.

Background Several biomarkers have been proposed to predict the occurrence of acute kidney injury (AKI); however, their efficacy varies between different trials. The aim of this study was to compare the predictive performance of different candidate biomarkers for AKI. Methods In this systematic review, we searched PubMed, Medline, Embase, and the Cochrane Library for papers published up to August 15, 2022. We selected all studies of adults (> 18 years) that reported the predictive performance of damage biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP)), inflammatory biomarker (interleukin-18 (IL-18)), and stress biomarker (tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 (TIMP-2 × IGFBP-7)) for the occurrence of AKI. We performed pairwise meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs) individually. Hierarchical summary receiver operating characteristic curves (HSROCs) were used to summarize the pooled test performance, and the Grading of Recommendations, Assessment, Development and Evaluations criteria were used to appraise the quality of evidence. Results We identified 242 published relevant studies from 1,803 screened abstracts, of which 110 studies with 38,725 patients were included in this meta-analysis. Urinary NGAL/creatinine (diagnostic odds ratio [DOR] 16.2, 95% CI 10.1–25.9), urinary NGAL (DOR 13.8, 95% CI 10.2–18.8), and serum NGAL (DOR 12.6, 95% CI 9.3–17.3) had the best diagnostic accuracy for the risk of AKI. In subgroup analyses, urinary NGAL, urinary NGAL/creatinine, and serum NGAL had better diagnostic accuracy for AKI than urinary IL-18 in non-critically ill patients. However, all of the biomarkers had similar diagnostic accuracy in critically ill patients. In the setting of medical and non-sepsis patients, urinary NGAL had better predictive performance than urinary IL-18, urinary L-FABP, and urinary TIMP-2 × IGFBP-7: 0.3. In the surgical patients, urinary NGAL/creatinine and urinary KIM-1 had the best diagnostic accuracy. The HSROC values of urinary NGAL/creatinine, urinary NGAL, and serum NGAL were 91.4%, 85.2%, and 84.7%, respectively. Conclusions Biomarkers containing NGAL had the best predictive accuracy for the occurrence of AKI, regardless of whether or not the values were adjusted by urinary creatinine, and especially in medically treated patients. However, the predictive performance of urinary NGAL was limited in surgical patients, and urinary NGAL/creatinine seemed to be the most accurate biomarkers in these patients. All of the biomarkers had similar predictive performance in critically ill patients. Trial registrationCRD42020207883, October 06, 2020.

Several research papers published in Critical Care throughout 2007 examined the pathogenesis, diagnosis, treatment and prognosis of sepsis and multiorgan failure. The present review summarizes the findings and implications of the papers published on sepsis and multiorgan failure and places the research in the context of other work in the field.

Appropriate care for patients with tracheostomies in hospital settings is an important issue. Each year more than 7000 patients receive tracheostomies in Australia and New Zealand alone. Many of these tracheostomy patients commence their care in the intensive care unit (ICU) and once stabilised are then transferred to a general ward. Insufficient skills and experience of staff caring for tracheostomy patients may lead to sub-optimal care and increased morbidity. The purpose of this review was to identify whether multidisciplinary tracheostomy outreach teams enable the reduction in time to decannulation and length of stay in acute and sub-acute settings, improve quality of care or decrease adverse events for patients with a tracheostomy.We included all relevant trials published in English. We searched Medline, CINAHL, All EBM and EMBASE in June 2009. Studies were selected and appraised by two reviewers in consultation with colleagues, using inclusion, exclusion and appraisal criteria established a priori.Three studies were identified which met the study selection criteria. All were cohort studies with historical controls. All studies included adult patients with tracheostomies. One study was conducted in the UK and the other two in Australia. Risk of bias was moderate to high in all studies. All papers concluded that the introduction of multidisciplinary care reduces the average time to decannulation for tracheostomy patients discharged from the ICU. Two papers also reported that multidisciplinary care reduced the overall length of stay in hospital as well as the length of stay following ICU discharge.In the papers we appraised, patients with a tracheostomy tube in situ discharged from an ICU to a general ward who received care from a dedicated multidisciplinary team as compared with standard care showed reductions in time to decannulation, length of stay and adverse events. Impacts on quality of care were not reported.These results should be interpreted with caution due to the methodological weaknesses in the historical control studies.

During 2009, Critical Care published nine papers on various aspects of resuscitation, prehospital medicine, trauma care and disaster response. One article demonstrated that children as young as 9 years of age can learn cardiopulmonary resuscitation (CPR) effectively, although, depending on their size, some may have difficulty performing it. Another paper showed that while there was a trend toward mild therapeutic hypothermia reducing S-100 levels, there was no statistically significant change. Another predictor study also showed a strong link between acute kidney injury and neurologic outcome while another article described a program in which kidneys were harvested from cardiac arrest patients and showed an 89% graft survival rate. One experimental investigation indicated that when a pump-less interventional lung assist device is present, leaving the device open (unclamped) while performing CPR has no harmful effects on mean arterial pressures and it may have positive effects on blood oxygenation and CO2 clearance. One other study, conducted in the prehospital environment, found that end-tidal CO2 could be useful in diagnosing pulmonary embolism. Three articles addressed disaster medicine, the first of which described a triage system for use during pandemic influenza that demonstrated high reliability in delineating patients with a good chance of survival from those likely to die. The other two studies, both drawn from the 2008 Sichuan earthquake experience, showed success in treating crush injured patients in an on-site tent ICU and, in the second case, how the epidemiology of earthquake injuries and related factors predicted mortality.

We review key research papers in cardiology and intensive care published during 2008 in Critical Care. We quote studies on the same subject published in other journals if appropriate. Papers have been grouped into three categories: (a) cardiovascular biomarkers in critical illness, (b) haemodynamic management of septic shock, and (c) haemodynamic monitoring.

We read with great interest the contribution by Strack van Schijndel and Burchardi [1]. The topic of intensive care unit (ICU) management deserves to be highlighted as it is a most complex task to undertake. In their paper, the authors refer to Covey's Seven Habits of Highly Effective People [2], but did not distinguish between leadership and management – two fundamentally different but not mutually exclusive concepts. To paraphrase Covey [2], 'Management is a bottom line focus: How do I best accomplish ...?' whereas 'Leadership deals with the top line: What do I want to accomplish ...?' The ICU is, as pointed out, a very stressful environment. Leadership, the provision of good working conditions, a supporting and team-building environment, adequate resources for individual assignments and scientific projects, and good utilisation of human resources are certainly an art in itself. The need for a more focused approach to ICU management is highlighted in recent papers [3,4], where a high frequency of burnout among ICU personnel was reported. This alarming finding was also accompanied by a high desire among ICU staff to leave their work, indicating that immediate actions are needed to adapt the critical care organisation to new professional demands, to the increasing workload and to increasing complexity. In the light of this and the well recognised shortage of ICU staff [5], it is paramount that the leadership and management of ICUs are given more recognition in order to enhance recruitment, to promote staff retention and to increase job satisfaction, while maintaining quality and effectiveness. Defining the requirements and skills of future ICU directors is an important step in this process. Modern critical care is rapidly developing into a profession where traditional boundaries between clinical specialities no longer apply. Its management must be performed in close synchrony to clinical activities, with preparedness for policy changes and capacity for multiprofessional liaison between physicians, nursing staff and personnel from other specialities. Typically, directors are recruited on clinical and scientific merits. This does not, however, necessarily assure that the candidate has the required leadership and managing skills. Finding oneself inadequately equipped with the necessary tools and training is very unfortunate and uncomfortable for an otherwise highly competent individual, and not least for staff and patients alike. More effort and research are needed to define the skills required for leading and managing an ICU, and it is appropriate to develop training programmes where those capabilities are enhanced and trained.

Professor Vincent, in an eloquent commentary in Critical Care, calls for a further trial into supraphysiological cortico-steroid therapy in vasopressor-resistant shock [1]. Together with editorials in several of the intensive care journals, he has pointed out many of the shortcomings in the Corticus trial [2]. We would like to add to this chorus by posing a further question to the authors and putting forward some suggestions. Regrettably, we are prohibited from addressing these directly due to the Letters policy of the journal in which the original paper was published. Data from numerous sources suggest that the earlier shock is reversed, the better the outcome – be it mortality, morbidity, length of stay or other surrogate endpoints. In the Corticus study, the median time to shock reversal was 2 to 3 days shorter in the hydrocortisone group (see Table ​Table1).1). Despite this, no outcome improvement was demonstrated. No investigation, or explanation, of this apparent discrepancy has been forthcoming. Sequential Organ Failure Assessment scores were performed at the time of study enrolment, but no serial Sequential Organ Failure Assessment score data are presented. If available, these data would be intriguing. Table 1 Time to shock reversal data from the Corticus study [2] Following the publication of the Corticus data, a consensus statement regarding the diagnosis and management of corticosteroid insufficiency in critically ill adult patients has been published [3]. Together with a detailed review by Dickstein and Saiegh [4], this statement suggests a working diagnostic paradigm. However, we would like to suggest the following three pragmatic definitions of functional hypoadrenalism, which future trial designers might with wish to consider and which we currently employ. First, patients with septic shock requiring high-dose vaso-pressors – defined as requiring ≥ 0.2 μg/kg/minute norepinephrine (or equivalent), who are not volume responsive (defined as a ≥ 10% increase in stroke volume following a 3 ml/kg fluid bolus administered in ≤ 5 min) and who are hyperdynamic (defined as a cardiac index ≥ 2.8 l/min/m2). Patients with evidence of acute myocardial depression or chronic insufficiency should be considered separately. Second, patients who, having been stable for ≥ 2 hours on a dose of vasopressor, develop increasing dose requirements (≥ 20% increase), are unresponsive to a volume bolus (as above) and are hyperdynamic (as above). Third, patients whose dose of vasopressor cannot be weaned ≥ 24 hours following initiation of appropriate broad-spectrum antimicrobial therapy and/or effective source control. Furthermore, this therapy should be withdrawn from patients who fail to demonstrate a ≥ 20% decrease in vasopressor requirement to maintain the same mean arterial pressure 60 minutes after the initial dose of hydrocortisone. Due to the pharmacokinetics of hydrocortisone, we favour a 100 mg intravenous bolus followed immediately by initiation of a 10 mg/hour intravenous infusion. Finally, we would like to promote two recently published papers that offer useful insights into the pharmacodynamics of supraphysiological steroid therapy in vasopressor-resistant shock. Firstly, Druce and colleagues make a convincing argument that the principal effect of hydrocortisone is as a mineralocorticoid and not as an anti-inflammatory [5]. Secondly, Kaufman and colleagues [6] found that hydrocortisone administered as described above does have some arguably clinically valuable anti-inflammatory effects but, in addition, enhances neutrophil phagocytosis. This has led us to conclude that, in the absence of a systemic form of fludrocortisone and with the unreliable enteral absorption of drugs, systemic hydrocortisone monotherapy at optimal mineralocorticoid doses should be the therapy of choice.

This review summarizes key research papers published in the fields of cardiology and intensive care during 2005 in Critical Care. The papers have been grouped into categories: haemodynamic monitoring; goal-directed therapy; cardiac enzymes and critical care; metabolic considerations in cardiovascular performance; thrombosis prevention; physiology; and procedures and techniques.

During 2005 Critical Care published several original papers dealing with resource management. Emphasis was placed on sepsis, especially the coagulation cascade, prognosis and resuscitation. The papers highlighted important aspects of the pathophysiology of coagulation and inflammation in sepsis, as well as dealing with the proper use of newly developed compounds. Several aspects of prognosis in critically ill patients were investigated, focusing on biological markers and clinical indexes. Resuscitation received great attention, dealing with the effects of fluid infusion in hemodynamics and the lung. The information obtained can be used to address unknown effects of established therapies, to enlighten current clinical discussion on controversial topics, and to introduce novel medical resources and strategies. Future clinical work will rely heavily on these preclinical and laboratory data.

Pneumonia (hospital-acquired and community-acquired) is commonly encountered in intensive care. Several papers recently published on this subject have shed more light on different aspects of this important topic. Hypothermia has been shown to improve post-arrest outcome, but how often do we use it? And finally, several papers have recently appeared in the journals related to the admission of the elderly to the critical care area and their outcome.

Globalization in business, politics and other aspects of our everyday life is viewed by many as an inevitable reality. The English language has undoubtedly benefited significantly from the new era, in gradually penetrating into other cultures in many fields such as music, arts, education, and more recently science. Previous reports indicate that such penetration is also evident in the field of biomedical sciences [1,2], primarily supported by the paper and online publication in the English language of the majority of about 6,000 journals indexed in PubMed. The adoption of a universal language in science, namely English, could facilitate communication between individuals from different countries and enhance the timely interchange of ideas among researchers and scientists with potential benefits to scientific advancement and development [3]. Language barriers could also potentially be eliminated and diffusion of knowledge could be promoted through the World Wide Web in real time. However, the dominance of the English language in the scientific field, including teaching, academic education, research publications, meetings, conferences and scientific societies, could also lead to poorer outcomes in the field of research and development because of the possible exclusion of those not able or not willing to adapt. It might also contribute to the gradual elimination of other languages and potentially other cultures, with unknown consequences for the advancement of science. Biodiversity in nature is viewed as an important factor in the maintenance of a balanced and healthy environment. Perhaps a similar diversity in languages and cultures promotes instead of obstructs scientific advancement [4]. German researchers have contributed significantly to science in many different fields, including the biomedical sciences. In the past century, the German language was recognized among Europeans as the language most frequently used in science [5]. To evaluate the possible penetration of English into the German language, we studied the use of English at a German national medical conference. We assessed the use of the English language in the published abstracts of a major German national conference, namely the German Interdisciplinary Conference of Intensive Care Medicine and Emergency Medicine (Deutscher Interdisziplinarer Kongress fur Intensivmedizin und Notfallmedizin, Deutschen Interdisziplinaren Vereinigung fur Intensivmedizin und Notfallmedizin (DIVI)). The abstract books of all seven DIVI conferences, organized between 1991 and 2004, were reviewed to count the number of abstracts presented at each conference as well as the subsets of abstracts presented in English. All abstracts presented in English were reviewed further to identify the country of origin of the authors. These abstracts were categorized into three groups. The first group included those abstracts presented solely by investigators based in German universities, hospitals or institutions. Abstracts that were the result of collaboration between investigators from Germany and other countries were included in a second category, and abstracts presented by investigators from countries other than Germany were classified into a third group. Table ​Table11 shows the total number of abstracts presented in the seven DIVI conferences, as well as the proportion of abstracts presented in English. As is shown, no abstract was presented in English during the first, second and third DIVI conferences. However, there was a gradual increase in the proportion of abstracts presented in English during the subsequent DIVI conferences (from 1.6% to 25.1%). Of the total of 98 abstracts presented in English during the last four DIVI conferences, 86 were written by solely German investigators, on the basis of the information provided. Three abstracts were the result of collaboration between investigators from Germany and other countries (Austria, Israel and the USA). The remaining nine abstracts were presented by investigators from countries other than Germany (Poland (4), UK (2), Austria (1), Slovakia (1) and the USA (1)). Table 1 Abstracts presented at the DIVI conferences (1991–2004) There is a growing debate around the world about the rapid penetration of the English language into various expressions of human activity, including science [6-9]. It is estimated that half of the world population will use English by the year 2015. The results of our analysis suggest that the penetration of English into a German national interdisciplinary medical conference that has been attended mostly by German-speaking investigators was astounding. The fact that about one-quarter of the abstracts were presented in English at the last DIVI conference (2004) deserves the attention of German scientists as well as the broad scientific community worldwide. It should also be noted that most (88%) of the abstracts in English were presented by investigators based solely in German universities, hospitals or other German institutions. There are several possible explanations for the observed penetration of the English language in the German national medical conference studied that might also operate in other scientific activities in most non-English-speaking countries. There is a language effect that pressures investigators to publish their work in journals indexed by Index Medicus and the Institute for Scientific Information because of the visibility of papers appearing in the PubMed database and the influence of their impact factor, respectively. Practical reasons might therefore guide investigators to prepare their work in English for submission for publication. In addition, the use of English can be considered an important qualification distinguishing researchers who are fluent in English from others lagging behind in many non-English-speaking countries. German investigators might also present abstracts in English at their national conference after those same abstracts have already been presented at an English-speaking international conference. Finally, it is possible that the organizing committee of the studied conference might have invited the use of English in an attempt to increase the number of non-German-speaking delegates. In conclusion, we found that about one-quarter of the abstracts presented at a German medical conference were written in English, indicating a significant penetration of the English language into a German national multidisciplinary conference. We believe that the results of our study merit attention from the scientific community around the world for two main reasons: first, because a considerable penetration of English was evident at a particular conference that is attended mostly by German-speaking scientists and clinicians, who elected to present their abstracts to a German-speaking audience in English, and second, because the German language, with its tradition and rich history in science as well as its popularity, was thought to be one of the most difficult languages in Europe to penetrate. Our findings suggest that researchers around the world should engage in an open and unbiased discussion about the future of languages in science.

The present paper describes the methods of data collection and validation employed in the Intensive Care National Audit & Research Centre Case Mix Programme (CMP), a national comparative audit of outcome for adult, critical care admissions. The paper also describes the case mix, outcome and activity of the admissions in the Case Mix Programme Database (CMPD). The CMP collects data on consecutive admissions to adult, general critical care units in England, Wales and Northern Ireland. Explicit steps are taken to ensure the accuracy of the data, including use of a dataset specification, of initial and refresher training courses, and of local and central validation of submitted data for incomplete, illogical and inconsistent values. Criteria for evaluating clinical databases developed by the Directory of Clinical Databases were applied to the CMPD. The case mix, outcome and activity for all admissions were briefly summarised. The mean quality level achieved by the CMPD for the 10 Directory of Clinical Databases criteria was 3.4 (on a scale of 1 = worst to 4 = best). The CMPD contained validated data on 129,647 admissions to 128 units. The median age was 63 years, and 59% were male. The mean Acute Physiology and Chronic Health Evaluation II score was 16.5. Mortality was 20.3% in the CMP unit and was 30.8% at ultimate discharge from hospital. Nonsurvivors stayed longer in intensive care than did survivors (median 2.0 days versus 1.7 days in the CMP unit) but had a shorter total hospital length of stay (9 days versus 16 days). Results for the CMPD were comparable with results from other published reports of UK critical care admissions. The CMP uses rigorous methods to ensure data are complete, valid and reliable. The CMP scores well against published criteria for high-quality clinical databases.

In April 2003, Critical Care made two important changes: firstly, only the abstracts of research articles now appear in print while the full text is open access (freely and universally accessible online); and secondly, all articles over two years old are free to access online – including commentaries, reviews and reports. All this is part of the journal's ongoing quest to be a good scientific citizen, and the publisher's ongoing drive to use the Internet to provide novel solutions to meet the information needs of the biomedical community. The move to have only the abstracts of research articles in the print journal with open access to full text online was logical. Publishing research articles online as soon as they are ready means they are likely to be picked up by the most interested parties via searching well before they would have been available in print. Those that browse the print journal are unlikely to read every research article word-for-word on publication [1]. Instead, most readers tend to browse titles, abstracts or conclusions, preferring to read in detail only after searching databases like PubMed. When such a search leads to an article in Critical Care [2], the journal's online functionality will assist further – you can search PubMed for other articles by authors, email articles to colleagues, post and read comments, download references or read the abstracts in PubMed, and even link to the full text of a reference (if it's made available by its publisher). Presenting research articles as abstracts in the print journal and providing open access, full text versions online, then, satisfies both types of users – the print browsers and the online searchers. Our new way of publishing research articles will have a new citation system. Previously, research articles published online were cited as "in press" until they were included in the print journal, at which point the allotted page numbers were incorporated to make the final citation. In the new system the research articles will be paginated as soon as they are published online and separately from other types of articles. Their page numbers will have the prefix "R". The abstracts of these research articles will appear subsequently and sequentially in the print journal according to the page numbers. This system has been accepted by databases such as PubMed, and the ISI Web of Knowledge, the company that calculates impact factors. Making articles over two years old free to access online was also logical. Subscribers – whether they be personal or institutional – pay to receive the latest information. So once again, it is the aforementioned online searchers who will benefit most from being able to access archived material without having to pay. However, given that it is now commonly asserted that textbooks are largely out of date by the time they are printed [3], does this mean that archived material is of limited use? No. Not all branches of medicine or science move that fast – an educational article about the physiological principles underlying pH measurements may be as relevant today as it was two years ago [4]. Furthermore, given that medical science is as prone to recycling fashionable trends as any other part of society, an "old" idea is quite likely to become tomorrow's big talking point – or at least, just as contentious as it was two years ago [5]. These two important changes compliment Critical Care's ongoing quest to be a good scientific citizen, at the core of which is our commitment to provide open access to research articles [6]. A discussion of the benefits of open access is beyond the scope of this editorial but there is growing acceptance of it as the best way to publish research, with our publisher, BioMed Central [7], having close to 100 open access journals, and with more and more institutes and funding bodies lending support. Meanwhile the Public Library of Science (PLoS) initiative [8], which largely failed to produce the much vaunted boycott by authors and referees of subscription based journals, has elected to start its own open access journals [9]. One of their core principles is that research should be open access to allow "unrestricted use, distribution and reproduction". Critical Care supports this aim – all research should be open access, including the recent paper on sepsis definitions [10]. As well as open access, there are other ways in which Critical Care has endeavoured to be a better scientific citizen. The journal can be accessed through the Health InterNetwork [11], the United Nations' and World Health Organisation's initiative to bridge the digital divide between rich and poor countries. We have also tried to provide continuous educational material for clinicians, including pro/con debates [12], detailed commentaries on pivotal research published elsewhere, a short, bimonthly review of recently published papers [13], authoritative reviews of all aspects of care from basic science [14,15] to clinical practice [16], as well as prompt and thorough peer review of research articles (on average, the first decision is given within eight weeks) and fast publication after acceptance (on average within three weeks). Recently we also consolidated our link to the International Symposium on Intensive Care and Emergency Medicine (ISICEM, Brussels) so that all attendees at the 2003 symposium received an online subscription to the journal as part of their registration fee [17]. Since 1997 we have been publishing the abstracts of the posters presented at the symposium, all of which – as with all our supplements – are free to access online. In the pipeline is an online manuscript submission and tracking system, online tools for referees, a section reviewing technology in clinical practice, a new article incorporating online voting on clinical scenarios, as well as added website functionality such as being able to store your searches and rerun them automatically, the results of which can be delivered straight to your inbox. We hope having open access to research, as well as unlimited access to all material two years old, will encourage readers to become familiar with what Critical Care has to offer, both online and in print.

In their recent paper, Dubin and coworkers [1] subjected anaesthetized, paralyzed sheep to decreases in oxygen delivery either by progressive bleeding (ischaemic hypoxia [IH] group) or by decreasing oxygen saturation (hypoxic hypoxia [HH] group). They found substantial increases in mesenteric venous–arterial blood partial carbon dioxide tension (PCO2) gradient (ΔPCO2) in the IH group, whereas ΔPCO2 remained unchanged both in the HH and in a sham operated control group. The authors concluded that intestinal tonometry has limited value in detecting the presence of anaerobic metabolism in tissues. Dubin and colleagues should be congratulated on the soundness and quality of their experiments, but in our opinion the conclusion of the study may be at odds with the data presented. The fundamental premise of comparable anaerobic states for both groups is based on the presence of oxygen dependence. This premise, however, may not be correct because it appears from the data presented that animals in the HH group did not reach an anaerobic state, and thus were unable to mount increases in ΔPCO2. When calculating oxygen extraction ratios (O2ER) from Fig. 1 of the paper, we find that maximal values for systemic and gut O2ER for the HH group were 48% and 59%, respectively. These values are lower than those reported for critical ERO2 in dogs [2], supporting our contention that animals in the HH group might not have reached a critical oxygen supply condition. Of note, the maximal gut O2ER in the sham control group was 51% – a value not too dissimilar from that in the HH group. Conversely, maximal systemic and gut O2ER levels for the IH group were much higher, at 83% and 90%, respectively, suggesting that these animals experienced greater hypoxic stress. Another parameter that may be used to determine the onset of an anaerobic state is the presence of increased H+ concentration in tissues and blood. Although both groups became acidaemic as oxygen delivery was decreased, it appears that the mechanism responsible for the low pH in the HH group was a respiratory acidosis, not the production of excess H+ by anaerobic tissues. The instillation of hydrochloric acid into the lungs of the HH animals probably produced extensive parenchymal damage and impaired carbon dioxide excretion. This is the probable cause of the low pH and increased PCO2 noted in the HH group. Moreover, we note a decline in bicarbonate from 18.0 to 10.2 mmol/l in the IH group after 90 min of dysoxia. On the other hand, the bicarbonate concentration remained relatively constant at 16.5 and 15.3 mmol/l for the HH group and the control group, respectively. The decline in bicarbonate in the IH group reflects buffering of nonvolatile acids, probably lactic acid. These data again support the notion of a severe dysoxic insult in the IH group but not in the HH group. Finally, one can infer the degree of excess carbon dioxide production from the respiratory exchange ratio (RER), which is defined as the ratio of carbon dioxide production to oxygen consumption. In aerobic tissues, RER depends on the substrate consumed and its value is ≤ 1.0. During anaerobic metabolism, additional carbon dioxide generated by the buffering of excess H+ may result in RER in excess of 1.0. We calculated RER as (change in carbon dioxide content)/(O2ER × arterial oxygen content) and found that RER for the IH group was 1.1 at 30 min and continued to rise to 1.7 for the remainder of the experiment. This is convincing proof that these animals were anaerobic and produced excess carbon dioxide. Conversely, systemic RER for the HH group, as well as that for the sham operated group, remained below 1.0 throughout the experiment, suggesting that the tissues were not anaerobic. Although there is some noise in the data, the same findings hold true for regional RER. The above arguments support our hypothesis that ΔPCO2 in these experiments was compared at different degrees of dysoxia. It possible, however, that the conclusion reached by Dubin and coworkers may be correct, in that arteriovenous ΔPCO2 fails to increase during HH. This conclusion was also reached by Vallet and coworkers [3] when they measured arteriovenous ΔPCO2 in the dog hindlimb. The concentration of an effluent species in a compartment depends on the mass balance between the rates of production and elimination. As flow increases, the difference between affluent and effluent concentrations will decrease, although the total mass leaving the system remains constant. In other words, higher flows will result in lower arteriovenous ΔPCO2. A similar reasoning may not hold true for the arterio-tonometer ΔPCO2, because the latter is an integrative process that allows equilibration of the tonometer fluid with tissue PCO2. Tissue PCO2 depends on convective as well as on diffusive processes. Whereas the former is a function of total organ blood flow, the latter is a function of microcirculatory phenomena and the ability of carbon dioxide to diffuse across tissues – processes that are often disturbed in disease states. Therefore, it may be possible for arteriovenous ΔPCO2 to remain relatively constant during tissue HH but (as shown by Neviere and coworkers [4]) for tonometer ΔPCO2 to increase in response to excess tissue carbon dioxide production. Another important issue raised by this excellent paper concerns the physiological significance of oxygen dependence. In other words, is oxygen dependence an infallible marker of anaerobic metabolism? If the answer is 'no', as appears to be the case in these experiments, then why did oxygen consumption decline in the HH group, even though other markers of tissue oxygenation suggest that these animals were not in an anaerobic state? Are there compensatory mechanisms to lower tissue metabolic rate and to decrease oxygen consumption in response to hypoxaemia? These are complex questions that await further experimental studies similar to the excellent work of Dubin and colleagues [1].

An amendment to this paper has been published and can be accessed via the original article.

An amendment to this paper has been published and can be accessed via the original article.

Thank you for the opportunity to respond to the letter by Karatzas et al. [1] commenting on our recent paper concerning the effects of IgM-enriched immunoglobulin preparations in severe sepsis [2]. It was mentioned in the letter that the study protocol of Karatzas et al. regarding the design and inclusion criteria (except the age) was similar to our study design. It seems that there is another important difference between two studies, which is the subgroup analysis. Because of the limited number of patients included in our study, it was not intended to focus on the role of immunotherapy in reducing the mortality rate of severe sepsis patients. Mortality rate analyses in the subgroups of patients with different admission Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were therefore not performed in our study. As Karatzas et al. noted, the APACHE II scores of our patients were lower than those found in their preliminary data analysis. This is an important difference indicating that the patient populations of their study and our study are far beyond similarity. Neurological evaluation in APACHE II scoring is based on the Glasgow coma scale (GCS) and is usually complicated by the frequent use of sedative agents in critically ill patients. It is often not clear whether to assume GCS in the absence of sedative drugs or to consider the actual GCS of the patient. Certainly this computation might be very confusing and prone to errors in data collection. In our clinical practice, we generally assume the mental state of the patients in the absence of sedative drugs while calculating the GCS. This might be the reason for relatively low levels of APACHE II scores in our study population. We agree with Karatzas et al. that the interpretation of data could be more relevant by homogenising the patients according to some clinical characteristics, especially in larger studies investigating the beneficial effects of immunotherapy in septic patients. Our study, which is the initial step of a new series of clinical investigations on this subject, was performed in a small group of patients with severe sepsis. We mentioned in our paper that recruiting this number of patients could confirm a change in severity and mortality of sepsis with the administration of IgM-enriched immunoglobulin preparations. As we pointed out in our paper, we think that in addition to investigating subgroups of septic patients, further studies should focus on laboratory and clinical measures to identify patients who might benefit from specific immunomodulatory therapies.

This commentary reflects on the paper reports published in the Critical Care Forum between 6 November 2001 and 8 January 2002 The paper reports presented here reflect the current leading issues in the intensive care literature, the search for the 'magic bullet' in sepsis being an obvious example. Many of the trials in sepsis that are currently being reported were presented at recent conferences [1]. This is the case for the KyperSept Antithrombin III Study [2]. The summary of this paper highlights the disappointment of the study: "ATIII [antithrombin III] joins a long list of promising experimental agents for sepsis that failed to show a significant benefit in a multicentre, randomised phase III clinical trial." Although some success has been reported with 'magic bullet' studies [3], the paper by Rivers and colleagues [4] puts these to shame by demonstrating a superlative outcome benefit with essentially good early resuscitative care in severe sepsis and septic shock. Goal-directed therapy in the emergency department for patients with severe sepsis and septic shock improved survival from 46.5% (control) to 30.5% (goal-directed therapy). This was achieved by targeting central venous saturation – an investigation that could easily be performed in most modern emergency departments – and the resultant treatment was by no means complicated or expensive: increased fluids and/or blood, and occasionally dobutamine for inotropic support. That study mirrors the already impressive and abundant evidence for goal-directed therapy in another patient population – the high-risk surgical patient [5]. It is incredible, yet disconcerting, that a relatively basic but successful and cheap treatment for the high risk or critically ill patient is not current practiced in many intensive care units. However, the expensive practice of magic bullets will no doubt be enthusiastically received, despite the fact that the results are far less impressive. The report of Rivers and colleagues [4] emphasizes the enormous benefits that may be achieved by early, good, basic critical care management. The benefits of noninvasive ventilation once again feature prominently in our paper reports [6]. Patients with acute hypoxaemic respiratory failure following lung resection were randomized to standard care with or without nonintermittent positive pressure ventilation. Not surprisingly, the need for extubation was significantly higher in the control group, as was hospital and 120-day mortality. It would be interesting to know whether this mortality benefit remained significant if the randomization had been to nonintermittent positive pressure ventilation versus invasive ventilation. Hormone therapy has always been popular in the critically ill, and one report [7] investigated intensive insulin therapy in nondiabetic surgical and critically ill patients. Crude hospital mortality was 7.2% in the intensive therapy group versus 10.9% in the control group (P = 0.01), and this benefit was associated with a 46% reduction in bloodstream infections. Finally a Canadian study [8] derived the 'Canadian C-spine rule' in order to allow more selective and specific ordering of C-spine X-rays in trauma patients who are alert and stable. The derived rule had a sensitivity of 100% and specificity of 42.5%. As was highlighted in the first paper report overview published back in November 1999 [9], there has been an exponential growth in the amount of literature specific to intensive care and related fields. "This is set against the background of an ever-increasing service commitment and so time is at a premium to reflect on important breakthroughs in the literature," it said. Our paper reporters, who are few in number as compared with the amount of evidence based literature out there, are not immune to these time constraints. If you, the reader, would like more papers critiqued, or even to join our 'merry band of reporters', contact us on editorial@ccforum.com.

We read with interest the paper by Sungar and Guven [1], which described a case series of organophosphorus pesticide (OP)-poisoned patients managed in their intensive care unit. It clearly demonstrates the difficulty in managing such patients in resource-poor areas [2]. However, we should like to query some issues in their management of OP poisoning and their use of pralidoxime. We cannot understand their assessment of risk–benefit in the use of atropine. Their regimen of 0.02–0.08 mg/kg atropine as an infusion over 1 hour would provide a maximum of 5.6 mg atropine in a 70 kg person. Stopping atropine therapy '24 hours after atropinization' may cause problems with the continued release of fat-soluble OPs, such as fenthion, from the fat depot. Those authors also do not state the time it took for atropinization to be achieved; however, if patients received atropine for a mean of '3.4 ± 2.1 days', then the mean time to atropinization was 2.4 ± 2.1 days. This appears far too long. Few clinical toxicologists would disagree that full and early atropinization with 2 mg atropine stat followed by 2 mg every 5–15 min has few risks and obvious benefits [3]. Their use of intravenous diltiazem or propranolol for tachydysrhythmias associated with OP poisoning is troubling. Hypotension and cardiac dysrhythmias are significant problems in OP poisoning [3]. Do the authors have any evidence that the benefits of these negative inotropic drugs outweigh the risks in such patients? The authors state that only one randomized controlled trial (RCT) has been carried out that assessed the efficacy of pralidoxime in OP poisoning. Unfortunately, the cited paper was a retrospective case series that compared the case fatality rate during a time when pralidoxime was not available in Sri Lanka with the rate at a time when it was, and as such is not a RCT [4]. We recently completed a systematic review of RCTs of pralidoxime that identified two small RCTs and two very small prospective studies [4]. The RCTs were carried out in Vellore, India, and assessed the value of 12 g pralidoxime given in an infusion over 3–4 days versus a 1 g bolus or placebo. The trials failed to show any benefit. However, recent World Health Organization guidelines [5] recommend far higher doses – at least 30 mg/kg bolus followed by an infusion of 8 mg/kg per hour. In practice, this becomes 2 g stat followed by 500 mg/h – a dose far higher than that used in the study of Sungur and Guven [1]. The authors also state that pralidoxime should not be used longer than 48 hours after ingestion. This may not be true for diethyl OPs. The time at which oxime administration is no longer useful depends on the rate of acetylcholinesterase ageing. In vitro, this occurs with a half-life of around 3 hours for dimethyl OPs and 33 hours for diethyl OPs. Taking four half-lives to be the latest that oximes can be effective, oximes may be useful for diethyl compounds when started up to 120 hours after ingestion [4,5]. Finally, we agree with Sungar and Guven that further controlled trials are required. We are now carrying out a large RCT in Sri Lanka in 1500 patients to test the efficacy of the dose of pralidoxime recommended by the World Health Organization.

We read with interest the paper by Tugrul et al. [1] regarding the effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis managed in their intensive care unit. Apart from the global interest of reading a paper in the field of the treatment of severe sepsis and septic shock, we have an almost similar project in progress. It is well known that the immunotherapy in sepsis is still a gray zone, and it will remain so as long as the relevant literature presents conflicting results [2]. From our understanding and the interim analysis of our data, it seems that we could expect some definitive immunotherapy informationin the near future. In our study, we have presently included 34 patients in the treatment group (IgM + IgG + IgA) and 34 in the control group. Analyzing our data in a manner comparable with that of Tugrul et al. [1], we reach a different conclusion regarding the results. The only difference that exists between our protocol and that of Tugrul et al. regarding the study design and the inclusion criteria is that we include only adults older than 18 years old (the lower age limit of Tugrul et al.'s study is 10 years, and adolescents are probably included). The number of patients needed per arm of the study in order to achieve a safe conclusion (statistical power analysis, 80%; P < 0.05 for a mortality decrease of 17%, which was the mortality decrease in our preliminary analysis) is 120 patients in each arm. In a study with a smaller number of patients, therefore, such as those of Tugrul et al. (21 patients in each arm) or ourselves (34 patients in each arm to the present time), any conclusion may be unsafe. Although the data in both studies (in our opinion) are so far not sufficient, a significant difference trend is recorded. The mean age in Tugrul et al.'s study is 42.0 ± 18 years in the IgM + IgG + IgA group and 49.3 ± 20.6 years in the control group. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score in that same study is 10.5 ± 4.6 in the IgM + IgG + IgA group and 14.0 ± 8.5 in the control group. Although there is no statistically significant difference, there is a strong tendency for the two means to become different (P = 0.10). In our preliminary data analysis, the mean age is 50.5 ± 3.33 years in the IgM + IgG + IgA group and 50.7 ± 7.36 years in the control group. The APACHE II score in our study is 21.27 ± 7.23 in the IgM + IgG + IgA group and 23.5 ± 7.91 in the control group. The 28-day mortality rate in Tugrul et al.'s study is 23.8% in the IgM + IgG + IgA group versus 33.3% in the control group. In our preliminary data analysis, the mortality rate is 22.35% and 40.0% in the IgM + IgG + IgA group and the control group, respectively. Although this difference is a statistically significant one, the analysis of the mortality rate of the subgroups according to the APACHE II scoring of inclusion to the study day is more interesting. The mortality rate in our preliminary data for the IgM + IgG + IgA group with an APACHE II score ranging between 20 and 29 was 22.22%, and that of the control group with the same APACHE II score range was 55%. As we pointed out earlier, in order to demonstrate the clinical effectiveness of immunotherapy in severe sepsis and septic shock, a number of 120 patients is necessary to be included in each arm of our study. Using our preliminary results in the same manner as those in Tugrul et al.'s paper [1], we could conclude that it is sometimes possible to present the data in such a way resulting in delusive conclusions. Analyzing the data by means of definitions of sepsis and septic shock, and assuming the patients to be a uniform group, we cannot demonstrate the special subgroups of patients in whom the administration of IgM-enriched immunoglobulin preparations may have highly beneficial effects. By grouping the patients according to some characteristics (such as APACHE II score or Simplified Acute Physiology Score IIscore), the beneficial effect of immunoglobulins could be shown. Using such an approach, a beneficial effect of IgG immunotherapy in a special subgroup of septic patients has already been shown in the study by Dominioni et al. [3]. In conclusion, it seems that there is a subgroup of patients with severe sepsis or septic shock in which the delivery of IgM-enriched immunoglobulin preparations may have a beneficial effect. Further study with more patients, either in our study or that of Tugrul et al., is necessary before we decide whether to use this type of immunotherapy in the treatment of severe sepsis.

The use of pharmacological agents in intensive care units (ICUs) is ever on the increase, with novel therapies appearing in the literature regularly. The complexities of polypharmacy are a challenge to the intensivist, and any guidance as to which drugs to use, when to use them and how much to use is always welcome. Happily, therefore, over the past 2 months a number of interesting papers and articles have appeared covering drugs both new and old. Cardiac arrest in the community is associated with a very high mortality rate. Ventricular fibrillation (VF) is both the most common mode of arrest and carries the best prognosis if early defibrillation is available [1]. However, a subgroup of patients with VF are resistant to direct current defibrillation, in which case an antiarrythmic agent is required, but very few randomized controlled trials (RCTs) have been conducted to verify the efficacy of any particular agent. Dorian and colleagues [2] compared lidocaine with amiodarone in the management of out-of-hospital, shock-resistant VF. In a double-blind RCT, 347 patients were randomly assigned to either lidocaine 1.5 mg/kg or amiodarone 5 mg/kg as an initial dose. In addition, a further 1.5 and 2.5 mg/kg, respectively, were given if required. The primary end-point was survival to hospital. A total of 41 patients (22.8%) in the amiodarone group and 20 patients (12.0%) in the lidocaine group survived to hospital (P = 0.009; odds ratio 2.17, 95% confidence interval 1.21–3.83). However, only nine patients in the amiodarone and five in the lidocaine group survived to hospital discharge. In this population, receiving amiodarone increased the chances of an individual arriving at hospital alive. Time to paramedic intervention (i.e. drug administration), however, was an equally important factor. Interestingly, time interval to first attempted defibrillation was not associated with a survival benefit, which is presumably a reflection of the refractory nature of the VF. Sadly, the survival rate to discharge – a more relevant outcome – between the groups was not significantly different, with overall survival to discharge being a dismal 4%. This low survival is consistent with out-of-hospital cardiac arrest. However, it seems reasonable to extrapolate these findings to the in-patient population, in which case administration of amiodarone as the first-line agent for shock-resistant VF may result in improved survival in the hospital setting. Staying with matters cardiac, an RCT that considered the management of acute exacerbations of chronic heart failure was published in March 2002 in the Journal of the American Medical Association [3]. The precise role of the selective phosphodiesterase inhibitor milrinone in intensive care remains obscure, with no survival benefit demonstrated. Acute exacerbation of chronic heart failure is a relatively common indication for admission into a critical care setting, but with few randomized outcome trials to guide our management. This study investigated whether a short course of milrinone could improve clinical outcomes. Patients were randomly assigned to a 48-hour infusion of milrinone (0.5 μg/kg per min initially) or placebo. The number of hospital days for management of cardiovascular problems 60 days after randomization did not differ between the two groups, and no difference was found for in-hospital or 60-day mortality. The milrinone group suffered higher incidences of hypotension requiring intervention and new atrial arrhythmias. The study adds weight to the feeling that the selective phosphodiesterase inhibitors contribute little to the general intensivists pharmacological arsenal. Singer and colleagues [4] reported on eight patients with septic shock refractory to fluid, catecholamine, corticosteroid and methylene blue therapy who were salvaged with the long-acting vasopressin analogue terlipressin. The use of vasopressin has previously been described in resistant hypotension secondary to sepsis, but is associated with troublesome rebound hypotension on withdrawal [5,6]. An intravenous bolus of terlipressin (1–2 mg) was given to each of eight patients demonstrating profound and resistant vascular hyporeactivity. Bolus terlipressin resulted in a progressive increase in mean arterial pressure, allowing withdrawal of noradrenaline (norepinephrine) in seven of the eight patients. This improvement in mean arterial pressure was maintained for 5 hours; one patient required a repeat bolus. Four patients went on to ICU discharge and three to hospital discharge. No negative sequelae were noted. The authors concluded that, although the mechanism of increased vasomotor sensitivity to terlipressin is not known, it offers a promising alternative for management of life-threatening and intractable hypotension in septic shock. Although such reports are somewhat anecdotal, the results are promising for a condition that is known to carry a high mortality rate, and it may be that the time for a larger outcome trial approaches. The March/April edition of Intensive Care Monitor [7] comments on a paper that examined the immunomodulatory effects of high-dose hydrocortisone in septic shock [8]. It is known that cortisol has permissive and suppressive effects on the immune response, and it has been reported that supraphysiological doses can reverse septic shock [9]. However, little is known regarding the cytokine response to high-dose hydrocortisone. In a small, double-blind, placebo-controlled RCT, 24 patients with septic shock were randomly assigned to either high-dose hydrocortisone or placebo [8]. End-points included time to shock reversal and effect on serum cytokine concentration. By day 3 the Sequential Organ Failure Assessment score was lower in the hydrocortisone group than in the placebo group (P < 0.05). No difference in mortality was found. Interleukin-6 and interleukin-8 were both significantly reduced in the treatment group, whereas interleukin-10 and tumour necrosis factor-α were similar between the two groups. The observed reduction in interleukin-6 levels is of significance because this proinflammatory cytokine has been correlated with severity of septic shock, and this may explain the quicker resolution of organ-related morbidity in the treatment group. This is consistent with findings reported in a more recent paper on the effects of methylprednisolone in unresolving acute respiratory distress syndrome [10], and may account for a therapeutic modality by which high-dose steroid therapy works. It is difficult to conclude a great deal more from this study, but it positively contributes towards a rationale for the use of steroids in management of the inflammatory response. Thromboembolic disease is a frequent cause of morbidity and mortality in ICU patients, and it often goes undetected. Low-molecular-weight heparins have been shown to reduce significantly the incidence of thromboembolic complications [11] and are now considered standard therapy, but the incidence remains high in critically ill patients when compared with that in other patient populations. A group from Amsterdam postulated in The Lancet that this may be partly due to lowered bioavailability resulting from vasopressor use in critically ill patients. They considered three groups of patients: ICU patients on vasopressors, ICU patients not on vasopressors and postoperative ward patients. Each patient had received at least three doses of nadroparin 2850 IU. Serial concentrations of factor Xa activity (do the authors mean anti-factor Xa activity?) were compared between the groups. The biological action of the low-molecular-weight heparin was found to be significantly less in ICU patients on vasopressors than in ICU patients not on vasopressors and in postoperative ward patients. This lower heparin activity may contribute to the observed high incidence of thromboembolism in the critically ill population. It is suggested that vasopressor therapy reduces the uptake of subcutaneously administered drug as a result of impaired peripheral perfusion, and therefore these patients should be given greater doses. In the absence of routine anti-factor Xa activity assays, some caution may be required before instituting blind dose increases for a group of patients who are at risk of occult bleeding and for a drug with effects that are difficult to reverse.

This commentary reflects on the paper reports published in the Critical Care Forum between 10 July 2001 and 10 September 2001 The volume of published research in critical care continues to increase with each passing month. In this issue of Critical Care a few of the less well publicised but clinically important papers are reported on. A continuing theme over recent months has been to reaffirm the potentially harmful effects of specific interventions. The Canadian Clinical Trials Group published the third paper from their investigations into the effects of a restrictive strategy of blood transfusion [1]. Their restrictive strategy sets the threshold for packed red cell transfusion at haemoglobin levels

2cc-2-1-001 Full text The results of the various sepsis intervention studies and doubts about the efficacy of the pulmonary artery (PA) catheter have cast a considerable shadow over the intensive care community. They serve to highlight the importance of the recent paper published by Sinclair et al [1], in which the authors convincingly demonstrated that elderly patients undergoing surgery for a fractured neck of femur had a slightly significantly better outcome if they were aggressively volume loaded with colloid intraoperatively. They showed that the administration of an average of 750 ml of colloid during the course of the operation resulted in a highly significant reduction in hospital stay and a lower complication rate. The wellmatched control group patients were treated conventionally, only receiving crystalloid. The range of volumes of colloid given to the protocol group of patients was considerable, and the cardiovascular effects of the infusion were monitored using an intraoesophageal Doppler device which measures descending aortic blood velocity and converts it into cardiac output using a built-in nomogram. Sinclair et al showed that, following colloid infusion, the protocol group of patients had significantly increased cardiac output and stroke volume when compared to their own baseline values and the control patients. This simple manoeuvre led to a 39% reduction in hospital stay and complication rate. The obvious question is, could they have achieved the same result simply by administering the volume of colloid without monitoring cardiac output, albeit with a relatively noninvasive device that is placed in the oesophagus. This is an important question because it is likely to determine whether such an approach to the management of similar high-risk patients will be generally accepted and become the standard. Others, including Shoemaker et al [2], Boyd et al [3] and more recently Bishop et al [4], have clearly shown that the recognition and very early optimisation of cardiac output in a wide range of high-risk surgical patients produces highly significant reductions in both morbidity and mortality. This approach is time consuming and requires, in some cases, admission to the intensive care unit some hours prior to surgery and the insertion of PA catheters for the measurement and manipulation of cardiac output. This makes the approach unattractive to many clinicians, with their doubts being further amplified by the recent controversies. Shoemaker et al (pers comm) have estimated that as many as 8-10% of all surgical patients should be considered at high risk from developing significant post-operative morbidity and mortality. These patients warrant further extensive study and the Sinclair investigation is a welcome addition to the growing list of papers that demonstrate the benefits that can be obtained with this approach. In general, the recent consensus meeting on efficacy of PA catheters [5] was unable to identify studies which offered scientific evidence that their use leads to clinical benefit, despite the fact that there is an annual world usage well in excess of 2 million, with the USA accounting for the large majority. The only area where benefit could in any way be ascribed to the use of the PA catheters was in those who fulfilled the criteria for being defined as high-risk surgical patients. In this group of patients the consensus felt there was evidence to suggest that systematically increasing oxygen delivery in the preoperative period leads to significant improvement in both mortality and morbidity. In most of the work identified, the increase in cardiac output was monitored using a PA catheter although two of the studies used the oesophagus Doppler instrumentation. Clearly the use or not of PA catheters arouses strong emotions and will undoubtedly continue to do so until the appropriate efficacy trials are undertaken. It is to be hoped that any such trials must include the category of high-risk surgical patients that statistically benefit from the insertion of a PA catheter. In addition, we should address the further question of whether alternative techniques for measuring cardiac output, including intra-oesophageal Doppler and indeed impedence plethysmography, are viable clinical alternatives to the PA catheter. Department of Intensive Care, St George’s Hospital,Blackshaw Road, London SW17 0QT, UK Bennett Critical Care 1998, 2:1 http://ccforum.com

The concept of net ultrafiltration (UFNET) mentioned in the paper by Murugan et al. in a recent issue of Critical Care does not equate to the real UFNET in patients with renal replacement therapy initiation. Furthermore, the baseline blood pressure among the groups had a statistically significant difference. Both of these two factors may affect the final results. Thus, we should be cautious interpreting the conclusions.

Circulatory shock is a common syndrome with a high mortality and limited therapeutic options. Despite its discovery and use in clinical and experimental settings more than a half-century ago, angiotensin II (Ang II) has only been recently evaluated as a vasopressor in distributive shock. We examined existing literature for associations between Ang II and the resolution of circulatory shock.We searched PubMed, MEDLINE, Ovid, and Embase to identify all English literature accounts of intravenous Ang II in humans for the treatment of shock (systolic blood pressure [SBP] ≤ 90 mmHg or a mean arterial pressure [MAP] ≤ 65 mmHg), and hand-searched the references of extracted papers for further studies meeting inclusion criteria. Of 3743 articles identified, 24 studies including 353 patients met inclusion criteria. Complete data existed for 276 patients. Extracted data included study type, publication year, demographics, type of shock, dosing of Ang II or other vasoactive medications, and changes in BP, lactate, and urine output. BP effects were grouped according to type of shock, with additional analyses completed for patients with absent blood pressure. Shock was distributive (n = 225), cardiogenic (n = 38), or from other causes (n = 90). Blood pressure as absent in 18 patients.For the 276 patients with complete data, MAP rose by 23.4% from 63.3 mmHg to 78.1 mmHg in response to Ang II (dose range: 15 ng/kg/min to 60 mcg/min). SBP rose by 125.2% from 56.9 mmHg to 128.2 mmHg (dose range: 0.2 mcg/min to a 1500 mcg bolus). A total of 271 patients with complete data were determined to exhibit a BP effect which was directly associated with Ang II. Subgroups (patients with cardiogenic, septic, and other types of shock) exhibited similar increases in BP. In patients with absent BP, deemed to be cardiac arrest, return of spontaneous circulation (ROSC) was achieved, and BP increased by an average of 107.3 mmHg in 11 of 18 patients. The remaining seven patients with cardiac arrest did not respond.Intravenous Ang II is associated with increased BP in patients with cardiogenic, distributive, and unclassified shock. A role may exist for Ang II in restoring circulation in cardiac arrest.

With imprecise definitions, inexact measurement tools, and flawed study execution, our clinical science often lags behind bedside experience and simply documents what appear to be the apparent faults or validity of ongoing practices. These impressions are later confirmed, modified, or overturned by the results of the next trial. On the other hand, insights that stem from the intuitions of experienced clinicians, scientists and educators-while often neglected-help place current thinking into proper perspective and occasionally point the way toward formulating novel hypotheses that direct future research. Both streams of information and opinion contribute to progress. In this paper we present a wide-ranging set of unproven 'out of the mainstream' ideas of our FCCM faculty, each with a defensible rationale and holding clear implications for altering bedside management. Each proposition was designed deliberately to be provocative so as to raise awareness, stimulate new thinking and initiate lively dialog., SCOPUS: re.j, info:eu-repo/semantics/published

Background Ventilator-associated pneumonia (VAP) can have a clear onset or may be a result of the gradual appearance of symptoms and signs of VAP (gradual VAP). The aim of this paper is to describe the VAP development process with the intention of discriminating between those pneumonias with a clear beginning and those that are diagnosed after a period of maturation. In addition, we evaluate the effect of the starting time of antibiotic treatment in both situations. Methods Consecutive ventilated patients fulfilling VAP criteria were included. The patients were monitored for clinical, microbiological, and inflammatory signs. Patients with VAP were classified into two groups: (1) nongradual VAP (patients in whom all VAP criteria were detected for the first time on the day of diagnosis) and (2) gradual VAP (progressive appearance of signs and symptoms throughout the pre-VAP period [24 h before VAP diagnosis]). Results A total of 71 patients with VAP were identified, of whom 43 (61 %) had gradual VAP, most of whom (n = 38, 88 %) had late-onset VAP. Antibiotic treatment was given to 34 (79 %) patients with gradual VAP in the pre-VAP period, and empirical antibiotic treatment was appropriate in 22 patients (51 %). The patients with an appropriate empirical treatment had a higher percentage of early clinical response to treatment (68 % [n = 15] vs. 28 % [n = 7]; p = 0.009). An attempt was made to find a diagnostic test capable of identifying the infectious process underway, but clinical scales and biomarkers of inflammation helped us to achieve acceptable results. Conclusions Gradual emergence of VAP, mainly of late onset, is a common condition. Clinicians should be aware of this gradual onset of the infection to establish an early antibiotic treatment, even before the classic diagnostic criteria for VAP are applied.

Background Heparin saline (HS) is theoretically superior to normal saline (NS) for maintaining the patency of central venous catheters (CVCs), but the comparative efficacy of them remains controversial. The aim of this systematic review and meta-analysis was to assess the efficacy of NS versus HS in the maintenance of the patency of CVCs in adult patients. Methods We searched PubMed, Embase and the Cochrane library databases. Randomized controlled trials (RCTs) evaluating the use of NS vs. HS to maintain the permeability of CVCs among adult patients were included in our meta-analysis. References of relevant papers were reviewed manually. No language restriction was applied. Non-human studies were excluded. Pooled relative risk (RR) was calculated using a Mantel-Haenszel random-effects model. We also performed subgroup analysis examining the effect of the duration of catheter placement on the outcome. All statistical tests were two-sided using a significance level of 0.05. Results Ten RCTs involving 7875 subjects (with analysis at patient, catheter, lumen and line access level) were included in this meta-analysis. Whether in terms of pooled or local analysis (RR with 95% confidence interval spans 1), NS can be equally, if not more effective, in keeping the CVCs open. Of studies reporting secondary outcomes (maneuver needed, heparin-induced thrombocytopenia, haemorrhage, central venous thrombosis and catheter-related bloodstream infection), heparinised saline was shown not to be superior to non-heparinised solution. Subgroup analysis in patients with short vs long term CVC placement was consistent with the main outcome partly and in particular for maintenance of catheter patency in patients with a long-term placement i.e. >30 days, the RR was 0.97 (n = 6589; 95% CI = 0.76 to 1.23; P = 0.796). However, for patients in whom the catheter was in place for

Mass casualty civilian shootings present an uncommon but recurring challenge to emergency services around the world and produce unique management demands. On the background of a rising threat of transnational terrorism worldwide, emergency response strategies are of critical importance. This study aims to systematically identify, describe and appraise the quality of indexed and non-indexed literature on the pre-hospital management of modern civilian mass shootings to guide future practice. Systematic literature searches of PubMed, Cochrane Database of Systematic Reviews and Scopus were conducted in conjunction with simple searches of non-indexed databases; Web of Science, OpenDOAR and Evidence Search. The searches were last carried out on 20 April 2016 and only identified those papers published after the 1 January 1980. Included documents had to contain descriptions, discussions or experiences of the pre-hospital management of civilian mass shootings. From the 494 identified manuscripts, 73 were selected on abstract and title and after full text reading 47 were selected for inclusion in analysis. The search yielded reports of 17 mass shooting events, the majority from the USA with additions from France, Norway, the UK and Kenya. Between 1994 and 2015 the shooting of 1649 people with 578 deaths at 17 separate events are described. Quality appraisal demonstrated considerable heterogeneity in reporting and revealed limited data on mass shootings globally. Key themes were identified to improve future practice: tactical emergency medical support may harmonise inner cordon interventions, a need for inter-service education on effective haemorrhage control, the value of senior triage operators and the need for regular mass casualty incident simulation.

We read with interest the paper of Tarvasmaki et al. [1] regarding the role of inotropes and vasopressors in patients with cardiogenic shock. The authors should be congratulated for their effort of prospectively collecting a huge amount of data in one of the most challenging settings. However, too much emphasis seems to be placed on the authors’ conclusions, especially taking into account some of the study’s limitations.

We read with interest the recent paper by Doenyas-Barak et al. [1] comparing the prognosis of extremely elevated plasma lactate levels between metformin (MET)-treated and MET-naive patients with septic shock. The most remarkable finding was a highly significant lower in-hospital mortality (56.8 vs. 88.1 %, p 20 mmol/L or pH ≤7.0, in case of shock or decreased level of consciousness, and when standard supportive measures fail [3]. Early IHD is the preferred mode of treatment. For several reasons, however, continuous RRT (CRRT) is thought to be physiologically more appropriate than IHD. First, because of its low molecular weight and minimal protein binding, MET is equally (highly) eliminated by ultrafiltration (convection) as compared to dialysis (diffusion). Second, and more importantly, its large volume of distribution within a two-compartment pharmacokinetic model implies that MET may be more effectively cleared by prolonged RRT. This was corroborated by Keller et al. [4] who recently showed a dramatic reduction of metabolic acidosis and decrease of MET plasma concentrations within the first 24 h after initiating CRRT in patients with MET-induced lactic acidosis, followed by normalization on the second day in all subjects. Finally, consensus exists that CRRT is better tolerated in hemodynamically unstable patients, and is also associated with a higher rate of renal recovery compared with IHD [5]. This will certainly benefit septic MET-imbedded patients who often present with catecholamine-dependent septic shock and faltering or lost kidney function.

There is an increasing focus on intensive care unit-acquired weakness, its underlying mechanisms and therapeutic options. In this article we offer a commentary on the paper by Bloch and colleagues entitled 'MiR-181a: a potential biomarker of acute muscle wasting following cardiac surgery'. There is a need for biomarkers for intensive care unit-acquired weakness, not only in clinical practice but also in order to streamline future therapeutic trials. MicroRNAs are attractive biomarkers, and may have an important role in this disease. We highlight the significance of the authors’ finding of miR-181a, a novel plasma biomarker for the development of acute muscle wasting in post-operative cardiac surgery patients and discuss future research that is needed in this field following on from the study findings.

Evidence based medicine is an attempt to optimize the medical decision process through methods primarily based on evidence coming from meta-analyses, systematic reviews, and randomized controlled trials ("evidence-based medicine"), rather than on "clinical judgment" alone. The randomized trials are the cornerstones of this process. However, the randomized trials are just a method to prove or disprove a given hypothesis, which, in turn, derives from a general observation of the reality (premises or theories). In this paper we will examine some of the most recent randomized trials performed in Intensive Care, analyzing their premises, hypothesis and outcome. It is quite evident that when the premises are wrong or too vague the unavoidable consequences will be a negative outcome. We should pay when designing the trial an equal attention in defining premises and hypothesis that we pay for the trial conduction.