Kimberly DiMaria; C.S. Mott Children’s Hospital, Ann Arbor, MichiganSurvival after in-hospital cardiac arrest is associated with resuscitation team performance and adherence to American Heart Association (AHA) resuscitation algorithms. The primary aim was increased resuscitation team performance during simulation scenarios as evidenced by improved modified Clinical Performance Tool (mCPT) scores. The secondary aim was improved adherence to AHA resuscitation guidelines during actual code events. Process measures, including frequency of simulations, were used to determine proof of concept.In 2021, a review of resuscitation events in the cardiac progressive care unit (CPCU) revealed poor compliance with AHA guidelines. One of the most critical times of code performance in the CPCU is during the initial response, before code team arrival, which prompted development of a simulation intervention that focused on improving team performance during the initial stages of resuscitation. A single-center, prospective, interventional quality improvement project, First 5-Minute Drills, was developed to provide concise, repeated opportunities for CPCU team members to practice low-frequency, high-risk skills, and crisis resource management principles. Team performance during simulations was directly observed and evaluated using an mCPT score, a 20-point scoring tool that measures team performance of 10 different skills. A t test was used to compare mean mCPT scores at 3 periods. Adherence to AHA algorithms during patient codes was assessed via a retrospective review. Patient resuscitations were evaluated using a standardized scorecard comprising 10 evidence-based treatment recommendations embedded within the AHA resuscitation algorithms.Over 19 months, 48 First 5-Minute Drills were conducted and 238 team members participated. The mCPT was administered at various time points during the study, and results demonstrated a 35% improvement in code team performance. There was a statistically significant increase in mCPT scores from 14.3 to 18.3 (P = .02). Pre-post analysis of 4 actual code events demonstrated a 50% improvement in adherence to AHA algorithms. First 5-Minute Drills resulted in improved simulation resuscitation team performance and adherence to AHA algorithms during real-time code events in the CPCU. The low-cost, high-yield First 5-Minute Drills intervention is generalizable to other departments and hospitals.Eunice Santos, Jimmy Nguyen; Cedars-Sinai Medical Center, Los Angeles, CaliforniaThe rate of central line [catheter]–associated bloodstream infections (CLABSIs) with pulmonary arterial catheter (PAC) use is high. In the advanced heart failure unit (AHFU), PAC CLABSIs are associated with increase morbidity, cost, and loss of eligibility for a heart transplant. The goal for this initiative was to determine whether the optimization of a nursing maintenance bundle created in 2018 in the AHFU to reduce PAC CLABSIs sustained fewer than 3 PAC CLABSIs per year for 5 years.In the AHFU, PACs are used for heart transplant evaluation and heart transplant listing. In 2017, there were 10 PAC infections at our institution. Feedback from case reviews for PAC CLABSIs in 2017 showed problems maintaining occlusive dressings in these catheters. In 2018, a quality improvement project was implemented to address challenges associated with PAC maintenance. The project introduced new PAC dressing kits and development of education for nurses caring for PACs in the AHFU. The standard central catheter dressing kit included a single transparent bandage, a chlorhexidine gluconate (CHG) swab, sterile gloves, and tweezers. The new PAC kit included a second anchoring transparent bandage and CHG swab. All the nurses were educated on the use of the PAC dressing kit—specifically the application of 2 transparent bandages to maintain an occlusive dressing, narrow beard clipping, and CHG bathing. In 2021, introduction of weekly central catheter rounds consisted of epidemiology nurse and nursing leadership rounding on patients with PACs. Sustainment of the project included permanent changes in nursing education, dressing kits, and close monitoring by epidemiology nurses and nursing leadership.PAC CLABSI rates were analyzed using the organization’s hospital-acquired infection dashboard from January 2018 to July 2023. Results showed that the PAC nursing maintenance bundle reduced PAC CLABSIs through the 5-year study period. In 2018, the year of implementation, there were 3 PAC CLABSIs in the AHFU. There was 1 PAC CLABSI in the AHFU in each of 2019, 2020, and 2023; there were 2 CLABSIs in 2021. Implementation of the PAC nursing maintenance bundle, multidisciplinary collaborations, continued nursing education, and adherence to the PAC nursing maintenance bundle during the 5-year period accomplished organizational goals in improving CLABSI rates and improving patient outcomes.Isabel Madrigal, Melissa Parodi; Doctors Hospital, Coral Gables, FloridaCentral line [catheter]–associated bloodstream infections (CLABSIs) are among the most common hospital-acquired infections (HAIs). CLABSIs are serious infections that can result in longer hospital length of stay, increased cost, and increased risk for death. In February 2021, the critical care unit (CCU) leadership team reviewed the unit CLABSI rates of 11.33 for the third quarter (Q3) of calendar year 2020 (CY20) and 9.32 for Q4 CY20. The CCU leadership team identified an opportunity to implement an inter-professional quality improvement team.In March 2021, the CLABSI interprofessional quality improvement team met to discuss the current CLABSI rates and review the specific patient cases. The team consisted of nurse leaders, clinical nurses, infection prevention nurses, performance improvement nurses, pharmacists, and In the CCU CLABSI rate was patient The interprofessional quality improvement team CLABSI prevention education for nurses and during the of and 2021. 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For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on arrhythmias contains a Special Article contribution entitled ‘1970–2020: 50 years of research on the long QT syndrome—from almost zero knowledge to precision medicine’, authored by Peter Schwartz from the IRCCS in Milan, Italy.1 A lot has been written about the long QT syndrome (LQTS) and there is a wealth of traditional reviews summarizing the existing knowledge on epidemiology, pathogenesis, clinical presentation, and the state of genetic testing.2,3 However, this Special Article is very special indeed. Professor Schwartz notes that those involved in clinical research rarely begin working on a rather obscure disease, still largely unexplored, following its ripening into a medical entity of great interest to clinicians and basic scientists alike, and to do so for exactly 50 years. This is what has been Professor Schwartz’s privilege in the relentless pursuit of the intriguing disease known as LQTS. This essay begins with the encounter with his first patient affected by LQTS when just a handful of cardiologists had seen similar cases, and continues with the series of efforts which eventually led—together with many brilliant partners and associates—to the description and understanding of the natural history of the disease and the most effective therapies. It then touches on how the International Registry for LQTS, with its well-documented family trees, constituted the necessary springboard for the major genetic discoveries of the 1990s. From the explosion of genetic data, his own interest focused first on the intriguing genotype–phenotype correlation and then on ‘modifier genes’, in an attempt to understand why family members with the same disease-causing mutation may have an opposite clinical history; and from there on to induced pluripotent stem cell (iPS)-derived cardiomyocytes, used for unravelling the specific mechanisms of action of modifier genes and for exploring novel therapeutic strategies. This long, and highly rewarding, journey continues because the fascination with and the attraction of the unknown is irresistible. Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to sudden cardiac death (SCD) by the Brugada brothers, although its eponymous title was only bestowed 4 years later. Eight patients had demonstrated an electrocardiogram (ECG) pattern of ‘right bundle branch block, normal QT interval and persistent ST-segment elevation in precordial leads V1 to V2–V3 not explainable by electrolyte disturbances, ischaemia or structural heart disease’.4 In a State of the Art Review article entitled ‘Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?’, Elijah Behr from St George’s University of London in the UK, and colleagues5 note that BrS was first described as a primary electrical disorder predisposing to the risk of SCD and characterized by right precordial lead ST elevation. Then, early descriptions of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. The authors propose that the final common pathway for BrS could be viewed as a disease of ‘reduced RVOT conduction reserve’ (Figure 1). Brugada syndrome (BrS) as a disease of impaired right ventricular outflow tract (RVOT) conduction reserve. Normally, intrinsic RVOT conduction reserve may be affected by a patient’s age and gender. In BrS, cellular and tissue abnormalities cause a reduction in RVOT conduction reserve: genetic abnormalities, whether mediated by a pathogenic SCN5A variant, an increased BrS-PRS, and/or additional genetic insults, may have direct effects on Nav1.5, as well as tissue effects causing RVOT inflammation, fibrosis, and gap junction abnormalities. Decreased Nav1.5 current, together with electrical discontinuity caused by RVOT structural changes, converges to disrupt normal depolarization, with or without secondary repolarization effects, leading to impairment of the conduction reserve of the RVOT. In this framework, the marginal conduction reserve can be exposed by acute modulators such as fever, drugs, and altered vagal tone which further impair conduction and expose the Brugada phenotype (from Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway? See pages 1073–1081). Brugada syndrome (BrS) as a disease of impaired right ventricular outflow tract (RVOT) conduction reserve. Normally, intrinsic RVOT conduction reserve may be affected by a patient’s age and gender. In BrS, cellular and tissue abnormalities cause a reduction in RVOT conduction reserve: genetic abnormalities, whether mediated by a pathogenic SCN5A variant, an increased BrS-PRS, and/or additional genetic insults, may have direct effects on Nav1.5, as well as tissue effects causing RVOT inflammation, fibrosis, and gap junction abnormalities. Decreased Nav1.5 current, together with electrical discontinuity caused by RVOT structural changes, converges to disrupt normal depolarization, with or without secondary repolarization effects, leading to impairment of the conduction reserve of the RVOT. In this framework, the marginal conduction reserve can be exposed by acute modulators such as fever, drugs, and altered vagal tone which further impair conduction and expose the Brugada phenotype (from Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway? See pages 1073–1081). Since its description, BrS has been the subject of increased scientific interest as a cause of SCD due to ventricular tachycardia/fibrillation in young and otherwise healthy individuals. BrS is believed to be a genetic disease, although the majority of clinically confirmed cases lack molecular validation, due to our current shortfall of understanding of the genetics of this syndrome.6,7 Despite SCN5A being the most commonly known mutated gene to date, the genotype–phenotype relationship is poorly understood and remains uncertain. In a clinical research article entitled ‘Brugada syndrome genetics is associated with phenotype severity’, Giuseppe Ciconte from the IRCCS Policlinico San Donato in Italy, and colleagues aimed to elucidate the genotype–phenotype correlation in BrS.8 BrS probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by means of epicardial arrhythmogenic substrate mapping and were allocated to two groups according to the presence or absence of the SCN5A mutation. Two hundred probands (mean age 43 years) were included in this study. SCN5A-positive patients exhibited a larger epicardial arrhythmogenic substrate area, more prolonged ECGs, and more frequently late potentials at non-invasive testing (Figure 2). The presence of an SCN5A mutation explained >26% of the variation in the epicardial arrhythmogenic substrate area and was the strongest predictor of a larger epicardial arrhythmogenic area. Brugada syndrome phenotypic expression predictors. (A) Large Brugada syndrome epicardial substrate in a male patient with spontaneous type 1 electrocardiogram pattern experiencing appropriate implantable cardioverter-defibrillator therapy. (B) Specific contribution of each variable (SCN5A mutations, spontaneous type 1 electrocardiogram pattern, and gender), in explaining the variance of the arrhythmogenic substrate. (C) Receiver-operating characteristic curve analysis demonstrating the accuracy of the model for the prediction of a large arrhythmogenic substrate (≥6.3 cm2) (from Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Calović Ž, Ghiroldi A, D’Imperio S, Benedetti S, Di Resta C, Rivolta I, Casari G, Petretto E, Pappone C. Brugada syndrome genetics is associated with phenotype severity. See pages 1082–1090). Brugada syndrome phenotypic expression predictors. (A) Large Brugada syndrome epicardial substrate in a male patient with spontaneous type 1 electrocardiogram pattern experiencing appropriate implantable cardioverter-defibrillator therapy. (B) Specific contribution of each variable (SCN5A mutations, spontaneous type 1 electrocardiogram pattern, and gender), in explaining the variance of the arrhythmogenic substrate. (C) Receiver-operating characteristic curve analysis demonstrating the accuracy of the model for the prediction of a large arrhythmogenic substrate (≥6.3 cm2) (from Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Calović Ž, Ghiroldi A, D’Imperio S, Benedetti S, Di Resta C, Rivolta I, Casari G, Petretto E, Pappone C. Brugada syndrome genetics is associated with phenotype severity. See pages 1082–1090). The authors conclude that in BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the phenotypic expression of BrS and provide possible explanations for the varying degrees of disease expression. The manuscript is accompanied by an Editorial by Connie R. Bezzina from the AMC Heart Center in Amsterdam, the Netherlands, and colleagues.9 The authors note that while we are still at the early stages of being able to offer individualized prognosis for BrS patients, studies like that of Ciconte and colleagues are beginning to illuminate the path between genetic risk factors and clinical outcomes. Although COVID-19 manifests primarily as a severe respiratory infection, numerous studies demonstrate that cardiovascular complications are common, and pre-existing cardiovascular conditions are predictors of survival in COVID-19.10–12 The first cases of COVID-19 in Sweden were reported in early February 2020. The Swedish Public Health Authority declared community spread in Sweden on 16 March. As a consequence, updated guidelines from the European Resuscitation Council (ERC) and the Swedish Resuscitation Council recommended that bystanders should avoid ventilation and focus their resuscitation attempts on chest compressions only in the case of suspected COVID-19.13 In a clinical research article entitled ‘Cardiac arrest in COVID-19: characteristics and outcomes of in- and out-of-hospital cardiac arrest. A report from the Swedish Registry for Cardiopulmonary Resuscitation’, Pedram Sultanian from the University of Gothenburg in Sweden, and colleagues investigated characteristics and outcomes among cardiac arrest cases with COVID-19 and differences between the pre-pandemic and the pandemic period in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA).14 The authors included all patients reported to the Swedish Registry for Cardiopulmonary Resuscitation from anuary to July 2020. Sultanian et al. enrolled ∼2000 cases of OHCA and 1000 cases of IHCA. During the pandemic, 10.0% of OHCAs and 16.1% of IHCAs had ongoing COVID-19 with regards to OHCA. Adjusted 30-day survival was 4.7% for patients with COVID-19, 9.8% for patients without COVID-19, and 7.6% in the pre-pandemic period (P = 0.03) with regards to IHCA. Adjusted 30-day survival was 23.1% in COVID-19-positive cases, 39.5% in patients without COVID-19, and 36.4% in the pre-pandemic period (P = 0.04). The authors conclude that this is, to the best of their knowledge, the most detailed report on characteristics and outcome in COVID-19 patients suffering cardiac arrest within and beyond the hospital perimeter, and that they report a number of unexpected findings, many of which highlight the severity of COVID-19 and the potential shift in the epidemiology of cardiac arrest brought about by this pandemic. The manuscript is accompanied by an Editorial by Xavier Jouven from the Université de Paris in France, and colleagues.15 The authors note that these findings highlight the importance of anticipation and planning in the management of healthcare crises. The observations with respect to the COVID-19 pandemic and cardiac arrest should serve as an important wake-up call for healthcare systems worldwide to develop blueprints and contingency plans for preparedness in the case of such eventualities. With improvements in pharmacological and device therapy, earlier and more aggressive cardiovascular prevention, and prompt coronary intervention, there has been a gradual and substantial reduction in SCD risk over the last two decades in patients with heart failure. Thus, one may even reasonably speculate whether the results of randomized trials on implantable cardioverter-defibrillators (ICDs) would be the same if conducted in the current era of heart failure management,16,17 as the evidence supporting guideline recommendations for ICDs dates from the late 1990s and early 2000s.18 There is a particular need to revisit the current status of routine primary prevention ICD implantation in women. This issue contains a Viewpoint article entitled ‘Time to revisit implantable cardioverter-defibrillator implantation criteria in women’ by Sérgio Barra from the Hospital da Luz Arrábida in Portugal, and colleagues.19 The authors note that the low level of participation of female patients in ICD trials is a long-standing problem, but physicians and guidelines continue to extrapolate from results derived mainly from men to recommend routine ICD implantation in women despite lack of clear proof of a reduction in mortality. Conversely, the benefit of an ICD in men may have been relatively underestimated when looking at the data in total. It is evident that the data being used for decision-making are both outdated and also weak with respect to potential benefit in women. Hence it can be strongly argued that true equipoise exists for new, well-designed randomized trials assessing the efficacy of primary prevention ICDs, particularly in female patients, in conjunction with current heart failure therapies. The issue is also complemented by two Discussion Forum contributions. In an article entitled ‘Prognostication after out-of-hospital cardiac arrest: biases and caveats’, Andrew Williams from the King’s College Hospital in London, UK and colleagues comment on the recent publication entitled ‘A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE2’ by Nilesh Pareek from the King’s College Hospital NHS Foundation Trust in the UK, and colleagues.20,21 Pareek and colleagues respond in a separate contribution.22 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
Cardiac arrests claim millions of lives each year. The condition can often be treated with a de\nfibrillator,buttimeisaverycriticalfactor. Asaconsequence,survivalratesarelow.\nRecent developments in drone technology have made civilian drones both cheap, easy to\noperate, and reliable. This paper looks into opportunities to use drones to deliver defibrilla\ntors to cardiac arrest victims faster than an ambulance, and focuses on unifying the needs of\nemergencyresponsewiththerulesandregulationsrequiredtooperatethedronessafely.\nThe study is performed as a literature study combined with interviews. The primary stake\nholderswereidentifiedasemergencyresponseandtheCivilianAviationAuthority.\nThe results showed that there was both a perceived use for ambulance drones and a way to\nlegally use them. The suggested approach involves using ambulance drones at sporting events\nsuch as "Birkebeinerrennet" as a proof of concept, before more advanced or permanent pro\ngramsareconsidered.
A recent meta-analysis of 79 studies involving 142 740 patients with out-of-hospital cardiac arrest of presumed cardiac aetiology documented a survival-to-hospital discharge rate of 7.6% (95% CI 6.7–8.4) [1]. This analysis showed that survival from out-of-hospital cardiac arrest has changed little over the last 30 years, although a few recent studies report improving survival rates [2, 3]. Bystander cardiopulmonary resuscitation (CPR) increases the chances of long-term survival after out-of-hospital cardiac arrest [1, 4] but bystander CPR rates are low: in England in 2004–2006 the bystander CPR rate was 36% (unpublished data, National Out-of-Hospital Cardiac Arrest Project), which is consistent with the 32% documented in the recent international meta-analysis [1]. Reasons for bystanders’ not attempting CPR include: no previous training [5]; panic; concern about causing harm; and unwillingness to perform mouth-to-mouth ventilation (rescue breathing) [6]. Is ventilation of the lungs absolutely necessary during CPR? Intuitively, the provision of oxygen, even if in the form of expired air (approximately 17% oxygen) ought to be essential if full neurological recovery is to be achieved after anything but a very brief period of cardiac arrest. Yet many animal studies of cardiac arrest have shown either no difference in survival [7] or reduced survival [8, 9] with the addition of ventilation to chest compressions. A limitation of these studies is that, in contrast to humans, the airways of the animals are generally patent when supine, which may enable chest compressions alone to generate some ventilation. In animal studies, frequent gasping occurs during good quality CPR and this provides significant ventilation [10]. Gasping is also common after cardiac arrest in humans but it decreases rapidly with time. Only 7.1% of patients with out-of-hospital cardiac arrest were noted to be gasping on arrival of emergency medical services (EMS) personnel in Japan [11], but in another study, gasping was present in 39 of 119 (33%) cardiac arrests that were witnessed by EMS personnel [12]. When the EMS arrival time was more than 9 min after cardiac arrest, gasping was present in just 25 of 338 (7%) patients [12]. Not surprisingly, gasping is associated with survival [13]. Animal models that incorporate an obstructed airway [14, 15] or paralysis of the animals [16] may better reflect the clinical situation: they show worse outcomes with compression-only CPR – in these studies arterial oxygenation decreased substantially with compression-only CPR. If airway patency is maintained, do chest compressions generate adequate ventilation in human cardiac arrest? A study of 17 patients in an emergency department who were undergoing chest compressions using a mechanical compression device (Lund University Cardiopulmonary Assist System – LUCAS), their tracheas intubated, documented a median tidal volume per compression of just 42 ml – considerably less than the dead space [17]. These patients had been in cardiac arrest for more than 40 min, which implies that their lung compliance was probably poor (lung compliance decreases with prolonged CPR). Almost five decades ago, Peter Safar [18] showed that following failed prolonged attempts at CPR, chest compressions alone produced zero ventilation in 10 out of 12 patients with intubated tracheas. To my knowledge, there are no human data on tidal volumes produced with chest compressions immediately after the onset of cardiac arrest, but high-quality compressions may prolong gasping, probably adding significantly to any ventilation achieved with compressions alone. Aside from the reluctance by laypeople and healthcare professionals to provide mouth-to-mouth ventilation [19-21], the latter has other disadvantages. Mouth-to-mouth ventilation is associated with a significantly increased risk of regurgitation compared with no CPR or compression-only CPR [22]. The time taken to attempt two rescue breaths, which may be as long as 14–16 s [23, 24], represents a significant interruption to chest compressions and contributes to the ‘no-flow’ time. In comparison with conventional CPR, compression-only CPR is easier to learn [25]. In a study of dispatch-assisted CPR (the caller is given instructions by the ambulance controller on how to do CPR), full instructions were more likely to be delivered completely when the ventilation component was omitted and survival was non-significantly higher in the compression-only group [26]. There are no prospective randomised trials comparing compression-only CPR with conventional CPR. However, eight observational studies have showed similar survival rates when bystanders delivered compression-only CPR instead of conventional CPR, and all showed that survival to hospital discharge was higher with compression-only CPR compared with no CPR [11, 27-33]. The methodology in all these studies was similar: on arrival at the scene, EMS personnel observed and documented the technique of bystander resuscitation (none, compression-only, or conventional CPR). Although compression-only CPR was not associated with statistically higher survival rates overall compared with conventional CPR, one of the studies documented subgroups in which the outcome was significantly better for the compression-only group, for example response times less than 4 min and shockable rhythms [11]. The interpretation of observational studies such as these is fraught with difficulties because of the strong possibility of undetected confounders. Despite this, there has been a strong plea from some experts for compression-only CPR to be incorporated into international guidelines [34, 35] and the American Heart Association has published an advisory statement on ‘hands-only’ CPR – this advocates compression-only CPR if the bystander is not trained in CPR or is not confident in the ability to provide high-quality conventional CPR with minimal interruptions for rescue breaths [36]. Should we stop teaching rescue breathing to laypeople, and instead teach them to perform compression-only CPR? The strongest reason to adopt this approach is that it ought to (although we have no proof) increase the chance of a bystander’s providing CPR – we know that ‘any CPR is better than no CPR’. This strategy should produce at least equivalent outcomes (compared with conventional CPR) for those patients in cardiac arrest from a cardiac cause and where EMS response times are short. Approximately 58% (Japan) [2] to 80% (Scotland) [37] of out-of-hospital EMS-treated cardiac arrests are of primary cardiac aetiology. Those with asphyxial cardiac arrests (e.g. children or drowning victims), or where response times are long, are likely to need early ventilation if they are to have any chance of surviving. The findings of a recent observational study (using the methodology described above) of outcome among children in Japan with out-of-hospital cardiac arrest impact significantly on the compression-only CPR debate [38]. Of 5170 paediatric (aged 17 years and younger) out-of-hospital cardiac arrests in Japan from 2005 to 2007, 71% were from non-cardiac causes. Within this subgroup, conventional CPR produced more favourable neurological outcome than did compression-only CPR (7.2% (45/624) vs 1.6% (1/380); odds ratio 5.54 (95% CI 2.52–16.99)). Among those children who had arrests from cardiac causes, favourable neurological outcome did not differ between conventional and compression-only CPR (9.9% (28/282) vs 8.9% (14/158), respectively; odds ratio 1.20 (95% CI 0.55–2.66)). New cardiopulmonary resuscitation guidelines will be published in October 2010; what should be advised in relation to CPR by laypeople? The 2005 International Consensus on CPR Science already includes the recommendation that: ‘Rescuers should be encouraged to do compression-only CPR if they are unwilling to do airway and breathing manoeuvres or if they are not trained in CPR or are uncertain how to do CPR’ [39]. This message is consistent with the advisory statement that was published later by the American Heart Association [36] and remains reasonable in the face of data published since then. This stance should encourage bystanders at least to attempt some CPR. More controversial is the suggestion that laypeople should be taught to provide compression-only CPR in preference to conventional CPR for witnessed, sudden collapse (even if they have been trained in conventional CPR) [40]; all the available data indicate that this is likely to be beneficial only if the EMS response times are short (4 min or less). If we want laypeople to provide conventional CPR for victims of asphyxial cardiac arrest (including most children), it implies that everyone still needs to be trained to provide mouth-to-mouth ventilation, which takes us back to where we are now. Handley has described a solution that would, at a minimum, get everyone trained to do compression-only CPR, while encouraging as many as possible to learn conventional CPR as well [41]. In this very sensible, staged approach, compression-only CPR is taught to the whole community; the training would be simple and brief and, with the use of a variety of media, could even be self-directed. Those completing this training could then be encouraged to attend ‘follow-up training’ where they would be taught conventional CPR. Those with a duty of care, for example lifeguards and healthcare professionals, should continue to be trained in conventional CPR. Whether or not this strategy is adopted in the 2010 European Resuscitation Council and Resuscitation Council (UK) Guidelines will be made known later this year.
In April 2008, the US Food and Drug Administration (FDA) performed a safety review of the US-approved perflutren microsphere contrast agents (Definity and Optison) and revised a previous black box warning. The new contraindications are much less restrictive than the previous contraindications and satisfy the needs of clinical echocardiography. These changes have come after an intensive debate with the American Society of Echocardiography but also with significant European support. The correction of the contraindication for contrast agents is a good example, how inadequate decisions by the health administration can be reversed by competent and decisive actions of scientific and professional bodies like the ASE and EAE. Before April 2008, the use of contrast agents was contraindicated in patients with unstable cardiopulmonary status, including patients with unstable angina, acute myocardial infarction, respiratory failure, or recent worsening congestive heart failure. The contraindications were established temporarily after the reports of 199 serious cardiopulmonary reactions including 11 deaths during and shortly after the administration of contrast agents in post-marketing use. Ten of the events were observed with Definity over 6 years with more than 2 million applications; one fatal event was reported with Optison for 1 million applications. At least six of these cases (five Definity and one Optison) occurred 1–12 h after dosing and were attributed to serous underlying conditions. The FDA revised the benefit/risk assessment for patients with unstable conditions and acknowledged that some of the fatal events may be coincidental and not related to the contrast media. Only four fatal events with Definity occurred within 30 min after the application of contrast agents. Within this time frame, a negative role of contrast agents appears to be possible, but this is difficult to prove or exclude. Indeed, two patients had severe heart failure and one patient was ventilated because of respiratory failure, sepsis, and multiple emboli. The FDA and European Medicines Agency (EMEA) usually are concerned about a temporal relation of an adverse event and administration of the drug. They assume a possible causal relation as long as there is no proof of another explanation. But even if we assume that all four cases are related to the ultrasound contrast agent, the fatal event rate would be only 1 in 500 000 for Definity and zero for Optison. This rate is far less than the fatal event rate in exercise and Dobutamine stress echocardiography. 1 Meanwhile, several studies demonstrate the safety of ultrasound contrast agents in more than 20 000 patients including stress echocardiography and myocardial perfusion imaging using the flash-replenishment technique. 2–5 In order to provide further safety data, external, independent safety monitoring boards for the agents will be established by the manufacturers. So, it is time to be less worried about the safety of contrast echocardiography and it is good news to have ultrasound contrast agents not contraindicated in unstable conditions. However, as good physicians we still have to be prepared for a serious adverse event, e.g. hypersensitivity reactions, even if they are very rare. Like in the angiography suite, there should always be appropriate equipment and skilled personnel for resuscitation available during administration of contrast agents. According to the FDA, the risk for severe adverse reactions may be increased among patients with pulmonary hypertension or unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, serious ventricular arrhythmias, or respiratory failure, including patients receiving mechanical ventilation). In these patients, vital signs, electrocardiography, and cutaneous oxygen saturation have to be monitored during the contrast agents application and for at least 30 min after DEFINITY® and OPTISON® administration. Surprisingly, the manufacturer of LUMINITY® (name of Definity in Europe) announced a temporary cessation of the marketing and supply of LUMINITY in Europe. There may be purely commercial reasons for that decision. For clinical echocardiography, OPTISON is not yet available in Europe. Thus, the only available contrast agent is SonoVue®. However, SonoVue has not been included in the FDA review, because it is not licensed in the US. For SonoVue, the contraindications have not changed yet! SonoVue remains contraindicated in acute coronary syndromes, patients with heart failure III and IV, serious ventricular arrhythmias, and respiratory failure. In the setting of an acute myocardial infarct, urgent and repeated echocardiographic examinations may be necessary to evaluate LV function, intracardiac thrombi, and other complications of myocardial infarction. Contrast agents have been shown to be useful to improve the image quality (endocardial definition) in 2D and 3D echocardiography. 6 Therefore, it appears to be straightforward to use contrast echocardiography for better image quality in those with suboptimal image quality. Contrast echocardiography also provides important information about myocardial perfusion. Using the state-of-the-art ultrasound scanners, LV cavity opacification is usually associated with myocardial tissue opacification, if the tissue is viable. Thus, contrast echocardiography after a coronary intervention shows the amount of non-reflow and necrosis in the myocardium. The prognostic significance of myocardial contrast echocardiography has been demonstrated: The extent of microvascular damage during myocardial contrast echocardiography was superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodelling. 7 , 8 But what is the real clinical benefit of a more accurate assessment of the LV early after acute myocardial infarction? The best way to address this question is to ask what would have been happened to the patients should they not have had a contrast echocardiography study. To my knowledge, there are no controlled clinical studies at all addressing the question, how the contrast agents applications changed the management of patients in acute myocardial infarction. Until such time that adjunctive therapies following primary percutaneous coronary intervention are shown conclusively to alter the outcome in relation to myocardial perfusion, the role of myocardial contrast echocardiography in this scenario will be limited. 7 At present, it is the approved indication for LV opacification and endocardial border delineation, which makes contrast agents valuable for patient management: by reviewing case studies, Grayburn 1 recently demonstrated the catastrophic sequences of inaccurate assessment of LV function and misdiagnosis of complications such as pseudoaneurysms and thrombi. Even if there would be a moderate risk by the contrast agent, the risk/benefit still would be very favourable for using contrast agents in acute myocardial infarction! Nucifora et al.9 provide further reassurance about the safety of LUMINITY in the acute phase of myocardial infarction: in 115 consecutive patients with ST-elevation, myocardial infarction contrast echocardiography was performed with LUMINITY. Administration of echo contrast did not induce any significant change in vital signs, physical examination, and ECG. There were no serous adverse events, and minor events occurred only in five patients. Of course, this study cannot rule out all concerns about the safety of ultrasound contrast agents in unstable patients. Firstly, only patients were included after coronary intervention. These patients are probably in a lower risk group compared with patients who would get a contrast agent before the intervention. Secondly, the number of patients is not large enough for a definite answer to our safety questions. However, I agree with the authors that the results of this pilot study should encourage studies in larger cohorts. In Europe, we need ultrasound contrast agents that can be used within the first 24 h after myocardial infarction. There are conditions, where there is no real alternative to the diagnostic value of bedside LV opacification. In the debate with the FDA, the clinical and scientific echocardiographic community has demonstrated their impact on the health administration. We should use this momentum in the discussions with the EMEA in order to achieve a revision of the contraindications of SonoVue. Multi-centre randomized studies are needed to demonstrate how myocardial contrast echocardiography can change patient management. Finally, we need a registry of patients who have got a contrast agent within 24 h after myocardial infarction or other conditions of clinical instability.
Epidemiology of Acute Renal Failure The development of acute renal failure (ARF) in the hospital setting continues to be associated with poor outcomes (1–7). Over the last three decades, several experimental models have identified pathophysiologic mechanisms associated with ARF and have enhanced our understanding of the disease (8–10). It is evident that ARF can result from alterations in renal perfusion, changes in glomerular filtration, and tubular dysfunction, and that correction of these factors can ameliorate the effects of ARF (11,12). On the basis of the identification of the underlying mechanisms, several new potential interventions have been developed that have been shown to alter the course of incipient and established ARF in experimental models (13–15). Application of these findings has resulted in improvements in the prevention of ARF due to radiocontrast agents, aminoglycoside antibiotics, and rhabdomyolysis (16,17). Several other agents are now in advanced stages of development or initial phases of clinical trials (18,19). In concert, advances in dialysis have occurred with the availability of continuous renal replacement therapies in addition to intermittent hemodialysis and acute peritoneal dialysis (20–22). It is well recognized that uncomplicated ARF can usually be managed outside the intensive care unit (ICU) setting and carries a good prognosis, with mortality rates less than 5% to 10% (23,24). In contrast, ARF complicating nonrenal organ system failure in the ICU setting is associated with mortality rates of 50% to 70%, which has not changed for several decades (6,25–30). These figures are in sharp contrast to the experience with acute myocardial infarction (AMI), where in-hospital mortality rates have declined from the range of 50% to approximately 6% over the past 25 to 30 yr. Much of the credit for improved AMI outcomes has been attributed to the use of coronary care units, cardiac catheterization, aspirin, β-adrenergic antagonists, thrombolytic therapy, and, more recently, specialized percutaneous coronary interventions and glycoprotein IIb–IIIa inhibitors (31–34). In spite of improved dialytic technology, including the development and refinement of continuous renal replacement therapies for the most critically ill patients, we have seen no material change in the high mortality rates associated with ARF. Indeed, we have not demonstrated any pharmacologic or other intervention effective in the early management of ARF. Interventions that have been deemed ineffective (or potentially harmful) include the following: loop and osmotic diuretic agents (35,36), “renal dose” dopamine (37,38), atrial natriuretic peptide (39,40), insulin-like growth factor-1 (41), and endothelin receptor antagonists (42). Although ARF may develop in 5% or more of hospitalized patients, the heterogeneity of ARF and associated comorbidity make its study more difficult than AMI and other, more discrete conditions. Among the impediments to progress in ARF research is the lack of a uniform definition of ARF that might be used to compare and contrast observational studies, and to allow for rational design of clinical trials. Relatively few studies have examined the incidence of hospital-acquired ARF. The oft-cited study by Hou et al. (23) reported an ARF incidence estimate of 4.9%. Shusterman et al. (24) conducted a similar study identifying ARF in 1.9% of hospitalized patients. A follow-up study recently published by Hou and colleagues (43) showed an increase in incidence (7%), but a similar spectrum of risk factors. ARF in the ICU setting has also been characterized in the last two decades. Lian[Combining Tilde]o et al. (6) found ICU patients with ARF to have associated organ failure, sepsis, and other complications. It is well recognized that the development of ARF is associated with an increase in mortality (22,25,26,44,45). It is also known that patients with ARF as part of multiorgan failure have the highest mortality rates. In several studies, sepsis-related ARF had a significantly worse prognosis than ARF in the absence of sepsis (46,47). It is also recognized that untreated ARF may contribute to a higher incidence of new-onset sepsis (48). Definition of ARF The spectrum of definitions in published studies of ARF is striking, ranging from severe (e.g., ARF requiring dialysis) to relatively modest observable increases in serum creatinine concentration (e.g., increase in serum creatinine of 0.3 to 0.5 mg/dl above baseline). Solomon et al. (36) used the definition of an increase in serum creatinine of 0.5 mg/dl within 48 h of radiocontrast exposure in a widely cited study that showed a borderline significant difference in ARF among individuals given saline infusion versus furosemide or mannitol before radiocontrast exposure. However, neither the Solomon et al. study nor others that use this ARF definition (including the Tepel et al. (49) and Kay et al. (50) publications on N-acetyl cysteine) have shown an association between a transient change in serum creatinine and morbidity, or the likelihood of long-term recovery of renal function. Many other definitions of ARF have been applied; some are outlined in Table 1. The most liberal of definitions have been used in intervention studies aimed at ARF prevention, usually in the context of radiocontrast exposure, one of the few instances in which ARF can be anticipated.Table 1: Alternative ARF definitions from several published studiesSeveral of the definitions are extremely complex (see Lian[Combining Tilde]o et al. (6) and others) and could allow excessive subjectivity in ARF determination. These would likely be impractical for prospective, multicenter investigations. Moreover, none of the definitions used to date take into account the modifying effects of age, gender, and race on creatinine generation (and thereby serum creatinine concentration in ARF). It is noteworthy that creatinine generation is typically higher among individuals who are younger, male, and African American (51). Therefore, at the same decrement in GFR, persons with different demographic characteristics may be more likely to “qualify” with ARF diagnoses, particularly those definitions that require a minimum peak creatinine (e.g., 50% increase, to at least 2.0 mg/dl). By use of this definition, we found a twofold increase in the incidence of amphotericin B–associated ARF among men (52). Whether male gender is a true risk for ARF or simply a risk for being diagnosed with ARF is unclear. Regardless, the association of ARF with male gender highlights one of the limitations of the use of a definition of ARF that is creatinine based and not age, gender, and race adjusted. Changes in serum creatinine are not specific and do not discriminate the nature and type of renal insult (e.g., ischemic, nephrotoxic) or the site and extent of glomerular or tubular injury, and levels are relatively insensitive to small changes in GFR (53). Moreover, changes in serum creatinine may lag behind changes (decline or recovery) in GFR by several days. Finally, because serum creatinine is influenced by one of the potential interventions for ARF (e.g., creatinine is removed by dialysis), its specificity for renal recovery is even more problematic. Empiric Evidence of the Focus on Creatinine and Urine Output We recently completed an analysis focusing on correlates of timing of nephrology consultation for ARF in the ICU (54). To avoid the complexities of comparing individuals whose ARF developed during a complicated ICU stay, we restricted our analysis to those patients with evidence of ARF at ICU admission and excluded individuals designated as “do not resuscitate.” We considered a wide array of demographic, clinical, laboratory, and physiologic variables (including pulmonary artery catheter data in some patients). The serum creatinine concentration and urine output (either as a continuous variable or the dichotomous “oliguria”) (<400 ml/d) were associated with the timing of consultation. There was no relation between the timing of consultation and hospital service, medical history, physiologic parameters, other laboratory studies, or the presence or absence of organ system failure, despite the fact that many of these factors have been shown to predict mortality in ARF in other studies. In other words, empiric evidence demonstrates that the definitions used in published reports are operative in practice, with little attention to risk profiles or associated nonrenal organ system failure. Analogous Definitions in Other Conditions Conceptual Framework for Disease Definitions. Disease definitions may be used to ascertain the presence of a disease in an individual or a population, guide the nature and timing of diagnostic and therapeutic interventions, and, in individual patients, help determine prognosis. The presence of any disease is inferred from a combination of clinical symptoms and signs, and alterations in biologic markers that can be reproducibly measured. Measures defining a disease should be responsive to change, track the natural history of the disease, and provide an assessment of the severity of injury. Consequences of the untreated disease and its response to specific interventions are additional criteria that might be considered when evaluating the choice of variables to define and classify a disease. Most disease definitions rely on the presence of specific markers that are measurably altered in response to an injury, and the sensitivity and specificity of any definition depends on the criteria used. These “response variables” may appear at varying time points in the disease and help define the course of the disease. Ideally, the magnitude and pattern of change of the response variable correlate with disease outcomes. For instance, AMI can be diagnosed with the combination of chest pain and elevated cardiac troponins or creatine phosphokinase. Gradations in the severity of signs (including electrocardiography) and symptoms and the levels of troponin and creatine phosphokinase profile allow further classification of the disease spectrum (e.g., angina, unstable angina, demand ischemia, silent ischemia, myocardial infarction). A key feature for AMI is that the clinical presentation is directly related to an underlying event (i.e., coronary thrombosis). Moreover, the markers are sensitive, specific, and correlate with the severity of injury, even in the absence of typical clinical features. In contrast, sepsis is heterogeneous in its presentation and affects multiple organs, so no single marker can be used to define the presence or absence of disease. Recognizing this limitation, a functional definition for sepsis has been based on events in the natural history of the sepsis syndrome: systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock (55). In the absence of specific markers, effective definitions for a disease rely on multiple parameters, some of which represent the specific response to the disease, whereas others reflect nonspecific consequences of the disease. Disease severity is graded on the basis of the presence of specific parameters. For instance, the transition from sepsis to severe sepsis requires the presence of sepsis-related organ dysfunction. These graded definitions are more readily applied to classify populations, although they have also been used to guide interventions in individual patients and research subjects (56,57). The multidimensional definition and classification construct has been applied to several diseases where a single specific diagnostic criterion is not available or is otherwise unsuitable. For example, the Ranson criteria enable early classification of severe acute pancreatitis (58). These criteria rely on the presence of three or more of the 11 criteria evident within 48 h of admission. Criteria include age and a series of laboratory parameters that reflect consequences of disordered pancreatic function (i.e., hyperglycemia in absence of diabetes, hypocalcemia, azotemia, anemia, hypoalbuminemia, leukocytosis, elevations of the hepatic enzymes lactate dehydrogenase and aspartate aminotransferase) and physiologic variables (i.e., metabolic acidosis, hypoxia) to grade the response. Interestingly, serum amylase and lipase, enzymes directly related to pancreatic injury (and analogous to creatinine in ARF), are not included in the scoring system. The number of positive criteria are associated with mortality ranging from <5% for zero to two criteria to 100% for seven to eight criteria (58). Similarly, the Child-Pugh classification is a means of assessing the severity of hepatic cirrhosis (59). It assigns scores for each of three laboratory parameters (bilirubin, albumin, and prothrombin time) and two clinical criteria representing the consequences of liver failure (encephalopathy and ascites). The individual scores are summed and then grouped as <7 (A), 7 to 9 (B), and >9 (C). A Child-Pugh “C” classification forecasts survival of less than 12 mo. Cancer staging similarly uses the tumor node metastasis grading system to classify malignant disease. to of these classification is the lack of any single criterion to the disease and on the consequences of the disease and on other factors the course of the disease for We that ARF be in a similar in of of and organ ARF has more in with sepsis or pancreatitis than with of in For any the to the disease is and where and when the in the natural history of the disease. The whereas the could time points for variables should allow of the disease and provide a to determine the time course of the disease. Renal functional alterations many (e.g., and markers specific for the site and pattern of injury are Several new are to study ARF and are to be for studies et al. and et al. demonstrated that may be an early marker for renal injury specific for the renal et al. and et al. have new markers for disease, including a new that is found in urine injury. Other studies have a spectrum of markers for renal injury but none have been in a number of patients advances in likely provide new for assessment Several for changes in GFR each has markers may be the most and for assessment of changes in GFR and these markers are being to be a marker for changes in GFR but requires in the ICU and other that use contrast agents are being in experimental models of ARF and could provide on the and extent of and the presence of renal It is evident that of the site and extent of injury would a of the underlying severity of renal dysfunction, could and could help guide specific therapeutic of for of from Other to ARF It is evident that definitions of ARF that rely on serum creatinine and urine output do not the spectrum of ARF in clinical in they do not the clinical to for therapeutic Indeed, in the timing of to renal injury has to heterogeneity in intervention studies in ARF and may be for the lack of It is also recognized that of care (including the timing of of of and the use of likely the course and outcomes ARF. diagnostic and classification are to allow for advances in ARF research and clinical We on two but related we to the of and specific markers to the site and severity of renal injury and to track functional change over we to more define the course of ARF in a of and factors that the renal response to injury and outcomes from ARF. this increase diagnostic specificity and allow for more of For instance, the of radiocontrast and underlying renal function determine the of creatinine and incidence of In most elevations in serum creatinine are seen within 48 h radiocontrast exposure, so that the of a or early therapeutic intervention can be In contrast, when the nature and timing of insult are less well characterized (e.g., of in a with in serum creatinine and urine output are less of the pattern of with the response could help to guide the timing of specific interventions, and compare two or more interventions in clinical trials. We the heterogeneity of ARF and the absence of specific markers for renal injury, an effective diagnostic and classification should parameters other than the renal response to injury. organ system also affects the ARF For instance, serum creatinine levels may the severity of renal in hepatic failure with elevated levels and the for may further GFR In other and response factors have been in the definition and classification of disease (see and the Failure classification for sepsis Criteria To the to we should into several factors that to injury, the nature and timing of the the response of the to the and the consequences of the ARF We that a new definition for ARF should from each of these would to a more definition for the and would the assessment of interventions in this Table a definition for ARF that variables from each of the is grade an risk of classification of acute renal a for staging ARF that is based on the criteria within each We based grade on the risk of ARF from studies. We grade the nature and timing of the insult on the basis of of the specific insult and the time from the insult to the of We grade the response variables the criteria by the Acute We define nonrenal organ by organ failure scores Gradations in the and reflect levels of risk for an whereas those in the and reflect an severity of We that at each of individual patients would be graded within each On the basis of the in the patients would be into the of ARF and would stages during the course of the disease and in ARF et al. demonstrated three of ARF On the basis of these is widely that clinical ARF has three and The of each on the basis of the presence of disease and the nature and type of et al. and have recently a classification for ARF that phases for this and recovery in response has also been established in experimental ARF the response can be graded on the basis of for the and this is being as a therapeutic (e.g., may the response to the in renal function in ARF. For any given the pattern of ARF on or to injury and the nature and severity or of injury. The renal response is likely to be on these two factors and may in determine nonrenal organ dysfunction. the course is nonrenal organ further the renal of acute renal failure aimed at the and established ARF. from with individuals on the basis of may be to more define the time course of disease and time points for intervention is similar in to sepsis syndrome, where of have been for therapeutic The multicenter of the to be within h of the organ system failure the nature and timing of the insult in ARF were one could a specific therapeutic to ameliorate the injury and the within a known therapeutic the renal response can be can be and on the presence or absence of the underlying nonrenal organ dysfunction, specific interventions, as dialysis could be the These The definitions could be used to the presence of disease by the response variable graded for the for ARF and of the increase in serum creatinine of mg/dl with a grade of and an insult grade of is more likely to represent significant injury (and to be by more than the and insult were and an grade of a similar increase in serum creatinine might require dialytic A of versus course could be in diagnostic and classification in aimed at and The multidimensional can be with A with creatinine and no grade seen h a contrast grade with a urine output of and a follow-up serum creatinine of mg/dl grade with no nonrenal grade would be A 48 h a change in serum creatinine to mg/dl and a in urine output to evidence of On the basis of these two time is evident that this has a in renal representing an from the injury or injury. the for change in renal function based on the timing of the contrast would have been a to creatinine within the from the response would an of the initial injury A therapeutic intervention with a that could ameliorate injury or could then be for this In a example, a who coronary artery and replacement is The is with a creatinine of 2.0 mg/dl and a history of serum creatinine from to mg/dl with urine output ml/d) on an There was no in during or and has not any There was no evidence for or on is with on and requires two to a of is 7 mg/dl and serum On the basis of of is to have of to and diagnostic would be considered to be acute on renal failure. Many and care (and would not with dialysis or in this because the is urine and has no By use of the classification this would be the presence of and in renal a could be to dialytic although is no evidence on which to make this data on outcomes associated with patients in clinical would be more to than data on patients as acute on renal a Framework for and Although a more diagnostic and classification system would be to could also be used to of For example, in a comparing dialysis or one could that dialysis should for subjects with of or with of or A more and classification could new and markers from and investigations. For instance, were that predict the renal these could be included as new criteria in the Similarly, new injury markers could be included in the insult and provide more specific on the nature and severity of disease. Other markers of renal function (e.g., or of organ (e.g., could be included to other and The definitions are based on in other as acute liver disease, and The criteria are and to The could be applied to a or for individual The could also and However, are several limitations to (and our we that the are but the and of each to the definition and classification has not been We do not these are the or are others that to be We do not have markers for defining the consequences of renal dysfunction. We to define the nature and severity of underlying disease with the markers at We that the established for response variables are related to outcomes and are We the of the variables to determine additional definitions would be It is evident that studies to the of the definition in several However, we a new diagnostic and classification to help management and into this ARF continues to be a a significant of time for and to the that ARF to outcomes in the critically little progress has been in this of the key impediments to progress is the lack of a uniform definition for this disease. definitions that rely on changes in serum creatinine and urine output are neither nor We a new classification for ARF that from other in an to data and, we studies to the of construct and to the and of within each we (or a is not a On the we more in ARF effective interventions, and, mortality rates in the single study was by a from the for and by The to in Acute Renal Disease study the of of and