Neuromuscular blockade in patients with ARDS: a rapid practice guideline.

The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) is to formulate an evidence-based guidance for the use of neuromuscular blocking agents (NMBA) in adults with acute respiratory distress syndrome (ARDS). The panel comprised 20 international clinical experts from 12 countries, and 2 patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines and followed a strict conflict of interest policy. We convened panelists through teleconferences and web-based discussions. Guideline experts from the guidelines in intensive care, development, and evaluation Group provided methodological support. Two content experts provided input and shared their expertise with the panel but did not participate in drafting the final recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence and grade recommendations and suggestions. We used the evidence to decision framework to generate recommendations. The panel provided input on guideline implementation and monitoring, and suggested future research priorities. The overall certainty in the evidence was low. The ICM-RPG panel issued one recommendation and two suggestions regarding the use of NMBAs in adults with ARDS. Current evidence does not support the early routine use of an NMBA infusion in adults with ARDS of any severity. It favours avoiding a continuous infusion of NMBA for patients who are ventilated using a lighter sedation strategy. However, for patients who require deep sedation to facilitate lung protective ventilation or prone positioning, and require neuromuscular blockade, an infusion of an NMBA for 48 h is a reasonable option.

Point-of-care sensors for the management of sepsis.

Point-of-care sensors that enable the fast collection of information relevant to a patient's health state can facilitate improved health access, reduce healthcare costs and improve the quality of healthcare delivery. In the diagnosis of sepsis - defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, and the leading cause of in-patient death and of hospital readmission in the United States - predicting which infections will lead to life-threatening organ dysfunction and developing specific anti-sepsis treatments remain challenging because of the significant heterogeneity of the host response. Yet the use of point-of-care devices could reduce the time from the onset of a patient's infection to the administration of appropriate therapeutics. In this Perspective, we describe the current state of point-of-care sensors for the diagnosis and monitoring of sepsis, and outline opportunities in the use of these devices to dramatically improve patient care.

A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators.

PURPOSE: To determine whether early goal-directed therapy (EGDT) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department (ED) with septic shock. METHODS: Using a search strategy of PubMed, EmBase and CENTRAL, we selected all relevant randomised clinical trials published from January 2000 to January 2015. We translated non-English papers and contacted authors as necessary. Our primary analysis generated a pooled odds ratio (OR) from a fixed-effect model. Sensitivity analyses explored the effect of including non-ED studies, adjusting for study quality, and conducting a random-effects model. Secondary outcomes included organ support and hospital and ICU length of stay. RESULTS: From 2395 initially eligible abstracts, five randomised clinical trials (n = 4735 patients) met all criteria and generally scored high for quality except for lack of blinding. There was no effect on the primary mortality outcome (EGDT: 23.2% [495/2134] versus control: 22.4% [582/2601]; pooled OR 1.01 [95% CI 0.88-1.16], P = 0.9, with heterogeneity [I(2) = 57%; P = 0.055]). The pooled estimate of 90-day mortality from the three recent multicentre studies (n = 4063) also showed no difference [pooled OR 0.99 (95% CI 0.86-1.15), P = 0.93] with no heterogeneity (I(2) = 0.0%; P = 0.97). EGDT increased vasopressor use (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and ICU admission [OR 2.19 (95% CI 1.82-2.65); P < 0.001]. Including six non-ED randomised trials increased heterogeneity (I(2) = 71%; P < 0.001) but did not change overall results [pooled OR 0.94 (95% CI 0.82 to 1.07); P = 0.33]. CONCLUSION: EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU resources.

A review of therapeutic attempts to recruit the microcirculation in patients with sepsis.

Microcirculatory dysfunction is a pivotal element of the pathogenesis of severe sepsis and septic shock. Technological development, including sidestream darkfield videomicroscopy, now allows for bedside assessment of the microcirculation. A number of clinical studies have established the importance of the microcirculation in sepsis. The objective of this review is to discuss human trials that have assessed interventions aimed at improving microcirculatory flow in patients with sepsis.

Acute care practices relevant to quality end-of-life care: a survey of Pennsylvania hospitals.

BACKGROUND: Improving end-of-life care in the hospital is a national priority. PURPOSE: To explore the prevalence and reasons for implementation of hospital-wide and intensive care unit (ICU) practices relevant to quality care in key end-of-life care domains and to discern major structural determinants of practice implementation. DESIGN: Cross-sectional mixed-mode survey of chief nursing officers of Pennsylvania acute care hospitals. RESULTS: The response rate was 74% (129 of 174). The prevalence of hospital and ICU practices ranged from 95% for a hospital-wide formal code policy to 6% for regularly scheduled family meetings with an attending physician in the ICU. Most practices had less than 50% implementation; most were implemented primarily for quality improvement or to keep up with the standard of care. In a multivariable model including hospital structural characteristics, only hospital size independently predicted the presence of one or more hospital initiatives (ethics consult service, OR 6.13, adjusted p = 0.02; private conference room in the ICU for family meetings, OR 4.54, adjusted p<0.001). CONCLUSIONS: There is low penetration of hospital practices relevant to quality end-of-life care in Pennsylvania acute care hospitals. Our results may serve to inform the development of future benchmark goals. It is critical to establish a strong evidence base for the practices most associated with improved end-of-life care outcomes and to develop quality measures for end-of-life care to complement existing hospital quality measures that primarily focus on life extension.

Sociodemographic differences in early access to liver transplantation services.

The question of whether health care inequities occur before patients with end-stage liver disease (ESLD) are waitlisted for transplantation has not previously been assessed. To determine the impact of gender, race and insurance on access to transplantation, we linked Pennsylvania sources of data regarding adult patients discharged from nongovernmental hospitals from 1994 to 2001. We followed the patients through 2003 and linked information to records from five centers responsible for 95% of liver transplants in Pennsylvania during this period. Using multinomial logistic regressions, we estimated probabilities that patients would undergo transplant evaluation, transplant waitlisting and transplantation itself. Of the 144,507 patients in the study, 4361 (3.0%) underwent transplant evaluation. Of those evaluated, 3071 (70.4%) were waitlisted. Of those waitlisted, 1537 (50.0%) received a transplant. Overall, 57,020 (39.5%) died during the study period. Patients were less likely to undergo evaluation, waitlisting and transplantation if they were women, black and lacked commercial insurance (p < 0.001 each). Differences were more pronounced for early stages (evaluation and listing) than for the transplantation stage (in which national oversight and review occur). For early management and treatment decisions of patients with ESLD to be better understood, more comprehensive data concerning referral and listing practices are needed.

Cost effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom.

Drotrecogin alfa (activated) is licensed in Europe for the treatment of severe sepsis in patients with multiple organ failure. We constructed a model to assess the cost effectiveness of drotrecogin alfa (activated) from the perspective of the UK National Health Service when used in adult intensive care units. Patient outcomes from a 28-day international clinical trial (PROWESS) and a subsequent follow-up study (EVBI) were supplemented with UK data. Cost effectiveness was assessed as incremental cost per life year and per quality adjusted life year saved compared to placebo alongside best usual care. Applying the 28-day mortality outcomes of the PROWESS study, the model produced a cost per life year saved of 4608 UK pounds and cost per quality adjusted life year saved of 6679 UK pounds. Equivalent results using actual hospital outcomes were 7625 UK pounds per life year and 11,051 UK pounds per quality adjusted life year. Drotrecogin alfa (activated) appears cost effective in treating severe sepsis in UK intensive care units.

Incidence and definition of sepsis and associated organ dysfunction.

AIMS: To discuss the incidence, outcome and predisposing factors to systemic inflammatory response syndrome (SIRS), sepsis, and multiple organ failure. METHODS: A qualitative review of the literature. RESULTS: Case definitions of sepsis and severe sepsis, though clarified recently, are still arbitrary. It seems, however, that SIRS is not useful in identifying severe sepsis while organ failure has become a cornerstone for this definition. Incidence of severe sepsis appears to be approximately 10% of all ICU admissions, totaling nearly one million cases annually in the U.S. alone, and rising. Mortality associated with these events is still high, especially among ICU patients. Recent studies have been demonstrating an association between a variety of genetic polymorphisms and progression to and dying from sepsis. CONCLUSION: Recently there has been an increasing amount of information enabling characterization of the epidemiology of sepsis, which may help to direct appropriate care in the coming years.

Genetic variation and risk of sepsis.

Sepsis is the leading cause of death in non-coronary intensive care unit patients. Sepsis is caused by the immune response to infection and is manifest by pain, fever and edema as the result of the activation of coagulation and inflammatory responses. In severe cases, sepsis leads to organ dysfunction and failure. Sepsis affects more than 750,000 people each year in the US alone, with a mortality rate of over 35 percent making it one of the leading causes of death in developed countries. In addition many patients that die of other diseases have their hospital courses complicated by sepsis. Most patients with infection do not develop severe sepsis and septic shock and yet those that do have a significantly increased risk of death. Genetic and environmental variables may influence why one patient with infection gets sicker than the next. For example, people may be programmed to respond to infection in different ways; some with aggressive immune responses that may be able to wipe out infection before it manifests itself in physical symptoms, while others may have less aggressive immune systems that allow them to get sick more often. The discovery of various common genetic polymorphisms in genes that control the inflammatory response (e.g. tumor necrosis factor) has lent credence to this hypothesis. Yet discovery of the actual relationship between risks of infection / severe sepsis and individual genotypes will require larger, more rigorously designed studies.

Epidemiology of neonatal respiratory failure in the United States: projections from California and New York.

We wanted to determine the incidence, cost, outcome, and patterns of care for neonates requiring mechanical ventilation (MV) in the United States. Using 1994 state hospital discharge data from California and New York, we conducted an observational study of all neonatal hospitalizations (n = 16,405) with MV, comparing outcomes at centers of different technological capability, and generating national projections using census and natality reports. The MV rate was 18 per 1,000 live births. Although the incidence was much higher in lower birth weight (BW) babies, one-third had normal BW. The incidence was higher in boys (20 versus 15.6 per 1,000) and in blacks (29 per 1,000). Hospital mortality was 11.1%, higher in minority groups, and associated with low BW, congenital anomalies, and major hemorrhage. Mean hospital length of stay and costs were 31.1 d and $51,700. Half of all deaths occurred at lower level centers. There are 80,000 cases per year in the United States with 8,500 deaths and total hospital costs of $4.4 billion. We conclude neonatal respiratory failure is common, expensive, and frequently fatal. There are a surprisingly large number of normal BW cases and there are large racial differences.

Epidemiology of sepsis: an update.

OBJECTIVE: We review the case definition, occurrence, and outcome of sepsis. We discuss whether the epidemiology of sepsis has changed over time and discuss issues important to our understanding of sepsis. DATA SOURCES: Literature review. DATA SUMMARY: Our understanding of the epidemiology of sepsis is hampered by the lack of a reliable case definition. Inconsistent application of sepsis definition criteria contributes to confusion and variability in the literature. Variability in the time course of sepsis also introduces difficulty. The Centers for Disease Control estimated an incidence of 73.6 per 100,000 population in 1979, rising to 175.9 per 100,000 in 1989. However, this study was of septicemia, not severe sepsis. There are several hospital-based studies of the occurrence of severe sepsis, defined using the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria. These studies reported variable hospital and intensive care unit (ICU) occurrence rates, ranging from 2% to 11% of all hospital or ICU admissions. Most of these data are from academic, tertiary care centers, which limits generalizability. More population-based studies are required to better delineate the incidence and risk factors of sepsis in the general population. Hospital mortality from sepsis has ranged from 25% to 80% over the last few decades. Although mortality may be lower in recent years, sepsis is clearly still a very serious condition. Achieving a better understanding of whether the mortality rate for sepsis is falling, however, is confounded by the lack of a uniform definition. Risk factors for adverse outcome include the degree of physiologic derangement, organ dysfunction, underlying illness, site of infection, and microbiological etiology. We do not know, however, the factors that predict response to new therapies. This dilemma has led researchers to explore whether markers of the inflammatory cascade might be more specific for sepsis, more accurate for risk prediction, or more useful for predicting response to therapy. However, there as yet is no equivalent of the CPK-MB for acute myocardial infarction. Whether we will find such a marker as we develop a greater understanding of the genetic control of the inflammatory cascade is uncertain but promising. One might assume intuitively that the epidemiology of sepsis is changing. For example, the number of patients being treated in ICUs has increased over time, the technologies used in the ICU have changed, and the choice and the use of antibiotics have changed. Predisposing factors, such as chemotherapeutic regimens, have also changed, and there have been marked changes in antibiotic resistance. Furthermore, there have been wide changes in the microbiological etiologies of diseases such as pneumonia and acute exacerbations of chronic bronchitis. However, lacking good case definitions and true incidence studies, we can only make inferences about whether the epidemiology of sepsis is truly changing. CONCLUSION: Many studies have documented many aspects of the epidemiology of sepsis. However, the composite picture they provide, although rich in many aspects, remains incomplete and emphasizes the heterogeneity of the condition. Unfortunately, few population-based prospective cohort studies exist that allow us to accurately delineate the risk factors for sepsis, its course, and its outcome. To place new information, such as the role of genetic predisposition, in the correct context, it is essential that such studies be conducted.

Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.

OBJECTIVE: To determine the incidence, cost, and outcome of severe sepsis in the United States. DESIGN: Observational cohort study. SETTING: All nonfederal hospitals (n = 847) in seven U.S. states. PATIENTS: All patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We linked all 1995 state hospital discharge records (n = 6,621,559) from seven large states with population and hospital data from the U.S. Census, the Centers for Disease Control, the Health Care Financing Administration, and the American Hospital Association. We defined severe sepsis as documented infection and acute organ dysfunction using criteria based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We validated these criteria against prospective clinical and physiologic criteria in a subset of five hospitals. We generated national age- and gender-adjusted estimates of incidence, cost, and outcome. We identified 192,980 cases, yielding national estimates of 751,000 cases (3.0 cases per 1,000 population and 2.26 cases per 100 hospital discharges), of whom 383,000 (51.1%) received intensive care and an additional 130,000 (17.3%) were ventilated in an intermediate care unit or cared for in a coronary care unit. Incidence increased >100-fold with age (0.2/1,000 in children to 26.2/1,000 in those >85 yrs old). Mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 yrs old. Women had lower age-specific incidence and mortality, but the difference in mortality was explained by differences in underlying disease and the site of infection. The average costs per case were $22,100, with annual total costs of $16.7 billion nationally. Costs were higher in infants, nonsurvivors, intensive care unit patients, surgical patients, and patients with more organ failure. The incidence was projected to increase by 1.5% per annum. CONCLUSIONS: Severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction. It is especially common in the elderly and is likely to increase substantially as the U.S. population ages.

Quality-adjusted survival in the first year after the acute respiratory distress syndrome.

There is little information on long-term outcome after acute respiratory distress syndrome (ARDS). We measured quality-adjusted survival in the first year after ARDS in a prospective cohort (n = 200). All patients met traditional criteria for ARDS. Patients with sepsis and acute nonpulmonary organ dysfunction at presentation were excluded. The cohort was healthy before onset of ARDS as evidenced by high functional status (mean Karnofsky Performance Status index: 82.2/100 where >/= 80 = able to perform normal activities independently) and minimal comorbid illness (mean Charlson-Deyo comorbidity score: 0.32/17 where 0 = absence of chronic illness). We determined quality-adjusted life-years (QALYs) using the Quality of Well-being (QWB) scale (0 to 1 scale where 1 = optimal well-being), measured at 6 and 12 mo. Survival was 69.5 +/- 5.0% at 1 month, fell to 55.7 +/- 3.7% at 6 mo, and did not change at 12 mo, yielding a survival of 59 life-years in the first year per 100 patients with ARDS. QWB was low at 6 and 12 mo (0.59 +/- 0.015 and 0.60 +/- 0.015), yielding a quality-adjusted survival of 36 QALYs per 100 patients (sensitivity range: 21 to 46 QALYs). We conclude that ARDS developing in previously healthy patients is associated with poor quality-adjusted survival. These data are important for cost-effectiveness analyses and long-term care.

Economics of end-of-life care in the intensive care unit.

End-of life care is in need of improvement, yet little is known about the effectiveness or cost of various end-of-life therapies. Economic analyses are used to help make decisions between two or more therapies when resources are constrained. In this chapter, we review the various types of economic analyses, the costs of dying, and how healthcare reform has impacted these costs. Finally, we discuss the unique issues associated with cost-effectiveness studies of palliative therapy, with emphasis on the problem of calculating a cost-effectiveness ratio when there is no good measurement for valuing the quality of death. It is likely that methods for conducting a cost-effectiveness analyses for end-of-life care will need to evolve or alternative strategies such as cost-benefit analysis or distributive justice will be needed to inform resource allocation decisions. As the national debate about healthcare costs, access, and quality continues, we will increasingly turn to economic analyses to help make resource allocation decisions. Cost-effectiveness analysis will continue to be the most popular form of economic analysis because it combines the results (effectiveness of treatment) with the costs of achieving the results. We must be aware of the limitations of cost-effectiveness analyses and the need for value judgments when using cost-effectiveness analyses to inform healthcare decisions.

Predicting hospital mortality for patients in the intensive care unit: a comparison of artificial neural networks with logistic regression models.

OBJECTIVE: Logistic regression (LR), commonly used for hospital mortality prediction, has limitations. Artificial neural networks (ANNs) have been proposed as an alternative. We compared the performance of these approaches by using stepwise reductions in sample size. DESIGN: Prospective cohort study. SETTING: Seven intensive care units (ICU) at one tertiary care center. PATIENTS: Patients were 1,647 ICU admissions for whom first-day Acute Physiology and Chronic Health Evaluation III variables were collected. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We constructed LR and ANN models on a random set of 1,200 admissions (development set) and used the remaining 447 as the validation set. We repeated model construction on progressively smaller development sets (800, 400, and 200 admissions) and retested on the original validation set (n = 447). For each development set, we constructed models from two LR and two ANN architectures, organizing the independent variables differently. With the 1,200-admission development set, all models had good fit and discrimination on the validation set, where fit was assessed by the Hosmer-Lemeshow C statistic (range, 10.6-15.3; p > or = .05) and standardized mortality ratio (SMR) (range, 0.93 [95% confidence interval, 0.79-1.15] to 1.09 [95% confidence interval, 0.89-1.38]), and discrimination was assessed by the area under the receiver operating characteristic curve (range, 0.80-0.84). As development set sample size decreased, model performance on the validation set deteriorated rapidly, although the ANNs retained marginally better fit at 800 (best C statistic was 26.3 [p = .0009] and 13.1 [p = .11] for the LR and ANN models). Below 800, fit was poor with both approaches, with high C statistics (ranging from 22.8 [p <.004] to 633 [p <.0001]) and highly biased SMRs (seven of the eight models below 800 had SMRs of <0.85, with an upper confidence interval of <1). Discrimination ranged from 0.74 to 0.84 below 800. CONCLUSIONS: When sample size is adequate, LR and ANN models have similar performance. However, development sets of < or = 800 were generally inadequate. This is concerning, given typical sample sizes used for individual ICU mortality prediction.

Caring for the critically ill patient. Current and projected workforce requirements for care of the critically ill and patients with pulmonary disease: can we meet the requirements of an aging population?

CONTEXT: Two important areas of medicine, care of the critically ill and management of pulmonary disease, are likely to be influenced by the aging of the US population. OBJECTIVE: To estimate current and future requirements for adult critical care and pulmonary medicine physicians in the United States. DESIGN, SETTING, AND PARTICIPANTS: Analysis of existing population, patient, and hospital data sets and prospective, nationally representative surveys of intensive care unit (ICU) directors (n = 393) and critical care specialists (intensivists) and pulmonary specialists (pulmonologists) (n = 421), conducted from 1996 to 1999. MAIN OUTCOME MEASURES: Influence of patient, physician, regional, hospital, and payer characteristics on current practice patterns; forecasted future supply of and demand for specialist care through 2030. Separate models for critical care and pulmonary disease. Base-case projections with sensitivity analyses to estimate the impact of future changes in training and retirement, disease prevalence and management, and health care reform initiatives. RESULTS: In 1997, intensivists provided care to 36.8% of all ICU patients. Care in the ICU was provided more commonly by intensivists in regions with high managed care penetration. The current ratio of supply to demand is forecast to remain in rough equilibrium until 2007. Subsequently, demand will grow rapidly while supply will remain near constant, yielding a shortfall of specialist hours equal to 22% of demand by 2020 and 35% by 2030, primarily because of the aging of the US population. Sensitivity analyses suggest that the spread of current health care reform initiatives will either have no effect or worsen this shortfall. A shortfall of pulmonologist time will also occur before 2007 and increase to 35% by 2020 and 46% by 2030. CONCLUSIONS: We forecast that the proportion of care provided by intensivists and pulmonologists in the United States will decrease below current standards in less than 10 years. While current health care reform initiatives and modification of existing practice patterns may temporarily forestall this problem, most anticipated effects are minor in comparison with the growing disease burden created by the aging US population. JAMA. 2000;284:2762-2770.