Derek C. Angus

SIR WILLIAM OSLER pointed out more than 100 years ago that pneumonia was a frequent, nonpainful, lethal event in elderly patients.¹ With advances in care, pneumonia no longer seems to portend such a poor prognosis. Many patients with community-acquired pneumonia (CAP) do not require hospitalization, and most who are admitted to the hospital survive to discharge. Nevertheless, CAP remains common and is still one of the leading causes of hospital admission and death throughout the world, including the United Kingdom² and United States.³ Key risk factors seem to be advancing age and underlying disease.^4-16

High quality research evidence is now available to guide and shape the practice of critical care. As the generation of such evidence increases, the challenge facing critical care medicine will be translation of this evidence into measurable improvement in patient outcome. Significant barriers to this process of translation exist that will require substantial effort and resources to overcome. We briefly review the nature of translational barriers to incorporation of research evidence into clinical practice and the conventional approach to surmounting these barriers, and provide examples of barriers and potential solutions to emerging therapies in critical care.

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.

To determine the incidence, cost, and outcome of severe sepsis in the United States. Observational cohort study. All nonfederal hospitals (n = 847) in seven U.S. states. All patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification. None. 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. 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.

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.

Meeting the health care needs of the American people in the coming decades requires accurate forecasts of likely requirements, not only in terms of dollars, but also in terms of staffing and facilities. Unfortunately, such forecasts are difficult because many factors influence health care delivery. One factor likely to increase demand for services is the aging of the US population. During the next 30 years, Medicare enrollment will grow by more than 50%.¹ Because the elderly consume considerable health care resources, demand for medical services is expected to outpace other indices of the economy.²

While knowledge and understanding of gram-negative sepsis have grown over the last 20 years, the ability to treat it successfully has not changed substantially.¹ Despite the introduction of more potent antibiotics and more sophisticated life-support technology, an estimated 200,000 Americans develop gram-negative sepsis each year with reported mortality rates of 30% to 65%.^2-5 The prime initiator of gram-negative sepsis is endotoxin, the lipopolysaccharide component of the bacterial outer membrane.^6-8 Endotoxin triggers the production of proinflammatory monokines (eg, tumor necrosis factor) which in turn stimulate a variety of proinflammatory and anti-inflammatory mediator cascades that result in the systemic signs and organ dysfunction that characterize clinical sepsis.⁹ Accordingly, it has been hypothesized that agents that bind endotoxin may mitigate the subsequent cascade, resulting in a decrease in the clinical manifestations of sepsis and improvement in outcome.^1,10,11

To evaluate the relationship between the postoperative Acute Physiology and Chronic Health Evaluation (APACHE) II score and mortality at hospital discharge and at 1 yr in liver transplant recipients. Adult orthotopic liver transplant (OLTX) recipients (n = 599) admitted to the intensive care unit postoperatively at a university hospital. The cohort was split randomly into development and validation sets. Three models were compared for each end point: a) the original APACHE II slope with the original APACHE II postgastrointestinal surgery intercept; b) the original APACHE II slope with an OLTX-specific intercept generated from the development set; and c) and OLTX-specific slope and intercept generated from the development set. Goodness-of-fit and calibration were assessed by the Hosmer-Lemeshow C statistic (where p > .05 suggests good fit) and standardized mortality ratios. Discrimination was assessed by receiver operator characteristic area under the curve analysis. Hospital and 1-yr mortality rates were 9.9% and 15.9%, respectively. The APACHE II score was strongly associated with mortality (chi-square, p < .0001), but when used with the original equation, it significantly overestimated hospital mortality (standardized mortality ratio, 0.73 [confidence interval, 0.58-0.99]). Using the OLTX-specific approaches, goodness-of-fit for both hospital and 1-yr mortality was good ( p = .2−.57) but discrimination was only moderate (receiver operator characteristic area under the curve, 0.675-0.723). APACHE II is a good predictor of short- and long-term mortality after liver transplantation, especially when using OLTX-specific coefficients. Because fit and calibration were better than discrimination, APACHE II will be most useful in the prediction of risk for groups of patients (e.g., in clinical trials or institutional comparisons) rather than for individuals. This study raises the possibility that APACHE II may be useful for long-term mortality prediction in other critically ill populations. The overestimation of mortality using the original equation suggests that orthotopic liver transplantation, by reversing the underlying pathophysiology, may modify risk.