Sepsis is the most common cause of death in infants and children in the world. According to the World Health Organization, the “big four” killers of children are severe pneumonia (1.9 million deaths per year), severe diarrhea (1.6 million deaths per year), severe malaria (1.1 million deaths per year), and severe measles (550,000 deaths per year) (1). (The term severe is used by the World Health Organization when children develop acidosis or hypotension or both.) Antibiotics improve outcomes in children in all four disease categories, suggesting that a common pathway of death is either secondary bacterial infection or that antibiotics have microbicidal activity against the inciting organism (e.g., malaria, enteric fevers).
Severe Sepsis in the United States
In the United States, there were >42,000 cases of severe sepsis in children aged ≤19 yrs in 1995 (2). Infants are at highest risk, with a rate ten times higher than that of older children. Low- and very low-birth-weight (VLBW) babies make up nearly one fourth of the pediatric severe sepsis population. Boys of <10 yrs of age had significantly higher rates of severe sepsis than girls, particularly among infants.
Age is a major influence on the epidemiology of severe sepsis in the United States. Differences are prevalent among children of different ages and between children and adults. Most strikingly, adults and children differ in physiology, predisposing diseases, and sepsis management strategies. For example, premature birth is an obvious risk factor for pediatric sepsis that is not relevant in adults. Similarly, national vaccination programs may have larger effects on sepsis in pediatric vs. adult patients. Severe sepsis among infants is dominated by perinatal events.
After infancy, epidemiologic borders between populations are less distinct; however, age-related differences continue to occur, especially regarding underlying diseases, which occur in nearly half (49%) of children who develop severe sepsis. The types of underlying disease vary with age. In infants, chronic lung disease and congenital heart disease are the most common, whereas neuromuscular diseases predominate among children aged 1–9 yrs, and cancer is more common among adolescents. Site of infection also varies by age. Infants tend to have primary bacteremia, whereas almost half of older children have infections of the respiratory tract.
Hospital mortality among U.S. children with severe sepsis was 10.3% (7.8% in previously healthy children and 12.8% in children with underlying disease). There were 4,400 U.S. deaths associated with pediatric severe sepsis in 1995.
A comparison of sepsis-associated deaths with those associated with other causes is presented in Table 1. Of all deaths in children in 1995, 7% were associated with an episode of severe sepsis (3), a number greater than the 2,275 pediatric deaths associated with cancer that year (4). Endocarditis and infections of the central nervous system were associated with the highest hospital mortality (21.1% and 17.1%, respectively); urinary tract infections had the lowest mortality (3.6%).
Children who develop severe sepsis consume substantial healthcare resources, with an average length of stay of 31 days and cost of $40,600. These averages are in excess of all medical conditions examined in a recent federal report (5). Resource use was highest among VLBW babies, who had an average length of stay of 74 days and hospital cost of $75,000. Older children (aged 1–19 yrs) had an average length of stay of 19 days and hospital costs of $19,000. Nationally, the total hospital cost associated with severe sepsis in children was $1.7 billion.
In preliminary analyses of data from 1999, we have found that rates of severe sepsis are increasing, whereas hospital mortality is decreasing (6). The total number of cases increased to 47,700 nationally, and the age- and sex-adjusted U.S. incidence increased by 11%. The increased incidence seemed to be primarily due to increased numbers of VLBW babies in the United States and an increased sepsis rate among those babies. Although hospital mortality was unchanged among previously healthy children, it decreased to 9.0% overall because of lower mortality among children with underlying disease (which decreased from 12.8% in 1995 to 10.5% in 1999). Average length of stay decreased by 1 day, whereas average costs increased by $4,300. The increased number of cases combined with higher average hospital costs led to an increase in estimated national costs of severe sepsis among children to $2.3 billion.
Sepsis is undoubtedly a marker and a cause of severe illness, and no study has determined to what extent patients die (or consume healthcare resources) from sepsis itself (7). For example, VLBW babies with severe sepsis may have prematurity-associated complications, which may not be related to sepsis but may be the main factors leading to the extremely high resource use in this population. However, VLBW and low-birth-weight infants with severe sepsis consumed over twice the average resources of those even with infant respiratory distress syndrome, a common and expensive complication of prematurity (5).
Worldwide, 1.6 million neonates die every year from infection, (8) and 60% of deaths in developing countries occur as a result of communicable disease (9). Fortunately, sophisticated diagnostic tests and treatment strategies are not requisite to improving sepsis outcomes. Graves and Rhodes (10) found the presence of tachycardia alone to be predictive of sepsis. In 4,350 newborns, 82 underwent sepsis evaluations. Tachycardia occurred in 92% of the 13 babies who had culture-positive sepsis, 9% of babies with negative cultures, and in only 3 of 4,268 babies who did not undergo a sepsis evaluation. Bang et al. (11) performed an interventional study in rural India in which healthcare workers gave a 5-day course of oral co-trimoxazole and intramuscular gentamicin to neonates with signs of sepsis (including apnea, tachypnea, poor feeding, temperature instability, or diarrhea). Ten percent of the population was treated with antibiotics, at a cost of $5 per baby. This treatment strategy resulted in a decrease in neonatal sepsis mortality from >16% to <3%.
In industrialized countries, the optimal use of antibacterial agents is not clear. There is currently concern that these agents are overused, and bacterial causes of infection are more frequently reported in the developing world than in industrialized countries. However, the design of some studies makes it difficult to determine the true magnitude of difference in pathogenesis. For example, in children in the developing world, nontypeable Haemophilus influenza is a leading cause of death from upper respiratory tract infections and pneumonia when lung aspiration bacterial culture is used. In contrast, studies in industrialized nations are less likely to report bacterial causes of upper respiratory tract infection and pneumonia, particularly nontypeable H. influenza. However, in industrialized countries, lung aspirates are not used as standard measures of infection, and many children are already receiving antibiotics at the time of study surveillance (12).
In both industrialized and developing countries, shock remains the most important risk factor for mortality. In infants, even when controlling for gestational age, birth weight, acidosis, prolonged prothrombin time, and neutropenia, refractory shock remains the main predictor of mortality (13,14). The World Health Organization guidelines for management of Dengue hemorrhagic fever (with disseminated intravascular coagulation) and shock syndrome stress early recognition and aggressive fluid resuscitation. Aggressive intravenous fluid resuscitation achieved 100% survival when administered in the first hour of presentation in a Vietnamese hospital in 222 children with stage III (rapid pulse with narrow pulse pressure) and eight children with stage IV (no palpable pulse or blood pressure) shock (15).
Sepsis among children is a significant health problem. It is a leading cause of death in children worldwide and is associated with substantial resource use in industrialized countries. Incidence and mortality rates vary by age and the presence of underlying disease. Improved management of underlying diseases may both increase the rate of severe sepsis (by increasing populations at risk for developing severe sepsis) and may improve sepsis-associated mortality. Conversely, improved prevention and treatment of sepsis could have a substantial effect on survival and quality of life of all children, both those who are otherwise healthy and those who are chronically ill.
Recent and impending developments in the health care of children may affect pediatric severe sepsis. Genetic and immunologic analysis may identify children at high risk of sepsis and could change many epidemiologic aspects. Multiple recent randomized trials of sepsis therapies have been performed only in adults, and therapies found effective among adults are often used in children after limited pediatric testing. The generalizability of adult studies is a legitimate concern, however. Differences in severe sepsis between children and adults are not trivial, particularly in those with underlying disease. The lower incidence and case fatality of pediatric severe sepsis requires innovative trial designs to determine effectiveness in children. Furthermore, even simple and basic interventions (antibiotics, early reversal of shock) can have a profound effect on the outcome of sepsis in children but are unevenly applied. These challenges underscore the need for a multidisciplinary approach and consistently applied definitions.
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