Scope and Epidemiology of Pediatric Sepsis.2

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  Scientific Reviews Scope and epidemiology of pediatric sepsis R. Scott Watson, MD, MPH; Joseph A. Carcillo, MD S epsis is the most commoncause of death in infants andchildren in the world. Accord-ing to the World Health Orga-nization, the “big four” killers of childrenare severe pneumonia (1.9 million deathsper year), severe diarrhea (1.6 milliondeaths per year), severe malaria (1.1 mil-lion deaths per year), and severe measles(550,000 deaths per year) (1). (The termsevere is used by the World Health Orga-nization when children develop acidosisor hypotension or both.) Antibiotics im-prove outcomes in children in all fourdisease categories, suggesting that acommon pathway of death is either sec-ondary bacterial infection or that antibi-otics have microbicidal activity againstthe inciting organism (e.g., malaria, en-teric fevers). Severe Sepsis in the UnitedStates In the United States, there were  42,000 cases of severe sepsis in childrenaged   19 yrs in 1995 (2). Infants are athighest risk, with a rate ten times higherthan that of older children. Low- and verylow–birth-weight (VLBW) babies makeup nearly one fourth of the pediatric se- vere sepsis population. Boys of   10 yrs of age had significantly higher rates of se- vere sepsis than girls, particularly amonginfants. Age is a major influence on the epide-miology of severe sepsis in the UnitedStates. Differences are prevalent amongchildren of different ages and betweenchildren and adults. Most strikingly,adults and children differ in physiology,predisposing diseases, and sepsis man-agement strategies. For example, prema-ture birth is an obvious risk factor forpediatric sepsis that is not relevant inadults. Similarly, national vaccinationprograms may have larger effects on sep-sis in pediatric vs. adult patients. Severesepsis among infants is dominated byperinatal events. After infancy, epidemiologic bordersbetween populations are less distinct;however, age-related differences continueto occur, especially regarding underlyingdiseases, which occur in nearly half (49%) of children who develop severesepsis. The types of underlying disease vary with age. In infants, chronic lungdisease and congenital heart disease arethe most common, whereas neuromus-cular diseases predominate among chil-dren aged 1–9 yrs, and cancer is morecommon among adolescents. Site of in-fection also varies by age. Infants tend tohave primary bacteremia, whereas almosthalf of older children have infections of the respiratory tract.Hospital mortality among U.S. chil-dren 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-associateddeaths with those associated with othercauses is presented in Table 1. Of alldeaths in children in 1995, 7% were as-sociated with an episode of severe sepsis(3), a number greater than the 2,275 pe-diatric deaths associated with cancer that year (4). Endocarditis and infections of the central nervous system were associ-ated with the highest hospital mortality(21.1% and 17.1%, respectively); urinarytract infections had the lowest mortality(3.6%).Children who develop severe sepsisconsume substantial healthcare re-sources, with an average length of stay of 31 days and cost of $40,600. These aver-ages are in excess of all medical condi-tions examined in a recent federal report From the Department of Critical Care Medicine(RSW, JAC), Center for Research on Health Care (RSW),and the Clinical Research, Investigation, and SystemsModeling in Acute Illness (CRISMA) Laboratory (RSW),University of Pittsburgh, Pittsburgh, PA.This work was supported by the Mannion FamilyFund—Center for the Critically Ill Child, Division ofCritical Care Medicine at Children’s Hospital Boston,the PALISI Network, and the ISF.Copyright © 2005 by the Society of Critical CareMedicine and the World Federation of Pediatric Inten-sive and Critical Care Societies DOI: 10.1097/01.PCC.0000161289.22464.C3 Objective:   To summarize the scope and epidemiology of pedi-atric sepsis. Design:   Review of published literature. Results:   Sepsis is a leading cause of death in infants andchildren, with  > 42,000 cases of severe sepsis annually in theUnited States and millions worldwide. Half of the children withsevere sepsis in the United States are infants, and half of infantsare low- or very low–birth-weight babies. Underlying diseaseoccurs in 49% of U.S. children with severe sepsis. Nationalhospital costs associated with severe sepsis in the United Stateswere $2.3 billion in 1999. Relatively simple strategies to identifyand treat children with sepsis in the developing world have shownremarkable success. These strategies have included empiricalantibiotics in babies at high risk of sepsis and aggressive fluidresuscitation in Dengue hemorrhagic fever. Conclusions:   Sepsis is a major health problem among childrenin both developing and industrialized countries. However, sepsisis both preventable and treatable. Improved prevention and treat-ment of sepsis could have a substantial effect on survival andquality of life of all children, both those who are otherwise healthyand those who are chronically ill. The variations in the epidemi-ology of pediatric sepsis underscore the need for a multidisci-plinary approach and consistently applied definitions. (Pediatr CritCare Med 2005; 6[Suppl.]:S3–S5)K  EY  W ORDS : sepsis; severe sepsis; epidemiology; incidence;mortality; outcome; pediatric S3Pediatr Crit Care Med 2005 Vol. 6, No. 3 (Suppl.)  (5). Resource use was highest among VLBW babies, who had an average lengthof stay of 74 days and hospital cost of $75,000. Older children (aged 1–19 yrs)had an average length of stay of 19 daysand hospital costs of $19,000. Nationally,the total hospital cost associated with se- vere sepsis in children was $1.7 billion.In preliminary analyses of data from1999, we have found that rates of severesepsis are increasing, whereas hospitalmortality is decreasing (6). The totalnumber of cases increased to 47,700 na-tionally, and the age- and sex-adjustedU.S. incidence increased by 11%. The in-creased incidence seemed to be primarilydue to increased numbers of VLBW ba-bies in the United States and an increasedsepsis rate among those babies. Althoughhospital mortality was unchanged amongpreviously healthy children, it decreasedto 9.0% overall because of lower mortal-ity among children with underlying dis-ease (which decreased from 12.8% in1995 to 10.5% in 1999). Average length of stay decreased by 1 day, whereas averagecosts increased by $4,300. The increasednumber of cases combined with higheraverage hospital costs led to an increasein estimated national costs of severe sep-sis among children to $2.3 billion.Sepsis is undoubtedly a marker and acause of severe illness, and no study hasdetermined to what extent patients die(or consume healthcare resources) fromsepsis itself (7). For example, VLBW ba-bies with severe sepsis may have prema-turity-associated complications, whichmay not be related to sepsis but may bethe main factors leading to the extremelyhigh resource use in this population.However, VLBW and low–birth-weightinfants with severe sepsis consumed overtwice the average resources of those even with infant respiratory distress syn-drome, a common and expensive compli-cation of prematurity (5). Sepsis Worldwide  Worldwide, 1.6 million neonates dieevery year from infection, (8) and 60% of deaths in developing countries occur as aresult of communicable disease (9). For-tunately, sophisticated diagnostic testsand treatment strategies are not requisiteto improving sepsis outcomes. Gravesand Rhodes (10) found the presence of tachycardia alone to be predictive of sep-sis. In 4,350 newborns, 82 underwentsepsis evaluations. Tachycardia occurredin 92% of the 13 babies who had culture-positive sepsis, 9% of babies with nega-tive cultures, and in only 3 of 4,268 ba-bies who did not undergo a sepsisevaluation. Bang et al. (11) performed aninterventional study in rural India in which healthcare workers gave a 5-daycourse of oral co-trimoxazole and intra-muscular gentamicin to neonates withsigns of sepsis (including apnea, tachy-pnea, poor feeding, temperature instabil-ity, or diarrhea). Ten percent of the pop-ulation was treated with antibiotics, at acost of $5 per baby. This treatment strat-egy resulted in a decrease in neonatalsepsis mortality from  16% to  3%.In industrialized countries, the opti-mal use of antibacterial agents is notclear. There is currently concern thatthese agents are overused, and bacterialcauses of infection are more frequentlyreported in the developing world than inindustrialized countries. However, thedesign of some studies makes it difficultto determine the true magnitude of dif-ference in pathogenesis. For example, inchildren in the developing world, non-typeable  Haemophilus influenza  is a lead-ing cause of death from upper respiratorytract infections and pneumonia whenlung aspiration bacterial culture is used.In contrast, studies in industrialized na-tions are less likely to report bacterialcauses of upper respiratory tract infectionand pneumonia, particularly nontypeable  H. influenza . However, in industrializedcountries, lung aspirates are not used asstandard measures of infection, and manychildren are already receiving antibioticsat the time of study surveillance (12).In both industrialized and developingcountries, shock remains the most im-portant risk factor for mortality. In in-fants, even when controlling for gesta-tional age, birth weight, acidosis,prolonged prothrombin time, and neu-tropenia, refractory shock remains themain predictor of mortality (13,14). The World Health Organization guidelines formanagement of Dengue hemorrhagic fe- ver (with disseminated intravascular co-agulation) and shock syndrome stressearly recognition and aggressive fluid re-suscitation. Aggressive intravenous fluidresuscitation achieved 100% survival when administered in the first hour of presentation in a Vietnamese hospital in222 children with stage III (rapid pulse with narrow pulse pressure) and eightchildren with stage IV (no palpable pulseor blood pressure) shock (15). Conclusion Sepsis among children is a significanthealth problem. It is a leading cause of death in children worldwide and is asso-ciated with substantial resource use inindustrialized countries. Incidence andmortality rates vary by age and the pres-ence of underlying disease. Improvedmanagement of underlying diseases mayboth increase the rate of severe sepsis (byincreasing populations at risk for devel-oping severe sepsis) and may improvesepsis-associated mortality. Conversely,improved prevention and treatment of sepsis could have a substantial effect onsurvival and quality of life of all children,both those who are otherwise healthy andthose who are chronically ill.Recent and impending developmentsin the health care of children may affectpediatric severe sepsis. Genetic and im-munologic analysis may identify childrenat high risk of sepsis and could changemany epidemiologic aspects. Multiple re-cent randomized trials of sepsis therapieshave been performed only in adults, andtherapies found effective among adultsare often used in children after limitedpediatric testing. The generalizability of adult studies is a legitimate concern,however. Differences in severe sepsis be-tween children and adults are not trivial,particularly in those with underlying dis- Table 1.  Leading causes of death in U.S. children in 1995InfantsNo. of Deaths  a Children 1–14 yrs oldNo. of Deaths  a 1 Congenital anomalies 6,554 1 Accidents 5,8242 Prematurity 3,933  2 Severe sepsis 1,570 3 Sudden infant death syndrome 3,397 3 Cancer 1,514 4 Severe sepsis 2,135  4 Congenital anomalies 1,1445 Respiratory distress syndrome 1,454 5 Homicide 1,0246 Complications of pregnancy 1,309 6 Diseases of the heart 5457 Accidents 787 7 Human immunodeficiency virus 399  a Number of deaths for severe sepsis are national estimates (2); numbers for all other causes arefrom the National Centers for Vital Statistics (3). S4 Pediatr Crit Care Med 2005 Vol. 6, No. 3 (Suppl.)  ease. The lower incidence and case fatal-ity of pediatric severe sepsis requires in-novative trial designs to determineeffectiveness in children. Furthermore,even simple and basic interventions (an-tibiotics, early reversal of shock) can havea profound effect on the outcome of sep-sis in children but are unevenly applied.These challenges underscore the need fora multidisciplinary approach and consis-tently applied definitions. REFERENCES 1. The World Health Report 1996: Fighting Dis-ease, Fostering Development. Geneva, WorldHealth Organization, 19962. Watson RS, Carcillo JA, Linde-Zwirble WT, etal: The epidemiology of severe sepsis in chil-dren in the United States.  Am J Respir CritCare Med   2003; 167:695–7013. Deaths from 282 selected causes by 5-yearage groups, race, and sex: Each state and theDistrict of Columbia, 1995, 1996, 1997, and1998. Hyattsville, MD, National Center forHealth Statistics. Available at: Accessed March 1, 20054. Cancer Incidence and Survival Among Chil-dren and Adolescents: United States SEERProgram, 1975–1995. Bethesda, MD, Na-tional Cancer Institute, SEER Program,1999, NIH publication 99-46495. Elixhauser A, Yu K, Steiner C, et al: Hospi-talization in the United States, 1997. Rock- ville, MD, Agency for Healthcare Researchand Quality, 2000, HCUP Fact Book 1, AHRQpublication 00-00316. Watson RS, Linde-Zwirble WT, Lidicker J, etal: The increasing burden of severe sepsis inU.S. children.  Crit Care Med   2001; 29(Sup-pl):A87. Kutko MC, Calarco MP, Ushay M, et al: Mor-tality of pediatric septic shock may be lowerthan previously reported.  Crit Care Med  2000; 28:A2018. The World Health Report 2004: ChangingHistory. Geneva, Switzerland, World HealthOrganization, 20049. The World Health Report 2000: Health Sys-tems: Improving Performance. Geneva, Swit-zerland, World Health Organization, 200010. Graves GR, Rhodes PG: Tachycardia as a signof early onset neonatal sepsis.  Pediatr Infect Dis  1984; 3:404–40611. Bang AT, Bang RA, Baitule SB, et al: Effect of home-based neonatal care and managementof sepsis on neonatal mortality: Field trial inrural India.  Lancet  1999; 354:1955–196112. Shann F:  Haemophilus influenzae  pneumo-nia: Type B or non–type B?  Lancet  1999;354:1488–149013. Mathur NB, Singh A, Sharma VK, et al: Eval-uation of risk factors for fatal neonatal sepsis.  Indian Pediatr   1996; 33:817–82214. Han YY, Carcillo JA, Dragotta MA, et al: Earlyreversal of pediatric-neonatal septic shock bycommunity physicians is associated with im-proved outcome.  Pediatrics  2003; 112:793–79915. Nhan NT, Phuong CXT, Kneen R, et al: Acutemanagement of dengue shock syndrome: A randomized double-blind comparison of 4 in-travenous fluid regimens in the first hour. Clin Infect Dis  2001; 32:204–213 S5Pediatr Crit Care Med 2005 Vol. 6, No. 3 (Suppl.)
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