Nobuaki ShimeTatsuya KawasakiOsamu SaitoYoko AkamineYuichiro TodaMuneyuki TakeuchiHiroko SugimuraYoshio SakuraiMasatoshi IijimaIkuya UetaNaoki ShimizuSatoshi Nakagawa

Incidence and risk factors for mortalityin paediatric severe sepsis: resultsfrom the national paediatric intensive careregistry in Japan

Received: 6 November 2011Accepted: 7 March 2012Published online: 18 April 2012 Copyright jointly held by Springer andESICM 2012

For the paediatric sepsis investigators,Japanese Society of Intensive CareMedicine-Paediatric Intensive Care UnitNetwork.

N. Shime ())Department of Anaesthesiologyand Intensive Care, Kyoto PrefecturalUniversity of Medicine, 465 Kajii-cho,Kamigyo-ku, Kyoto 602-8566, Japane-mail: shime@koto.kpu-m.ac.jpTel.: ?81-75-2515633Fax: ?81-75-2515843

T. Kawasaki I. UetaDepartment of Paediatric Critical Care,Shizuoka Childrens Hospital,Shizuoka, Japan

O. Saito N. ShimizuDepartment of Paediatric Emergency andCritical Care Medicine, Tokyo MetropolitanChildrens Medical Centre, Fuchu, Japan

Y. AkamineDepartment of Paediatric Intensive CareMedicine, Nagano Childrens Hospital,Auzumino, Japan

Y. TodaDepartment of Anaesthesiology andResuscitology, Okayama UniversityHospital, Okayama, Japan

M. TakeuchiDepartment of Anaesthesiology andIntensive Care Medicine, Osaka MedicalCenter and Research Institute for Maternaland Child Health, Izumi, Japan

H. SugimuraDepartment of Intensive Care Medicine,Chiba Childrens Hospital, Chiba, Japan

Y. SakuraiDepartment of Paediatrics, Saitama MedicalUniversity, Kawagoe, Japan

M. IijimaDepartment of Paediatrics, Jikei MedicalUniversity, Tokyo, Japan

S. NakagawaDepartment of Critical Care Medicine,National Centre for Child Healthand Development, Tokyo, Japan

Abstract Purpose: To assess theincidence, background, outcome andrisk factors for death of severe sepsisin Japanese paediatric intensive careunits (PICUs). Methods: A dataanalysis of a prospective, multicentre,3-year case registry from nine medi-cal-surgical Japanese PICUs.Children with severe sepsis, aged015 years, who were consecutivelyadmitted to the participating PICUsfrom 1 January 2007 to 31 December2009 were enrolled. The incidence,background, causative pathogens orinfective foci, outcome and risk fac-tors for death caused by severe sepsis

were analysed. Results: One hun-dred forty-one cases were registered.After the exclusion of 14 patientsbecause of incomplete data or inap-propriate entry, 127 patients wereeligible for the analysis. There were60 boys and 67 girls, aged 23 [568](median [IQR]) months and weighed10 [5.516.5] kg. The incidence was1.4 % of total PICU admissions.Sepsis was community-acquired in35 %, PICU-acquired in 37 % andacquired in hospital general wards in28 %. Methicillin-resistant Staphylo-coccus aureus was the most frequentpathogen. The crude 28-day mortalitywas 18.9 %, comparable to the meanPIM-2 predicted mortality (17.7 %).The mortality rate in patients withshock was significantly increased to28 % compared to those withoutshock (5 %). The presences of exist-ing haematological disorders (OR8.97, 95 % CI, 1.5651.60) and shock(OR 5.35, 1.0427.44) were signifi-cant factors associated with mortalityby multivariate analysis. Conclu-sions: The mortality from severesepsis/septic shock in Japanese PICUswas *19 %. Haematological disor-ders and presence of shock wereassociated with death.

Keywords Severe sepsis Septic shock Paediatric Mortality Risk factors

Intensive Care Med (2012) 38:11911197DOI 10.1007/s00134-012-2550-z PEDIATRIC ORIGINAL

Introduction

Severe sepsis (a systemic inflammatory response andacute organ failure due to infection) is a leading cause ofdeath in patients receiving intensive care [1, 2], and itsimpact on healthcare systems is increasing [3]. Epidemi-ological studies performed in the US have suggested acomparable impact of sepsis in paediatric subpopulations,although the absolute incidence and mortality are rela-tively lower than those in adults [4]. In 2005, theterminology of paediatric sepsis and associated disorderswas defined in which paediatric physiology and age-spe-cific definitions were determined in the InternationalPaediatric Sepsis Consensus Conference [5]. However,there has been a paucity of epidemiological data fromcountries outside high-income western countries. Con-ducting an exploratory epidemiological study in a high-income Asian country, where such data have not beenreported before, might prove worthwhile.

The authors thus constructed a nationwide multicenterregistry for paediatric severe sepsis in Japan through thePaediatric Intensive Care Unit (PICU) Network in theJapanese Society of Intensive Care Medicine (JPICU-net).The aim of this study was to assess the incidence, back-ground, outcome and risk factors for death caused bysevere sepsis in Japanese PICUs.

Methods

Registry data were collected from nine PICUs in JPICU-net that voluntarily participated in this project betweenJanuaruy 2006 and December 2008. The median numberof PICU beds was eight (420, minimummaximum).The Ethics Committee of the central research facility(Kyoto Prefectural University of Medicine) approved thisstudy (E-198) and waived the need for informed consent.Approval for informed consent at each participatingfacility was decided according to local regulations.

Consecutive data from all children, newborn to15 years old, who were admitted to the participating PI-CUs were reviewed in this study. Inclusion criteria for thisregistry were all consecutive patients who matched defi-nitions of paediatric severe sepsis (systemic inflammatoryresponse syndrome with cardiovascular dysfunction, acuterespiratory distress syndrome or other multiorgan dys-function caused by infection) [5]. For each patient, thefollowing information was recorded: age, gender, place ofoccurrence (in general wards, PICU or the community),presence of chronic diseases and immunodeficiency[haematological disorders (malignant haematologicaldiseases, chemotherapy, neutropenia, bone marrow trans-plantation), steroid therapy, haemodialysis, liver cirrhosis,asplenia and chronic human immunodeficiency virusinfection]. Four age group classifications were adopted:

newborns (030 days), infants (112 months), children(112 years) and adolescents (1315 years). Other vari-ables included the application and length of mechanicalventilation, length of stay in the PICU and in the hospital,diagnosis on discharge, and survival outcome at 28 daysor on hospital discharge. Sites of infection were classifiedas respiratory infection, catheter-related bloodstreaminfection, urinary tract infection, central nervous systeminfection, intra-abdominal infection, cardiovascularinfection including mediastinitis, others and unknown.The definition of each infection was based on the Inter-national Sepsis Forum consensus statements [6]. Causativepathogens and antibiotic therapies (empiric and pathogen-specific) were recorded, and appropriateness of each initialempiric therapy was assessed using in vitro sensitivity datafor each pathogen. Application of therapeutic interven-tions including steroids, immunoglobulin, antithrombin IIIconcentrates and continuous renal-replacement therapy forsevere sepsis treatment was recorded.

The Paediatric Index of Mortality (PIM2) was calcu-lated at the onset of sepsis [7]. Shock was defined ascardiovascular dysfunction despite fluid resuscitation [5].Numbers of organ dysfunctions newly developed duringsepsis were calculated using the PELOD score [8].

Statmate III (Atoms, Tokyo, Japan) and the Mac Ju-myo Model (Esumi, Tokyo, Japan) were used forstatistical analysis. Statistical comparisons were assessedfor discrete and continuous variables as appropriate. Asthe distribution of the data was not normal for any of thecontinuous variables, a nonparametric test was used. AP value less than 0.05 was considered significant.

We divided all the cases into two groups (survivorsand non-survivors) based on the 28-day outcome. Weaimed to explore predicting factors for death among theparameters presenting at the first diagnosis of septicpatients in PICU. We initially performed the bivariateanalyses to explore the candidates for multivariate anal-ysis. Data showing statistical significance (P \ 0.05) bybivariate analysis were included in the multivariateanalysis. Potentially associated factors were adopted asindependent variables for multiple logistic regressionanalysis.

Results

Demographics and site of sepsis occurrence

One hundred forty-one cases were registered. After theexclusion of 14 patients due to incomplete data or inap-propriate entry, 127 patients were eligible for the analysis.This comprised 1.4 % of total admissions. The back-ground and outcome data are shown in Table 1. Crude28-day mortality was 18.9 % and was almost identical tothat predicted from PIM2 scoring (17.7 %, standardised

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mortality ratio, 1.07). Median duration of mechanicalventilation and stay in the ICU were 11 and 14 days,respectively. Forty-seven (37 %) patients developed sep-sis during their PICU stay, whereas 44 (35 %) developedthe condition in general wards and 36 (28 %) in com-munity settings. There were significant differences inoutcome among the three different setting groups. Mor-tality in patients with sepsis acquired in hospital generalwards was higher (33.3 %) compared to 13.6 % in thecommunity and 10.6 % in the PICU. In contrast, patientswho developed sepsis in the community setting showedlow standardised mortality ratios and shorter duration ofmechanical ventilation or PICU stay.

Associated parameters and mortality

Table 2 shows the frequency of associated parameters and28-day outcome. There were no statistically significantdifferences in mortality associated with age, althoughthere was a trend toward increasing mortality in olderpatients. Patients with haematological disorders had sig-nificantly higher mortality (58 vs. 14 %, p \ 0.001),while the existence of chronic comorbidities or immu-nosuppression, both of which included haematologicaldisorders, were not associated with increased mortality.Eleven of the 12 haematological disorders were in chil-dren (112 years), contributing to high mortality in thisage group. No patients suffered from chronic humanimmunodeficiency virus infection. Shock was diagnosedin 72 (57 %) children and was associated with signifi-cantly higher mortality compared with patients withoutshock (n = 55) (28 vs. 5 %, p \ 0.001). If a patientsuffered from five or more organ dysfunctions, mortalitywas significantly increased compared with patients withfewer organ dysfunctions (29 vs. 20 % in three or four

organ dysfunctions and 0 % in one or two organ dys-functions, p = 0.01). If a patient had PIM2-predictedmortality C10 %, the odds of death were significantlyincreased (40 vs. 4 %, p = 0.01).

Infection site and microbiology

The distribution of sites of infection is shown in Table 2.The lung was the most frequent infection at 28 (22 %),followed by unknown foci at 26 (29 %) and the centralnervous system at 20 (16 %). The highest mortality(31 %) was observed in patients with unknown foci,followed by the central nervous system and intravascularcatheter infections (25 %). The causative pathogen wasdetected by culture in the vast majority of patients [112(88 %)]. Gram-negative pathogens were most frequentlyisolated (n = 56, 44 %), followed by gram-positivepathogens (n = 39, 31 %).

The most frequent causative bacterial pathogen wasmethicillin-resistant Staphylococcus aureus (MRSA) (18,14 % in the pathogen-detected group), followed bycoagulase-negative staphylococci (14, 11 %), Pseudo-monas aeruginosa (11, 9 %), streptococci including fourcases of Streptococcus pneumoniae (11, 9 %) and Hae-mophilus influenzae (10, 8 %) (Table 3). There were nocases of meningococcal infections.

Therapeutic interventions

Therapeutic interventions applied for sepsis and itsassociation with mortality are represented in Table 4. Theuse of steroid therapy was significantly associated withincreased mortality (p = 0.03). Other therapeutic inter-ventions showed no effect on mortality.

Table 1 Background data

Out of hospital In hospital, wards In hospital, PICU Total

Numbers (%) 44 (35 %) 36 (28 %) 47 (37 %) 127 (100 %)Age (months)* 24 (7.7570.5) 28 (11.75108) 10 (1.5-3.9) 20 (568)Weight (kg) 10 (6.818) 10 (7.0520.5) 7.07 (4.0511.25) 9.0 (5.516.5)Male, n (%) 23 (52 %) 22 (61 %) 15 (32 %) 60 (47 %)Mortality (%)PIM2-predicted 19.7 % 21.9 % 12.6 % 17.7 %28-day* 13.6 % 33.3 % 10.6 % 18.9 %SMR 0.69 1.52 0.84 1.07

In hospital* 18.1 % 41.6 % 21.3 % 26.8 %MVPerformed, n (%) 41 (93 %) 35 (97 %) 40 (85 %) 116 (91 %)Duration, days* 8 (513) 10 (618) 16.5 (731) 11 (620.25)

Length of PICU stay, days* 9 (6.7514.5) 13.5 (7.7524.35) 21 (1039) 14 (735)

Values are median (IQR)PIM Paediatric Index of Mortality, SMR standarised mortality ratio, MV mechanical ventilation, PICU paediatric intensive care unit* Significant differences among the groups

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Multivariate analysis

After performing multivariate logistic regression analysisby selecting parameters that showed significant differ-ences in bivariate analyses (Table 2), we found that three

factors presenting at the diagnosis of sepsis in the PICUwere significantly associated with death: PIM2 score (OR1.02, 95 % CI 1.001.04), haematological disorders (OR8.97, 1.5651.60) and shock (OR 5.35, 1.0427.44)(Table 5). If the multivariate analysis was performed byadding steroid therapy as a variable, no significantassociation of steroids with mortality was found, whereasthe aforementioned parameters were still significantly

Table 2 Associated parameters at the diagnosis for risk of death

n Death,n (%)

P

Age groupNeonates 8 1 (13 %) nsInfants 72 10 (14 %)Children 43 11 (26 %)Adolescents 4 1 (25 %)

SettingsOut of hospital 44 6 (14 %)In hospital, wards 36 12 (33 %)* 0.005 vs.

othersIn hospital, PICU 47 5 (11 %)

SexMale 60 13 (22 %) nsFemale 67 10 (15 %)

Chronic comorbidities n (%)No 37 7 (19 %) nsYes 90 16 (18 %)

Immunosuppression n (%)No 85 12 (14 %)Yes 42 11 (26 %) 0.08

Haematological disorders n (%)No 115 16 (14 %)Yes 12 7 (58 %)* \0.001

Shock n (%)No 55 3 (5 %)Yes 72 20 (28 %)* \0.001

Organ dysfunctions n (%)1 or 2 32 0 (0 %)3 or 4 50 10 (20 %)5 or 6 45 13 (29 %)* 0.01 vs.

othersPIM2-predicted mortality\10 % 76 3 (4 %)C 10 % 51 20 (40 %)* \0.001

FocusCNS 20 5 (25 %)Lung 28 3 (11 %)Abdomen 14 2 (14 %)Urogenital 3 0 (0 %)Cardiovascular and

mediastinum15 0 (0 %)

CVC 12 3 (25 %)Other foci 9 2 (22 %)Unknown 26 8 (31 %)* 0.02 vs.

othersPathogensGP 56 10 (18 %) nsGN 39 9 (23 %)Fungi 7 1 (14 %)Virus 10 1 (10 %)Unknown 15 2 (13 %)

PICU paediatric intensive care unit, CNS central nervous system,CVC central venous catheter, GP gram-positive bacteria, GN gram-negative bacteria, PIM-2 Paediatric Index of Mortality-2, ns notsignificant* Significant differences between (among) the groups

Table 3 Top ten pathogens

Pathogens n (%)

MRSA 18 (14)CoNS 14 (11)Pseudomonas aeruginosa 11 (9)Streptococci 11 (9)Haemophillus influenzae 10 (8)MSSA 9 (7)Klebsiella sp. 8 (6)Escherichia coli 5 (4)Enterococci 5 (4)Candida sp. 4 (3)

MRSA methicillin-resistant Staphylococcus aureus, MSSA methi-cillin-sensitive Staphylococcus aureus, CoNS coagulase-negativestaphylococci

Table 4 Associated therapeutic factors for risk of death

n Death, n (%) p

SteriodsNo 56 5 (9 %)Yes 71 18 (25 %)* 0.03

ImmunoglobulinNo 68 11 (17 %)Yes 59 12 (20 %) ns

Antithrombin IIINo 76 12 (16 %)Yes 51 11 (22 %) ns

CRRTNo 110 17 (15 %)Yes 17 6 (35 %) ns

Appropriate empiric ABxNo 14 2 (14 %) nsYes 76 14 (18 %)N/A 37 7 (19 %)

CRRT continuous renal-replacement therapy, ABx antibiotics* Significant differences between the groups

Table 5 Multivariate analysis for the factors of death at the onsetof severe sepsis

Parameters OR 95 % CI P

PIM-2 predicted mortality 1.02 1.001.04 0.01Shock 5.35 1.0427.44 0.04Haematological disorders 8.97 1.5651.60 0.01Unknown focus 2.97 0.929.65 0.06

OR odds ratio, CI confidence interval, PIM Paediatric Index ofMortality

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associated with death (data not shown). There was nostatistically significant association between the number oforgan dysfunctions and mortality.

Discussion

This is the first multicentre epidemiological studyexploring paediatric severe sepsis based on case registrydata in a high-income Asian country. This study revealedthat the mortality of severe sepsis managed in JapanesePICUs was 19 %, which was comparable to PIM-2 pre-dicted mortality. The presence of existing haematologicaldisorders and septic shock were significant independentfactors associated with mortality by multivariate analysis.

There have been scarce data regarding the epidemiol-ogy of severe sepsis in paediatric populations [3]. To ourknowledge, only two multicentre studies have been con-ducted to estimate paediatric severe sepsis at a nationallevel in developed countries [8, 9], although several datafrom single centres and smaller numbers of centres ordiagnosis-related categories exist [1013]. We believe thepresent study is the first reported outside western coun-tries. We received data from nine PICUs, accounting forapproximately 40 % of Japanese PICU beds. The inci-dence of severe sepsis (1.4 %) appears to be lower thanthose published from other countries. The Italian, Cana-dian and French studies reported the incidence of severesepsis/septic shock as 3.8 % [8], 6 % [10] and 6 % [11],respectively. This may be due to differences in healthcaresystems (vaccination policies, intensive care regionalisa-tion or patient case mix), or aetiological differencesbetween infections. For example, Neisseria meningitidis, asignificant pathogen for severe sepsis in western countries[9, 14], is extremely rare in Japan. No patient sufferedfrom this infection in this analysis. No patient sufferedfrom human immunodeficiency virus infection, whichmight be a factor associated with fungal infection in othersettings [4]. National immunisation programmes forHaemophilus influenzae and Streptococcus pneumonia,which effectively contribute to decreasing the incidence ofsevere sepsis due to these community-acquired pathogens[15, 16], were not established in Japan when this study wasconducted. A final consideration is the potentially insuf-ficient number of PICUs in Japan, with only 200 bedsavailable for 130 million people, which mostly providepostoperative care. These factors may have affected theincidence of sepsis seen in this study and highlight theimportance of studying the epidemiology of paediatricsepsis in different geographical settings.

Haematological disorders were a significant indepen-dent factor associated with death, particularly in childrenaged 112 years old. Although some recent studies havesuggested a lack of association between death from sepsisin those with haematological disorders and those without

[17, 18], our report is comparable to data published byother authors [4, 8] and indicates that children with hae-matological disorders and severe sepsis are still avulnerable population.

Another significant factor associated with mortalitywas the presence of shock. Mortality related to septicshock has decreased over time, with 67 % mortality in1997 [11], 51 % in 2004 [8] and currently *2025 % [9,19]. Despite the relatively lower absolute mortality of25 %, our study suggests that there is still room forimprovement in therapeutic strategies in this population.Universal application of early goal-directed therapyincluding aggressive time- and volume-sensitive fluidresuscitation and inotropic/vasopressor support shouldlower mortality still further [1922]. Moreover, efforts torecognise evolving shock early before the occurrence ofhypotension are warranted. Children transferred to PICUsfrom wards and other hospitals might have receivedinadequate initial treatment for shock [9, 23, 24], andmultiple organ dysfunction or fluid- and catecholamine-resistant shock might already be present at the moment ofPICU admission. Attempts to provide earlier recognitionand prompt initiation of resuscitation strategies across allmedical settings outside PICUs [19, 20], and prompttransport to referral centres, might reduce the mortality ofsevere sepsis/septic shock [9].

No significant association with therapeutic interven-tions and death was found. Of note, there was a trendtoward increased mortality with steroid therapy, althoughthis was not substantiated on multivariate analysis. Cur-rent meta-analyses on adult severe sepsis showed nosurvival benefit to using steroids [25]. Taken together,routine use of steroids cannot be recommended for pae-diatric patients with severe sepsis.

Limitations

This study, conducted in nine Japanese PICUs, whichmainly provide care for children post-operatively, mightnot represent a complete picture in Japanese children withsevere sepsis. It is suspected that many children withsevere sepsis remain on general wards or in adult ICUs,given the scarcity of PICUs in this country. Unfortunately,we lack data on how many septic children are managed inother settings. Moreover, the participating physiciansvolunteered to join the case registry, which may havecaused selection bias. These factors, in combination,might have affected the low incidence and mortality in thisregistry. Further studies on a national basis would benecessary to correctly depict the current status of septicchildren in this country. Secondly, this study did notevaluate the performance of early goal-directed fluid andhaemodynamic resuscitation [2023], which is a signifi-cant factor affecting improved outcome for septic shock.This registry was not set up to accurately evaluate whether

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initial goal-directed resuscitation was adequate and timely,which is difficult to evaluate unless in the emergencyroom. Finally, this study was underpowered to separatelyanalyse risk factors in children in each setting that mighthave different characteristics and outcomes. Specifically,patients with sepsis occurring in the community could beseparately evaluated from patients who had sepsis duringthe hospital stay, as the former group had relatively betteroutcomes than predicted and faster recovery. Attempts toanalyse further large-scale registries with longer periods ofenrollment might be necessary in the future to separatelyanalyse children with sepsis from different acquisitionsources (e.g., community vs. hospital).

In conclusion, we have shown that the mortality ofsevere sepsis in Japanese PICUs was as low as *19 %,comparable to PIM2-predicted mortality. Comorbid hae-matological disorders and the presence of shock atdiagnosis were significant factors associated with death.

Acknowledgments The authors would like to thank all the par-ticipants in this registry and Dr. Graeme MacLaren (NationalUniversity of Singapore) for his assistance in English editing. Thisstudy was conducted without any financial support.

Conflicts of interest The authors have no potential conflict ofinterest to disclose.

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Incidence and risk factors for mortality in paediatric severe sepsis: results from the national paediatric intensive care registry in JapanAbstractIntroductionMethodsResultsDemographics and site of sepsis occurrenceAssociated parameters and mortalityInfection site and microbiologyTherapeutic interventionsMultivariate analysis

DiscussionLimitations

AcknowledgmentsReferences