Special Article

World Federation of Pediatric Intensive Care and Critical CareSocieties: Global Sepsis Initiative*

Niranjan Kissoon, MD; Joseph A. Carcillo, MD; Victor Espinosa, MSc; Andrew Argent, MD, PhD;Denis Devictor, MD, PhD; Maureen Madden, RN, MSN; Sunit Singhi, MD; Edwin van der Voort, MD;Jos Latour, RN, PhD; and the Global Sepsis Initiative Vanguard Center Contributors

I n 2005, the World Health Organi-zation (WHO) announced that80% of global child deaths wererelated to five severe infections,

namely pneumonia, malaria, measles,neonatal sepsis, and diarrhea (1, 2). Ac-cording to WHO–Integrated Managementof Childhood Illnesses guidelines, sepsisis defined as infection with tachypnea andtachycardia; severe sepsis is defined bysepsis with acidosis or other organ fail-

ure; and septic shock is defined as stageIII shock with tachycardia and poor per-fusion and stage IV shock with hypoten-sion (2). Mortality increases as diseaseprogresses from sepsis, to severe sepsis,and to septic shock. Remarkably, trialsdemonstrate that simple interventionsincluding immunization, vitamin andmineral supplements, antibiotics, fluidresuscitation, and inotropic support re-duce mortality from these conditions 10-

to 100-fold in a cost-effective manner(Fig. 1).

The World Federation of Pediatric In-tensive Care and Critical Care Societies(WFPICCS) announced at the World Con-gress in Geneva Switzerland in 2007 thatit intended to launch its first globalhealth initiative, a quality improvementprogram with the goal of realization ofthese simple interventions for children.The Global Pediatric Sepsis Initiative has nowbegun at http://www.wfpiccs.org/sepsis andhttp://www.pediatricsepsis.org. Here, ed-ucational materials, protocols, evidence-based clinical practice parameters, inter-active education sepsis videos, Web sitesepsis bundle/checklist registration, andWeb site clinical research registration arepresent. Three sets of published evi-dence-based guidelines for the manage-ment of sepsis (Integrated Managementof Childhood Illnesses–World HealthOrganization) (2, 3), severe sepsis (Sur-

*See also p. 589.From the University of British Columbia (NK), BC Chil-

dren’s Hospital, Vancouver, BC, Canada; University of Pitts-burgh School of Medicine (JAC), Pittsburgh, PA; Child andFamily Research Institute (VE), University of British Columbia,Vancouver, BC, Canada; Red Cross War Memorial Children’sHospital (AE), Rondebosch, Cape Town, South Africa; Hospi-tal Bicetre (DV), University of Paris, Sud 11, Bicetre, France;Robert Wood Johnson Medical School (MM), New Bruns-wick, NJ; Postgraduate Institute of Medical Education andResearch (SS), Chandigarh, India; and SophieChildren’sHospital (EvdV, JL), Rotterdam, The Netherlands.

The authors have not disclosed any potential con-flicts of interest.

On behalf of the WFPICCS and Contributors, seeAppendix.

For information regarding this article, E-mail:nkissoon@cw.bc.ca

Copyright © 2011 by the Society of Critical CareMedicine and the World Federation of Pediatric Inten-sive and Critical Care Societies

DOI: 10.1097/PCC.0b013e318207096c

Background: According to World Health Organization esti-mates, sepsis accounts for 60%–80% of lost lives per year inchildhood. Measures appropriate for resource-scarce and re-source-abundant settings alike can reduce sepsis deaths. In thisregard, the World Federation of Pediatric Intensive Care andCritical Care Societies Board of Directors announces the GlobalPediatric Sepsis Initiative, a quality improvement program de-signed to improve quality of care for children with sepsis.

Objectives: To announce the global sepsis initiative; to justifysome of the bundles that are included; and to show some pre-liminary data and encourage participation.

Methods: The Global Pediatric Sepsis Initiative is developed asa Web-based education, demonstration, and pyramid bundles/checklist tool (http://www.pediatricsepsis.org or http://www.wfpiccs.org). Four health resource categories are included. Cat-egory A involves a nonindustrialized setting with mortality rate<5 yrs and >30 of 1,000 children. Category B involves a nonin-dustrialized setting with mortality rate <5 yrs and <30 of 1,000children. Category C involves a developing industrialized nation.In category D, developed industrialized nation are determined andseparate accompanying administrative and clinical parametersbundles or checklist quality improvement recommendations are

provided, requiring greater resources and tasks as resource al-location increased from groups A to D, respectively.

Results: In the vanguard phase, data for 361 children (categoryA, n � 34; category B, n � 12; category C, n � 84; category D,n � 231) were successfully entered, and quality-assurance re-ports were sent to the 23 participating international centers.Analysis of bundles for categories C and D showed that reductionin mortality was associated with compliance with the resuscita-tion (odds ratio, 0.369; 95% confidence interval, 0.188–0.724; p <.0004) and intensive care unit management (odds ratio, 0.277;95% confidence interval, 0.096–0.80) bundles.

Conclusions: The World Federation of Pediatric Intensive Careand Critical Care Societies Global Pediatric Sepsis Initiative is online.Success in reducing pediatric mortality and morbidity, evaluatedyearly as a measure of global child health care quality improve-ment, requires ongoing active recruitment of international partic-ipant centers. Please join us at http://www.pediatricsepsis.org orhttp://www.wfpiccs.org. (Pediatr Crit Care Med 2011; 12:494–503)

KEY WORDS: children; critical illness; infection; outcomes; qual-ity assurance; sepsis; shock

494 Pediatr Crit Care Med 2011 Vol. 12, No. 5

viving Sepsis Campaign) (4, 5), and sep-tic shock (American College of CriticalCare Medicine [ACCM]/Pediatric Ad-vanced Life Support [PALS]/AmericanHeart Association [AHA]) (6 – 8) areavailable at the Web site. The sepsisbundles/checklists were developedbased on the recommendations of thesethree sets of internationally sanctionedguidelines. Implementation of theseguideline-derived bundles/checklistsand subsequent evaluation of their ef-fectiveness require worldwide docu-mentation of clinician practice and pa-tient outcome, which is the ultimategoal of the Global Pediatric Sepsis Ini-tiative.

Although the success of this initiativedepends entirely on voluntary participa-tion by the world’s pediatric critical careprofessionals, most deaths from sepsisoccur globally in locations without inten-sive care units. Many of these deaths canbe prevented when using less sophisti-cated measures recommended, in part, inWHO–Integrated Management of Child-hood Illnesses guidelines. Participation ofcolleagues in the developed and develop-ing countries in the initiative will enablea better understanding of regional re-source limitations and potentially im-prove outcomes with implementation ofresource-appropriate quality improve-ment programs. Recognizing the impor-

tance of resource disparities, the GlobalSepsis Initiative incorporates separatequality improvement recommendationsor bundle/checklists according to the re-source settings recognized by WHO.First, participants log into the initiativeat http://www.pediatricsepsis.org or athttp://www.wfpicccs.org. Here, they canclick on educational, guideline, research,or quality-assurance icons. Participantswho wish to join in the quality-assuranceinitiative first register and answerprompts that result in their placementinto categories depending on the infor-mation they provide regarding resourcesthat are available. Based on this informa-tion, they are directed to guideline basedrecommendations that are condensedinto bundles of tasks or “checklists” thathave been created for use according tothese regional child mortality rates andeconomic parameters. These four re-source-specific categories based on WHOrecommendations are: 1) category A:nonindustrialized setting with �5-yrmortality �30 of 1,000 children; 2) cate-gory B: nonindustrialized setting with�5-yr mortality and �30 of 1,000 chil-dren; 3) category C: industrialized devel-oping nation; and 4) category D: indus-trialized developed nation.

Each category has separate adminis-trative and clinical care bundles, withrecommendations for more technolo-gies and interventions as child mortal-ity rates decreases and wealth increases.Because institutions may not fit wellinto one category or another, partici-pants are given the opportunity tochoose the category that they feel bestfits their needs.

Depending on the category assigned,the participant is then directed to enterthe individual patient data aided by a se-ries of prompts. Before entering data,participants are asked to review theguidelines available on the site and todetermine whether a given interventionwas needed. For each recommendation,the participant enters “yes” if it was per-formed, “no” if it was not performed, and“not applicable” if it was not performedbut was not applicable to this particularpatient. For example, if a patient needed amechanical ventilator and it was not pro-vided, then the participant enters “no.” Ifthe participant did not receive a ventila-tor because it was not needed, then theparticipant enters “not applicable.” If aventilator is provided, then the partici-pant enters “yes.” A quarterly report isgenerated and sent back to the partici-

Figure 1. The sepsis initiative administrative bundles pyramid. This pyramid demonstrates theadministrative recommendations according to levels of health resources from the health resource-scarce (level A) to health resource-abundant (level D). The foundation of care is level A. It is expectedto be provided to populations with �5-yr child mortality and �30 of 1,000 children. Level B isdistinguished from level A by the ability to deliver oxygen and intravenous therapies. It is expected tobe provided to populations with �5-yr child mortality and �30 of 1,000 children. Category A indicatesnonindustrialized setting with child mortality rate �30 of 1,000 children; category B indicates nonindus-trialized setting with child mortality rate �30 of 1,000 children; category C indicates industrializeddeveloping nation; and category D indicates industrialized developed nation. Level C is distinguishedfrom level B by the ability to deliver machine-driven therapy to all. It is expected to be provided in thedeveloping industrialized setting. Level D is distinguished from level C by the presence of an organizedtransport system and the ability to deliver extracorporeal therapies to all. It is expected to be providedin the developed industrialized setting. Categories A and B are in the nonindustrialized setting.Categories C and D are in the industrialized setting. In category A Bang et al, demonstrated aneight-fold reduction in neonatal mortality when intramuscular (IM) gentamicin and oral cotrimoxa-zole were administered by rural healthcare workers. In category B, investigators in Thailand, Vietnam,and Kenya demonstrated that administering high-flow oxygen (O2) and isotonic intravenous fluidboluses reduced mortality from pneumonia, dengue shock, and severe malaria. In category C, deOliveira et al demonstrated a four-fold reduction from septic shock with American College of CriticalCare Medicine/Pediatric Advanced Life Support goal-directed therapy. In Rotterdam and London,investigators demonstrated a ten-fold reduction in mortality from purpura and meningococcemia witha transport team and tertiary center care. IV, intravenous; PICU, pediatric intensive care unit; npCPAP,nasopharyngeal continuous positive airway pressure; HCW, healthcare worker; ScvO2, superior venacava oxygen saturation; pRBC, packed red blood cells; NP, nasopharyngeal.

495Pediatr Crit Care Med 2011 Vol. 12, No. 5

pant for comparison with the previousperformance and with the other anon-ymous institutions in the same cate-gory to allow for tracking of adminis-trative and clinical practice progress inquality improvement initiatives. The in-tention of tracking these bundles is toevaluate outcomes over time in eachparticipating center and, most impor-tantly, globally. This initiative is an at-tempt to provide a global progress re-port on international child health carefor sepsis and to spur initiatives to im-prove outcomes. The anonymous re-sults will be reported every 4 yrs at theWFPICCS World Congress and submit-ted for publication to Pediatric CriticalCare Medicine. This is the first suchreport to our knowledge on the van-guard phase of the initiative.

QUALITY ASSURANCEPROGRAM

The sepsis bundles/checklists providedaccording to each WHO resource-specificcategory were derived from clinical rec-ommendations in the WHO–IntegratedManagement of Childhood Illnesseshandbook, the ACCM/PALS hemody-namic support guidelines, and the Pedi-atric subcommittee of the Surviving Sep-sis Campaign. These source documentsare also available on the Web site. Theserecommendations present evidence whenavailable and the experience and consen-sus of experts when it is not.

Category A: NonindustrializedSetting With Child MortalityRate >30 of 1,000 Children

Table 1 shows the resource-specificcategory A bundle/checklist. There isstrong evidence that the following pre-ventive interventions reduce mortalityfrom the common causes of sepsis indeveloping countries where child andneonatal mortality is high: breast feeding,immunizations, clean water, sanitationand hygiene, clean birthing process, an-tibiotics for premature rupture of mem-branes, and vitamin A and zinc supple-mentation (9). Level 1 evidence alsoexists for antibiotic treatment for pneu-monia, antibiotics for sepsis and dysen-tery, the use of zinc in the treatment ofdiarrhea, and vitamin A in the treat-ment of measles. Bang et al (10, 11)reported an eight-fold reduction in allneonatal mortality in rural India whenrural health workers provided a 5-day

course of intramuscular gentamicinand oral sulfamethoxazole to neonateswho had diarrhea, tachypnea, or poorfeeding (16% to 2%). Brooks et al (12)reported a dramatic decrease in deathfrom pneumonia (10 of 1000 to 0 of1000) when infants in Bangladesh wereadministered daily or weekly oral zincsupplementation.

Category B: NonindustrializedSetting With Child MortalityRate <30 of 1,000 Children

Table 2 shows the resource-specificcategory B bundle/checklist. Four ran-domized controlled studies have shownthat isotonic fluid resuscitation in theemergency department attains nearly100% survival in children with WHO

classification stage III and stage IVshock (13–16). A series of studies showthat intravenous fluid resuscitation ofsevere malaria (malaria plus acidosis orhypotension) with 5% albumin reducesmortality from 18% to 4% compared tofluid resuscitation with isotonic crystal-loid (17–19). A 10% dextrose-contain-ing solution at maintenance fluid rate(with sodium added to prevent hypona-tremia) provides needed glucose re-quirements. In adults, every hour thatgoes by without administering antibiot-ics increases mortality by 7%. Becausemicrobes grow just as quickly in chil-dren as in adults, antibiotics and anti-malarials should be administered early(20). High-flow nasal cannula O2 or na-sal continuous positive airway pressure

Table 1. Administrative bundle

Clean water provided Yese Noe

Rural/urban health workers provided Yese Noe

Immunizations provided Yese Noe

Zinc/vitamin A supplementation provided Yese Noe

Clinical practice parameter bundle

Parent education provided on signs to call for health worker YeseNoe

Tachypnea, poor feeding, diarrhea YeseNoe

Five days of intramuscular gentamicin and oral cotrimoxazole(or trimethoprim-sulphamethoxizole)

YeseNoeNAe

Oral World Health Organization hydration YeseNoeNAe

Oral antimalarials in malaria belts YeseNoeNAe

NA, not applicable.

Table 2. Administrative bundle

Clean water provided Yese Noe

Rural/urban health workers provided Yese Noe

Immunizations provided Yese Noe

Zinc/vitamin A supplementation provided Yese Noe

Provide hospital emergency room/clinic stocked with IV fluids (D10, normal saline,lactated Ringers)

Yese Noe NAe

Albumin (malaria belt) Yese Noe

IV catheters Yese Noe

IV antibiotics/antimalarials Yese Noe

Oxygen with high-flow capabilities (pneumonia) Yese Noe

Clinical parameter bundle

Parent education provided on signs to call for health worker YeseNoe

Tachypnea, poor feeding, diarrhea YeseNoe

Five days of intramuscular gentamicin and oral clotrimaxazole and oralWorld Health Organization hydration

YeseNoeNAe

Oral antimalarials in malaria belts YeseNoeNAe

Capillary refill restored to �2 secs and blood pressure restored to normalin ED/first hour

YeseNoe

Administer IV fluids in ED/first half-hour for stage III/IV shock YeseNoeNAe

Administer IV antibiotics/antimalarials if appropriate in ED/first hour YeseNoeNAe

Administer high-flow oxygen/nasal continuous positive airway pressure inED/first hour for tachypnea/pneumonia

YeseNoeNAe

D10 with sodium administered at maintenance to prevent hypoglycemia YeseNoe

IV, intravenous; ED, emergency department; NA, not applicable.

496 Pediatr Crit Care Med 2011 Vol. 12, No. 5

can be adequate for up to 40% of pa-tients with respiratory distress andpneumonia (21), and the systematic de-tection of hypoxemia and administra-tion of oxygen substantially reducesmortality from pneumonia in rural hos-pitals (22).

Category C: IndustrializedDeveloping Nation

Table 3 shows the resource-specificcategory C bundle/checklist. Mortalityfrom meningococcal septic shock wasreduced from 22% to 2% when commu-nity physicians administered aggressive4% albumin resuscitation and inotropicsupport, intubated with ketamine, andtransported children to a tertiary center(number needed to treat � 5) (23–25).Newborns and children with all-comerseptic shock also have decreased mor-tality, 6% vs. 38% (number needed to

treat � 3), when stepwise emergencyaccess, fluid resuscitation, and inotro-pic therapy are started in the commu-nity hospital setting (26). Mortality in-creases two-fold for every hour withoutrestoration of capillary refill �2 secsand normal blood pressure. Althoughthese data are obtained from industri-alized developed countries, they areequally applicable to this setting. Thisis evidenced by the improved outcomesseen in dengue shock syndromes whenaggressive treatment is administered (adecrease in mortality from 16.5% to6.3%) even in a resource-limited set-ting (15). Titration of therapies tomaintain normal mean arterial andcentral venous pressure differences(mean arterial pressure � central ve-nous pressure) and mixed venous O2

saturation �70% reduced mortalityfrom 39% to 12% (number needed to

treat � 3.8) (27). Three factors that canhelp survival from septic shock are: 1)adherence to ACCM/PALS guidelinesfor hemodynamic support; 2) timely ad-ministration of the proper antibioticwith removal of any surgical nidus ofinfection; and 3) withdrawal of immunesuppressants in patients receiving im-munosuppressant therapy that preventstheir ability to kill infection. Use ofinsulin for hyperglycemia, intravenousimmunoglobulin, and clindamycin fortoxic shock, lung protection strategy,and diuretics/dialysis are recommendedfor severe sepsis by the Surviving SepsisCampaign (5).

Category D: IndustrializedDeveloped Nation

Table 4 shows the resource-specificcategory D bundle/checklist. Developedcountries have increased resources thatcan be used to further reduce mortalityand morbidity during the emergencydepartment, transport, and pediatric in-tensive care unit interface, and in thepediatric intensive care unit. Organizedcoordinated specialty transport systemsin the developed world settings reducemortality substantially by reducing theseverity of illness of patients at the timeof transport (23–25). Monitoring of car-diac output can be attained noninva-sively using ultrasound, or invasivelyusing pulmonary artery, peripherallyinserted continuous cardiac output, orfemoral artery thermodilution cathe-terization. Multiple organ system extra-corporeal support therapies are used tosupport cardiopulmonary function (ex-tracorporeal membrane oxygenation)and renal function (continuous renalreplacement therapy), and to reversethrombocytopenia-associated multipleorgan failure (plasma exchange forthrombotic microangiopathy) (28, 29).High-frequency oscillatory ventilationand inhaled nitric oxide may reduce theneed for extracorporeal membrane oxy-genation for cardiopulmonary failure inacute respiratory distress syndrome andpersistent pulmonary hypertension ofthe newborn (6, 7).

Statistical Analysis of BundleCompliance and Relationship toOutcome

Analysis of the associative effect ofbundle compliance was performed forthe “resuscitation” phase (high-flow ox-

Table 3. Administrative bundle

ED/intensive care unit available for patients Yese Noe

High-flow oxygen/nasopharyngeal continuous positive airway pressureavailable to all patients

Yese Noe

Ventilator available for all patients Yese Noe

Peripheral and central IV catheters available to all patients Yese Noe

Inotropes available for all patients Yese Noe

Intravascular pressure monitoring available for all patients Yese Noe

Superior vena cava or inferior vena cava/RA pressure, oxygen saturationmonitoring available for all patients

Yese Noe

Dialysis available for patients Yese Noe

Infusion pumps available Yese Noe

Clinical parameter bundle

Capillary refill restored to �2 secs in ED/first hour YeseNoe

Blood pressure restored to normal in ED/first hour YeseNoe

Administer IV fluids in ED/first half-hour for stage III/IV shock YeseNoeNAe

Administer IV antibiotics/antimalarials if appropriate in ED/first hour YeseNoeNAe

Administer high-flow oxygen/nasopharyngeal continuous positiveairway pressure in ED/first hour for tachypnea/pneumonia

YeseNoeNAe

D10 with sodium administered at maintenance to preventhypoglycemia

YeseNoe

Fluid resuscitation �20 mL/kg up to 60 mL/kg administered in firsthour if appropriate

YeseNoeNAe

Peripheral epinephrine administered in first hour if appropriate YeseNoeNAe

Central epinephrine for cold shock/norepinephrine for warm shock infirst hour if appropriate

YeseNoeNAe

Normal mean arterial pressure–central venous pressure and superiorvena cava or inferior vena cava/RA oxygen saturation �70% targetedin intensive care unit

YeseNoeNAe

Absolute adrenal insufficiency treated with steroids YeseNoeNAe

Ketamine used as sedation agent for intubation/central line placement YeseNoeNAe

Ventilator provided for respiratory failure YeseNoeNAe

Tidal volume maintained at 6-8 mL/kg YeseNoeNAe

Appropriate (sensitive) antibiotic administered in first 2 hrs YeseNoeNAe

Immunosuppressants held if using immune suppressive therapy YeseNoeNAe

Hyperglycemia controlled by insulin YeseNoeNAe

Intravenous immunoglobulin/clindamycin administered for toxic shock(group A Streptococcus or Staphylococcus)

YeseNoeNAe

Surgical nidus removed if appropriate YeseNoeNAe

ED, emergency department; IV, intravenous; NA, not applicable; RA, right atrium.

497Pediatr Crit Care Med 2011 Vol. 12, No. 5

ygen, appropriate sensitive antibiotic,restoration of normal blood pressureand capillary refill, fluid resuscitation,peripheral inotrope, mechanical venti-lator) and ongoing intensive care unitmanagement phase (all other subse-quent checklist tasks). Compliance wasconsidered complete if all “applicable”tasks were accomplished. Categorieswere included for analysis in this van-guard phase only if they had data for�50 patients entered. Hence, statisticalanalysis was performed only for re-source-specific categories C and D.

Treatment effects were evaluated usingodds ratios, including 95% confidenceintervals, and using logistic regressionmodels. Six logistic regression modelswere built to encompass all possiblecombinations of treatments (resuscita-tion, subsequent management) andoutcomes (alive, neurologic morbidity,other morbidity). Cases of death werediscarded from morbidity outcomes.Logistic models fit was assessed usingchi-square test for dispersion and Waldtest was used for the proportion of log-likelihood accounted for by the model.

Information was extracted from theWeb database and analyzed using SPSS17.0 (SPSS, Chicago, IL).

RESULTS

The Vanguard of the WFPICCSGlobal Sepsis Initiative

The initiative was conceived and am-bassadors were assembled through volun-teerism at the WFPICCS World Congressin Geneva, 2007. The Web site was devel-oped and brought to full operation in2009. Data for 361 children were enteredfrom 23 international participating cen-ters. The greatest enrollment was in levelD (n � 231), followed by level C (n � 84),level A (n � 34), and level B (n � 12).Figures 2 through 5 show the quality-assurance reports sent according to re-source-specific category to the participat-ing centers. The participants alsoreceived their own performance analysis(not shown) as well the anonymousgroup performance analysis (Figs. 2–5),which they were then able to use forongoing quality-assurance improvementat their respective institutions.

As the categories progressed from A toD, the mortality rates decreased (A �30%; B � 16.7%; C � 29.8%; and D �11.3%), the neurologic morbidity ratesdecreased (A � 16%; B � 10%; C �11.9%; D � 2.0%), and the non-neuro-logic morbidity rates decreased (A �5.9%; B � 8.3%; C � 6.8%; D � 1.0%).There were 35 virus infections, 70 Gram-negative infections, 120 Gram-positiveinfections, eight fungal infections, and 32mixed infections. The most commonwere respiratory syncytial virus, Esche-richia coli, Enterobacter and Klebsiellaspecies, Streptococcus pneumonia, Me-ningococcus, Staphylococcus aureus,and Candida species, respectively.

Only categories C and D had �50 pa-tients, so the relationship between com-pliance and outcome was only evaluatedin this sample. There were no differencesin gender in categories C (50% female)and D (41.6% female) or in age in cate-gories C (51.12 � 51.94) and D (74.68 �77.91). There was less bundle compliancein category C vs. category D (resuscita-tion bundle 23.8% vs. 51.9% and subse-quent management bundle 9.5% vs.25.1%). There was more death and dis-ability in category C vs. category D. Theodds ratio of mortality for a patient wasreduced when considering compliancewith the resuscitation bundle/checklist

Table 4. Administrative bundle

ED/intensive care unit available for patients Yese Noe

High-flow oxygen/nasopharyngeal continuous positive airway pressure availableto all patients

Yese Noe

Ventilator available for all patients Yese Noe

Peripheral and central IV catheters available to all patients Yese Noe

Infusion pumps available Yese Noe

Inotropes available for all patients Yese Noe

Intravascular pressure monitoring available for all patients Yese Noe

Superior vena cava or inferior vena cava/RA pressure/oxygen saturationmonitoring available for all patients

Yese Noe

Cardiac output monitoring available for all patients Yese Noe

Continuous renal replacement therapy available for all patients Yese Noe

Plasma exchange available for all patients Yese Noe

Extracorporeal membrane oxygenation available for all patients Yese Noe

High-flow oxygen ventilation available for all patients Yese Noe

Inhalable nitric oxide available for all patients for persistent pulmonaryhypertension of the newborn

Yese Noe

Clinical parameter bundleCapillary refill restored to �2 secs in ED/first hour Yese Noe

Blood pressure restored to normal in ED/first hour Yese Noe

Administer IV fluids in ED/first half-hour for stage III/IV shock Yese Noe NAe

Administer IV antibiotics/antimalarials if appropriate in ED/first hour Yese Noe NAe

Administer high flow oxygen in ED/first hour for tachypnea or pneumonia Yese Noe NAe

D10 with sodium administered at maintenance to prevent hypoglycemia Yese Noe

Fluid resuscitation �20 mL/kg up to 60 mL/kg administered in first hour ifappropriate

Yese Noe NAe

Peripheral epinephrine administered in first hour if appropriate Yese Noe NAe

Central epinephrine for cold shock/norepinephrine for warm shock in firsthour if appropriate

Yese Noe NAe

Normal mean arterial pressure–central venous pressure and superior venacava or inferior vena cava/RA oxygen saturation �70% targeted inintensive care unit

Yese Noe NAe

Yese Noe NAe

Absolute adrenal insufficiency treated with steroids Yese Noe NAe

Ketamine used as sedation agent for intubation/central line placement Yese Noe NAe

Ventilator provided for respiratory failure Yese Noe NAe

Effective tidal volume maintained at 6-8 mL/kg Yese Noe NAe

Appropriate (sensitive) antibiotic administered in first 2 hrs Yese Noe NAe

Immunosuppressants held if using immune suppressive therapy Yese Noe NAe

Hyperglycemia controlled by insulin Yese Noe NAe

Intravenous immunoglobulin/clindamycin administered for toxic shock(group A Streptococcus or Staphylococcus)

Yese Noe NAe

Surgical nidus removed if appropriate Yese Noe NAe

Cardiac index maintained between 3.3 and 6.0 using American College ofCritical Care Medicine guidelines

Yese Noe NAe

Continuous renal replacement therapy used for fluid overload andmultiorgan failure before 3 days if appropriate

Yese Noe NAe

Plasma exchange used to treat thrombocytopenia-induced multiorgan failureuntil resolution of thrombocytopenia

Yese Noe NAe

High-flow oxygen ventilation used if peak inspiratory pressure �35 cmH2O Yese Noe NAe

Inhalable nitric oxide used for persistent pulmonary hypertension of thenewborn

Yese Noe NAe

Extracorporeal membrane oxygenation used for refractory cardiopulmonaryfailure

Yese Noe NAe

ED, emergency department; IV, intravenous; NA, not applicable; RA, right atrium.

498 Pediatr Crit Care Med 2011 Vol. 12, No. 5

(odds ratio, 0.369; 95% confidence inter-val, 0.188–0.724; p � .004) or the sub-sequent intensive care unit managementbundle/checklist (odds ratio, 0.277; 95%confidence interval, 0.096–0.800; p �.018). The models have an acceptable fit(Omnibus chi-square test, 9.282, degreesof freedom � 1, p � .002 and Wald test �8.392, degrees of freedom � 1, p � .004for resuscitation bundle; and Omibus chi-square test, 7.556, degrees of freedom �1, p � .006 and Wald test � 5.628, de-grees of freedom � 1, p � .018 for sub-sequent management bundle).

DISCUSSION

The Pediatric Global Sepsis Initiativehas begun. There are functioning videolinks with lectures and interactive cases,source guideline documents, and the qual-ity-assurance bundle/checklist program.Thus far in the vanguard phase, 23 centershave participated and received quality-assurance reports to inform local qualityimprovement programs. In a participatingcenter (Joseph A. Carcillo), the reports werefound to be helpful. The participants con-gratulated themselves when they foundthey were administered antibiotics andfluid resuscitation in the emergency de-

partment at a rate commensurate with ourresource-specific category group but weresurprised to find that our emergency de-partment was not starting peripheral ino-tropes. They were performing below ourresource-specific category in this part ofthe checklist and are now embarking on aroot cause analysis to determine what bar-riers exist to this recommended practice inour local setting.

The initiative now needs continuedparticipation by the 23 centers and,more importantly, recruitment of othercenters. The numbers of patients ad-mitted in centers with administrativebundles A and B who participated werefew and entered few patient data in thedatabase despite many centers complet-ing the initial registration. This may bebecause of a variety of reasons, includ-ing limited resources to enter patientdata and overwhelming workloads, asare already recognized in many of theseareas. However, it is in these very areaswhere large numbers of patients pres-ent with sepsis and many die with theseinfections even before arriving to defin-itive therapy within institutions (30). Itis therefore imperative that these cen-ters not be ignored and that more effort

be placed on determining the reasonsand in facilitating their participation inthis project. At the upcoming WFPICCSWorld Congress, new approaches willneed to be developed to outreach thesecenters.

Centers with high resources (catego-ries C and D) were able to enter data.However, most of the data were contrib-uted by five centers, with most of thepatients in category D. Individuals inthese centers indicated that all consecu-tive patients with sepsis were enrolledand, hence, this represents the likelytreatment that would be obtained in cen-ters C and D. Our data indicate that mostpatients whose data were entered wereyounger than 6 yrs and that the manage-ment bundle and resuscitation bundleswere not applied rigorously. These dataare in keeping with the experience fromthe adult Surviving Sepsis CampaignWeb-based bundles/checklist quality-assurance initiative that, although beinga more mature project (165 sites and15,022 subjects), demonstrated that com-pliance with the entire resuscitation bun-dle was only 31% and compliance withthe entire subsequent management bun-

Figure 2. The Global Sepsis Initiative category A bundle report. The participants enter their own administrative data and then are assigned their respectivehealth resource level. Members in the A level received this report of all participants as well as their own anonymous single-center report for use in qualityassurance and process improvement. Yes indicates that the treatment was warranted and was administered. No indicates the treatment was notadministered even though it was warranted. Not applicable or not appropriate (n/a) indicates the treatment was not warranted and therefore it was notadministered. Three treatments are recommended in category A. Antibiotics were administered in a timely manner to �60%. Mortality was 30%.OralGlyMeningitis, oral glyercol for meningitis; WHO, World Health Organization.

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dle was only 36% by the end of the secondyear (31).

Studies involving adults have shownthat improvement in survival is related tothe number of bundle interventions com-pleted. For instance, Castellanos-Ortegaet al (32) using a quasi-experimental de-sign with a historical comparison groupin a single center described the effective-ness of the campaign bundles with regardto implementation and outcome in pa-tients with septic shock and determinedthe contribution of the various bundleelements to outcome. They found thatin-hospital mortality was reduced from57% in the historical group to 38% in theinterventional group (p � .001). Further-more, improvements in survival were re-lated to the number of bundle interven-tions completed (32). In support of thisfinding, we also observed that improvedsurvival was associated with increasedbundle compliance in our vanguardphase. It is expected that individual cen-ters will review their data regarding com-pliance with therapies relevant to their

environment and determine oversight ordeficiencies in care that need to be ad-dressed. With this approach, we expect tosee a decrease in mortality from sepsis asadherence to comprehensive bundles isincreased. This is the overall goal of theinitiative. To achieve this, centers canexpect to see their scorecard of adherenceto individual recommendations and asummary of their outcomes, as well ascomparison to other centers with similarresources. Although the denominator ofthis activity (the total number of sepsisadmissions) cannot be verified withouton-site audits, individuals have commit-ted to submit data from all patients. Thiswill be reinforced by periodic remindersbut cannot be guaranteed.

Our low compliance rate is similar tothat observed in the concurrent audit ofthe U.K. pediatric intensive care studygroup. Inwald et al (33), in an observa-tional study of pre-intensive care unitcare in the United Kingdom involving 17pediatric intensive care units, reportedthat the ACCM/PALS guidelines were not

followed in 62% of cases. Furthermore,the odds ratio for death if shock was pres-ent on intensive care unit admission was3.8 (95% confidence interval, 1.4–10.2;p � .008). In the U.K. study, failure torecognize shock and inadequate fluid andinotropic support in the first crucialhours contributed to unresolved shock(33). The ACCM/PALS guidelines wereonly followed in 36% of instances inthose patients in whom shock was notresolved when entering the intensive careunit. There is also the issue of perceptionvs. practice gap, as outlined by Brunk-horst et al (34), which may present bar-riers to adoption of sepsis bundles. This isan important finding because failure toprovide aggressive treatment was associ-ated with poor outcomes in our interna-tional sample as well. The odds for sur-vival for a given patient was reducedmore than three-fold if the subsequentmanagement procedures were not under-taken, and it was reduced almost three-fold when resuscitation procedures werenot undertaken. This mirrors the U.K.

Figure 3. The Global Sepsis Initiative category B bundle report. The participants enter their own administrative data and then are assigned their respectivehealth resource level. Members in the B level received this report of all participants as well as their own anonymous single-center report for use in qualityassurance and process improvement. Yes indicates the treatment was warranted and was administered. No indicates the treatment was not administeredeven though it was warranted. Not applicable or not appropriate (n/a) indicates the treatment was not warranted and therefore it was not administered.Seven interventions are recommended on the checklist for category B. More than 60% received antibiotics in a timely manner, 90% received high-flowoxygen (O2), and all received intravenous (IV) fluids. Mortality was 18%. OralGlyMeningitis, oral glyercol for meningitis; ED, emergency department; Na,sodium.

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audit result. At the upcoming WFPICCSWorld Congress, we will discuss betterways to learn about and overcome barri-ers to implementation.

The initiative is a nascent work inprogress. We hope to have spirited dis-cussion on many topics related to thePediatric Global Sepsis Initiative at theWFPICCS international meeting in Syd-ney, Australia, in 2011. How many local-ities in category B have emergency clin-ics? How many hospitals in developingcountries have the capacity to ventilatemore than a few patients? Who shouldenter the data in the initiative? Shouldthe data be quality-controlled? How doesone decide if an intervention is applica-ble? How will data be analyzed? Shouldseverity of illness data be included? Howshould one address difficulties in alloca-

tion to category? Presently, if a partici-pant is in a developing country but can-not provide a mechanical ventilator to allchildren in the unit, then the programdefaults to category B, not category C asthe participant may wish. Also, partici-pants in the developed world may nothave a transport team or extracorporealsupport available. The program will de-fault this participant to category C, notcategory D as the participant may wish.The participants can override the deci-sion and pick the category of their choice.Is this acceptable? What human subjectsprotection thinking relates to globalquality-assurance programs such as theWHO hospital infection surveillance pro-grams? What are the barriers to bundlecompliance? Is it lack of available equip-ment? Is it lack of agreement with WHO–

Integrated Management of Childhood Ill-nesses, ACCM-PALS, and SurvivingSepsis recommendations? Is it lack ofagreement that the checklist representsthese recommendations? Is it lack oforganization or human effort? This ar-ticle is intended to highlight thelaunching of the initiative, to outlineits potential benefits, and to raise theissue that we need input from memberorganizations and individuals to resolveto improve the deliverables from thisinitiative. It is hoped that discussions ofthese questions will lead to understand-ing systems in various parts of theworld to further inform what needs tobe accomplished to improve interna-tional participation and attainment ofthe child health goals of the initiative.In addition, further understanding of

Figure 4. The Global Sepsis Initiative category C bundle report. The participants enter their own administrative data and then are assigned their respectivehealth resource level. Members in the C level received this report of all participants as well as their own anonymous single-center report for use in qualityassurance and process improvement Yes indicates the treatment was warranted and was administered. No indicates the treatment was not administeredeven though it was warranted. Not applicable or not appropriate (n/a) indicates the treatment was not warranted and therefore it was not administered.Twenty-one interventions are recommended for category C. Appropriate timing of antibiotics occurred in 70%, 80% received fluids in the emergencydepartment (ED), 85% received mechanical ventilation, and peripheral epinephrine was administered to 10%. Mortality was 29.8%. OralGlyMeningtis, oralglycerol for meningitis; MAP, mean arterial pressure; CVP, central venous pressure; SVC, superior vena cava; IVIG, intravenous immunoglobulin; Na,sodium; BP, blood pressure; IV, intravenous.

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the contribution of various componentsof the bundle to outcome also needs tobe undertaken. This can be accom-plished with ongoing enrollment andmaturation of this child health pro-gram.

The bundle/checklist component of theSurviving Sepsis Campaign for adult severesepsis has been considered successful indecreasing sepsis adverse outcomes glob-ally. The Federation is confident thatthe same can be attained for our chil-dren. Please become ambassadors forthe Pediatric Global Sepsis Initiativeand join the initiative by contacting usonline or meeting us at the Pediatric Crit-ical Care World Congress in Sydney,Australia, March 13–17, 2011. Please join

us at http://www.pediatricsepsis.org orhttp://www.wfpiccs.org.

REFERENCES

1. World Health Organization: The MillenniumDevelopment Goals Report 2005. Availableat: http://millenniumindicators.un.org/unsd/mi/pdf/MDG%20Book.pdf. Accessed December12, 2008

2. Integrated Management of Childhood Ill-nesses: WHO/UNICEF Initiative IntegratedManagement of Childhood Illness. Availableat: http://www.Who.Int/Child-Adolescent-Health/New_Publications/IMCI/Imci.Htm.Accessed December 12, 2008

3. United Nations Children’s Fund: The state ofthe world’s children 2006. Excluded and in-visible. Available at: http://www.unicef.org/

sowc06/pdfs/sowc06_full report.pdf. AccessedDecember 12, 2008

4. Levy MM, Fink MP, Marshall JC et al: 2001SCCM/ESICM/ACCP/ATS/SIS InternationalSepsis Definitions Conference. IntensiveCare Med 2003; 29:530–538

5. Surviving sepsis. Available at: http://www.survivingsepsis.org/hcp_campaign_description.html. Accessed December 12, 2008

6. Carcillo JA, Fields AI: Clinical practice pa-rameters for hemodynamic support of pedi-atric and neonatal patients in septic shock.Available at: http://www.sccm.org/SCCM/Professional_Resources/Guidelines. AccessedDecember 12, 2008

7. Brierly J, Carcillo JA, Choong K, et al: Clin-ical practice parameters for hemodynamicsupport of pediatric and neonatal septicshock: 2007 update for the American College

Figure 5. The Global Sepsis Initiative category D bundle report. The participants enter their own administrative data and then are assigned their respectivehealth resource level. Members in the D level received this report of all participants as well as their own anonymous single-center report for use in qualityassurance and process improvement Yes indicates the treatment was warranted and was administered. No indicates the treatment was not administeredeven though it was warranted. Not applicable or not appropriate (n/a) indicates the treatment was not warranted and therefore it was not administered.Twenty seven interventions are recommended in Category D. Appropriately timed antibiotics were delivered in over 70%, early fluid resuscitation occurredin 99%, mechanical ventilation was given to 90%, and peripheral epinephrine to �50%. Mortality was 11.3%.OralGlyMeningitis � Oral glycerol formeningitis; MAP, mean arterial pressure; CVP, central venous pressure; SVC, superior vena cava; IVIG, intravenous immunoglobulin; Na, sodium; BP, bloodpressure; IV, intravenous iNO, inhaled nitric oxide; ECMO, extracorporeal membrane oxygenation; PPHN, persistent pulmonary hypertension of thenewborn; CRRT, continuous renal replacement therapy; CI, confidence interval.

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of Critical Care Medicine Crit Care Med2009; 33:666–688

8. Goldstein B, Giroir B, Randolph A: Interna-tional pediatric sepsis consensus conference:Definitions for sepsis and organ dysfunctionin pediatrics. Pediatr Crit Care Med 2005;6:2–8

9. Bryce J, Black RE, Walker N, et al: Can theworld afford to save the lives of 6 millionchildren each year? Lancet 2005; 365:2193–2200

10. Bang AT, Bang RA, Baitule SB, et al: Effect ofhome-based neonatal care and managementof sepsis on neonatal mortality: Field trial inrural India. Lancet 1999; 354:1955–1961

11. Bang AT, Reddy HM, Deshmukh MD, et al:J Perinatol 2005; 25(Suppl):S92–S107

12. Brooks WA, Santosham M, Naheed A, et al:Effect of weekly zinc supplements on inci-dence of pneumonia and diarrhoea in chil-dren younger than 2 years in an urban, low-income population in Bangladesh:Randomised controlled trial. Lancet 2005;366:999–1004

13. Ngo NT, Cao XT, Kneen R, et al: Acute man-agement of dengue shock syndrome: A ran-domized double-blind comparison of 4 intra-venous fluid regimens in the first hour ClinInfect Dis 2001; 32:204–213

14. Dung NM, Day NP, Tam DT, et al: Fluidreplacement in dengue shock syndrome: Arandomized double blind comparison of fourintravenous fluid regimens. Clin Infect Dis1999; 29:787–794

15. Ranjit S, Kissoon N, Jayakumar I: Aggressivemanagement of dengue shock syndrome maydecrease mortality rate: A suggested proto-col. Pediatr Crit Care Med 2005; 6:412–419

16. Wills BA, Nguyen MD, Ha TL, et al: Compar-ison of the three fluid solutions for resusci-tation in dengue shock. N Engl J Med 2005;353:877–889

17. Maitland K, Pamba A, English M, et al: Ran-domized trial of volume expansion with al-bumin or saline in children with severe ma-laria: Preliminary evidence of albuminbenefit. Clin Infect Dis 2005; 40:538–545

18. Maitland K, Pamba A, English M, et al: Pre-transfusion management of children with se-vere malarial anemia: A randomized con-trolled trial of intravascular expansion. Br JHaematol 2005; 128:393–400

19. Pamba A, Maitland K: Capillary refill: Prog-nostic value in Kenyan children. Arch DisChild 2004; 89:950–955

20. Kumar A, Robert D, Wood KE, et al: Durationof hypotension before initiation of effectiveantimicrobial therapy is the critical determi-

nant of survival in human septic shock. CritCare Med 2006; 34:1589–1596

21. Cam BV, Tuan DT, Fonsmark L, et al: Ran-domized comparison of oxygen mask treat-ment vs. nasal continuous positive airwaypressure in dengue shock syndrome withacute respiratory failure. J Trop Pediatr2002; 48:335–339

22. Duke T, Frank D, Mgone J: Hypoxaemia inchildren with severe pneumonia in PapuaNew Guinea. Int J TB lung Dis 2000;5:511–519

23. Pollard AJ, Brto J, Nadel S, et al: Emergencymanagement of meningococcal disease. ArchDis of Child 1999; 80:290–296

24. Maat M, Buysse CM, Spanjaard L, et al: Im-proved survival of children with sepsis andpurpura: Effects of age, gender, and era. CritCare 2007; 11:R112

25. Carcillo JA, Kuch BA, Han YY, et al: Mortalityand functional morbidity after use of PALS/APLS by community physicians. Pediatrics2009; 124:500–508

26. Han YY, Carcillo JA, Dragotta MA, et al: Earlyreversal of pediatric-neonatal septic shock bycommunity physicians is associated with im-proved outcome. Pediatrics 2003; 112:793–799

27. de Oliveira CF, de Oliveira DS, GottschaldAF, et al: ACCM/PALS haemodynamic sup-port guidelines for paediatric septic shock:An outcomes comparison with and withoutmonitoring central venous oxygen satura-tion. Intensive Care Med 2008; 34:1065–1075

28. Foland FA, Fortenberry JD, Warshaw BL, etal: Fluid overload before continuous hemo-filtration and survival in critically ill chil-dren: A retrospective analysis. Crit Care Med2004; 32:1771–1776

29. Fortenberry JD, Paden ML: Extracorporealtherapies in the treatment of sepsis: Experi-ence and promise. Semin Pediatr Infect Dis2006; 17:72–79

30. Kissoon N: Out of Africa: A mother’s Journey.Pediatr Crit Care 2010; Jan 9 [Epub ahead ofprint]

31. Levy MM, Dellinger RP, Townsend SR, et al:Surviving Sepsis Campaign: Results of aninternational guideline-based performanceimprovement program targeting severe sep-sis. Crit Care Med 2010; 38:367–374

32. Castrellanos-Ortega A, Suberviola B, Garcia-Astudilo L, et al: Impact of the survivingsepsis campaign protocols on hospital lengthof stay and mortality in septic shock patients:Results of a three year follow up quasi exper-imental study. Crit Care Med 2010; 38:1036–1043

33. Inwald DP, Tasker RC, Peters MJ, et al:Emergency management of children with se-vere sepsis in the United Kingdom: The re-sults of the Paediatric Intensive Care Societysepsis audit. Arch Dis Child 2009 May; 94:348–353

34. Brunkhorst FM, Engel C, Ragaller M, et al:Practice and perception–A nationwide surveyof therapy habits in sepsis. Crit Care Med2008; 36:2719–2725

APPENDIX

List of contributors to site develop-ment (last name, first name: e-mail ad-dress)

Brandao, Marcelo: mbbrandao1964@yahoo.com; mbbrandao@globo.com

Carcillo,Joseph:carcilloja@ccm.upmc.edu

Choueiry, Elie: eliechoueiry@hotmail.com

Crespo, Johana: johana_belara@yahoo.esDursun, Oguz: oguzdursun@akdeniz.

edu.trFernandez, Mauricio: mauriciof@une.

net.coFioretto, Jose: jrf@fmb.unesp.brGarcia, Pedro Celiny: celiny@pucrs.brJaramillo-Bustamante, Juan Camilo:

juancajara@une.net.coKhaldi, Ammar: ammarkhaldi@yahoo.frKlonin, Hilary: hilary@lama.karoo.

co.ukKrahn, Gordon: gkrahn@cw.bc.caLatour, Jos: j.latour@erasmusmc.nlMalik, Mohammad: mtmalik@gmail.

comMangia, Cristina: crismangia@netscape.

netMartic, Jelena: jmartic@net2yu.netMartin, Daniel: mata_da@hotmail.

comMelgaco,Juliana:melgacojm@hotmail.

comRinge, Hannelore: Hannelore.

ringe@charite.deSideri,Georgia:Georgia_sideri@yahoo.

co.ukThorp, Jess: jessthrp@yahoo.co.ukTinsley, Cynthia: ctinsley@llu.eduUdani, Soonu: drudani@hotmail.com

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