Hospital-acquired infections have a higher mortality

Transcription

1 Dignosis nd Tretment of Ventiltor-Associted Infection: Review of the Criticl Illness Stress-Induced Immune Suppression Prevention Tril Dt Dougls F. Willson, MD 1 ; Angel Webster, PhD 2 ; Sbrin Heidemnn, MD 3 ; Kthleen L. Meert, MD 3 ; the Eunice Kennedy Shriver Ntionl Institute of Child Helth nd Humn Development (NICHD) Collbortive Peditric Criticl Cre Reserch Network (CPCCRN) Objectives: The Criticl Illness Stress-Induced Immune Suppression prevention tril ws rndomized, msked tril of zinc, selenium, glutmine, nd metocloprmide compred with whey protein in delying nosocomil infection in PICU ptients. One fourth of study subjects were dignosed with nosocomil lower respirtory infection, which contributed to subjects receiving ntibiotics 74% of ll ptient dys in the PICU. We nlyzed dignostic nd tretment vribility mong the prticipting institutions nd compred outcomes between nosocomil lower respirtory infection subjects (n = 74) nd intubted subjects without nosocomil infection (n = 1 55). Design: Post hoc nlysis. Setting: Eight hospitls in the Collbortive Peditric Criticl Cre Reserch Network. Ptients: Criticl Illness Stress-Induced Immune Suppression study subjects. Interventions: None. Mesurements nd Min Results: Vribility cross institutions existed in the frequency nd mnner by which respirtory secretion cultures were obtined, processed, nd results reported. Most results were reported semiquntittively, nd both Grm stins nd ntibiotic sensitivities were frequently omitted. The nosocomil lower respirtory infection dignosis ws ssocited with incresed PICU lengths of sty compred with those who 1 Children s Hospitl of Richmond t Virgini Commonwelth University, Richmond, VA. 2 University of Uth, Slt Lke City, UT. 3 Children s Hospitl of Michign, Detroit, MI. This work ws supported, in prt, by the following coopertive greements from the Eunice Kennedy Shriver Ntionl Institute of Child Helth nd Humn Development (NICHD), Ntionl Institutes of Helth (NIH), Deprtment of Helth nd Humn Services (DHHS): U10HD050096, U10HD049981, U10HD050009, U10HD049945, U10HD049983, U10HD050012, nd U01HD The uthors hve disclosed tht they do not hve ny potentil conflicts of interest. For informtion regrding this rticle, E-mil: Dougls.willson@vcuhelth.org Copyright 2016 by the Society of Criticl Cre Medicine nd the World Federtion of Peditric Intensive nd Criticl Cre Societies DOI: /PCC were intubted without nosocomil infection (24 ± 19 vs 9 ± 6 d; p < 0.001) nd ntibiotic use (38 ± 29 vs 15 ± 20 ntibiotics dys; p < 0.001). Despite ntibiotic tretment, the sme bcteri persisted in 45% of follow-up cultures. Conclusions: The Criticl Illness Stress-Induced Immune Suppression dt demonstrte tht the nosocomil lower respirtory infection dignosis is ssocited with longer lengths of sty nd incresed ntibiotic use, but there is considerble dignostic nd tretment vribility cross institutions. More rigorous stndrds for when nd how respirtory cultures re obtined, processed, nd reported re necessry. Bcteril persistence lso complictes the interprettion of follow-up cultures. (Peditr Crit Cre Med 2016; XX:00 00) Key Words: hospitl-cquired infection; lower respirtory infection; respirtory filure; ventiltor-ssocited infection Hospitl-cquired infections hve higher mortlity thn ny of the top 10 leding illnesses in the United Sttes (1), nd this fosters low threshold for inititing ntibiotics in criticlly ill ptients. Although erly nd ggressive use of ntibiotics cn be lifesving, their indiscriminte use contributes to the emergence of multiresistnt microbes. Thus, ccurte nd expedient dignosis of nosocomil infection in the ICU is impertive to ssure dequte tretment while voiding unnecessry ntibiotic exposure. Ventiltor-ssocited infections (VAIs) re the most common nosocomil infections in the PICU nd the most frequent reson for ntibiotic use (2). The high degree of vribility in reported incidence (3 5), however, reflects the mbiguity nd subjectivity of the Centers for Disese Control nd Prevention (CDC) dignostic criteri (6). No gold stndrd exists for the dignosis of VAI, nd the recent doption of the ventiltor-ssocited event (VAE) criteri (7) in dult medicine is in lrge prt responsive to the indequcies of the previously estblished CDC criteri (6). Unfortuntely, despite their greter objectivity, the new VAE criteri do not ddress the indictions for ntibiotics (8). Peditric Criticl Cre Medicine 1

2 Willson et l The Criticl Illness Stress-Induced Immune Suppression (CRISIS) prevention tril (9) illustrtes the problems with the CDC VAI criteri nd their impct on ntibiotic use. CRISIS ws rndomized, msked comprtive effectiveness tril of combintion of zinc, selenium, glutmine, nd metocloprmide (ZSGM) compred with whey protein in delying the onset of nosocomil infection in PICU ptients. While the study filed to demonstrte benefit with ZSGM, one fourth of the study subjects (26%) were dignosed with one or more episodes of VAI, specificlly lower respirtory infection (LRI), bsed on the CDC criteri. The CDC LRI criteri require only isoltion of pthogen from respirtory secretion culture in the presence of fever, hypothermi, chills, or hypotension (6). The frequency of this dignosis ws mjor contributor to the fct tht subjects in the study spent 74% of ll ptient dys in the PICU on one or more ntibiotics. We questioned the significnce of the nosocomil LRI dignosis nd frequent use of ntibiotics in the CRISIS study. Consequently, we nlyzed the study dt to evlute dignostic nd tretment vribility mong the prticipting institutions, to identify the puttive pthogens isolted from respirtory secretion cultures nd their response to ntibiotics, nd to ssess whether the nosocomil LRI dignosis ws ssocited with morbidity or mortlity reltive to subjects who required mechnicl ventiltion, but were not dignosed with nosocomil infection. METHODS The study ws n nlysis of the limited dtset from the CRI- SIS study mde vilble nd pproved by the Eunice Kennedy Shriver Ntionl Institute of Child Helth nd Humn Development Collbortive Peditric Criticl Cre Reserch Network. No privte helth informtion ws included in the dtset nd, s such, the study did not constitute humn reserch nd institutionl review bord pprovl ws not sought. The CRISIS prevention tril ws rndomized, msked comprtive effectiveness tril of the combintion of ZSGM compred with whey protein lone in delying the onset of nosocomil infection in criticlly ill children. Entry criteri included ges 1 18 yers, enrollment within 48 hours of PICU dmission, the presence of one or more invsive devices (centrl venous ctheter, urinry ctheter, or endotrchel tube), nd the expecttion tht the subject would hve venous or rteril ccess for the purpose of blood drws during the first 3 dys of the study. Subjects were rndomized to receive dily enterl whey protein powder or ZSGM for 28 dys or until PICU dischrge, whichever cme first. The subjects were followed for the development of nosocomil infection in the PICU nd up to 5 dys fter PICU dischrge for mximum of 33 dys. A totl of 293 subjects were rndomized cross eight hospitls ffilited with the Collbortive Peditric Criticl Cre Reserch Network (CPCCRN). The study ws conducted from April 2007 to November CDC criteri were used to define nosocomil infection (9). Clinicl sepsis ws dignosed when subject (> 1 yr old) hd fever ( 38 C), hypotension ( 90 mm Hg systolic pressure), or oliguri ( 20 ml/hr) nd the clinicin-initited ntibiotics without positive culture or other recognized cuse. Nosocomil infection ws dignosed when microbiologiclly proven infection (culture, ntigen, polymerse chin rection, or ntibody) ws observed in subject hospitlized beyond 48 hours with fever, hypothermi, chills, or hypotension. If the culture ws obtined from respirtory secretions, it ws deemed LRI irrespective of chest rdiogrph or ny dditionl clinicl findings. CPCCRN members blinded to tretment rm djudicted ll infections t the Network qurterly meetings. Other thn the dministrtion of the study intervention, decisions regrding ll spects of clinicl cre remined the purview of the treting physicins. Specificlly, there were no protocols regrding when or how cultures or other studies were to be obtined or for the use of ntibiotics. Three investigtors (D.F.W., K.L.M., S.H.) extrcted dt from subject cse report forms (CRFs). To confirm relibility of dt extrction, two of the investigtors independently reviewed 1 in 10 of the CRFs chosen t rndom nd compred results. Specific elements extrcted included results of ll respirtory cultures nd their method of collection (trchel spirtion vs broncholveolr lvge [BAL]), identifiction nd sensitivities (if performed) of the microorgnism, nd ntibiotic tretment. Subject demogrphics nd outcomes hd been previously entered into the study dtbse. To determine the significnce of the nosocomil LRI dignosis, we compred clinicl chrcteristics nd outcomes between subjects dignosed with nosocomil LRI nd those intubted but not dignosed with LRI or ny other nosocomil infections or sepsis. In this explortory nlysis, we excluded subjects with less thn 3 dys of follow-up in the PICU fter PICU dmission. Specificlly, 289 of the 293 rndomized children were included. Of these 289 subjects, 155 (54%) were intubted, but nosocomil infection or sepsis did not develop in the subjects, nd 74 (26%) were dignosed with nosocomil LRI (Fig. 1). We compred subject chrcteristics, outcomes, ntibiotic usge, respirtory cultures, nd intubted dys between the two cohorts (LRI; intubted without nosocomil infection). We lso described the dignostic nd tretment vribility mong the prticipting institutions using descriptive sttistics. Ctegoricl vribles re summrized s bsolute counts nd percentges. Continuous vribles re summrized s mens nd sds. Sttisticl significnce of differences between cohorts with respect to ech chrcteristic ws ssessed by the Person chi-squre or Fisher exct test for ctegoricl vribles nd the Wilcoxon rnk sum test for continuous vribles. Reported significnce levels re not djusted for multiple comprisons, s this nlysis is considered explortory. Anlyses were performed using SAS softwre, version 9.4 (SAS Institute, Cry, NC). RESULTS As previously reported (9), totl of 93 nosocomil LRIs were dignosed in 74 of the study subjects (26%). Tble 1 compres the clinicl chrcteristics of subjects dignosed with LRI (n = 74) compred with intubted subjects without nosocomil infection (n = 155). The two groups were comprble demogrphiclly nd in severity of illness, but fewer LRI subjects were immune compromised (1% vs 9%) nd fewer hd endotrchel 2 XXX 2016 Volume XX Number XXX

3 Feture Article Figure 1. Subject flow digrm. LRI = lower respirtory infection. tubes in plce (88% vs 97%) t rndomiztion. The dignosis of nosocomil LRI ws ssocited with significntly longer durtions of intubtion nd lengths of hospitl nd PICU sty (Tble 2). There ws no difference in mortlity. Becuse subjects were intubted n verge of 5 dys prior to the development of n LRI, we lso seprtely compred subjects with durtion of intubtion greter thn 5 dys. In tht subgroup of subjects, the verge durtion of intubtion ws 9 dys (± 5 d) for intubted subjects without nosocomil infection (n = 50) compred with 15 dys (± 8 d) for intubted subjects with nosocomil LRI (n = 64) (p < ). Thirteen subjects were dignosed with two or more LRI events. The verge durtion of intubtion ws 12 dys for subjects with only one LRI event compred with 20 dys for those with two or more events (p = 0.01), nd the verge PICU sty ws 23 nd 26 dys (p = 0.08), respectively. The study protocol did not dictte how respirtory cultures were to be obtined. In subjects dignosed with LRI, 80% of the initil culture specimens were obtined by simple trchel spirte nd 20% by BAL. One center routinely obtined cultures by BAL (8 of 12 initil cultures) while most did simple trchel spirtes. Overll, 33% Tble 1. Subject Chrcteristics Subject Chrcteristics Intubted Without Nosocomil Infection (n = 155) Nosocomil Lower Respirtory Infection (n = 74) p Age (yr), men (sd) 8 (6) 9 (6) 0.16 Gender (% mle) Rce n = 149 n = % White % Blck % Asin or other 6 6 Ethnicity n = 149 n = % Hispnic Peditric risk of mortlity, men (sd) 9 (6) 10 (7) 0.34 Peditric logistic orgn dysfunction, men (sd) 11 (9) 12 (10) 0.51 Orgn filure index, men (sd) 2 (1) 2 (1) 0.35 Existing infection or clinicl sepsis 72% 59% 0.07 Present t rndomiztion, % Endotrchel tube Centrl line Urinry ctheter Immune compromised, % As defined by Criticl Illness Stress-Induced Immune Suppression study criteri (9). Peditric Criticl Cre Medicine 3

4 Willson et l Tble 2. Outcomes Outcomes Intubted Without Nosocomil Infection (n = 155) Nosocomil Lower Respirtory Infection (n = 74) p 28-D mortlity (%) 12 (8) 9 (12) 0.30 PICU length of sty (LOS), men (sd) 9 (6) 24 (19) < Hospitl LOS, men (sd) 18 (19) 34 (24) < Intubted dys, men (sd) 5 (4) 14 (9) < Three subjects in the intubted without nosocomil infection group re excluded becuse their mortlity sttus ws unknown. (178 of 536) of ll the respirtory cultures obtined were positive in tht orgnisms judged to be pthogenic were identified on culture. Stphylococcus ureus, Cndid, nd Pseudomons were the most common orgnisms isolted (Tble 3). Of the 93 dignosed LRIs, 59 (63%) hd one or more subsequent respirtory secretion cultures performed t times rnging from 1 to 17 dys fter the initil positive culture. In 75 of 166 of these follow-up cultures (45%), the sme orgnism ws identified s in the previous culture (Tble 4). In nerly ll of these infection episodes, subjects were on ntibiotics for which the orgnisms hd either demonstrted sensitivity or re generlly considered to be pproprite tretment (e.g., vncomycin for S. ureus; pipercillin tzobctm for Pseudomons). Pseudomons (40%) nd S. ureus (29%) were the most common persistent bcteri Tble 3. Microbes in Initil Positive Cultures Bcteri Cultures % Stphylococcus ureus Cndid/ Yest Pseudomons Hemophilus influenz Enterobcter 6 6 Morxell 5 5 Klebsiell 3 3 Stenotrophomons 3 3 Serrti 3 3 Strep species 2 3 Acinetobcter 2 2 Eikenell 1 1 Influenz 1 1 Enterococcus 1 1 Cryptococcus 1 1 Streptococcus pneumoni 1 1 Citrobcter 1 1 Numbers dd to > 93 becuse some cultures hd more thn one identified orgnism. in follow-up cultures. In severl subjects, the sme bcteri persisted in cultures despite multiple chnges in ntibiotics (dt not shown). Lbortory processing nd reporting of culture nd Grm stin results ws vrible both cross nd within institutions. BAL-obtined culture results were routinely reported quntittively, wheres trchel spirte obtined cultures nd Grm stins were reported semiquntittively (i.e., 1+, 2+, etc., or few, moderte, mny ) with respect to both numbers of orgnisms nd WBCs. None of the lbortories relted the semiquntittive reports to ny stndrd for comprison purposes. Of the initil positive cultures (n = 74), Grm stin identified bcteri in only 66%, with mny or 3+ polymorphonucleocytes reported in 41%. Antibiotic sensitivities for bcteri identified from the initil cultures were reported in only 34% of the isoltes. Certin bcteri, such s Morxell nd Klebsiell, were lwys tested for ntibiotic sensitivity; however, the two most commonly isolted bcteri, S. ureus nd Pseudomons, were only tested 33% nd 53% of the time, respectively. The frequency with which respirtory cultures were obtined vried cross the eight prticipting centers (Tble 5). One site rrely performed respirtory cultures (totl of 14 respirtory cultures for 31 subjects) nd identified no episodes of LRI. Antibiotics were used frequently, with subjects enrolled in the study receiving one or more ntibiotics 74% of ll ptient dys in the PICU. Most subjects (66%) were lredy receiving ntibiotics t dmission for n existing infection or dignosis of clinicl sepsis. In subjects dignosed with LRI, 80% were strted on n verge of 2.7 ntibiotics t the time the respirtory culture ssocited with the LRI ws obtined. The three most common initil ntibiotics were cephlosporins (36%), vncomycin (23%), nd pipercillin/tzobctm (8%). Subjects dignosed with LRI received n verge of 38 (± 29) ntibiotic dys in the PICU compred with 15 (± 20) ntibiotic dys in intubted subjects with no nosocomil infection events (p < ). DISCUSSION The CRISIS study protocol dictted tht identifiction of puttive pthogen from respirtory secretion culture be considered n LRI if ccompnied by clinicl symptoms tht included fever, hypothermi, chills, or hypotension. While the study protocol did not mndte ntibiotic tretment, subjects dignosed with LRI received, on verge, more thn double 4 XXX 2016 Volume XX Number XXX

5 Feture Article Tble 4. Follow-Up Cultures of Lower Respirtory Infection Subjects Institutions Subjects Lower Respirtory Infection With Follow-Up Cultures Positive Cultures b Hospitl Hospitl Hospitl Hospitl Hospitl Hospitl Totls (45%) Hospitls 5 nd 6 hd no lower respirtory infections. b Pseudomons: 30 of 75 = 40%; Stphylococcus: 22 of 75 = 29%. Tble 5. Site Vribility in Cultures Performed Institutions Subjects Intubted Dys Respirtory Cultures Respirtory Cultures/ 100 Intubted Dys Lower Respirtory Infection/ 100 Intubted Dys Hospitl Hospitl Hospitl Hospitl Hospitl 5 nd Hospitl Hospitl Overll Note tht hospitls 5 nd 6 re prt of the sme institution. the number of ntibiotics reltive to subjects intubted without nosocomil infection. This behvior is consistent with recently reported survey of peditric intensivists (10) nd is illustrtive of why suspected VAI is the most common reson for ntibiotic use in the PICU (2). The necessity nd efficcy of ntibiotics in the setting of positive respirtory secretion culture is open to question. While the lung is generlly considered sterile (lthough not completely so [11]), endotrchel tube plcement provides direct route for bcteril contmintion from spirtion of secretions (12, 13) nd the endotrchel tube biofilm (14). Coloniztion of the irwy with orophryngel flor occurs rpidly, nd identifiction of bcteri on culture cnnot distinguish coloniztion from ctul infection. We previously demonstrted tht mjority of trchel spirte cultures in intubted children grew greter thn 10 4 bcteri by dy 4 of intubtion, mny of them considered pthogens, nd this did not correlte with clinicl signs or symptoms of infection (15). The CDC criteri defines greter thn 25 WBCs per low power field s indictive of infection, but the sme study (15) showed this ws seen in the mjority of subjects. At present, no lbortory or other studies re ble to distinguish coloniztion from infection. Studies in dults hve demonstrted similr findings (16, 17). The indictions for ntibiotic tretment in the fce of positive culture re uncler, but ntibiotics hve not been found to prevent progression from so-clled ventiltor-ssocited trcheitis to ventiltor-ssocited pneumoni (18, 19). Indeed, the persistence of positive cultures with the sme orgnism despite pproprite ntibiotics in 45% of follow-up cultures in this study demonstrtes tht ntibiotics my not erdicte even sensitive bcteri. Even ssuming ntibiotics re ble to trnsiently erdicte bcteri from the trche, re-inocultion from the endotrchel biofilm is likely whenever the ptient is suctioned becuse ntibiotics re unble to penetrte the biofilm. The current terminology for VAIs is confusing nd imprecise. The CDC LRI criteri require only isoltion of pthogen from respirtory secretion culture in the presence of fever, hypothermi, chills, or hypotension (6). This could eqully define ventiltor-ssocited trcheitis (VAT), s the term is currently pplied (18 22), nd which is now thought to be more common thn ventiltor-ssocited pneumoni (VAP) in peditric ptients (23). VAT is distinguished from VAP presumbly by the bsence of new or progressive pulmonry Peditric Criticl Cre Medicine 5

6 Willson et l infiltrte (24), lthough the bility to distinguish new or progressive pulmonry infiltrtes on portble chest rdiogrphs is problemtic (25). The mbiguity of mny of the criteri in conjunction with the imprecision of the terminology undoubtedly contributes to indiscriminte use of ntibiotics. This study demonstrtes the vribility with which cultures re obtined, processed, nd reported in PICUs. BAL is stndrd in dult medicine, but limittions in size preclude its routine use in children. In the CRISIS study, prctice ws vrible with one center using primrily BAL to obtin cultures, wheres the other seven centers obtined cultures lmost exclusively by trchel spirtion. The mnner by which trchel spirtion ws performed ws lso not protocolized. Our own studies suggest tht technique my differ cross institutions (10) nd cn significntly ffect rtes of positivity (15). The lck of stndrdiztion of culture nd Grm stin results ws lso remrkble. The CDC VAP criterion for purulence of secretions is quntittive (> 10 4 bcteri nd/or > 25 WBCs per low power field [7]), but trchel spirte results in this study were reported semiquntittively (1+, 2+, etc.). However, the lck of stndrdiztion in how cultures were obtined nd reported my hve been inconsequentil becuse clinicins elected to tret with ntibiotics if ny pthogenic bcteri were identified irrespective of the quntity. The lck of ntibiotic sensitivity testing is lso notble, since subjects were frequently dministered severl ntibiotics for the presumed infection nd ntibiotics brodened or chnged when the sme bcteri persisted in subsequent cultures. Previous studies hve demonstrted the ssocition between VAI nd prolongtion of ventiltion (19, 23, 26, 27). In this study, subjects dignosed with LRI hd significntly longer durtions of intubtion even fter considering the verge 5-dy time to onset. As with previous studies, however, the dt do not elucidte whether the LRI ws the cuse or the effect of the longer durtion of intubtion. Both coloniztion nd infection rtes increse with durtion of ventiltion (15 17). Any child intubted longer thn 3 or 4 dys is likely colonized nd, consequently, respirtory culture obtined t tht time for evlution of fever or other signs or symptoms hs high probbility of being positive (15). The specificity of positive culture for infection is questionble nd, consequently, the impct of the LRI dignosis s well s the ntibiotic tretment on outcomes remins uncertin. Severl of the study findings merit emphsis (1): there is considerble vribility cross institutions in how often respirtory cultures re performed, how they re obtined, nd how lbortories process nd report them. This renders the interprettion of results difficult nd ntibiotic tretment decisions somewht rbitrry (2); the dignosis of lower respirtory infection (now more likely termed ventiltor-ssocited trcheitis ) is common, but pproprite tretment is still in question. The CRISIS study dt confirm its ssocition with longer durtion of intubtion, but it is not cler whether this ssocition is custive (3); ntibiotic tretment frequently my not erdicte pthogenic bcteri from trchel secretions even if the orgnism is demonstrted to be sensitive. This my relte less to the sensitivity of the microorgnism thn to re-inocultion from the endotrchel tube biofilm. Irrespective of the reson, brodspectrum ntibiotic therpy is ssocited with incresingly resistnt microorgnisms both in ptients nd in our ICUs. Post hoc nlysis of study dt is subject to significnt limittions, prticulrly when the nlysis pertins to spects tht were not the focus of the originl study. Our purpose ws to document the vribility regrding the dignosis of VAI even within the context of prospective study nd the consequences of the dignosis with regrd to ntibiotic use. The intent ws to elucidte the need for more rigorous pproch to this dignosis nd its ssocited therpy. CONCLUSIONS Bsed on these dt, there is need for more rigorous pproch to the dignosis of nosocomil LRI nd other VAIs. Identifiction of puttive pthogenic orgnism lone my be insufficient justifiction for ntibiotic tretment becuse it does not discriminte infection from simple coloniztion. Discrimintion is further hmpered by inconsistencies in the mnner by which respirtory cultures re obtined, processed, nd reported. Given the incresing emergence of resistnt microbes, prticulrly in the ICU, methods for the dignosis of VAI should be stndrdized nd greter discrimintion in the use of ntibiotics my be needed. REFERENCES 1. Institute of Medicine: To Err Is Humn. Wshington, DC, Ntionl Acdemy Press, Fischer JE, Rmser M, Fnconi S: Use of ntibiotics in peditric intensive cre nd potentil svings. Intensive Cre Med 2000; 26: Venktchlm V, Hendley JO, Willson DF: The dignostic dilemm of ventiltor-ssocited pneumoni in criticlly ill children. Peditr Crit Cre Med 2011; 12: Morrow BM, Mowzer R, Pitcher R, et l: Investigtion into the effect of closed-system suctioning on the frequency of peditric ventiltorssocited pneumoni in developing country. Peditr Crit Cre Med 2012; 13:e25 e32 5. Elwrd AM, Wrren DK, Frser VJ: Ventiltor-ssocited pneumoni in peditric intensive cre unit ptients: Risk fctors nd outcomes. Peditrics 2002; 109: Klomps M: Complictions of mechnicl ventiltion The CDC s new surveillnce prdigm. N Engl J Med 2013; 368: Centers for Disese Control: CDC/NHSN Surveillnce Definitions for Specific Types of Infections. Jnury 2016, p. 21. Avilble t: Accessed November, Klein Klouwenberg PM, vn Mourik MS, Ong DS, et l; MARS Consortium: Electronic implementtion of novel surveillnce prdigm for ventiltor-ssocited events. Fesibility nd vlidtion. Am J Respir Crit Cre Med 2014; 189: Crcillo JA, Den JM, Holubkov R, et l; Eunice Kennedy Shriver Ntionl Institute of Child Helth nd Humn Development (NICHD) Collbortive Peditric Criticl Cre Reserch Network (CPCCRN): The rndomized comprtive peditric criticl illness stress-induced immune suppression (CRISIS) prevention tril. Peditr Crit Cre Med 2012; 13: Willson DF, Kirby A, Kicker JS: Respirtory secretion nlyses in the evlution of ventiltor-ssocited pneumoni: A survey of current prctice in peditric criticl cre. Peditr Crit Cre Med 2014; 15: Chrlson ES, Bittinger K, Hs AR, et l: Topogrphicl continuity of bcteril popultions in the helthy humn respirtory trct. Am J Respir Crit Cre Med 2011; 184: Chstre J, Fgon JY; Ventiltor-ssocited pneumoni. Am J Respir Crit Cre Med 2002; 122: XXX 2016 Volume XX Number XXX

7 Feture Article 13. Amnté SL, Piv JP, Snches PR, et l: Orophryngel spirtion in peditric ptients with endotrchel intubtion. Peditr Crit Cre Med 2004; 5: Adir CG, Gormn SP, Feron BM, et l: Implictions of endotrchel tube biofilm for ventiltor-ssocited pneumoni. Intensive Cre Med 1999; 25: Willson DF, Conwy M, Kelly R, et l: The lck of specificity of trchel spirtes in the dignosis of pulmonry infection in intubted children. Peditr Crit Cre Med 2014; 15: Dennesen PJ, vn der Ven AJ, Kessels AG, et l: Resolution of infectious prmeters fter ntimicrobil therpy in ptients with ventiltor-ssocited pneumoni. Am J Respir Crit Cre Med 2001; 163: Brm D, Hulse G, Plmer LB: Stble ptients receiving prolonged mechnicl ventiltion hve high lveolr burden of bcteri. Chest 2005; 127: Tmm PD, Turnbull AE, Milstone AM, et l: Ventiltor-ssocited trcheitis in children: Does ntibiotic durtion mtter? Clin Infect Dis 2011; 52: Crven DE, Chroneou A, Zis N, et l: Ventiltor-ssocited trcheobronchitis: the impct of trgeted ntibiotic therpy on ptient outcomes. Chest 2009; 135: Horn TC, Andrus M, Dudeck MA: CDC/NHSN surveillnce definition of helth cre-ssocited infection nd criteri for specific types of infections in the cute cre setting. Am J Infect Control 2008; 36: Plmer LB, Smldone GC, Chen JJ, et l: Aerosolized ntibiotics nd ventiltor-ssocited trcheobronchitis in the intensive cre unit. Crit Cre Med 2008; 36: Simpson VS, Biley A, Higgerson RA, et l: Ventiltor-ssocited trcheobronchitis in mixed medicl/surgicl peditric ICU. Chest 2013; 144: Wheeler DS, Whitt JD, Lke M, et l: A cse-control study on the impct of ventiltor-ssocited trcheobronchitis in the PICU. Peditr Crit Cre Med 2015; 16: Dlls J, Kollef M: VAT vs VAP: Are we heding towrd clrity or confusion? Chest 2009; 135: Wunderink RG, Woldenberg LS, Zeiss J, et l: The rdiologic dignosis of utopsy-proven ventiltor-ssocited pneumoni. Chest 1992; 101: Srinivsn R, Asselin J, Gildengorin G, et l: A prospective study of ventiltor-ssocited pneumoni in children. Peditrics 2009; 123: Gupt S, Boville BM, Blnton R, et l: A multicentered prospective nlysis of dignosis, risk fctors, nd outcomes ssocited with peditric ventiltor-ssocited pneumoni. Peditr Crit Cre Med 2015; 16:e65 e73 Peditric Criticl Cre Medicine 7