Preventing ventilator-acquired pneumonia and pediatric ventilator-associated events in infants: a systematic review of individual interventions and practice care bundles

Introduction

Ventilator-acquired pneumonia (VAP) is a common hospital-acquired infection in neonatal intensive care units (NICUs) and pediatric intensive care units (PICUs) increasing morbidity, mortality, and length of hospital stay (1-3). VAP pathogenesis in infants is multi-factorial and is theorized to occur when pathogenic bacteria enter the respiratory system and lung parenchyma through endogenous or exogenous sources, including tracheal secretions, micro-aspiration of gastrointestinal secretions, biofilm on respiratory equipment, and via the introduction of pathogens from contaminated surfaces (1,2,4). While some risk factors for VAP, such as prolonged mechanical ventilation (MV), are common to both adults and infants, there are some unique risk factors for preterm infants, such as the use of uncuffed endotracheal tubes (ETTs), immature innate and adaptive immune systems, and premature airway epithelium (1,2,4-6). Socioeconomic status of a country and diagnostic criteria used across different units or hospitals have led to a great degree of variability in reported VAP rates, as reflected in various NICU and PICU settings in the literature (7).

VAP is defined by the Centers for Disease Control and Prevention (CDC) as pneumonia occurring in patients that are mechanically ventilated via an endotracheal or tracheostomy tube for greater than two days (8). Unlike in adults, the gold standard of obtaining specimens from lower respiratory tract via bronchoalveolar lavage in neonates or infants can be technically challenging (9). Therefore, defining VAP in neonatal and pediatric patients poses many challenges, as traditional pneumonia definitions relied on the subjective interpretation of chest radiographs and clinical respiratory features (2). Within the last decade, the CDC released a definition for pediatric ventilator-associated event (PedVAE), suggesting that monitoring VAEs (rather than VAP) provides a more objective means of conducting surveillance and informing prevention efforts for ventilator-related hospital acquired conditions (10). PedVAE events are defined by increase in the fractional inspired oxygen (FiO₂) needs (increase of minimum FiO₂ values >25% from baseline, sustained over 48 hours) and mean airway pressure (MAP) needs (increase of minimum MAP values by ≥4 cmH₂O, sustained over 48 hours) (10). However, PedVAE criteria do not necessarily differentiate between many pulmonary conditions that could result in increased ventilatory requirements, such as pneumonia, atelectasis, pulmonary edema, and barotrauma (10,11).

VAP prevention interventions have been the focus of previous systematic reviews; however, a small number of included studies in two pertinent reviews reported infant specific data (3,12). While preterm neonates are cared for in the NICU, neonates or term infants with surgical or medically complex conditions may be admitted to either the NICU or the PICU based on local practice; therefore, it is important that evaluation of VAP for infants is based on patient age rather than care environment. The objective of this review is to appraise the comparative effectiveness of single and bundled interventions on the prevention of VAP/PedVAE in infants less than twelve months of age. In addition, we studied whether these effects differed among preterm and term infants. We present this article in accordance with the PRISMA reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-25-79/rc) (13).

Methods

The protocol for the review was registered with PROSPERO (CRD42023400903) (14). We included randomized controlled trials (RCTs) as well as non-randomized studies with a control group that enrolled infants less than or equal to 12 months of age admitted to the NICU or PICU setting, mechanically ventilated through an oral or nasal ETT or tracheostomy, and evaluated the impact of an individual intervention or a care bundle on the prevention of VAP/PedVAE. For studies enrolling PICU patients, the corresponding authors were contacted for infant subgroup data if not available within the published text. PICU studies were excluded if authors were unresponsive or unwilling to provide requested infant data. As smaller studies are known to overestimate effect size and are at greater risk of bias (ROB), we excluded studies enrolling less than 20 subjects (15). We also excluded studies where infants received non-invasive ventilation only. VAP and PEdVAE were defined per CDC definitions (8,10). Studies that did not use the CDC definition for VAP, but included radiological, clinical, pathological and/or microbial criteria were also considered for inclusion (16).

Literature search

The research team worked together to identify terms to include in the search strategy. A health sciences librarian conducted searches in Ovid Medline, Embase, CINAHL, Cochrane CENTRAL trials database, Scopus, Proquest Dissertations and Theses Global and Web of Science from database inception until Feb 24, 2023. The search was subsequently updated on August 14, 2025. The search combined subject headings and free-text terms for two concepts: infants and VAP. The search strategy was optimized for each database and no date, language, publication type, or study design filters were applied. Articles in languages other than English that could be translated to English by a member of the study team were included. A google search for grey literature was initially performed in September 2023 and updated in October 2025. Reference lists of included articles and relevant reviews were searched for additional studies. The details of the search strategy are in Appendix 1.

Study selection

Results from the search were exported into the Covidence web-based platform (17). Screening of articles for inclusion was independently carried out by two members of the review team and disagreements were resolved in a team meeting by consensus.

Data extraction and methodological quality assessment

Data was extracted onto a form developed by the research team. Data extraction included: study characteristics such as country, year of publication, duration of study, study design, patient population, sample size, and route of MV; intervention details including bundle components; VAP/PedVAE definition and outcome data; other outcomes reported; and conclusions of study authors. For bundled interventions, information on all bundle elements was extracted. Data was extracted by one reviewer and verified by a second reviewer. Other outcomes of interest were length of stay (LOS), duration of MV, bronchopulmonary dysplasia (BPD) rates, bloodstream infection (BSI) rates, and mortality. ROB was assessed using the Cochrane risk-of-bias tool for randomized trials (ROB-2) (18). The Newcastle-Ottawa Scale (NOS) was used for assessing non-randomized studies (19). Two reviewers independently assessed the ROB for each of the included studies, and disagreements were resolved in a team meeting by consensus.

Synthesis approach

We did not perform meta-analyses due to clinical heterogeneity noted in the included studies in terms of varying interventions used (or their comparators), variations in patient populations and study designs, or in the methods of recording outcome data. As an alternative, the Synthesis without Meta-analysis (SWiM) guideline was used (20). Results were organized into tables differentiating single and bundled interventions. Results of single intervention studies were further organized by intervention type. Results of the included studies were standardized by calculating risk ratios (RRs) with their 95% confidence intervals (95% CIs) for the outcomes of VAP incidence and VAP rate/1,000 ventilation days.

Results

Electronic database searches retrieved 2,512 articles after removing duplicates. Figure 1 shows the flow of studies through the screening process, with 34 studies meeting inclusion criteria. Four of the included studies were in the PICU/pediatric setting (21-24) with infant subgroup data provided by authors, and the rest were in the NICU setting.

Figure 1 PRISMA flow diagram for systematic review. Template adopted from: Page MJ, McKenzie JE, Bossuyt PM, et al. BMJ 2021;372:n71. doi: 10.1136/bmj.n71.

Study characteristics

We identified 20 studies of single interventions (15 RCTs, 5 non-randomized studies) and 14 of intervention bundles (all pre-post-intervention). Study characteristics are summarized in Table 1. Studies were published between 2001 and 2025, with 32 studies published in English, and 2 in Chinese. Included studies were conducted in 20 countries spanning 5 continents. The number of patients ranged from 41 to 361 in the single intervention studies, and from 41 to 6,829 in the bundled intervention studies. Three bundled intervention studies had missing details about the pre- or post-intervention sample size (44,47,50) that prevented one or more comparisons. All included VAP studies except for 8 (26,30,31,33-35,41,46) referenced the CDC definition of VAP; these 8 studies (26,30,31,33-35,41,46) met protocol inclusion criteria and used VAP definitions as shown in Table 3. A single study reported PedVAE outcome data (40). While the National Healthcare Safety Network (NHSN) (8) specifies to report VAP as a rate/1,000 ventilator days, only 17/33 included VAP studies reported a VAP rate/1,000 ventilator days (Table 4). The review team was able to calculate VAP rate/1,000 ventilation days for an additional three studies based on the number of VAP cases and the days of MV included within these publications (24,32,52). Fifteen/34 authors reported both VAP incidence and VAP rate/1,000 ventilator days in their publication.

Methodological quality

ROB-2 (18) was used to assess the ROB in the 15 RCTs evaluating single interventions. Seven studies were assessed at high ROB (22,27,30,31,33,34,39), five had some concerns (25,28,29,32,35), and three were assessed at low ROB (21,26,38) (Figure 2). The five remaining non-randomized single intervention studies were assessed using the NOS tool, with one at high ROB (37), one moderate ROB (42), and three low ROB (36,40,41) (Figure 3). The NOS tool was used to determine methodological quality of all 14 VAP prevention bundle studies; two were high ROB (43,44), four moderate ROB (23,48,53,54), and eight low ROB (24,45-47,49-52) (Figure 3).

Figure 2 ROB assessments of randomized controlled trials of single interventions (21,22,25-35,38,39). ROB, risk of bias.

Figure 3 Newcastle-Ottawa Scale (NOS) risk of bias assessments for non-randomized studies (23,24,36,37,40-54).

Single intervention studies: interventions and outcomes

Fifteen RCTs and 4 non-randomized studies of single interventions reported VAP outcomes for nine groups of interventions (Table 4). One non-randomized study reported PedVAE outcome data. All were single center studies except for one RCT (28) that was completed in two centers, and the 80% of the studies (16/20) enrolled preterm NICU infants. A brief description of the results for each intervention are presented below.

Oral gel/rinse

Two RCTs assessed chlorhexidine as an oral care intervention for infants less than 12 months of age (21,22). The method of applying 0.12% chlorhexidine gluconate differed slightly between studies. Both studies reported a non-significant increase in VAP incidence for infants less than 12 months of age with the chlorhexidine oral care intervention. A third RCT assessed the use of Biotene OralBalance^® gel as an oral care intervention for mechanically ventilated preterm infants born at ≤28 weeks gestation (25). The gel was described as having similar properties to human saliva and contains enzymes such as lactoperoxidase, lysozyme, and lactoferrin that naturally occur in human milk. The authors reported a non-significant decrease in VAP outcomes with its use (25). Overall, the oral gel/rinse interventions reported in a total of three studies resulted in non-significant changes in VAP outcomes.

Oropharyngeal administration of colostrum/breast milk

Seven RCTs assessed oropharyngeal administration of colostrum/breast milk and VAP outcomes (26-32). These studies varied in terms of the dose, frequency, and method of colostrum/breast milk administration. For example, Sharma et al. (28) evaluated oropharyngeal administration of colostrum every 2 hours during the first 24-96 hours of life, while Abd-Elgawad et al.’s study (27) trialed oropharyngeal colostrum until full oral feeds were established. Six of these studies included preterm infants, with differing gestational age inclusion criteria that ranged between 22 to 34 weeks gestation (26-29,31,32). The RCTs that enrolled preterm infants compared colostrum/breast milk administration to no colostrum/breast milk or sterile water. However, the number of infants who were ventilated for a minimum of 48 hours to qualify for the assessment of VAP was not properly reported in these studies. The seventh RCT enrolled term mechanically ventilated infants and was a 3-group design that compared oral care with sodium bicarbonate and colostrum, to colostrum alone, and sodium bicarbonate alone (30). Of these 7 RCTs, only Abd-Elgawad et al. (27) and Mannan et al. (31) (both assessed as high ROB) showed a significant decrease in VAP incidence with the intervention [Abd-Elgawad et al. (RR =0.27; 95% CI: 0.08, 0.95, P=0.04); Mannan et al. (RR =0.31; 95% CI: 0.10, 0.91, P=0.03)] (Figure 4). The outcomes LOS, duration of MV, and sepsis were variably reported across these studies, and 3 reported a decrease in LOS (27,28,30); 3 studies noted a decrease in duration of MV (27,30,31); and one reported a decrease in clinical sepsis (32) (data provided in Table 4).

Figure 4 Forest plot of VAP incidence (data for Edzards 2022 study is for PedVAEs). Bi/BiCarb, sodium bicarbonate; CI, confidence interval; Col, colostrum; HVAC, heating, ventilation, and air conditioning; M-H, Mantel-Haenszel; PedVAE, pediatric ventilator-associated event; UV-C, ultraviolet C; UVGI, ultraviolet germicidal irradiation; VAP, ventilator-acquired pneumonia.

Probiotics

Two RCTs studied VAP incidence with the use of probiotics, in predominantly preterm infants (33,34). Wu et al. (33) used 100 million units of Bifidobacterium given twice daily via a nasogastric tube, and reported a statistically significant decrease in VAP incidence (RR =0.28; 95% CI: 0.12, 0.68; P=0.005). Li et al. (34) used a Bifidobacterium preparation with three strains and also reported a significant decrease in VAP incidence [RR =0.66 (95% CI: 0.43, 0.99); P=0.048]. In summary, both trials of probiotic use reported a decrease in VAP incidence and were assessed at high ROB.

Ventilator circuit change

Two studies evaluated the frequency of ventilator circuit changes and VAP outcomes (35,36). Makhoul et al. (35) compared changing ventilator circuit tubing every 24 hours versus every 72 hours in an RCT, and Chu et al. (36), in a pre- and post-intervention design study, assessed the impact of changing tubing every 2 versus 7 days. Both studies showed no statistically significant differences in VAP rate or VAP incidence, LOS, mortality, and BSIs when tubing change frequency was prolonged (Table 4).

Closed inline suction system

Two studies compared open suction versus closed inline suction of ETT secretions (37,38). Khamis et al. (37), in their non-randomized study, enrolled primarily preterm infants within the first 24 hours of MV for any cause. Khamis et al. reported a non-significant decrease in VAP incidence (RR =0.60; 95% CI: 0.33, 1.11; P=0.10) with closed inline suctioning (Figure 4). Gahan et al. (38), in an RCT, enrolled ventilated neonates ≥28 weeks gestation and had only a few cases of VAP identified in either of the trial groups to make any conclusions (RR =2.85; 95% CI: 0.31, 26.28; P=0.35) (Figure 4). Overall, closed inline suction did not result in a decrease in VAP in the two studies that evaluated this intervention.

ETT flush solution

Two studies evaluated ETT flush solutions (39,40). An RCT by Ezzeldin et al., assessed at high ROB, evaluated the impact of nebulized hypertonic saline twice daily via the ETT for 10 days (or until extubation) as compared to usual care in ventilated preterm infants, and reported a statistically significant decrease in VAP incidence (RR =0.35; 95% CI: 0.18, 0.66; P=0.001), duration of MV, and BSI (Figure 4) (39). However, the VAP rate/1,000 ventilation days was not significantly different between the two trial groups (RR =0.55; 95% CI: 0.26, 1.16; P=0.12) (Figure 5). A separate study by Edzards et al. enrolled preterm infants that were intubated and mechanically ventilated for a minimum of 3 days, and evaluated the use of polymyxin B sulfate ETT flushes on PedVAE rates (40). Though the authors had a concurrent control group, polymyxin flush use was dependent on attending physician’s preference, with sicker patients more likely to have received the intervention (personal communication from the corresponding author), as reflected in the higher PedVAE incidence detected in the intervention group (RR =2.70; 95% CI: 1.05, 6.95, P=0.04) (40).

Figure 5 Forest plot of VAP rate per 1,000 ventilator days (data for Edzards 2022 study is for PedVAEs). CI, confidence interval; M-H, Mantel-Haenszel; PedVAE, pediatric ventilator-associated event; VAP, ventilator-acquired pneumonia.

In summary, of the two studies that evaluated two different ETT flush solutions, i.e., nebulized hypertonic saline and polymyxin B sulfate solution, only Ezzeldin (39) demonstrated a significant decrease in VAP incidence with use of nebulized hypertonic saline, but with no significant decrease in the VAP rate/1,000 days of MV with the intervention (Figure 5).

Ultraviolet germicidal irradiation in HVAC system

A pre- and post-intervention study by Ryan et al. evaluated the impact of using enhanced ultraviolet germicidal irradiation (eUVGI) in the heating, ventilation, and air conditioning (HVAC) system (41). The VAP incidence in preterm infants ventilated for over 14 days was noted to be lower with eUVGI use (RR =0.68; 95% CI: 0.50, 0.94; P=0.02) (Figure 4). The results of the study may be biased because of a serious conflict of interest declared for one of the study authors who was related to a former chief executive officer (CEO) of the company (41).

Ultraviolet C (UV-C) disinfection and copper plating

de la Rosa-Zamboni et al., in a pre- and post-intervention study design, looked at staged implementation of UV-C disinfection and copper plating (42). Incubators were disinfected twice per week via UV-C for a six-month period and subsequently copper adhesive plates were added to frequent contact surfaces in the NICU. There was no significant change in VAP rate or incidence noted with the intervention (VAP rate: RR =0.76; 95% CI: 0.17, 3.38; P=0.72) (Table 4).

Bundled intervention studies: interventions and VAP outcomes

Fourteen studies reported results of VAP care bundles; all were pre- and post-implementation study design, and were conducted in NICU settings with the exception of two studies (one medical/surgical PICU; one pediatric cardiac surgery ICU) (23,24). The bundles included between 5 to 14 interventions as their components, with specific bundle components displayed in Table 2. All studies were single center studies except for the study by Rosenthal et al. (43). While there were some similarities noted between the bundles used, certain interventions such as oral care had a great degree of heterogeneity between studies; 3 implementing normal saline (46,48,52); 2 chlorhexidine (24,47); 2 breast milk or sterile water (44,50); 1 sterile water (53); 1 distilled water (51); and 3 studies with unspecified oral care (43,49,54). Twelve/14 bundles included hand hygiene or glove use guidelines; 11/14 implemented head of the bed (HOB) elevation, varying from 10 to 45 degrees; 10/13 included daily assessment of readiness to extubate; 10/14 specified ventilator circuit changes when visibly soiled. Some of the other common bundle elements included: minimizing duration of invasive ventilation (7/14), draining ventilator circuit for condensation (6/14), allocating separate suction tubing for ETT and oral suctioning (3/14), suctioning the ETT as needed (3/14) and using cuffed ETTs when possible (3/14).

VAP (rate/1,000 ventilator days, incidence, or both) was a primary outcome of interest in all bundled intervention studies and outcomes of each study are summarized in Table 4. VAP rate/1,000 ventilator days was provided by authors, or able to be calculated by the review team, for 11/14 studies; VAP incidence was reported in 11/14 studies, and both VAP outcomes (rate and incidence) were reported in-text for 6/14 studies. Pre-intervention VAP rates varied between 4.3 to 81.8 episodes/1,000 ventilator days, whereas post-implementation they were between 0 to 51 episodes/1,000 ventilator days. All studies claimed that the implementation of an intervention bundle decreased VAP outcomes; however, only seven bundles had statistically significant results (43,45,46,50,51,53,54). Two studies presented data in format that prevented any statistical comparison; these studies simply stated VAP rates for pre- and post-implementation periods without providing any comparison statistic (e.g., P value or 95% CIs) or raw data needed to conduct statistical comparison (44,47).

For the two studies of pediatric prevention bundles, the impact of the applied interventions are difficult to generalize. Montoya et al. studied the application of a series of preventative interventions in pediatric cardiac surgery patients to reduce healthcare associated infections such as VAP, BSIs relating to central catheters, surgical site infections, and urinary tract infections (23). Many of the study interventions were targeted to infections other than VAP. The two VAP-specific prevention interventions in this study were inflating the ETT cuff and 24/7 respiratory therapy support, and the study did not report significant change in VAP incidence with implementation (23). In the other PICU study by Peña-López et al. (24), VAP cases in the pre-bundle period were only reported in ventilated patients with a tracheostomy, the patients at a much higher baseline risk of ventilator-associated infection. There were no VAP cases recorded in the ventilated patients without a tracheostomy in the pre- and post-implementation phase.

Evaluation of non-VAP outcomes was presented for infants in 9 bundles (Table 4). Five bundle studies assessed the impact of VAP bundles on mortality, with Zhou (45) reporting a lower mortality (P<0.001), while others reported either a non-statistically significant change, or did not provide data for statistical comparison (46,49,51,52). LOS was evaluated in seven studies (Table 4), and was lower in only one study by Suman et al. (53) (P<0.001). Duration of MV was evaluated in eight VAP bundles (Table 4), and only Azab et al. reported a statistically significant difference in duration of MV (P<0.001) (46).

Discussion

This systematic review synthesizes results from 34 studies evaluating the impact of individual interventions and multi-component care bundles for VAP and PedVAE prevention in infants. A small portion (6/19) of studies of individual interventions resulted in statistically significant improvements in VAP outcomes, and a single study assessing PedVAE outcome did not support intervention efficacy. The paucity of studies on PedVAE prevention was unanticipated given the NHSN’s support for PedVAE surveillance. Half (7/14) of the studies that implemented VAP prevention bundles reported lowering VAP incidence or VAP rate/1,000 ventilated days. Other clinical outcomes, such as LOS, duration of MV, BPD, BSI, and mortality, were reported inconsistently in the included studies.

Over 80% of the studies (28/34) reported VAP outcomes for preterm NICU patients. As increased rates of invasive MV are associated with extremely low birth weight and low gestational age infants, it is not surprising that over 80% of the studies in our review evaluated preterm infants (55). Of the remaining six studies, two studies (30,42) were focussed on term infants (one single intervention RCT, one pre-post single intervention study) and four studies (21-24) evaluated older infants less than or equal to 12 months of age (two single intervention RCTs, two pre-post intervention studies). Due to heterogeneity in VAP prevention interventions and infant characteristics, these 6 studies provide limited utility in clarifying the effectiveness of VAP prevention interventions for infants outside of the preterm population.

When considering VAP outcomes reported in the single intervention studies and care bundle studies, there could be several possible reasons that less of the single intervention studies reported lower VAP rates in the intervention group. Fifteen out of 20 of the studies of individual interventions were RCTs, a more rigorous design for efficacy testing. In comparison, all studies of intervention bundles were pre-post intervention design, the results of which are more likely to be at ROB and may overestimate efficacy resulting from confounding factors (56). Additionally, many of the studies of intervention bundles were much larger in terms of the number of patients enrolled and VAP events noted, thus had greater statistical power than the individual intervention studies. It is also possible that effective VAP prevention requires addressing multiple VAP risks that may co-exist in a sick ventilated infant, and as such single interventions are more often not sufficient to prevent VAP in this population.

While some commonalities were seen between the bundle elements in our review, each VAP bundle had a unique complement of interventions. Delineation of the effectiveness of each bundle element is challenging due to limitations of pre-post intervention study design (3,56). To help contextualize the evidence generated, we compared common bundle elements of the studies included in our systematic review within the framework of existing pediatric/neonatal VAP prevention bundles published by leading patient safety and infection networks. Two such networks are Solutions for Patient Safety (SPS) and the Society for Healthcare Epidemiology (SHEA) (57,58). SPS’s VAP prevention bundle (59) has four elements, whereas SHEA’s VAP prevention bundles include 9 “essential” preterm practices, and 11 “essential” pediatric practices (58).

Oral care is a common intervention noted across single intervention studies and bundled intervention studies. Oral care is also a recommended bundle element in the SHEA preterm and pediatric bundles (58), and in the SPS bundle (59); however, SHEA cites low quality evidence for this bundle element. SHEA suggests that colostrum may be considered as an “additional” approach for preterm infants if a program continues to struggle with VAP rates (58). Our review also does not demonstrate the effectiveness of oral care with colostrum, as only 2/7 (27,31) of the colostrum/breast milk RCTs resulted in a statistically significant decrease in VAP outcomes, with both of these studies assessed at high ROB, suggesting that the evidence for oral colostrum/breastmilk as a VAP prevention intervention is lacking.

In contrast, two existing meta-analyses on oropharyngeal administration of colostrum/breast milk in preterm infants, including several of the trials from our review, reported a statistically significant decrease in VAP rates (60,61). We chose not to perform meta-analysis on the data from these trials in our review, as only a fraction of the infants enrolled in these trials were invasively ventilated at study onset or anytime during the hospital stay. As such, the true denominator for VAP outcomes (i.e., the number of infants that were ventilated for a minimum of 48 hours to qualify for the assessment of VAP; or total ventilation days for each group) was not known for these studies.

Oral care with an antiseptic or Biotene is not recommended by SHEA for preterm infants due to concerns about absorption via oral mucosa and microflora disruption (58). While the impact of chlorhexidine on older patients, such as pediatric patients with teeth, has been reported as safe, SHEA states that oral antiseptics do not have an impact on pediatric VAP rates, and it is therefore not a supported VAP prevention bundle element for preterm or pediatric patients (58). Two PICU studies included our review that studied intervention efficacy of oral chlorhexidine did not result in a statistically significant decrease in VAP outcomes for infants less than 12 months of age (21,22).

Daily assessment of readiness to extubate was included in 10/14 of the bundles in our systematic review. This component is also found in SHEA’s pediatric and neonatal bundles, as well as the SPS bundle (58,59). Minimizing the duration of MV was another common bundle component in our review (6/14 bundles), and is recommended in SHEA’s preterm bundle (58). Other prevention interventions supported by SHEA to minimize length of MV include: strategic use of non-invasive positive pressure ventilation (preterm and pediatric patients), using caffeine to facilitate extubation (preterm infants), and avoiding unplanned extubation (preterm and pediatric patients). Those interventions, however, were not evaluated singularly in any of the studies in our review.

Changing the ventilator circuit when grossly contaminated was a component in 10/14 of the bundles in our review and is also found in the SPS bundle and in the SHEA’s preterm and pediatric bundles (58,59). While ventilator circuit change on an as-needed basis was not specifically evaluated in our review, the two single intervention studies that studied the impact of extending the duration between ventilator circuit changes did not report a difference in VAP rates (35,36).

HOB elevation was a common bundle element found in 9/12 of the NICU VAP prevention bundles. HOB elevation is not a standard intervention in the SPS or SHEA preterm/neonatal bundles; however, SHEA specifies that lateral recumbent positioning and reverse Trendelenburg positions may be considered as additional measures for preterm patients (but not as routine measures) with low quality evidence (58,59). In contrast, SPS and SHEA both support routine HOB elevation for older pediatric patients outside of the NICU. In our review, we did not identify any single intervention studies that evaluated HOB elevation for VAP prevention, and it is difficult to delineate whether the HOB elevation in preterm NICU patients plays a role in bundle intervention efficacy.

While closed inline suction may appear to be an intuitive VAP-reducing intervention due to a perceived decrease in contamination during disconnection and reconnection, research to support this as a VAP prevention intervention is sparse. Two single intervention studies in preterm infants in our review reported non-significant changes in VAP outcomes with closed inline ETT suction (37,38). Inline suction was studied in a Cochrane review by Taylor et al.; however, VAP was not assessed as an outcome, and the review’s main conclusion was that suctioning without disconnection may improve short term outcomes such as decreased hypoxic episodes (62). SHEA’s guideline suggests that closed suction may be considered as an “additional” approach for preterm patients, and they provide no recommendation for pediatric patients given low quality data (58).

It is important to highlight that, while it is not commonly presented as a specific bundle element, staff compliance with prevention bundles is heavily dependent on team training environment, internal process optimization, and strategic knowledge translation (54). Additionally, VAP prevention bundles require a multidisciplinary team for their implementation to achieve desired results (54). Some examples of educational strategies within the bundles were: annual mandatory computer modules (44), videos (54), regularly scheduled quarterly educational activities (45), staff tests (24), and re-demonstrations (54). Bundle compliance rates varied amongst studies with one author reporting high compliance rates for certain elements such as hand hygiene (96%), elevating the HOB (100%), and cleaning of the palate protector (88%); though they reported that “newer” interventions such as oral care/suctioning took longer to incorporate, and specific values for compliance of these interventions are not reported (44). Elsaeed illustrated that bundle compliance increased from a mean score of 50.7% to 89.3% immediately post intervention, and dropped down to 73.3% 3 months post-intervention (54). Gokce et al. reported much lower compliance rates (12.8% pre-bundle, and 24.3% active bundle), raising the question of whether these low compliance rates contributed to lack of improvement in VAP outcomes within their study (48).

We also identified a few interventions in VAP prevention bundles that are contrary to current evidence. First, three of the NICU VAP bundles included routine checks of gastric residual volume (47,52,54). A recent systematic review and meta-analysis in preterm infants concluded that this practice should be abandoned, as omitting routine monitoring of gastric residuals was associated with less late-onset sepsis, reaching full feeds earlier, and earlier hospital discharge (63). Second, the PICU VAP prevention bundle studied by Peña-López et al. used gastrointestinal bleeding prophylaxis (unspecified agents) for all patients ventilated for more than 24 hours, which is currently not recommended (24,58). Third, Elsaeed et al.’s (54) NICU bundle included routine pre-suction chest physiotherapy, an intervention flagged for further research to determine its value and safety in pediatric and neonatal populations (64).

Limitations

Our systematic review has a few limitations. First, meta-analyses could not be done due to clinical heterogeneity in the included studies. Second, we did not perform a formal assessment of publication bias due to a limited number of studies identified for each intervention. Third, despite significant effort, only a small portion of publications in PICU settings provided infant subgroup data. Fourth, we excluded studies enrolling fewer than 20 patients, as smaller studies are known to overestimate effect size and are at greater ROB; however, this may have added a potential risk for selection bias. Fifth, not all studies reported data on VAP as a rate/1,000 ventilator day as recommended by the CDC and reported only VAP incidence rate. The efficacy estimates from these studies could be at a greater ROB as the number of cases of VAP were not standardized for the duration of MV during each period. Sixth, many clinically relevant outcomes such as LOS, duration of MV, BPD, BSI, and patient mortality were inconsistently reported in the included studies. Seventh, we used the NOS for assessing ROB in non-randomized studies; however, the scale is not specifically designed for assessing confounding and other biases in pre- and post-intervention studies. Finally, we did not study economic evaluation of the bundles as part of the review, which could affect implementation feasibility in different settings.

Conclusions

Our systematic review shows limited efficacy for individual interventions for VAP prevention, with 6/20 single intervention studies reporting statistically significant changes in VAP outcomes. VAP prevention bundles demonstrated lower VAP outcomes in 50% (7/14) of the studies with bundle implementation compared to the pre-bundle epoch. The majority (28/34) of the studies in our review were focused on preterm NICU infants, with two studies evaluating term infants, and four studies reporting outcomes for infants up to 12 months of age. Common elements of care bundles included hand hygiene, daily assessment for readiness to extubate, oral care, minimizing duration of invasive ventilation, ventilator circuit changes when visibly soiled, and head of bed elevation. Given limited efficacy noted for any particular intervention in the RCTs of single interventions, relative importance of individual components of care bundles cannot be estimated. Future studies should prioritize well designed single intervention studies evaluating VAP outcomes, adhere to harmonized VAP definitions, and include cost-effective analyses, to inform development of clinical guidelines. Given a serious lack of studies evaluating PedVAE in this population, it should be included as an outcome in future trials.

Acknowledgments

The review team would like to thank Monika Igali for the extensive time spent contacting authors with requests for infant subgroup data and VAP definitions.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-25-79/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-25-79/coif). J.T. serves as an unpaid editorial board member of Pediatric Medicine from January 2026 to December 2027. M.K. serves as an unpaid editorial board member of Pediatric Medicine from January 2025 to December 2026. M.S.P.H. received salary support from the Women and Children’s Health Research Institute (WCHRI) Innovative Grant program and start-up funding from Dr. J.T. The funding sources did not have involvement in study design, manuscript preparation, or decision to submit article for publication. The other authors have no conflicts of interest to declare.

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