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Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
SUMMARY INTRODUCTION OUTCOMES Recommendations for Current Practice and Future Research DIAGNOSIS Clinical Criteria Invasive Testing in Adults Invasive Testing in Children Computerized Surveillance Recommendations for Current Practice and Future Research MICROBIOLOGY RISK FACTORS FOR VAP IN NICU PATIENTS RISK FACTORS FOR VAP IN PICU PATIENTS Recommendations for Current Practice and Future Research PREVENTION Head-of-Bed Elevation In-Line Suctioning H2 Blockers/Sucralfate Hand Hygiene Selective Decontamination Oral Hygiene The Bundle Approach Educational Interventions Recommendations for Current Practice and Future Research VAP TREATMENT Empirical Therapy Specific Treatment Duration of Therapy Recommendations for Current Practice and Future Research CONCLUSION REFERENCES
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| INTRODUCTION |
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NICU VAP rates vary by birth weight category as well as by institution. Two large studies are summarized in Table 1. The most recent National Nosocomial Infection Surveillance (NNIS) data from 2002 to 2004 show NICU VAP rates ranging from 1.4 to 3.5 per 1,000 ventilator days (68). In 1998, a cross-sectional study of hospital-acquired infections in 50 children's hospitals was performed by the Pediatric Prevention Network (88). Of 43 children's hospitals that returned questionnaires reporting NICU and PICU surveillance data, the VAP rate by device days was reported by 19 hospitals, and 12 hospitals provided VAP rates stratified by birth weight groups (Table 1). In this cross-sectional survey, VAP rates were highest for the 1,001- to 1,500-g and <1,000-g birth weight categories.
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NNIS definitions for VAP were revised in 2002, resulting in a more stringent definition of VAP. Studies of VAP incorporating these revised definitions reported lower rates of VAP, making it difficult to know if VAP was previously overdiagnosed or is now underdiagnosed. The revised definitions must also be considered when VAP rates are compared over time. Applying the Centers for Disease Control and Prevention (CDC) definitions for VAP in low-birth-weight infants introduces additional complexity in defining the incidence of VAP. CDC definitions for VAP exist for infants <1 year of age, but there are no specific definitions for low- or very-low-birth-weight infants. These patients often have comorbidities such as bronchopulmonary dysplasia, hyaline membrane disease, bloodstream infections (BSIs), and necrotizing enterocolitis that obscure clinical, laboratory, and radiographic evidence of VAP.
| OUTCOMES |
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Presumed VAP is also associated with additional resource utilization with respect to antibiotic administration. VAP is the most common reason for the initiation of empirical antibiotics among PICU patients. A prospective cohort study at an academic tertiary care center performed in a PICU (n = 456) found that over half (56.6%) of all patients (n = 258) received antibiotics (33). Treatment for suspected VAP comprised 616 of 1,303 (47%) of the antibiotic treatment days. Those authors reviewed medical records to determine whether patients had evidence of an alternative explanation for the symptoms attributed to VAP, such as a viral infection. For 40% of the antibiotic days (552/1,303 treatment days), patients were classified as having no infection (i.e., did not meet clinical criteria as defined by the CDC) or as having a viral infection. Those authors concluded that an intervention targeted at decreasing antibiotic use for VAP would have the greatest impact on antibiotic use.
In pediatric populations, the published data are unmatched for severity of illness and univariate but suggest that pediatric patients with VAP may have excess mortality and length of PICU and NICU stay. The European Multicenter Trial examined the epidemiology of hospital-acquired infections in 20 units (5 PICUs, 7 neonatal units, 2 hematology-oncology units, and 8 general pediatric units) in eight countries, with a total of 14,675 admissions (710 admission in PICUs) (77). Those investigators found the infected patients had a longer mean length of stay in the PICU (26.1 ± 17.3 versus 10.6 ± 6 days; P < 0.001) than uninfected patients. The mortality rate was 10% for PICU patients with nosocomial infections. The mortality and length of stay associated specifically with VAP were not reported, although VAP accounted for 53% of the nosocomial infections in PICU patients. Mortality among uninfected PICU patients was not reported. Similarly, PICU length of stay in a 9-month prospective cohort study in an academic tertiary care center revealed that patients with VAP (n = 30) had a mean PICU length of stay of 27 days versus 6 days for uninfected patients (n = 595) (P = 0.001) (28). In that same study, the mortality rates with and without VAP were 20% and 7%, respectively (P = 0.065). Outcomes between patients on mechanical ventilation for more than 8 days with VAP (n = 30) and those without VAP (n = 62) were also compared. PICU length of stay was longer for VAP patients (27.53 ± 20.09 versus 18.72 ± 35 days), as was hospital length of stay (52.63 ± 37.43 versus 33.77 ± 49.51 days), but no differences in mortality rates for VAP (20%) or uninfected patients (21%) were found. Almuneef et al. (1) determined in a prospective cohort study (n = 361) that PICU lengths of stay with (n = 37) and without (n = 324) VAP were longer for patients with VAP (33.70 ± 30.28 versus 14.66 ± 17.34 days; P = 0.001). Statistically significant differences in mortality rates between patients with VAP and those without VAP were not found (P = 0.362). Both of those studies performed only univariate analyses to compare mortality rates among patients with and without VAP. Multivariate analysis of predictors of mortality among PICU patients with sufficient numbers of VAP controlling for severity of illness both at admission and at the time of VAP as well as other potential predictors of death is necessary to determine the true attributable mortality of VAP in pediatric patients.
VAP has also been shown to increase hospital costs. The cost of VAP was analyzed in a 2-year study of PICU patients (n = 1919) with a single admission (38). The direct cost for patients with VAP (n = 56) was $38,614, and that for patients without VAP was $7,682. In a multivariate analysis controlling for other predictors of cost including age, severity of illness, underlying disease, and ventilator days, VAP was independently associated with a direct cost of $30,931 (95% confidence interval [CI], $18,349 to $82,638) (38). This is a single study from an academic tertiary care center; further studies are needed to determine whether the results from this single center are generalizable.
| DIAGNOSIS |
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1 year of age). However, in patients without underlying pulmonary or cardiac disease (respiratory distress syndrome, bronchopulmonary dysplasia, pulmonary edema, or chronic obstructive pulmonary disease), one definitive chest radiograph is acceptable. In addition to abnormal chest radiographs, a patient must have at least one of the following symptoms: fever (>38°C) with no other recognized cause, leukopenia (<4,000 white blood cells [WBC]/mm3) or leukocytosis (
12,000 WBC/mm3), and at least two of the following criteria: new onset of purulent sputum, change in character of sputum, increased respiratory secretions, or increased suctioning requirements; new onset of or worsening cough, dyspnea, or tachypnea; rales or bronchial breath sounds; and worsening gas exchange (e.g., O2 desaturations [e.g., PaO2/FiO2 levels of 240], increased oxygen requirements, or increased ventilation demand). The criteria described above may be used to diagnose VAP in children; however, specific diagnostic criteria for VAP have been developed for infants 1 year of age and children >1 and 12 years of age. Infants that are 1 year old must have worsening gas exchange (oxygen desaturations, increased oxygen requirements, or increased ventilator demand) and at least three of the following criteria: temperature instability with no other recognized cause; new onset of purulent sputum, change in character of sputum, increased respiratory secretions, or increased suctioning requirements; apnea, tachypnea, nasal flaring with retraction of chest wall, or grunting; wheezing, rales, or rhonchi; cough; and bradycardia (<100 beats/min) or tachycardia (>170 beats/min). Children >1 and 12 years of age must meet at least three of the following criteria: fever (>38.4°C or >101.1°F) or hypothermia (<37°C or 97.7°F) with no other recognized cause; leukopenia (<4,000 WBC/mm3) or leukocytosis (15,000 WBC/mm3); new onset of purulent sputum, change in character of sputum, increased respiratory secretions, or increased suctioning requirements; rales or bronchial breath sounds; and worsening gas exchange (O2 desaturations [pulse oximetry of <94%], increased oxygen requirements, or increased ventilation demand). NNIS/CDC criteria do not require microbiologic confirmation to diagnose pneumonia.
In summary, many of the diagnostic criteria are similar for the 1-year-old and >1- or 12-year-old age groups. Temperature instability is a diagnostic criterion for the 1-year-old age group; either temperature elevation or hypothermia is a criterion for the >1- and 12-year-old age group. For the <1-year-old group, cough, bradycardia, tachycardia, nasal flaring, grunting, and wheezing are diagnostic criteria not listed for the >1- or 12-year-old age groups, although for the older age group, dyspnea without further specific definition is a diagnostic criterion. Worsening gas exchange, change in character or amount of sputum, cough, rales, or bronchial breath sounds are criteria for diagnosis in all three age groups. We suggest that a consistent use of the age-specific definitions are preferred, although we were unable to find any published studies directly comparing the sensitivity and specificity of the age-specific definitions to those for any age group.
Clinical definitions for VAP may be applied inconsistently, and the lack of specific definitions of components of the clinical definition such as worsening gas exchange, oxygen desaturations, increased oxygen requirements, and increased ventilator demand may exacerbate this. Cordero et al. (19) determined differences in the application of the CDC definitions using NICU patients (n = 37) diagnosed with VAP by interpretation of CDC definitions by infection control practitioners (ICPs) and a positive tracheal aspirate culture. A panel of neonatologists reviewed the clinical and laboratory evidence as well as the radiographs. The neonatologists diagnosed VAP in only seven patients. The neonatologists categorized the other patients as having asymptomatic airway colonization (n = 12), BSI (n = 7), and airway colonization with equivocal signs of infection (n = 11). Among 8 of the 11 patients with equivocal signs of infection, the general radiologist report stated that the radiographic changes were suggestive of VAP; the neonatologist panel, reviewing the same radiographs, concluded that VAP was unlikely in these patients. Those authors concluded that an isolated positive tracheal aspirate does not distinguish between airway colonization and VAP and that routine radiology reports without definitive clinical and laboratory evidence may be misleading.
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103 CFU/ml identified all patients with histologically proven pneumonia. In patients treated with antibiotics, four patients had microorganisms isolated by PSB with concentrations of >103 CFU/ml not found in the lung tissue cultures. Fabregas and colleagues (30) sought to determine the accuracy of clinical criteria and microbiologic testing for the diagnosis of VAP. The clinical pulmonary infection score (CPIS) was used to compare microbiological criteria, clinical criteria, and sampling techniques. Lung biopsies were performed for 25 mechanically ventilated patients immediately after death. The reference standard was the presence of positive histology for pneumonia or positive lung cultures. Chest X-ray infiltrates and at least two of three clinical criteria achieved sensitivity and specificity of 69% and 75%, respectively. The CPIS sensitivity and specificity were 77% and 42%, respectively. Noninvasive and invasive techniques achieved similar results. All diagnostic techniques combined (PSB, BAL fluid, and protected BAL fluid) achieved sensitivity and specificity of 85% and 50%, respectively.
A meta-analysis done in 2005 (n = 628) determined whether invasive testing altered the management and mortality of VAP in critically ill adults (84). VAP was confirmed bronchoscopically in 44 to 69% of the patients. Overall, antibiotics were almost three times as likely to be changed if a bronchoscopy was performed. In a separate pooled analysis of prospective uncontrolled trials, alteration in antibiotic prescription occurred 50% (36 to 65%) of the time. To our knowledge, no similar meta-analyses exist for pediatric populations.
Gauvin et al. (42) performed a 27-month prospective cohort study of PICU patients suspected of having VAP in a tertiary academic care center. Of 30 patients, 10 were diagnosed with VAP and 9 were diagnosed with ventilator-associated tracheitis by an expert panel. The expert panel was used as the reference standard; they were given clinical, radiographic, and microbiologic data but were blinded to the BAL results. A bacterial index (sum of the log of all species obtained from BAL) of >5 had the highest correlation with the reference standard (concordance, 83%; kappa = 0.61), a sensitivity of 78%, a specificity of 86%, a positive predictive value of 70%, and a negative predictive value of 90% (42). Intracellular bacteria and gram stain from BAL were specific (95% and 81%, respectively) but not sensitive (30% and 50%, respectively) for the diagnosis of pediatric VAP, whereas clinical criteria and endotracheal cultures were sensitive (100% and 90%, respectively) but not specific (15% and 40%, respectively). That study concluded that blind BALs with a bacterial index of >5 are the most reliable method for diagnosing VAP in mechanically ventilated children. The study did not describe what proportion of patients were on antibiotics or the duration of antibiotic exposure prior to BAL.
Labenne et al. (60) also investigated the sensitivity and specificity of PSB and BAL in PICU patients with suspected VAP. The gold standards used by those investigators were a positive pleural fluid culture, computed tomography scan with pulmonary abscesses, histopathological evidence, positive lung biopsy (>104 CFU/gram), the same bacteria isolated in blood and endotracheal aspirate without another source, or clinical diagnosis using CDC guidelines established independently by two investigators blinded to PSB/BAL culture results. Of 103 patients, 29 were diagnosed with VAP, 10 were labeled as "uncertain," and 64 were classified as not having VAP. Thirteen of 64 patients with negative PSB and BAL cultures had antibiotics stopped after 48 h, 25 of 64 had negative cultures, and antibiotics were not used at all, and 28 of 38 had a positive tracheal aspirate culture but negative PSB and BAL, so antibiotics were discontinued prior to the standard 7-day treatment in that center. The sensitivity and specificity for BAL fluid culture were 72% and 88%, respectively. The intracellular bacteria and the BAL combined had sensitivity and specificity of 79% and 88%, respectively. Use of PSB culture results in combination with intracellular bacteria and BAL further increased the sensitivity and specificity to 90% and 88%, respectively. The PSB and BAL are effective methods of collecting distal samples and were helpful in diagnosing VAP. However, a combined diagnostic approach was superior to either one alone.
The safety of the NB-BAL in children has also been determined by several studies; few adverse experiences (n = 18) have been reported (12, 42, 60, 66, 79). The types of adverse events were sustained oxygen desaturation requiring increased ventilatory support (n = 11), pneumothorax (n = 4), hypotension (n = 2), and significant increase in intracranial pressure (n = 1). Of the 11 patients who experienced sustained oxygen desaturations, 7 patients were diagnosed with acute respiratory distress syndrome and saturations in the low 80s before the procedure was performed. Pneumothorax occurred in patients less than 1 month of age (n = 4). Hypotension occurred in patients requiring dopamine before the NB-BAL procedure began.
The safety of NB-BAL and BAL have been examined in a study evaluating the diagnosis of infectious and interstitial lung disease in children (n = 32) (79). That study found that both NB-BAL and the BAL were safe, as respiratory rate, heart rate, and oxygen saturation were monitored during the procedure and a minimum of 6 h afterwards. Patients did not require increased supplemental oxygen after the procedure, and no major airway bleeding occurred.
Computerized surveillance has the potential for considerable time savings, particularly if electronic surveillance of the radiographic reports could be combined with that of microbiology and vital signs and validated against the current practical gold standard of application of CDC/NNIS definitions by an experienced clinician who has reviewed the complete medical record. Additional computerized surveillance studies are necessary to help further understand the impact that computerized surveillance may have on diagnosing pneumonia.
| MICROBIOLOGY |
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Two studies reported differences in the microbiologies of early-onset and late-onset nosocomial pneumonia among children. Group B streptococci were most commonly isolated from infants with maternally acquired pneumonia (31.8%), while these organisms were rarely isolated in cases of late-onset pneumonia (1.3%). The frequency of Staphylococcus aureus increased from 2.4% of maternally acquired cases to 18.7% of non-maternally-acquired cases of pneumonia, and Pseudomonas aeruginosa frequency increased from 2.9% of maternally acquired cases to 12.9% of non-maternally-acquired cases of pneumonia (43).
A 41-month prospective surveillance study of nosocomial infections in a NICU divided pneumonia into early-onset (onset of symptoms within first 48 h of life) and late-onset (onset of symptoms more than 48 h after birth) infections (98). There were 35 cases of definite or probable early-onset pneumonia. In 26 of these cases, potential pathogens were identified: 18 (76.9%) group B streptococci, 1 (3.8%) group F streptococcus, 3 (11.5%) Streptococcus pneumoniae isolates, and 2 (7.7%) nontypeable Haemophilus influenzae infections. Late-onset pneumonia occurred in 36 of 358 (10%) neonates who were ventilated for over 24 h. Cultures were taken from endotracheal tubes or nasopharyngeal secretions for 41 episodes of late-onset nosocomial pneumonia. The most commonly isolated organisms were coliform spp. (n = 18; 43.9%), Pseudomonas aeruginosa (n = 14; 34.1%), and Staphylococcus aureus (n = 6; 14.6%).
| RISK FACTORS FOR VAP IN NICU PATIENTS |
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Neonates have unique characteristics predisposing them to nosocomial infections. These patients’ immature immune systems place them at increased risk for infection (24). Skin and mucous membranes are more permeable and are less effective barriers to infection (47). Abnormal granulocyte migration and bacterial digestion in these patients have been demonstrated. Additionally, decreased activity of complement, particularly complement opsonization, occurs in newborns (40). Lastly, hypogammaglobulinemia occurs in premature newborns. Maternal immunoglobulin G (IgG) is transported to the fetus in the second and last trimesters of pregnancy, and fetal IgG levels reach maternal levels by term (58). Levels of IgG are lower in premature newborns, as maternal levels have not yet been attained. In the initial months following birth, maternal IgG levels drop, and it takes the infant months to produce ample levels of IgG and other immunoglobulins.
Low birth weight has been shown to be a risk factor for the development of nosocomial pneumonia. A 41-month surveillance study demonstrated a significant association between a birth weight of <1,500 g and a higher rate of nosocomial pneumonia (48). However, low birth weight may be a marker for an increased duration of mechanical ventilation. That study was limited by the lack of a specific control for the duration of mechanical ventilation. Apisarnthanarak et al. (3) focused on estimated gestational age (EGA) rather than birth weight in their 10-month-long case control study of 211 intubated NICU patients. VAP rates were much higher in babies with an EGA of <28 weeks (19 VAP cases) than in babies with an EGA of 28 weeks (5 VAP cases) (P < 0.001) (3). The VAP rate per 1,000 ventilator days was also higher in babies with an EGA of <28 weeks (6.5/1,000 ventilator days) than in babies with an EGA of 28 weeks (4.0/1,000 ventilator days) but was not statistically significant (P = 0.34) (3). Not all investigators found an inverse relationship between birth weight and frequency of nosocomial pneumonia. A prospective surveillance study of nosocomial infections in seven Brazilian NICUs found that the rate of nosocomial pneumonia was actually higher in neonates with birth weights of >1,500 g than in babies with birth weights of 1,500 g (4.4/1,000 patient days versus 2.8/1,000 patient days) (72).
Prior BSIs have been identified as a being a risk factor for VAP in NICU patients. In babies with an EGA of <28 weeks, history of a prior BSI was the only significant risk factor for the development of VAP in multivariate analyses after controlling for the duration of mechanical ventilation (P = 0.03). Although none of the cases of VAP were caused by the same organism as that which caused the BSI, those authors suggested that prior BSI may serve as a surrogate for severity of illness rather than actually contributing to VAP (3).
The design of the NICU may also have an effect on the incidence of nosocomial infections and specifically VAP. A 5-year prospective study of nosocomial infections in a NICU was performed (44). Midway through that study, the NICU location was moved from cramped quarters adjacent to a busy medical ward to a new facility. The new nursery had a 50% increase in staffing and improved infection control features. In the old nursery, 16 of 492 patients had pneumonia, whereas in the new nursery, only 1 patient of 419 had pneumonia. While the new nursery had improved structural infection control measures such as more space per patient, a large number of sinks, and a separate isolation room, it is not clear if other practices of care, such as head-of-bed elevation or suctioning, changed after the move to the new unit. Those authors did not report any changes in infection control surveillance or diagnosis in the new nursery.
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| PREVENTION |
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Closed endotracheal suction systems present the potential for bacterially contaminated secretions to pool in the lumen of the tube, with reinoculation of the respiratory tract with each repeated suctioning. On the other hand, a closed system could potentially decrease environmental contamination of the respiratory device. Many studies of critically ill adults have compared the incidence of airway colonization and nosocomial pneumonia in patients on a closed multiuse system to that in patients on a single-use open suction system. The frequency of airway colonization has been shown to be significantly more frequent in patients on the closed suction system (23). However, studies have not demonstrated an increased frequency of nosocomial pneumonia in patients on the closed suction system (23, 54). Indeed, a more recent prospective randomized study of 102 ventilated adults demonstrated an increased risk of VAP for patients with an open suction system compared to a closed suction system (adjusted risk, 3.5; 95% CI, 1.0 to 12.33) (17). There are currently no CDC recommendations regarding the preferential use of closed or open suction systems, nor are there recommendations regarding the frequency of change for multiuse closed suctioning systems in a single patient (89).
A single study has compared open and closed suction systems in critically ill children. Cordero et al. (20) monitored 133 ventilated NICU patients who were alternately assigned to a closed or open suction system for bacterial airway colonization, nosocomial pneumonia, BSI, and bronchopulmonary dysplasia. A definition of nosocomial pneumonia required radiographic evidence of "probable" pneumonia (new airspace disease or a parenchymal process) and positive blood cultures and tracheal culture for a respiratory pathogen. Colonization patterns from tracheal cultures were comparable between groups, with gram-positive colonization occurring by the second week of intubation and gram-negative colonization occurring after the third week of ventilation. There were no significant differences in the incidences of VAP or BSIs or mortality between patient groups. Additionally, the numbers of endotracheal suctions per day, the numbers of reintubations, the incidences and severities of bronchopulmonary dysplasia, and the numbers of infants discharged on supplemental oxygen were similar between groups. Finally, 40 of 44 (91%) NICU nurses judged the closed suction system to be easier to use, less time-consuming, and better tolerated by NICU patients.
Two clinical trials compared the risk of VAP with various methods of stress ulcer prophylaxis in pediatric patients. A retrospective study included 155 PICU patients who had a nasogastric tube in place and were mechanically ventilated for >48 h: 54 were given ranitidine, 53 were give sucralfate, and 48 were not on stress ulcer prophylaxis (62). There was no significant difference in the incidences of VAP between patients treated with ranitidine and patients treated with sucralfate (11.1% versus 7.5%; 
2 = 0.40; P = 0.52). That study had several limitations. Patients were not randomized into study groups, and patient characteristics differed between patients given stress ulcer prophylaxis and those who were not given prophylaxis. The retrospective nature of the study may have resulted in errors in diagnosing VAP.
A prospective study was performed to study the incidence of VAP and associated mortality among patients randomized to one of four groups for stress ulcer prophylaxis in Turkey (101). That study included 160 PICU patients: 38 received sucralfate, 42 received ranitidine, 38 received omeprazole, and 42 did not receive prophylaxis. VAP occurred in 70 of 160 (44%) patients, ranging from 41 to 48% in individual treatment groups. There was no difference in the incidence of VAP across treatment groups. The overall mortality rate was 35 of 160 (22%) and did not differ significantly among treatment groups, ranging from 21 to 23% across groups. The overall incidence of VAP (44%) in this study was much higher than that reported in other pediatric studies from referral hospitals (5.1% to 10.2%) (1, 28). It is possible that VAP was overdiagnosed in that study, although diagnostic criteria used in that study were similar to criteria used in this country. If VAP was overdiagnosed, this effect would likely be distributed throughout all study groups. That study may also have been underpowered to detect differences in the incidences of VAP among these patient groups.
Both of those studies failed to demonstrate a difference in the incidence of VAP in patients treated with sucralfate compared to those treated with agents that alter gastric pH. Additionally, neither study demonstrated an increased risk of VAP in patients treated with agents that alter gastric pH compared to that in patients with no treatment. The microbiologies of infections were similar across treatment groups, and many infections were caused by organisms that are not likely to be affected by stress ulcer prophylaxis. It is possible that the study sizes presented were simply too small to appreciate a significant difference in the incidence of VAP, or it is possible that stress ulcer prophylaxis is not associated with VAP in the pediatric population. Larger prospective randomized studies of children are needed to asses the impact of stress ulcer prophylaxis on VAP and whether sucralfate has a protective effect compared to medications that decrease gastric acidity.
A prospective study of a 3-month-long implementation of an intervention to decrease rates of nosocomial infection in NICU patients was undertaken (69). The intervention consisted of three parts: (i) grouping of all blood-taking tasks to reduce the number of daily blood draws, (ii) reducing the frequency of blood investigations after stabilization of acute illness, and (iii) using an aseptic delivery system of drugs though a central venous catheter to reduce peripheral intravenous access. The incidences of nosocomial infection in the NICU between the 1-year preintervention period and the 1-year postintervention period were compared. VAP rates declined from 3.3/1,000 ventilator days to 1.0/1,000 ventilator days after the intervention. Again, that study was limited by the before-after nature of the design. Those authors acknowledged that practices regarding mechanical ventilation also changed during the study period, as patients were weaned from the ventilator more aggressively and as soon as possible. Earlier weaning may have contributed to lowering the VAP rates, as prolonged intubation is a risk factor for VAP in children (62).
The importance of hand hygiene in preventing horizontal transmission of pathogens among mechanically ventilated patients was highlighted by a study performed by Sole et al. (86) to evaluate the proportion of suctioning devices colonized with pathogenic bacteria and to correlate the bacteria found on respiratory equipment with those found in patients’ mouths and sputum. Those investigators found that within 24 h of changing to new suctioning equipment, 94% of tonsil suction tubing, 83% of in-line suction tubing, and 61% of distal suction connectors were colonized with pathogenic bacteria similar to those found in the patients’ oropharynx and sputum (86).
Many investigators have studied the efficacy of selective digestive tract decontamination (SDD) in preventing VAP. SDD traditionally consists of a regimen of topical antimicrobials applied to the oropharynx and through a nasogastric tube, with the aim of reducing the burden of pathogenic bacteria in aspirated secretions. While the majority of trials have focused exclusively on the use of topical antimicrobials, many have also used a short course of intravenous antimicrobial therapy. Seven meta-analyses of randomized, controlled trials of SDD in adults all showed a significant reduction in the risk of VAP, and four of those analyses also demonstrated a significant reduction in mortality in patients treated with SDD (16). One recent meta-analysis divided trials into those that used topical antibiotics alone and those that used a combination of topical and systemic antimicrobials for the prevention of nosocomial respiratory infections (61). That analysis included 32 randomized, controlled trials including a total of 5,185 adult patients. A protective effect was demonstrated in trials comparing patients on a combination of systemic and topical antibiotics with controls (OR, 0.35; 95% CI, 0.29 to 0.41) and in trials comparing patients on topical antibiotics alone with controls (OR, 0.52; 95% CI, 0.43 to 0.63). A significant reduction in mortality was seen only in trials that used a combination of topical and systemic therapy (OR, 0.78; 95% CI, 0.68 to 0.89). Mortality from VAP was not reduced when topical therapy alone was used (OR, 0.97; 95% CI, 0.81 to 1.16).
Recent evidence suggests that results from some of those trials may be overly optimistic. A meta-analysis of 32 primary trials of SDD was performed to assess the impact of study methodology on results (97). Study methodology was evaluated based on allocation and concealment, patient selection, patient characteristics, blinding, and definition of nosocomial pneumonia. That analysis found an inverse relationship between the methodologic quality and benefit of SDD on the incidence of pneumonia, suggesting that the benefit of SDD for the prevention of VAP may be overestimated by many clinical trials (97).
Studies focusing on the use of SDD to prevent VAP in children have conflicting results. A prospective study of SDD in 226 PICU patients randomized study subjects into a treatment (n = 116) or control (n = 110) group (81). The treatment group received colistin, tobramycin, and nystatin orally or through a nasogastric tube every 6 h, and patients were monitored for the development of nosocomial infection in any body site. There were 87 episodes of any nosocomial infection in 65 of 226 (28.8%) patients. The most common nosocomial infections were catheter-related bacteremia, sepsis, pneumonia, and urinary tract infection. The overall incidence of nosocomial infection across all sites did not differ between treatment and control groups. However, when infections were studied by body site, patients in the treatment group had a significantly lower frequency of pneumonia (2.6% versus 7.2%). In multivariate analyses, SDD retained a protective effect against pneumonia (OR, 0.21; 95% CI, 0.06 to 0.8). There was no significant difference in overall mortality between the treatment and control groups (six versus five patients). Patients in that study were randomized and were well matched for most variables with the exception of severity of illness; the treatment group had more severely ill patients. This difference in severity of illness would be expected to skew the results toward the null hypothesis, but there were actually fewer cases of pneumonia in the more severely ill group who were treated with SDD.
A prospective, randomized, double-blinded study was performed to determine the efficacy of SDD in preventing nosocomial infections in severely burned (>30% total body surface area) PICU patients (7). Patients were randomized to the treatment group (n = 11) or control group (n = 12). The treatment group was given a mixture of polymyxin E, tobramycin, and amphotericin B four times daily by nasogastric tube. No significant differences regarding demographics, underlying conditions, inhalation, injury, or percent of surface area burned between patient and control groups existed. There was no difference in the proportion of patients with colonization of wounds, feces, nasogastric aspirates, or sputum between groups at the start of the study or throughout the study. No significant differences between groups were noted with regard to the serious complications measured: sepsis, pneumonia, gastrointestinal bleeding, respiratory distress syndrome, and mortality. The group treated with SDD had a higher incidence of diarrhea than the control group (82% versus 17%; P = 0.003). Results from that study suggest that SDD may not prevent nosocomial infections in pediatric patients. However, that study was limited by a small sample size (n = 23). Additionally, results of that study may not be generalizable to all PICU patients, as that study was restricted to burn patients.
A prospective nonrandomized cohort study was performed to determine the impact of SDD on nosocomial infections in NICU patients (49). The decision to administer decolonization was left to attending physicians. Investigators later determined if patients had received well-performed decolonization (decolonization within the first 5 days with oral polymyxin E, tobramycin, and nystatin), incorrect decolonization (started after 5 days or less than three drugs used), or no decolonization. The incidence of nosocomial respiratory infection was lower in patients given well-performed (2.5%) or incorrect (7%) decolonization (P value not given). Interestingly, the incidence of nosocomial respiratory infection was lowest in patients who were not decolonized (1%). However, because patients were not randomized into treatment groups, significant underlying differences between groups, including gestational age, birth weight, NICU length of stay, exposure to central catheters, and respiratory support, existed. To control for these differences, investigators performed logistic regression and found that well-performed selective intestinal decolonization exerted a protective effect toward nosocomial infections of intestinal origin (OR, 0.17; 95% CI, 0.03 to 0.83). This group of infections included respiratory tract infections, sepsis, surgical wound infections, and urinary tract infections. The investigators did not supply a separate analysis of the impact of SDD on respiratory infections alone.
Fitch et al. (35) demonstrated that an oral care protocol and scores developed by a dental hygienist could be used by ICU nurses to improve oral health in critically ill adult patients. Mean oral inflammation scores were significantly lower after the implementation of a standard oral care protocol using toothpaste, antibacterial mouthwash, and oral gel (3.9 [standard error of the mean, 3.0] versus 12.4 [standard error of the mean, 2.2]; P = 0.03). Those investigators also noted lower mean scores for oral candidiasis, purulence, bleeding, and plaque, but the differences were not statistically significant. The dental hygienist and nurses’ assessments had a high degree of interrater reliability (kappa = 0.64). The scores used in that study were developed by one of the investigators and reviewed by other dental faculty members but were not validated in other patient populations. In addition, those investigators did not examine the effect of the standard oral care protocol on the incidence of VAP or bacterial oropharyngeal colonization.
Bergmans et al. (9) performed a prospective, randomized, placebo-controlled, double-blind study in adult ICU patients to determine if VAP was preventable by the modulation of bacterial flora in the oropharynx. Those investigators compared topical prophylaxis to the buccal cavities with 2% each gentamicin, colistin, and vancomycin (n = 87) to an Orabase placebo group (n = 78) (group A) and a second control group of patients admitted to an ICU where no topical preparation was used (n = 61) (group B). Topical prophylaxis eradicated a significantly higher proportion of organisms present on admission in the oropharynx in the treatment group than in either control group (75% of the treatment group versus 0% in the placebo group and 9% in the no-preparation ICU group; P < 0.00001). Topical prophylaxis was also effective in eradicating organisms from the trachea (treatment group, 52%; group A, 22%; group B, 7% [P 0.03]). The incidence of VAP was also lower in the treatment group (10%) than in the controls (group A, 31% [P = 0.001]; group B, 23% [P = 0.04]). That study concluded that preventing oropharyngeal colonization is protective against VAP, with an absolute risk reduction of 0.21 (95% CI, 0.09 to 0.33); treating five patients with topical antibiotics would prevent one case of VAP. VAP was defined prospectively using CDC definitions and confirmed with BAL or PSB. However, it is unclear whether the person who determined whether the patients had VAP was blinded to the treatment group. In addition, the treatment group received enteral feeds more frequently than controls, which could alter oropharyngeal flora. The placebo group (group A) was significantly more likely than the treatment group to receive sucralfate, another potential confounder of oropharyngeal colonization.
Pineda et al. (73) performed a meta-analysis to determine if oral chlorhexidine treatment reduced the incidence of VAP. Four randomized controlled trials including 1,202 patients met inclusion criteria for the meta-analysis. Patients in the chlorhexidine treatment group were less likely to develop VAP than those in the control group (4% [24 of 587] versus 7% [41 of 615]), although the difference did not reach statistical significance (OR, 0.42; 95% CI, 0.16 to 1.06; P = 0.07). ICU length of stay and duration of mechanical ventilation did not differ between the groups. Mortality was not significantly different between the two groups (OR, 0.77; 95% CI, 0.28 to 2.11; P = 0.6). The magnitude of the protective OR is striking, as is the proximity of the CIs to statistical significance, suggesting that additional studies with larger sample sizes might demonstrate a significant protective effect from oral chlorhexidine rinses. Of note, patients in those studies received either a 0.12% chlorhexidine rinse twice a day (n = 914) or 0.2% chlorhexidine gel three times a day (n = 288).
A meta-analysis of seven randomized controlled trials (n = 1,650 patients) performed by Chlebicki and Safdar (15) revealed a similar protective effect with a relative risk (RR) of 0.74 (95% CI, 0.56 to 0.96; P = 0.02) using a fixed-effects model and a RR of 0.70 (95% CI, 0.47 to 1.04; P = 0.07) using a random-effects model for patients treated orally with chlorhexidine. The risk reduction was even higher in cardiac surgery patients (RR, 0.41; 95% CI, 0.17 to 0.98; P = 0.04) (15).
The team approach using the IHI bundle has been shown to be successful in reducing VAP (21). The bundle approach has been used at the Children's Hospital in Boston and at Vanderbilt Children's Hospital. In the latter, an education and intervention termed "ZAP VAP" was put into practice, with their efforts emphasizing the IHI bundle (21). Prevention included hand washing, elevating the head of the bed 30° to 45°, monitoring gastric residuals every 4 h to prevent aspiration, providing aggressive oral care (and documentation) every 2 h, managing hypopharyngeal secretions, providing in-line endotracheal suction, and providing equipment care. During the first 6 months of implementation, the time between VAP occurrences has nearly tripled.
Not all lapses in infection control measures result from a lack of knowledge. A survey of NICU health care workers was performed to investigate the knowledge, beliefs, and practices regarding nosocomial infections and infection control measures (56). The survey revealed some areas in which health care workers’ actions arose from unawareness of data related to infection control. For instance, few participants believed that nosocomial infections were related to health care workers’ rings (40%), artificial fingernails (61%), or long fingernails (48%). However, that study also revealed some disconnects between knowledge and practice. Although 96% of respondents believed that using sterile techniques for catheter insertion and care reduces a patient's risk for BSI, only 67% reported using full sterile barriers at least 76% of the time when participating in inserting a line. Likewise, 91% of participants believed gloves are important for preventing the spread of nosocomial infections, but only 53% reported changing their gloves in all indicated situations. That study demonstrated the need for increased educational efforts to bridge the gaps in knowledge of infection control recommendations. Additionally, the study demonstrated that a lack of knowledge alone does not account for the lapses in infection control practices in the NICU studied. The most common barriers to infection control perceived by respondents included logistics (54%), time (48%), and lack of supplies (47%).
Interventions that lower rates of VAP may have temporary effects, with VAP rates eventually rising following the conclusion of the intervention, indicating the need for continuous reinforcement of interventional measures (55). Factors associated with noncompliance with hand hygiene exist at the individual, group, and institutional levels (74). A proposed framework for the promotion of hand hygiene includes 12 factors: (i) education, (ii) routine observation and feedback, (iii) engineering controls, (iv) patient education, (v) reminders in the workplace, (vi) administrative sanctions and rewards, (vii) change in hand hygiene agents, (viii) promotion of workers’ skin care, (ix) active participation at the individual and institutional level, (x) maintenance of an institutional safety climate, (xi) enhancement of individual and institutional self-efficacy, and (xii) avoidance of overcrowding, understaffing, and excessive workload (74). The diversity of these factors emphasizes the need for a multipronged and continuous approach necessary to maintain high levels of compliance with infection control measures.
A summary of interventional measures to decrease the incidence of VAP in children is provided in Table 3.
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Infection with potentially antibiotic-resistant organisms accounts for a large proportion of VAP in adults (95). When selecting empirical therapy, physicians should be aware of the patient's risk factors for infection with multidrug-resistant (MDR) bacteria, the antibiotics that the patient has recently received, and the local antibiotic resistance patterns. Risk factors for VAP with MDR pathogens in adults include mechanical ventilation for at least 7 days, prior antibiotic use, and prior exposure to broad-spectrum antibiotics (imipenem, broad-spectrum cephalosporins, or fluoroquinolones) (95). In children, it has been postulated that patients may be colonized with organisms from their own preexisting endogenous flora in response to antibiotic pressure (92). Risk factors for colonization with antibiotic-resistant gram-negative organisms in PICU patients include younger age, increasing PRISM (pediatric risk of mortality) score, previous PICU admissions, intravenous antibiotic use in the past 12 months, and exposure to chronic care facilities (91, 93). Additional special considerations for the pediatric population include premature infants with an increased risk of Staphylococcus epidermidis infections and immunocompromised patients with an additional need for empirical antifungal therapy (52).
Monotherapy for empirical coverage is recommended for adult patients with early-onset VAP without risk factors for infection with MDR pathogens, while combination therapy should be used for coverage of potential infection with MDR organisms or late-onset VAP based on a local antibiogram. Additionally, patients should be treated with antibiotics differing in class from those that they have recently received in case colonizing bacteria have developed antibiotic resistance from previous exposures (2). No consensus guidelines for empirical coverage of suspected VAP in children exist.
Empirical therapy should be discontinued or altered based on culture results and clinical status. The fear that negative culture results may have missed an infection in critically ill children often leads to prolonged empirical antimicrobial therapy in neonates (87). A study of late-onset sepsis evaluations in neonates was undertaken to determine a sufficient time point for the discontinuation of empirical therapy. Those investigators found that 99% of blood cultures were positive within 48 h, and investigators used this finding as a basis for decreasing empirical coverage from 72 h to 48 h for suspected late-onset sepsis in neonates
