How to cite this article: Izelo-Flores D, Solórzano-Santos F, Miranda-Novales MG. Ventilator associated pneumonia in a neonatal intensive care unit. Rev Med Inst Mex Seguro Soc. 2015;53 Suppl 3:S254-60.
Received: August 14th 2014
Accepted: September 1st 2015
Dassaev Izelo-Flores,a Fortino Solórzano-Santos,b María Guadalupe Miranda-Novalesc
aDepartamento de Infectología, Hospital de Pediatría
bDirección Médica, Hospital de Pediatría
cUnidad de Investigación en Epidemiología Hospitalaria, Coordinación de Investigación en Salud
Centro Médico Nacional Siglo XXI, Distrito Federal, México
Communication with: María Guadalupe Miranda-Novales
Telephone: (55) 5627 6900, extensiones 22507 y 21071
Background: The studies that describe risk factors for the development of ventilator-associated pneumonia (VAP) in newborn infants report dissimilar information, possibly related to the type of intensive care unit and population included. The objective of this study was to identify risk factors for the development of VAP in a neonatal intensive-care unit.
Methods: Case-control study. Patients with the diagnosis of VAP were classified as cases and compared with two controls of the same gestational age, weight, and diagnosis at admission. We analysed the data using descriptive and inferential statistics: chi-squared test, Student’s t-test, odds-ratio, 95 % confidence interval and logistic regression analysis.
Results: A total of 45 cases and 90 controls were analysed. The risk factors statistically significant in the univariate analysis were: previous episode of sepsis, reintubation, airway malformation, exclusive parenteral nutrition, and days of mechanical ventilation. In the logistic regression analysis we obtained these data: reintubation (OR 41.26, CI 95 % 11.9-158.4, p = 0.001), airway malformation (OR 19.5, CI 95 % 1.34-282.3, p = 0.029), and days of mechanical ventilation (OR 8.9, CI 95 % 1.9-40.8, p = 0.005). These were the only risk factors independently associated to VAP.
Conclusion: Of the significant risk factors, it is possible to intervene in reintubation events, by securing the endotracheal cannula with an adequate fixation, mobilize the patient ensuring safety, and follow a decannulation protocol to reduce ventilation days.
Keywords: Ventilator-associated pneumonia, Newborn infant, Nosocomial infections, Neonatal intensive care units.
Nosocomial infection is defined as the localized or generalized condition resulting from adverse reaction to the presence of an infectious agent or toxin that was not present or incubating at the time of patient admission to a hospital. Bacterial infections can appear within 48 to 72 hours of patient admission, and fungal infections after five days of stay.1 In pediatric intensive care units, bacteremia (28%), pneumonia (21%), and urinary tract infections (15%) occupy the top three spots in frequency. The common feature is the presence of an external device.2,3
In various publications, the most common infections that occur in the neonatal intensive care unit (NICU) are catheter-associated bloodstream infections and ventilator-associated pneumonia (VAP).4-7 In a NICU in South Korea, Jeong et al. reported a cumulative incidence of nosocomial infections of 30.3 per 100 admissions. The most common infections were pneumonia (28%), bacteremia (26%) and conjunctivitis (22%).8 In a study in China, a rate of 14.58% was recorded in a NICU; incidence density was 19.52 per 1,000 patient days and VAP was the most common infection, with an incidence density of 48.8 per 1000 ventilator days.9 A study conducted in the NICU of the Hospital de Pediatría of the Centro Médico Nacional Siglo XXI in 2008 found an incidence density of 25.6 per 1,000 patient days, and the most common infections were catheter-related bacteremia (35.5%), sepsis in second place (28.8%), in third surgical site infection (8.7%) and pneumonia in fourth place (8%).10 One of the problems for the registration of VAP is the lack of diagnostic criteria with newborns: most of the items use the definitions for children under one year.11-12
Information on risk factors for VAP is diverse. The study from Elward et al. reported as factors with statistically significant difference: chronological age of the patient, genetic syndromes, reintubation, and transport outside the intensive care unit.13 Srinivasan et al. found in a multivariate analysis that female gender, admission for postoperative care, enteral feeding, and narcotic use are associated with VAP development.14 In another study with extremely premature patients, bloodstream infection that preceded pneumonia was found as the only independent factor (adjusted OR 3.5, 95% CI 1.2-10.8).15 In Thailand, Petdachai found three factors: umbilical catheterization (adjusted OR 2.5, 95% CI 1.3-4.7; p = 0.007), respiratory distress syndrome (adjusted OR 2.0, 95% CI 1.0-3.9; p = 0.03) and gastric tube use (adjusted OR 3.0, 95% CI 1.3-7.2; p = 0.01).16 In China, the statistically significant factors were reintubation (OR 5.3, 95% CI 2.0-14.0), duration of mechanical ventilation (OR 4.8, 95% CI 2.2-10.4), opioid therapy (OR 3.8, 95% CI 1.8-8.5) and endotracheal suction (OR 3.5, 95% CI 1.6-7.4).17 The recorded risk factors and etiology depend on the type of hospital unit and the characteristics of the population, so the aim of this study was to identify risk factors for the development of VAP in newborns.
The study was conducted in the NICU of the Hospital de Pediatría of the Centro Médico Nacional Siglo XXI of the Instituto Mexicano del Seguro Social, which is a tertiary care unit that treats patients from general hospitals in the southern area of Mexico City and the states of Guerrero, Queretaro, Chiapas, and Morelos. The NICU has 24 beds. A case and control study was performed that included hospitalized patients requiring mechanical ventilation assistance for at least 48 hours between January 2008 and December 2012. Patients who developed VAP according to the criteria of the National Healthcare Safety Network of the Centers for Disease Control and Prevention (CDC/NHSN)12 in the United States were classified as cases, whereas patients who did not develop ventilator-associated pneumonia were controls. Patients with VAP acquired in another hospital and patients with non-ventilator-associated pneumonia were excluded. Patients were discarded in whom a diagnosis other than infection was established as a cause of respiratory symptoms. When the diagnosis of VAP was confirmed, two controls were selected for each case, with the following characteristics: same gestational age and weight, reason for admission (medical or surgical), date of admission ± two weeks from the date of admission of the case, and at least 48 hours of use of mechanical ventilation assistance. Data were taken from the clinical record. The variables recorded were: nosocomial sepsis prior to pneumonia diagnosis, transfusions, reintubation, surgery, congenital malformations of upper or lower airways, transfer outside the NICU, fasting, feeding type (enteral, parenteral or mixed), use of orogastric tube, use of H2 blockers and proton pump inhibitors, antimicrobial use, and duration of mechanical ventilation assistance. For microbiological diagnostic, bronchial aspirate culture reports were reviewed. As for the type of sample, patients were included who had a report high in bronchoalveolar lavage obtained by bronchoscopy > 104/mL, by shielded brushing > 103/mL, and by tracheal aspirate > 105/mL.
A calculation of sample size was made to detect an odds ratio significantly different from 1, with the following assumptions: frequency of exposure among cases: 0.40; frequency of exposure among controls: 0.10; odds ratio looked for 2.00; alpha: 0.05, and power: 0.80. The result was 31 cases and 62 controls.
Descriptive statistics were used to calculate simple frequencies and percentages. Inferential statistics were also used: for the association of qualitative variables, Mantel-Haenszel chi-squared, Fisher’s exact test, and Student’s t test were used. For comparison of quantitative variables, the odds ratio was calculated with confidence intervals at 95% and multivariate logistic regression analysis was performed. Statistical analysis was performed using SPSS, version 20.
This study was conducted within the norms established in the Ley General de Salud of Mexico, contained in Title IV on health research, Article 17 of the second section, which states that this is an investigation without risk, given that documentary research techniques and methods were used and no intervention or intentional modification was made in the physiological, psychological, or social variables of the individuals who participated in the study. All information was collected and stored confidentially. The protocol was approved by the Local Research Ethics Committee under number R-2012-3603-51.
During the study period 45 cases were collected that met the inclusion criteria, with two controls per case for a total of 135 patients. For the cases, 23 female patients (51%) and 22 male patients (49%) were obtained. Median birth weight was 1420 grams, median gestational age 32 weeks, and 73% were premature. For days of hospital stay, the median was 45 days; for total days of ventilation the median was 53 days; and for days of ventilation before VAP diagnosis, the median was 32 days. For the controls 31 female patients (34%) and 59 male patients (66%) were obtained. Median birth weight was 1700 grams, with 62% premature patients. The median gestational age was 33 weeks. The median hospital stay was 18 days, and for total days of ventilation the median was 22 days (Table I). The total ventilation days and days of hospital stay were higher in patients with VAP, with statistically significant difference (p < 0.05).
|Table I Demographic characteristics of population|
|Variable||Cases (n= 45)||Controls (n= 90)|
|Median||Interquartile range /Minimum-maximum||Median||Interquartile range /Minimum-maximum|
|Gestational age (in weeks)||32||25-42||33||25-42|
|Weight (in grams)||1420||590-3550||1700||640-4040|
|Days of ventilation (total)||53||15-130||22||6-109|
|Days of ventilation
|Days of stay in NICU||45||16-130||18||6-109|
|NICU = neonatal intensive care unit; NA = not applicable|
For diagnoses on admission, most patients had heart disease and in second place gastrointestinal tract malformations (Table II).
|Table II Diagnoses of admission|
|Complex heart disease||10||22||19||21|
|Patent ductus arteriosus||10||22||23||26|
|Gastrointestinal tract malformations||9||20||10||11|
|* Intraventricular hemorrhage, Rh incompatibility, airway injury, neonatal sepsis|
Of patients diagnosed with VAP, 60% had microbiological isolation and 40% of patients had negative cultures, bacterial growth in non-significant count, or no sample at the time of diagnosis of pneumonia. Of patients with microbiological isolation, 63% were Gram negative bacilli, of which Klebsiella pneumoniae and Pseudomonas aeruginosa were the most frequent. Gram positive cocci were isolated in 22%, and there was equal frequency of Staphylococcus aureus and coagulase-negative Staphylococci. In four patients more than one organism was cultivated, with two Gram-negative bacilli per culture, so of the total of patients with isolation, 77.7% had development of Gram negative bacilli (Table III).
|Table III Microorganisms isolated in bronchial aspirate|
|Gram negative bacilli||17||63|
In univariate analysis, five variables showed statistically significant difference: sepsis prior to diagnosis of pneumonia, (OR 3.09, 95% CI: 3.09-8.39, p = 0.001), reintubation events (OR 7.6, 95% CI: 4.18-13.8 , p = 0.0001), malformations of the airways, which included patients with tracheoesophageal fistula, pulmonary hypoplasia, adenomatoid disease, and diaphragmatic hernia (OR 6.14, 95% CI: 1.62-25.12, p = 0.002), exclusive parenteral nutrition (OR: 3.32; 95% CI 1.11-10.04, p = 0.014), and days of mechanical ventilation, with a median of 32 versus a median of 22 in controls, p = 0.001 (Table IV). Antimicrobial use was reported in 84% of patients in the case group and 79% in the control group. In the group of cases, the indication was prophylactic in 24%, compared with 72% in the control group. This difference was also statistically significant (OR 0.12, 95% CI: 0.04 to 0.33, p < 0.0001).
|Table IV Univariate analysis of risk factors for development of mechanical ventilator-associated pneumonia in newborn infants|
|Days of mechanical ventilation||32||7-97||22||6-109||0.001 *|
|n||%||n||%||OR (CI 95%)||p‡|
|Episode of sepsis prior to diagnosis
|Malformation of airways§||10||22||4||4||6.14 (1.62-25.16)||0.002?|
|Transfer out of NICU||31||69||66||73||0.81 (0.34-1.9)||0.58|
|Orogastric tube||43||96||88||98||0.8 (0.58-1.09)||0.52|
|Use of gastric secretion inhibitors||10||22||22||24||1.5 (0.20-11)||0.59|
|* Student's t
? Fisher's test
‡ Mantel-Haenszel test
§ Tracheoesophageal fistula, pulmonary hypoplasia, diaphragmatic hernia, adenomatoid disease
M = medium; IR = interquartile range
Multivariate analysis found that three of the six factors were independently statistically significant for the development of VAP. The first was reintubation, with an OR of 41.7 (95% CI: 10.97-158.4, p < 0.0001); the second was airway malformations, OR 14.9 (95% CI: 1.62-136.7, p = 0.017), and the third was days of ventilation, OR 8.9 (95% CI: 1.9-40.8, p = 0.005). The development of VAP was significantly associated with greater lethality, OR 3.2 (95% CI: 1.13-9.02, p = 0.02). Finally, while a history of transfusion was not statistically significant, the OR was the highest of all the factors analyzed in the model (OR 64, 15, 95% CI: 0.722-570.8) (Table V).
|Table V Multivariate logistic regression analysis of risk factors for ventilator-associated pneumonia|
|Malformation of airways||19.483||1.344-282.337||0.029|
|Transfer out of NICU||0.841||0.112-6.301||0.866|
|Use of inhibitors||0.956||0.074-12.327||0.972|
|Use of antimicrobial prophylaxis||0.573||0.063-5.244||0.622|
|Days of ventilation||8.906||1942-40.840||0.005|
|OR = odds ratio; CI = confidence interval|
During their hospital stay in the ICU, patients require the installation of medical devices for monitoring and care (endotracheal tube, venous catheters, gastric, pleural, and urinary tubes), which, coupled with the procedures performed, increases risk for acquiring nosocomial infections. The NICU of the Hospital de Pediatría is a referral unit for patients requiring surgical treatment mostly either for heart disease, or gastrointestinal or respiratory tract malformations. As expected, most patients are premature. In this study we decided to pair the controls by gestational age and weight; it has already been established that patients with younger age and lower weight are at increased risk of acquiring a nosocomial infection.5 Unlike what is observed in older children and adult patients, the moment of infection is late (one month into mechanical ventilation),13,15 and therefore most VAP-causing organisms are Gram negative (Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, and Acinetobacter spp). These microorganisms have colonized the patient’s airway during their stay, and are similar to those reported in other units.15-17
Of the risk factors for VAP development analyzed in the study, in univariate analysis sepsis prior to diagnosis of pneumonia showed a statistically significant difference, as in the study by Apisarnthanarak15 with extremely premature patients, in which it was the only independent factor associated with VAP (adjusted OR 3.5; 95% CI: 1.2-10.8). In our study, the median gestational age was 33 weeks and there were few extremely premature patients. Prior sepsis was not a common condition, but it was found more frequently in the case group than in controls (22% versus 3%, p = 0.001); however, this factor was ruled out in multivariate analysis.
The presence of airway malformations (tracheoesophageal fistula, pulmonary hypoplasia, adenomatoid disease, diaphragmatic hernia, etc.) also showed statistically significant difference. Disorder of the airway formation or anatomy makes patients more susceptible because of the difficulty in mobilizing and removing secretions, and, since most require the use of inhalation therapy equipment from birth, colonization by pathogenic bacteria increases, which subsequently causes lower respiratory infection.18 Other authors have reported this risk factor for VAP development,19 possibly because these patients are transferred to referral centers for care.
Recently, after the conclusion of this study, a meta-analysis was published to review the observational studies reporting risk factors associated with VAP in newborns. Eight studies with 370 cases and 1071 controls were included. Ten risk factors were found: length of stay in the NICU (OR 23.45), reintubation (OR 9.18), enteral feeding (OR 5.59), mechanical ventilation (OR 4.04), transfusion (OR 3.32), low birth weight (OR 3.16), prematurity (OR 2.66), parenteral nutrition (OR 2.30), bronchopulmonary dysplasia (OR 2.21), and endotracheal intubation (OR 1.12).20 The authors commented that because of limitations on the amount and quality of the studies reviewed, it is necessary confirm these factors with a suitable design. A further study, also published after this work, said the only independent factor in VAP was weight less than 626 g.
In the present study parenteral nutrition was discarded in the multivariate analysis. Extubation and ventilation assistance were confirmed, but evaluated in days (a difference of 10 days of ventilation between the case group and the control group), as the variable per se is a necessary condition for the diagnosis of VAP. Both are factors that can be changed and that are noted in the important points for prevention.21 Of the other factors, history of transfusion had the highest risk according to OR, but was not statistically significant. The width of the confidence interval reflects the need to increase the sample size to improve the accuracy, and that findings from the meta-analysis should be evaluated in subsequent studies. In particular transfusion of globular packets has been reported in adult patients as a factor associated with VAP.22 Studies published since the meta-analysis have not added additional factors to those already described.23
Among the limitations of this study, one should note the difficulty in diagnosing VAP in newborns. The diagnosis was confirmed with the note from Neonatology, Infectious Diseases, and in the reporting of the Hospital Epidemiology Division. The need to increase the sample size has already been mentioned. The calculation was made based on two publications on newborns, taking the variable with the smallest difference, and selecting two controls for each case. However, given these results and even with a greater number of cases than required according to the sample size, one must consider that the difference may be smaller and therefore may not be detected with the current sample size.
The three independent factors associated with development of VAP were days of mechanical ventilation assistance, airway malformations, and reintubation events. Of these, it is possible to influence reintubation events, by ensuring adequate fixation of the endotracheal tube, taking extra care when moving the patient, and assessing the optimal time for extubation.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.