Introduction
Ventilator-associated pneumonia (VAP) is the most common nosocomial infection among intensive care unit (ICU) patients who are receiving mechanical ventilation via endotracheal tubes. VAP is associated with longer hospital and ICU stays, higher hospital costs, and greater in-hospital mortality [
–
]. Patients who are undergoing major oncological surgery for head and neck cancer (SHNC) are a particularly high-risk population during the post-operative period given the increased incidences of nosocomial infections and associated mortality during this period [
–
]. However, information on the risk factors and outcome of VAP in this setting is limited and needs to be updated.
There is a considerable difference in the reported incidence of VAP in patients who received mechanical ventilation. In this population, the incidence of VAP ranges from 8% to 28% and is dependent on the types of received surgery and pulmonary complications [
,
–
] in addition to the patients’ ages and underlying conditions. The observed VAP rate in the present study (19.6%) was in the range of that previously reported. In contrast to the present study, however, one earlier study found that VAP was rarely recorded after SHNC [
]. Previous studies confined their analyses to patients with VAP who did not require post-operative mechanical ventilation [
] because mechanical ventilation is a powerful independent predictive risk factor for VAP [
,
].
Mortality in the VAP group is higher than in the non-VAP group and is consistent with the rate usually reported for this complication [
,
]. However, it is presently impossible to distinguish VAP-related mortality from mortality related to other underlying diseases, such as acute respiratory distress syndrome (ARDS), cardiac insufficiency, immunosuppression, neurological disease, diabetes mellitus, and chronic obstructive pulmonary disease (COPD) [
,
,
].
Numerous studies have evaluated risk factors for VAP in the general ICU population [
,
] and in head-trauma patients [
,
]. Few studies, however, have focused on patients who are undergoing major SHNC [
]. Therefore, we conducted a retrospective study of VAP in patients who underwent SHNC in our institution over a three-year period. We aimed to assess the various characteristics of patients who developed VAP, identify specific risk factors of VAP, and describe the bacteriology of VAP.
Materials and methods
Patient population
The present study is a retrospective case-control study that utilized prospectively collected data. We screened 465 patients who had undergone major oncological SHNC at a large tertiary care hospital in Kunming between June 2011 and June 2014. The mean age of the patients was 60.9±16.1 years (range: 18–92 years), with a male predominance (61.9% male, 38.1% female). The eligibility criteria were as follows: (1) patients with histologically confirmed diagnosis of a malignant neoplasm in the head and neck; (2) patients who underwent mechanical ventilation (orally intubated or tracheostomized) from the beginning of the study; (3) patients with potentially contaminated surgeries, with simultaneous exposure of the oral and/or pharyngeal mucosa and skin; and (4) patients aged 18 years or older. The time lapse between intubation and the beginning of the study protocol was<24 h in all cases. Selective digestive decontamination was not administered in any case. Subglottic drainage was not applied in any patient. The exclusion criteria were severe immunosuppression (organ transplantation, neutropenia of<1 × 109/L), acquired immune deficiency syndrome, and evidence of pulmonary infection or a suspicion of gross aspiration before SHNC. Patients on mechanical ventilation before SHNC were excluded from the analysis. The study was approved by the hospital ethics committee. Informed consent was obtained from close relatives or next of kin of every patient. In all patients, perioperative care, including anesthesia, and monitoring techniques were standardized and were performed in accordance with local standard protocols. All the patients received perioperative antibiotic therapy during the study period. Ampicillin or cefmetazole was administered for antimicrobial chemoprophylaxis during surgery. Antibiotics were administered at a dose of 1 g once an hour before surgery, once during surgery, and twice a day for 3 days after surgery.
Definitions
Pneumonia was clinically suspected upon the presence of new and/or progressive pulmonary infiltrates in a chest radiograph along with two of the following criteria: hyperthermia (≥38.0 °C) or hypothermia (≤36.0 °C), leucocytosis (≥12 000/ml) or leucopenia (≤4000/ml), and purulent pulmonary secretions [
]. VAP was defined as pneumonia that occurred in patients who received post-operative mechanical ventilation for 48 h or longer with the ventilator in place at the time of or 24 h before the event. Distal tracheal samples were obtained from patients with suspected pneumonia via Combicath or fiberoptic bronchoscopy. The samples were collected with a protected specimen brush or bronchoalveolar lavage. A diagnosis of pneumonia was confirmed only if more than 10
3, 10
4 or 10
5 colony-forming units (CFU/ml) were found on the protected specimen brush, bronchoalveolar lavage, and Combicath, respectively. Pneumonia was considered as ventilator-associated when it occurred after tracheal intubation.
Microbiological data were collected from the Hospital Database and comprised cultures from the lower respiratory tract (sputum, tracheal or bronchial aspirate) and from blood. Cultures from pleural fluid were also obtained if a puncture was indicated. Sputum was obtained by spontaneous expectoration or with the aid of nebulized saline. Microbial identification and susceptibility tests were performed using standard methods. Polymicrobial pneumonia was defined when more than one pathogen was identified. The presence of multidrug-resistant pathogens was recorded.
Data collection and study variables
Demographic, clinical, and treatment data were collected from all patients, including: age, sex, body mass index (BMI), smoking status, comorbid illnesses, simplified acute physiological score (SAPS), antibiotic treatment, Glasgow Coma Score (GCS), tumor site and size, and serum albumin level (g/dl). In addition, data were obtained on chest examination upon admission, tracheostomy, prior antibiotic therapy, and statin use. Data were also obtained for length of stay in the ICU, duration of ventilation, duration of surgery, and number of deaths in the ICU. Patients were initially screened for VAP by reviewing chest X-ray data. VAP was confirmed using respiratory cultures, medication records, or both. The primary outcome was VAP development, which was treated as a binary variable. Secondary outcomes included death during stay in the ICU, length of stay in the ICU, and duration of ventilation.
Statistical analysis
Results were expressed as total numbers (percentage) for categorical variables. Results were expressed as mean±standard deviation or median (25–75th percentiles), as appropriate, for continuous variables using an unpaired Student’s t-test or a nonparametric (Mann–Whitney) test. Categorical variables were compared using the Chi-square test or Fisher’s exact test, as appropriate. Variables that were identified as potential risk factors in univariate analysis with a cut-off of 0.05 were included in an unconditional logistic regression. In a subsequent multivariate analysis of the occurrence of VAP, variables were introduced in a stepwise manner based on a criterion of P<0.05. A condensed model of VAP occurrence was developed with crude odds ratios (ORs) and 95% confidence intervals (CIs). A value of P<0.05 was taken to indicate statistical significance. Calibration was assessed using the Hosmer and Lemeshow goodness-of-fit test. Statistical analysis was performed using SAS statistical software (9.2, Cary, NC, USA).
Results
Study population
The mean BMI was 25.1±4.2 kg/m2, the mean GCS upon admission was 6.9±2.1, and the mean SAPS II score was 43.6±10.7. Only 36.7% of the patients were active smokers. Two or more comorbidities (up to five morbidities) were present in 147 (31.6%) of the patients (Table 1).
The occurrence rate of VAP was 19.6% (n = 95) in the population under study. VAP was diagnosed 3.6±0.8 days after the surgery. The length of stay in the ICU varied from 2 to 96 days (mean, 10.8 days; median, 7 days) (Table 2). There was a statistically significant difference between the median lengths of stay of VAP patients in the ICU (8.0 days) versus those without VAP (6.5 days, P<0.0001). The mean duration of mechanical ventilation was 13.4±4.4 days, and the duration of mechanical ventilation was statistically significantly longer than among those who developed VAP (P<0.0001). Univariate analysis revealed no statistically significant difference in the length of surgery between patients with VAP and those without VAP (P = 0.081) with a mean length of surgery of 4.60±1.0 h. Sixteen of 95 VAP patients died (16.8%) and 31 of 370 non-VAP patients died (8.4%) (P<0.0001).
A total of 68 microorganisms were isolated from 53 of the 95 pneumonia cases (55.7%) (Table 3). A single type of pathogen was detected in 34 (71.7%) of the patients, and two to three pathogens were detected in the other 15 (28.3%) patients. The most commonly isolated bacterial species were Staphylococcus (37.7%). Enterobacteriaceae (32.1%), Pseudomonas (20.8%), and Hemophilus (16.9%).
To determine the risk factors for VAP, 20 variables between the VAP group and the non-VAP group were compared. Pearson’s chi-square-test was used when categorical variables were compared, whereas the Student’s t-test was used when continuous variables were compared. Of these 20 variables, the following seven showed a statistically significant difference (P<0.05) between the two groups: age, smoking status, immunosuppression, COPD, mean SAPS II on admission, serum albumin level (g/dl), and tracheostomy (Table 1). Univariate analysis revealed that the following variables did not exhibit any significant association with VAP: gender, BMI, ARDS, cardiac insufficiency, neurological disease, diabetes mellitus, lung trauma, mean GCS on admission, abnormal chest examination on admission, prior antibiotic therapy, tumor size, and statin usage. Variables with a P value of less than 0.05 in univariate analysis were entered into logistic regression. The outcomes of the multivariable regression model are shown in Table 4. Four independent risk factors for VAP were identified: advanced age (OR= 1.15, 95% CI= 1.04‒1.28, P = 0.01), current smoking (OR= 4.37, 95% CI= 1.40–8.22, P<0.0001), COPD (OR= 2.35, 95% CI= 1.30‒4.77, P = 0.0001), and higher SAPS II on admission (OR= 1.21, 95% CI= 1.06–1.70, P = 0.013). Tracheostomy (OR= 0.72, 95% CI= 0.55–0.98, P = 0.005) remained an independent protective factor for VAP. Smoking was the strongest predictor of VAP development. Current smokers were 4.37-fold more likely to have VAP than patients who had never smoked or had quit smoking. Older subjects were more likely to experience VAP in this cohort. The likelihood of VAP increased by more than 1.15-fold per one-year increase in age. Compared with patients without COPD, patients with COPD were 2.35-fold more likely to develop VAP. In the control group, a tracheostomy was predictive of VAP and decreased the risk of VAP by almost 3-fold. The area under the ROC curve (AUC) was 0.8914 (95% CI=0.84–0.94; P = 0.025) (Fig. 1). The resulting logistic model had a sensitivity of 95.3% and specificity of 69.4%. The sensitivity of the model is the percentage of the group accurately identified by the model as having VAP and the specificity is the percentage correctly identified as not having VAP.
Discussion
The present study found that the rates of VAP and the post-operative mortality in mechanically ventilated patients who underwent SHNC at our hospital were 19.6% and 10.1% (47/465), respectively. The regression model showed good discriminative power for identifying patients at risk of VAP, as indicated by the AUC of 89.14%. We identified advanced age, smoking, COPD, and a higher SAPS II upon admission as the four risk factors for VAP. Tracheostomy was an independent protective factor for VAP. The clinical and potential economic impact of VAP was attributed to a significantly extended stay in the ICU and increased rate of mortality.
Advanced age increases the risk of developing pulmonary complications following major head and neck surgery [
]. Advanced age in patients who underwent major SHNC was also suggested as a specific risk factor for pulmonary complications [
]. In accordance with these data, our results showed that advanced age is an important risk factor for VAP. The latter might be attributed to compromised defense mechanisms against pneumonia as the body ages, such as decreased immunoglobulin levels and cellular immune responses [
].
Previous studies have demonstrated that smoking is an independent predictor of post-operative pulmonary complications, including VAP [
,
]. Our results confirmed that smoking is the strongest predictor of VAP in patients who underwent major SHNC. Smoking cessation prior to surgery may prevent post-operative pulmonary complications [
]. However, several studies have reported that short-term (less than 4 weeks) smoking cessation is not associated with a decreased risk of post-operative pulmonary complication [
,
], which may be explained by sputum retention, delayed improvement in inflammatory functions, and a possible reduction in irritant-induced coughing [
]. In the present study, two intra-operative risk factors for VAP were also identified: COPD and SAPS II on admission. Previous studies have concluded that COPD comorbidity is associated with ICU mortality in VAP patients [
,
]. This conclusion is in accordance with the results of this study, in which COPD history was related to VAP development. An earlier study has reported that patients with severe COPD (i.e., GOLD stage IV) have a longer duration of ventilation and hospital stay than patients without COPD; moreover, COPD comorbidity and worse survival among VAP patients are associated [
]. The poorer outcomes among patients with COPD likely resulted from advanced age, more frequent previous use of corticosteroids, the complex pathobiology of inflammation in advanced COPD, adverse impacts of COPD on respiratory muscle function, and the patient’s nutritional status [
,
–
]. The results of the present study also showed that tracheostomy is a protective factor for VAP, in accordance with the findings of previous studies [
,
]. Although one study found no association between tracheostomy and VAP in mechanically ventilated adult ICU patients [
], other studies have demonstrated that tracheostomy reduced total mechanical ventilation time, shortened ICU and hospital stays, reduced in-hospital mortality, improved hospital resource use, increased patient comfort, and increased tolerance of mechanical ventilation and facilitated patients’ care [
–
].
The overall mortality rate of our settings was 10.1% (47/465), which is consistent with that reported in previous studies by other groups [
,
]. In our study, the median ICU length of stay for patients with and without VAP was 8.0 and 6.5 days, respectively (
P = 0.006). The mean ventilation duration was 15.1 and 13.0 days, respectively, in the two populations (
P<0.0001), which is similar to the findings of others [
3,
,
,
]. However, logistic regression analysis did not identify length of stay in the ICU and ventilation duration as potential risk factors for VAP because it is very difficult to accurately prove a causal link between VAP and long ICU and hospital stays. Given the disadvantages of retrospective case control studies, there are no findings on whether VAP has caused longer stays in the ICU and hospital, and vice versa. Moreover, family economic conditions and disease severity are closely related to the duration of hospitalization. It is therefore critical that large and well-designed prospective cohort study should be performed to evaluate the association.
Two large epidemiological pneumonia studies have reported that
Staphylococcus aureus and
Pseudomonas aeruginosaare the most common etiological agents in post-operative nosocomial pneumonia [
,
]. However, there are major differences in the bacterial spectrum of post-operative pneumonia in different settings and geographical regions. One study in Japan found that
Pseudomonas species,
S. aureus, and
Enterococcus faecalis are the most important etiological agents in post-operative pneumonia after major abdominal surgery [
]. In the present study,
Staphylococcus species (37.7%) were the most prevalent microorganisms isolated from patients with VAP, followed by Enterobacteriaceae (32.1%) and
Pseudomonas species (20.8%); these results are consistent with those of a VAP study in China [
].
Our study has several limitations. First, given that this study was conducted in a single center, institution-specific variables may have influenced our findings. Therefore, our results may not be generalizable to patients in other ICUs. Second, there was no microbiological documentation in 44.2% of cases. However, this is an inevitable situation in clinical practice. Third, the data presented were collected during routine management and were not specifically collected for this study. Moreover, only documented VAP cases in patients who underwent ventilation were considered (i.e., non-ventilated patients were not included). This likely resulted in the overestimation of the real incidence of VAP. Fourth, the present study is a retrospective observational analysis. Thus, the results support an association, and not necessarily causation, between VAP and potential risk factors. Prospective studies are needed to confirm our results. Fifth, some trends observed in the present study might have statistical significance if study sample had been larger. For example, smokers may have more serious COPD than non-smokers, and cigarette consumption increases with age. Although COPD and smoking remained significant in the multivariate logistic regression analysis, their interactions and/or synergistic effects on VAP remain unknown. Finally, our study only collected data for the duration of inpatient stay. This limits the analysis to immediate post-operative outcomes and omits relevant data related to patient outcomes after discharge, such as functional outcomes, 30-day morbidity, and mortality or related re-admissions.
Our results revealed that SHNC patients had high incidence of VAP and that predictive risk factors for VAP included advanced age, smoking, COPD, and a higher SAPS II on admission, but not tracheostomy. VAP was associated with increased mortality and a longer duration of ventilation and ICU stay. Efforts should be made to reduce the incidence of VAP in these patients and to initiate prompt and adequate treatment when VAP is suspected.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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