Late-onset ventilator-associated pneumonia (VAP) is challenging, because it is frequently caused by potentially antibiotic-resistant bacteria.1–4 The aspiration of contaminated oropharyngeal secretions into the lower airway is the major route for VAP.5–8 Nutritional support has evolved as an essential component in the care of critically ill patients, and there has been discussion of the impact of enteral nutrition (EN) and delayed gastric emptying on the risk of acquiring VAP.9–14 Although there is abundant literature on VAP, there are very few studies designed to determine the factors associated with the acquisition of late-onset VAP, and most were performed in critically ill trauma patients.15,16 For these reasons, we performed a prospective observational study designed to assess factors associated with acquisition of late-onset VAP in a population of nontrauma intensive care unit (ICU) patients, with special focus on EN and manifestations of EN intolerance.
From February 1, 2005 to June 26, 2007, we conducted a prospective, single-center, observational study in tracheally intubated patients with mechanical ventilation (MV) duration of 6 days or more. None of them were trauma patients. The outcome was the development of microbiologically confirmed late-onset VAP. The protocol was approved by our IRB. Because it was an observational study, the requirement for written informed consent was waived by the IRB.
Patients were eligible for the study if they were 18 yr or older, placed on MV upon admission to the ICU or <24 h before admission to the ICU, and if no decision was made to withdraw treatment in the first 5 days of MV. Patients were followed for VAP until death, ICU discharge, or decision for palliative treatment. All patients were orally intubated from the beginning of MV with an endotracheal tube (ETT) with a polyvinyl cuff (Hi-Lo Lanz™, Mallinckrodt Medical, Athlone, Ireland). Most patients received continuous infusions of midazolam and morphine for sedation, which was conducted by the physician in charge based on our protocol for sedation.
Briefly, patients received first boluses of midazolam (0.05 mg/kg) or propofol (1 mg/kg) to achieve tolerance to MV, followed by continuous infusions of midazolam and morphine at 1–2 mg/h, both increased and decreased in increments of 1–2 mg/h to achieve the sedation goal, which was to maintain a Ramsay score of 3–4 as early as possible. The protocol required that a Ramsay score of 6 be obtained when patients received continuous infusions of paralytic drugs. Ramsay score was assessed at least every 4 h by nurses in charge. Daily interruption of sedative infusions was not routinely used. Red blood cell transfusions were conducted with a restrictive strategy17 and leukocyte-depleted red blood cell units were given. Measurements of blood glucose were performed at 1- to 4-h intervals with the use of a glucose analyzer (MediSense® Optium™, Abbott Laboratories, Maidenhead, UK). In our medical ICU, the general goal was to maintain glucose levels lower than 10 mmol/L but not to obtain strict normalization of blood glucose levels.
Measures to Prevent VAP
In addition to handwashing and use of protective gowns and gloves, we had a standard care protocol to prevent VAP in which a semirecumbent body position was maintained if possible, the oropharynx cavity was cleaned 4 times daily with chlorhexidine, and intracuff pressures were periodically verified. Subglottic drainage was not applied to any patients, and we did not use closed suctioning systems. In addition, no systemic antibiotic regimen for nosocomial pneumonia prophylaxis or selective decontamination of the digestive tract was prescribed during the period of the study. Maintenance of ventilator circuits did not change over the study period. Except for patients with chronic obstructive pulmonary disease (COPD) and those with acute respiratory distress syndrome (ARDS), heat and moisture exchangers (Humid-Vent® Filter Compact S, Teleflex Medical, High Wycombe, UK) were used during the first 5 days of MV and changed at 72-h intervals if not grossly soiled. From the start of MV for patients with COPD and ARDS and from Day 6 for the other patients, heated humidifiers with wire-heated circuits (MR 730 device, Fisher & Paykel Healthcare, Auckland, New Zealand) were used.
The feeding policy in our ICU consisted of starting EN as soon as possible via a nasogastric tube by using a peristaltic pump. In patients with shock, EN is usually deferred until patients are considered hemodynamically stable by the physician in charge. In practice, patients admitted to the ICU with shock rarely received EN within the first day of admission. Patients were fed over a 24-h period with Fresubin Original® (1 kcal/mL) or Fresubin Energy® (1.5 kcal/mL) (Fresenius Kabi, Paris, France). Glutamine and fish oil supplements were not used. Gastric residual volumes (RVs) were measured by aspiration with a 60-mL syringe at least every 12 h after initiation of EN. The policy of our ICU called for returning a gastric RV ≤200 mL to the patient. When the recovered volume was ≥300 mL, EN was started again after a 4-h break. When the recovered volume was >500 mL or when vomiting was present, feeding was discontinued. The initial rate was set at 20 mL/h, and the feeding goal was 25–30 kcal · kg−1 · day−1. There was no written protocol for guiding the increase in the rate of feeding. The decision to increase the rate of feeding or to stop feeding was made at the discretion of the attending physician based on gastric residuals recovered and findings of the daily abdominal examination. EN was stopped during MV in the prone position and transports outside the ICU. During the study period, the use of prokinetic drugs was not protocolized.
In addition to variables related to nutrition, we recorded variables previously described as potentially associated with the occurrence of VAP, including those related to the use of invasive medical devices and those reflecting the severity of the illness during the period of the first 5 days of MV.1,2,8,18,19 On the first day of ICU stay, the data compiled for each patient consisted of demographic data: age, sex, body mass index (BMI), preexisting conditions (current smoking, diabetes mellitus, and immunosuppression), type of admission (medical, scheduled surgery, or unscheduled surgery), Glasgow coma scale score, and severity of illness assessed by the simplified acute physiology score (SAPS) II. The length of hospital stay before intubation, the reason for MV (acute respiratory failure, acute exacerbation of COPD, neurological problem, postoperative, and miscellaneous), failure of noninvasive ventilation, and aspiration before intubation were also noted.
Within the first 5 days of MV, the following data were recorded: transport outside of the ICU,20 presence of ARDS2,21 and sepsis, reintubation,22 dialysis or continuous venovenous hemodiafiltration, and transfusion of red cell packs.23 Among treatments received by patients during this period, we noted antibiotics, vasopressors, sedatives, morphine, treatments for stress ulcer prophylaxis,1,2,24 and steroids.15 The following variables related to patients' nutrition were collected daily until the fifth day of MV: route of alimentation, delay from the time of EN initiation to the time of intubation, gastric RV, vomiting, and regurgitation of food received. To quantify hyperglycemia, we checked on a daily basis whether glucose concentrates were >11.1 mmol/L.25
The diagnosis of VAP was based on new, persistent, or progressive infiltrate(s) on chest radiograph(s) consistent with pneumonia, along with 1) purulent bronchial sputum, 2) body temperature >38°C or <36°C, 3) leukocyte count >12,000/mm3 or <4500/mm3, and 4) bronchoalveolar lavage results demonstrating ≥104 colony-forming units/mL. Aspiration was defined as witnessed or suspected aspiration of gastric contents into the airways, and coma by a Glasgow coma scale score <9. Immunocompromised patients were those with hematological malignancy, those who had received cytotoxic drugs within 3 mo of admission to the ICU, those receiving immunosuppressive therapy, and those who received >20 mg/d prednisolone for at least 2 wk or lower daily doses for at least 3 mo. EN was considered early when started within 48 h of MV onset. Sepsis and ARDS were defined according to the generally accepted criteria.26,27 The use of vasopressive drugs was defined as epinephrine, norepinephrine, or dobutamine, whatever the dose, administered for a period ≥24 h. We considered that patients received continuous sedation and analgesia when the daily infusion was given for a minimum period of 12 consecutive hours. Based on the results published by Rubinson et al.,28 who found that failure to provide ≥25% of the American College of Chest Physicians guidelines (i.e., approximately 6 kcal · kg−1 · day−1) was associated with bloodstream infections in medical ICU patients, patients were distinguished by whether daily caloric intake provided within the first 5 days of MV was <6 kcal · kg−1 · day−1 or ≥6 kcal · kg−1 · day−1.
In 2004, 205 patients admitted to our ICU received MV for >5 days, and 61 (30%) had late-onset VAP, including patients with MV duration >24 h before admission to the ICU. To detect a two-sided difference in the proportion of patients who acquired late-onset VAP from 25% (patients with early EN) to 10% (patients who received EN after 48 h of MV onset) with α = 0.05 and β = 0.10, a minimum of 130 patients for each group (early versus no early EN) was required. Patients were divided into 2 groups according to the presence (late-onset VAP group) or absence (no late-onset VAP group) of VAP during the follow-up period. Continuous data are expressed by the median and interquartile range. Univariate analysis was conducted to determine potential risk factors associated with development of late-onset VAP. The χ2 test or Fisher's exact test was used to compare qualitative variables, and the Mann-Whitney U-test for quantitative variables. The level of significance was set at P < 0.05. Multivariate analysis was performed to assess the independent effect of each variable with P value <0.1 in univariate analysis on the development of late-onset VAP. For this purpose, forward stepwise logistic regression was performed with an adjustment for the duration of MV before the diagnosis of late-onset VAP. The results of multivariate analysis are presented with odds ratios and 95% confidence intervals.
There were 2255 patients admitted to the ICU during the study period, 476 (21%) of whom received MV via an ETT for 6 days or more. Among these patients with prolonged MV, 115 (24%) were excluded from the study, mainly because invasive MV had already been in place for 24 h or more when they were admitted to the ICU (Fig. 1). Of the 361 patients studied, 76 (21%) developed late-onset VAP. The microorganisms isolated in significant concentrations are listed in Table 1. Infection was polymicrobial in 27 patients (36%). The median duration for MV before the diagnosis of VAP was 11 days (8–15 days). Mortality rate was significantly higher in the late-onset VAP group than in the no late-onset VAP group (30 patients [39%] vs 60 patients [21%], respectively, P < 0.01).
The comparisons of baseline characteristics and variables recorded during the first days of MV for the no late-onset VAP and the late-onset VAP group are presented in Table 2. Patients with late-onset VAP did not differ significantly from those with no late-onset VAP with regard to baseline characteristics, type of admission, and reason for MV. On the other hand, they had a higher severity of illness as measured by SAPS II and differed significantly from patients with no late-onset VAP for most of the processes of care and in some of the outcome variables recorded within the first 5 days of MV. Sixty-six patients (87%) in the late-onset VAP group and 235 patients (82%) in the no late-onset VAP group received paralytic drugs (P = 0.35). In both the late-onset VAP and no late-onset VAP groups, median duration of treatment with paralytic drugs was 1 day. The proportion of patients with at least one episode of hyperglycemia >11.1 mmol/L was significantly higher in patients with late-onset VAP, but such a situation was encountered in close to 60% of those who never developed late-onset VAP. Patients with late-onset VAP received larger ETTs, with a tube size ≥7.5 in 79%, whereas only 64% of the patients who did not have late-onset VAP received a tube size ≥7.5 (P = 0.01). Almost half of the studied population received steroids during the first 5 days of MV. We found no significant differences in the antibiotics received during the first 5 days of MV, regardless of whether patients did or did not acquire late-onset VAP.
Stress ulcer prophylaxis was similar in the 2 groups, as was the proportion of patients who received parenteral nutrition (Table 3). Patients had similar amounts of gastric RV recovered and volumes of EN received during the first 5 days of MV. Proportions of patients with average daily caloric intake <6 kcal/kg and medians for total caloric intake during this period did not differ significantly between groups.
Table 4 shows the results of the multivariate analysis. SAPS II, presence of ARDS during the first 5 days of MV, and ETT tube size ≥7.5 were independently associated with development of late-onset VAP.
We examined the risk factors for late-onset VAP diagnosed by bronchoalveolar lavage and occurring in 21% of a large population of nontrauma ICU patients. Most patients received antibiotics during the first 5 days of MV, and the distribution of bacteria responsible for late-onset VAP in this study was similar to that reported in most studies.2,18 The crude mortality rate was significantly higher in patients with late-onset VAP than in those who did not develop late-onset VAP. SAPS II, presence of ARDS within the first 5 days of MV, and large tube size were the factors independently associated with development of late-onset VAP. Neither EN received early nor the other variables related to nutrition or nutritional intolerance were associated with a higher risk of late-onset VAP. Continuous sedation and continuous analgesia were significantly longer in the late-onset VAP group than in the no late-onset VAP group in the univariate analysis, but did not remain significantly associated with late-onset VAP in the multivariate analysis.
Data regarding the impact of early EN on the risk of developing late-onset VAP are scarce. On one hand, in some studies,9,12,29 early enteral feeding was associated with an increased incidence of VAP in medical ICU patients. On the other hand, a low caloric intake is a risk factor for bloodstream infections in critically ill patients,28 and a growing body of evidence suggests that when the gastrointestinal (GI) tract is intact, nutrition should be administered through the enteral route to avoid GI mucosal atrophy and to preserve the GI tract immunologic functions.30–32 Ibrahim et al.29 reported that attempts to deliver 100% of nutritional goals via enteral feeding very early (i.e., Day 1 of intubation and ventilation) were associated with increased VAP. We did not find that early EN was associated with a higher incidence of late-onset VAP. We think that episodes of gastric overdistention were less frequent in our population because we used daily volumes of nutrition smaller than those used in the study by Ibrahim et al.29 Upper digestive intolerance is frequent in critically ill patients and was associated with the occurrence of VAP in some studies.10,12,33 There are wide variations in the literature as to what constitutes an excessive RV,10,14,31,33 and the use of RV as a marker for the risk of aspiration has been discussed.34 In this study, patients with and without late-onset VAP did not significantly differ in the amount of gastric RV recovered daily during the first 5 days of MV.
Impairments of host systemic and lower respiratory tract defense mechanisms predispose to the development of late-onset VAP, as does the presence of an ETT. SAPS II was independently associated with late-onset VAP in this study. Severity of illness was previously identified among host factors for VAP.2,19 Similarly, because phagocytic functions of alveolar macrophages are impaired in ARDS, it was not surprising for ARDS to be independently associated with late-onset VAP. Previous authors21,35 demonstrated that the VAP rate was higher in patients with ARDS than in other mechanically ventilated patients. On the other hand, the fact that tube size ≥7.5 was independently associated with late-onset VAP occurrence was unexpected. To the best of our knowledge, the size of an ETT has not been previously assessed among risk factors for late-onset VAP. When we compared the patients who were intubated with an ETT ≥7.5 with those who were intubated with an ETT <7.5 for all the variables listed in the Methods section, we found that they differed significantly only for gender (205 males of 232 patients [88%] vs 38 males of 129 patients [29%], respectively, P < 0.01) and BMI (25 kg/m2 [22–29] vs 23 kg/m2 [21–28], respectively, P < 0.01). However, gender and BMI were not significantly different in our population when patients with late-onset VAP were compared with those who did not develop late-onset VAP (Table 2). With regard to the choice of ETT size, there is no written protocol in our ICU. The type of ETT used may influence the likelihood of aspiration. Several studies demonstrated that some modifications made to the ETT had a significant impact on the risk of developing VAP. To avoid the progression of subglottic secretions around the ETT cuff and into the lower respiratory tract, some authors proposed adding a separate dorsal lumen to the ETT for removing secretions by subglottic secretion drainage and/or incorporating an ultra-thin polyurethane cuff, which reduces channel formation and fluid leakage from the subglottic area.36,37 Other authors demonstrated a statistically significant reduction in the incidence of VAP with the use of a silver-coated ETT, which reduces bacterial adhesion and biofilm formation on the device.38,39 Clearly, our finding is difficult to explain and needs to be confirmed by others. Is there a positive relationship between the size of ETT and the area of the infected biofilm on the inner and outer lumens, and consequently more important subsequent embolization to the distal airway with the use of large tubes?
Our study has several important limitations. First, it was performed within a single ICU, and the results may therefore not be applicable to other ICUs. Second, tube colonization was not determined by daily swab cultures from the inner tube surface.39 Third, data collection was restricted to the period of the first 5 days of MV. Fourth, this study, like all observational studies, cannot exclude the possibility of unmeasured confounders. Fifth, there was no written protocol for guiding the increase in the rate of enteral feeding; consequently, volumes of EN varied greatly among patients.
In conclusion, in this large population of nontrauma critically ill patients with long-term ventilation, early EN was not associated with late-onset VAP, a result probably explained in part by the fact that limited volumes of enteral feeding were given during the first 5 days of MV (Table 3). During this period, proportions of patients with signs of upper digestive intolerance and the caloric intakes were similar in the no late-onset VAP and the late-onset VAP groups. SAPS II and ARDS were independently associated with late-onset VAP. Our results suggest that the size of the ETT could play a role in the pathogenesis of VAP. The impact of the size of the ETT on the risk of developing late-onset VAP should be evaluated in future studies.
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