Torsten T. Bauer

Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial

BACKGROUND Risk factors for nosocomial pneumonia, such as gastro-oesophageal reflux and subsequent aspiration, can be reduced by semirecumbent body position in intensive-care patients. The objective of this study was to assess whether the incidence of nosocomial pneumonia can also be reduced by this measure. METHODS This trial was stopped after the planned interim analysis. 86 intubated and mechanically ventilated patients of one medical and one respiratory intensive-care unit at a tertiary-care university hospital were randomly assigned to semirecumbent (n=39) or supine (n=47) body position. The frequency of clinically suspected and microbiologically confirmed nosocomial pneumonia (clinical plus quantitative bacteriological criteria) was assessed in both groups. Body position was analysed together with known risk factors for nosocomial pneumonia. FINDINGS The frequency of clinically suspected nosocomial pneumonia was lower in the semirecumbent group than in the supine group (three of 39 [8%] vs 16 of 47 [34%]; 95% CI for difference 10.0-42.0, p=0.003). This was also true for microbiologically confirmed pneumonia (semirecumbent 2/39 [5%] vs supine 11/47 [23%]; 4.2-31.8, p=0.018). Supine body position (odds ratio 6.8 [1.7-26.7], p=0.006) and enteral nutrition (5.7 [1.5-22.8], p=0.013) were independent risk factors for nosocomial pneumonia and the frequency was highest for patients receiving enteral nutrition in the supine body position (14/28, 50%). Mechanical ventilation for 7 days or more (10.9 [3.0-40.4], p=0.001) and a Glasgow coma scale score of less than 9 were additional risk factors. INTERPRETATION The semirecumbent body position reduces frequency and risk of nosocomial pneumonia, especially in patients who receive enteral nutrition. The risk of nosocomial pneumonia is increased by long-duration mechanical ventilation and decreased consciousness.

Clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies

BACKGROUND A study was undertaken to assess the diagnostic value of different clinical criteria and the impact of microbiological testing on the accuracy of clinical diagnosis of suspected ventilator associated pneumonia (VAP). METHODS Twenty five deceased mechanically ventilated patients were studied prospectively. Immediately after death, multiple bilateral lung biopsy specimens (16 specimens/patient) were obtained for histological examination and quantitative lung cultures. The presence of both histological pneumonia and positive lung cultures was used as a reference test. RESULTS The presence of infiltrates on the chest radiograph and two of three clinical criteria (leucocytosis, purulent secretions, fever) had a sensitivity of 69% and a specificity of 75%; the corresponding numbers for the clinical pulmonary infection score (CPIS) were 77% and 42%. Non-invasive as well as invasive sampling techniques had comparable values. The combination of all techniques achieved a sensitivity of 85% and a specificity of 50%, and these values remained virtually unchanged despite the presence of previous treatment with antibiotics. When microbiological results were added to clinical criteria, adequate diagnoses originating from microbiological results which might have corrected false positive and false negative clinical judgements (n = 5) were countered by a similar proportion of inadequate diagnoses (n = 6). CONCLUSIONS Clinical criteria had reasonable diagnostic values. CPIS was not superior to conventional clinical criteria. Non-invasive and invasive sampling techniques had diagnostic values comparable to clinical criteria. An algorithm guiding antibiotic treatment exclusively by microbiological results does not increase the overall diagnostic accuracy and carries the risk of undertreatment.

Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies

BACKGROUND Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention. METHODS We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores. FINDINGS Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20-29 and simplified acute physiology score [SAPS 2] 35-58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing risk analyses could be done for 5162 patients from 19 studies, and the overall daily hazard for intensive care unit (ICU) mortality after ventilator-associated pneumonia was 1·13 (95% CI 0·98-1·31). The overall daily risk of discharge after ventilator-associated pneumonia was 0·74 (0·68-0·80), leading to an overall cumulative risk for dying in the ICU of 2·20 (1·91-2·54). Highest cumulative risks for dying from ventilator-associated pneumonia were noted for surgical patients (2·97, 95% CI 2·24-3·94) and patients with mid-range severity scores at admission (ie, cumulative risks of 2·49 [1·81-3·44] for patients with APACHE scores of 20-29 and 2·72 [1·95-3·78] for those with SAPS 2 scores of 35-58). INTERPRETATION The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay. FUNDING None.

Effect of Nasogastric Tube Size on Gastroesophageal Reflux and Microaspiration in Intubated Patients

Gastroesophageal reflux of bacteriologically contaminated gastric contents and subsequent microaspiration of these contents to the lower airways may increase the risk for nosocomial pneumonia (1). The nasogastric tube in ventilated patients is partially responsible for reflux (2) and has been recognized as a risk factor for nosocomial pneumonia (3, 4). Impairment of closure of the lower esophageal sphincter secondary to the nasogastric tube has been suggested as a major contributing factor in gastroesophageal reflux (5). Reducing the bore size of the nasogastric tube may therefore be an appropriate prophylactic measure for both reflux and pneumonia (6). However, because of insufficient evidence, the use of small-bore tubes for prevention of nosocomial pneumonia has not yet been recommended by the Centers for Disease Control and Prevention (7). We compared gastroesophageal reflux and microaspiration of gastric contents to the lower airways in patients intubated with a conventional large-bore nasogastric tube or a small-bore tube. Methods Patients Intubated patients in an intensive care unit for more than 72 hours who were clinically stable were consecutively chosen. Exclusion criteria were previous abdominal surgery, documented macroscopic gastroesophageal reflux or aspiration, paralytic ileum, gastrointestinal bleeding, or severe hemodynamic impairment. Study Design Our study was a randomized, two-period crossover trial. Patients were randomly assigned to receive a small-bore (2.85-mm) nasogastric tube (Flexiflo, Ross Laboratories, Columbus, Ohio) or a large-bore (6.0-mm) nasogastric tube (Salem Sump, Sherwood Medical, Tullamore, Ireland); tubes were inserted 24 hours before the study began. The position of the tube was confirmed by auscultation and abdominal radiography. All measurements were repeated 72 hours after the first measurements were taken with the alternate size of nasogastric tube. All patients were studied in the semirecumbent position (45). Therapy with all medications and enteral feeding through the nasogastric tubes were stopped 12 hours before each study period. The protocol was approved by the ethics committee of our institution, and written informed consent was obtained from each patients next of kin. Measurement of Radioactivity Thirty-seven MBq (1 mL) of colloidal radioactive technetium (99mTc-Re) sulfide (TCK-1, CIS Bio International, Gif-sur-Yvette, France), a nonabsorbable radiopharmaceutical agent, was instilled through the nasogastric tube (8). Samples of serum, gastric juice, and pharyngeal and tracheal secretions were obtained before the first dose was administered and 1, 2, 3, 4, 5, and 17 hours after the first dose was administered. We took measurements 2 and 4 hours after giving the first dose of 99mTc-Re sulfide and then administered additional doses. Radioactive counting was done by using a camera (Packard 800c, Downers Grove, Illinois). Results were corrected for decay and are expressed as a decimal logarithm of counts per minute per mL (cpm [log10]). Statistical Analysis Radioactive counting in all samples (reported as the mean [SE]) was examined by one-way analysis of variance for repeated measurements. We calculated the significance of the time course and of the difference from baseline of any time point during follow-up. We used paired Student t-tests to compare mean and cumulative counts during the 17 hours that elapsed between changes in type of nasogastric tube. Gastroesophageal reflux was assumed when radioactive counts in pharyngeal aspirates increased by one log10 unit compared with baseline at any time point during follow-up. Aspiration was defined accordingly as an increase of more than one log10 unit in radioactive counts in tracheal aspirates. Frequencies of reflux and aspiration were compared by using the chi-square test or the Fisher exact test (if adequate). All data were processed with SPSS for Windows (SPSS, Inc., Chicago, Illinois), and the level of significance was set to 0.05 (all tests were two-tailed). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Patient Data Seventeen patients (mean age [SD], 64 17 years; 15 men, 2 women) were included in the study. Data were not evaluable in 1 of the 17 patients (6%) because no samples were available before administration of the first dose of 99mTc-Re sulfide on either study day. Data in another patient (1 of 17 [6%]) were evaluable on only 1 day. The mean Simplified Acute Physiology State-II score for all patients upon admission to the intensive care unit was 35 15. Reasons for admission to the intensive care unit were acute respiratory failure (9 of 17 patients [53%]), neurologic disease (3 of 17 patients [18%]), cranial trauma (2 of 17 patients [12%]), cardiac arrest (2 of 17 patients [12%]), and coma (1 of 17 patients [6%]). Three patients (3 of 17 [18%]) died in the intensive care unit. Mean Absolute Radioactive Count The time course of the radioactive count was significant in pharyngeal aspirates (P=0.004) and gastric juice (P<0.001) for the two types of nasogastric tube. The radioactive count in pharyngeal aspirates was significantly greater than the baseline count at any time point during follow-up (P=0.005 1 hour after the first dose of 99mTc-Re sulfide; P<0.001 2 hours after the first dose of 99mTc-Re sulfide to 17 hours after the first dose). Accordingly, radioactive counts in gastric juice were also significantly greater than baseline counts during the entire follow-up (P<0.001). The time course was not significant in tracheal aspirates (P>0.2) or serum (P=0.067) for the two types of nasogastric tube. Mean radioactive counts did not differ between the two nasogastric tubes for any type of sample at any time point (Figure 1). Figure 1. Scintigraphic radioactivity counts (mean cpm [log ] SE) of pharyngeal aspirates ( top left ), tracheal aspirates ( top right ), gastric aspirates ( bottom left ), and serum ( bottom right ). Mean Cumulative Counts For both types of nasogastric tubes, the cumulative counts taken 17 hours after the first dose of 99mTc-Re sulfide were significantly greater than baseline counts in pharyngeal secretions (3.2 0.4 compared with 0.9 0.3; difference, 2.3 [95% CI, 1.3 to 3.3; P=0.001]). However, cumulative counts were not greater in tracheal aspirates (1.7 0.3 compared with 0.8 0.3; difference, 0.9 [CI, 0.3 to 2.1; P=0.197]) (Figure 2). We did not find significant differences between the small-bore and large-bore nasogastric tubes 17 hours after the first dose of 99mTc-Re sulfide when comparing the cumulative counts in samples from the pharynx (3.1 0.4 compared with 3.3 0.3; difference, 0.3 [CI, 1.6 to 1.0; P>0.2] or trachea (1.7 0.3 compared with 1.8 0.3; difference, 0.1 [CI, 1.4 to 1.1; P>0.2]. Figure 2. Scintigraphic 17-hour cumulative radioactive counts (mean cpm [log ] SE) of pharyngeal aspirates ( left ) and tracheal aspirates ( right ). Individual Data for Gastroesophageal Reflux and Aspiration Gastroesophageal reflux occurred in 23 of 31 evaluable studies (74%); aspiration occurred in 8 of these 31 studies (26%). Small-bore and large-bore nasogastric tubes did not differ significantly with respect to frequencies of reflux (10 of 15 patients [67%] compared with 13 of 16 patients [81%]; difference, 14 percentage points [CI, 16.6 to 44.6 percentage points; P>0.2]) or aspiration (3 of 15 patients [20%] compared with 5 of 16 patients [31%]; difference, 11 percentage points [CI, 19.4 to 41.4 percentage points; P>0.2]). A trend toward greater frequency of aspiration was seen in studies with reflux compared with studies without reflux (8 of 23 [35%] compared with 0 of 8 [0%]; difference, 35 percentage points [CI, 15.5 to 54.5 percentage points; P=0.076]. Aspiration did not occur in studies without reflux. Discussion In our study, gastroesophageal reflux and microaspiration of gastric contents to the lower airways were not influenced by the size of the nasogastric tube. Two previous studies (8, 10) that used the same isotope technique showed that gastroesophageal reflux is common in mechanically ventilated patients. The potential mechanisms that contribute to reflux in these patients are functional derangement of the upper esophageal sphincter caused by the pressure of the endotracheal tube cuff (8); use of drugs that impair esophageal motility, such as sedatives, curarizing agents, and adrenergic agonists (10); and use of nasogastric intubation that impairs function of the lower esophageal sphincter (2, 5). Despite the controversy about the role of the gastric reservoir in colonization of the oropharynx with abnormal flora (11, 12), microaspiration of contaminated gastric contents to the lower airways seems to play a role in the etiopathogenesis of nosocomial pneumonia (13-17). The prevention of gastroesophageal reflux may therefore be relevant to the prevention of nosocomial pneumonia. Previous studies (8, 9) have shown that the semirecumbent position may reduce gastroesophageal reflux. In these studies, all patients were intubated with a large-bore tube; therefore, the influence of the bore of the nasogastric tube on reflux could not be studied. Ibaez and coworkers (2) found that presence or absence of a nasogastric tube was a key factor for reflux in intubated and mechanically ventilated patients. Use of a nasogastric tube cannot always be avoided. Reducing the size of the tube, however, may improve the closure of the lower esophageal sphincter and thus prevent or reduce gastroesophageal reflux. The effects of the size of the nasogastric tube on gastroesophageal reflux have been investigated in healthy volunteers (18); no differences were seen among participants with no nasogastric tube, participants with a small-bore tube, and participants with a large-bore tube. Accordingly, we did not find any significant differences in gastroesophageal refl

Comparison of systemic cytokine levels in patients with acute respiratory distress syndrome, severe pneumonia, and controls

BACKGROUND The inflammatory response has been widely investigated in patients with acute respiratory distress syndrome (ARDS) and pneumonia. Studies investigating the diagnostic values of serum cytokine levels have yielded conflicting results and only little information is available for the differential diagnosis between ARDS and pneumonia. METHODS Clinical and physiological data, serum concentrations of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and quantitative cultures of lower respiratory tract specimens were obtained from 46 patients with ARDS and 20 with severe pneumonia within 24 hours of the onset of the disease and from 10 control subjects with no inflammatory lung disease. Cytokine concentrations were compared between groups and determinants in addition to the diagnosis were tested. RESULTS Serum TNF-α levels were significantly higher in ARDS patients (67 (57) pg/ml) than in patients with severe pneumonia (35 (20) pg/ml; p = 0.031) or controls (17 (8) pg/ml; p = 0.007). For IL-1β and IL-6 the observed differences were not statistically significant between patients with ARDS (IL-1β: 34 (65) pg/ml; IL-6: 712 (1058) pg/ml), those with severe pneumonia (IL-1β: 3 (4) pg/ml, p = 0.071; IL-6: 834 (1165) pg/ml, p = 1.0), and controls (IL-1β: 6 (11) pg/ml, p = 0.359; IL-6: 94 (110) pg/ml, p = 0.262). TNF-α (standardised coefficient β = 0.410, p<0.001) and IL-1β (standardised coefficient β = 0.311, p = 0.006) were most strongly associated with the degree of lung injury, even when the diagnostic group was included in the statistical model. CONCLUSIONS Serum TNF-α levels were higher in patients with ARDS than in those with severe pneumonia or in control subjects. Multivariate results suggest that the levels of systemic TNF-α and IL-1β reflect the severity of the lung injury rather than the diagnosis.

Sampling methods for ventilator-associated pneumonia: validation using different histologic and microbiological references.

ObjectiveTo validate sampling techniques (tracheobronchial aspirates, protected specimen brush, and bronchoalveolar lavage, both conventional and protected) for the detection of ventilator-associated pneumonia (VAP) and causative microorganisms according to different histologic and microbiological references. DesignImmediate, multiple bilateral lung biopsy, postmortem study. SettingRespiratory intensive care unit of a 1,000-bed teaching hospital. PatientsTwenty-five mechanically ventilated patients (>72 hrs) who died in our intensive care unit. MeasurementsLung tissue histologic examination and quantitative cultures (16 specimens/patient). The following four references for the diagnostic techniques were used: histology of guided lung biopsy, histology of blind lung biopsy, combined guided and blind lung biopsy histology and microbiology of lung tissue, and microbiology of lung tissue. ResultsSensitivities when histologic reference tests were used ranged from 16% to almost 40%, whereas specificity rates were always <80%. When we combined both lung histology of guided or blind specimens and microbiology of lung tissue, all diagnostic techniques achieved considerably higher but still limited diagnostic yields (sensitivity range 43% to 83%; specificity range 67% to 91%). Causative organisms were missed in a significant number of cases by all techniques (17% to 83%). ConclusionsThe diagnostic performances of different diagnostic techniques strongly depend on the reference used. All techniques for detecting VAP are of limited value. Finding a balance between clinical judgment and microbiological results is crucial to appropriately manage patients with VAP.

Nursing-home-acquired pneumonia in Germany: an 8-year prospective multicentre study

Objective To determine differences in aetiologies, initial antimicrobial treatment choices and outcomes in patients with nursing-home-acquired pneumonia (NHAP) compared with patients with community-acquired pneumonia (CAP), which is a controversial issue. Methods Data from the prospective multicentre Competence Network for Community-acquired pneumonia (CAPNETZ) database were analysed for hospitalised patients aged ≥65 years with CAP or NHAP. Potential differences in baseline characteristics, comorbidities, physical examination findings, severity at presentation, initial laboratory investigations, blood gases, microbial investigations, aetiologies, antimicrobial treatment and outcomes were determined between the two groups. Results Patients with NHAP presented with more severe pneumonia as assessed by CRB-65 (confusion, respiratory rate, blood pressure, 65 years and older) score than patients with CAP but received the same frequency of mechanical ventilation and less antimicrobial combination treatment. There were no clinically relevant differences in aetiology, with Streptococcus pneumoniae the most important pathogen in both groups, and potential multidrug-resistant pathogens were very rare (<5%). Only Staphylococcus aureus was more frequent in the NHAP group (n=12, 2.3% of the total population, 3.1% of those with microbial sampling compared with 0.7% and 0.8% in the CAP group, respectively). Short-term and long-term mortality in the NHAP group was higher than in the CAP group for patients aged ≥65 years (26.6% vs 7.2% and 43.8% vs 14.6%, respectively). However, there was no association between excess mortality and potential multidrug-resistant pathogens. Conclusions Excess mortality in patients with NHAP cannot be attributed to a different microbial pattern but appears to result from increased comorbidities, and consequently, pneumonia is frequently considered and managed as a terminal event.

The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study

Objectives Owing to novel therapy strategies in epidermal growth factor receptor (EGFR)-mutated patients, molecular analysis of the EGFR and KRAS genome has become crucial for routine diagnostics. Till date these data have been derived mostly from clinical trials, and thus collected in pre-selected populations. We therefore screened ‘allcomers’ with a newly diagnosed non-small cell lung carcinoma (NSCLC) for the frequencies of these mutations. Design A cohort study. Setting Lung cancer centre in a tertiary care hospital. Participants Within 15 months, a total of 552 cases with NSCLC were eligible for analysis. Primary and secondary outcome measures Frequency of scrutinising exons 18, 19 and 21 for the presence of activating EGFR mutation and secondary codon 12 and 13 for activating KRAS mutations. Results Of the 552 patients, 27 (4.9%) showed a mutation of EGFR. 19 of these patients (70%) had deletion E746-A750 in codon 19 or deletion L858R in codon 21. Adenocarcinoma (ACA) was the most frequent histology among patients with EGFR mutations (ACA, 22/254 (8.7%) vs non-ACA, 5/298 (1.7%); p<0.001). Regarding only ACA, the percentage of EGFR mutations was higher in women (16/116 (14%) women vs 6/138 (4.3%) men; p=0.008). Tumours with an activating EGFR mutation were more likely to be from non-smokers (18/27; 67%) rather than smoker (9/27; 33%). KRAS mutation was present in 85 (15%) of all cases. In 73 patients (86%), the mutation was found in exon 12 and in 12 cases (14%) in exon 13. Similarly, ACA had a higher frequency of KRAS mutations than non-ACA (67/254 (26%) vs 18/298 (6.0%); p<0.001). Conclusions We found a lower frequency for EGFR and KRAS mutations in an unselected Caucasian patient cohort as previously published. Taking our results into account, clinical trials may overestimate the mutation frequency for EGFR and KRAS in NSCLC due to important selection biases.

Serum glucose levels for predicting death in patients admitted to hospital for community acquired pneumonia: prospective cohort study

Objective To examine whether acute dysglycaemia predicts death in people admitted to hospital with community acquired pneumonia. Design Multicentre prospective cohort study. Setting Hospitals and private practices in Germany, Switzerland, and Austria. Participants 6891 patients with community acquired pneumonia included in the German community acquired pneumonia competence network (CAPNETZ) study between 2003 and 2009. Main outcome measures Univariable and multivariable hazard ratios adjusted for sex, age, current smoking status, severity of community acquired pneumonia using the CRB-65 score (confusion, respiratory rate >30/min, systolic blood pressure ≤90 mm Hg or diastolic blood pressure ≤60 mm Hg, and age ≥65 years), and various comorbidities for death at 28, 90, and 180 days according to serum glucose levels on admission. Results An increased serum glucose level at admission to hospital in participants with community acquired pneumonia and no pre-existing diabetes was a predictor of death at 28 and 90 days. Compared with participants with normal serum glucose levels on admission, those with mild acute hyperglycaemia (serum glucose concentration 6-10.99 mmol/L) had a significantly increased risk of death at 90 days (1.56, 95% confidence interval 1.22 to 2.01; P<0.001), and this risk increased to 2.37 (1.62 to 3.46; P<0.001) when serum glucose concentrations were ≥14 mmol/L. In sensitivity analyses the predictive value of serum glucose levels on admission for death was confirmed at 28 days and 90 days. Patients with pre-existing diabetes had a significantly increased overall mortality compared with those without diabetes (crude hazard ratio 2.47, 95% confidence interval 2.05 to 2.98; P<0.001). This outcome was not significantly affected by serum glucose levels on admission (P=0.18 for interaction). Conclusions Serum glucose levels on admission to hospital can predict death in patients with community acquired pneumonia without pre-existing diabetes. Acute hyperglycaemia may therefore identify patients in need of intensified care to reduce the risk of death from community acquired pneumonia.

Emerging Human Middle East Respiratory Syndrome Coronavirus Causes Widespread Infection and Alveolar Damage in Human Lungs

Acknowledgment: The authors are grateful to Rosalind Simmonds, the staff within the Nuclear Medicine and Histopathology Department at Addenbrooke’s Hospital, and the Wellcome Trust Clinical Research Facility, Cambridge. They acknowledge the help of the Histopathology Departments at the Royal Brompton and Princess Alexandra Hospitals. They also thank the Cambridge Biomedical Research Centre and BRC Core Biochemistry Assay Laboratory and acknowledge the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The study was approved by Cambridgeshire Research Ethics Committee (09/H0308/ 119) and the Administration of Radioactive Substances Advisory Committee of the UK (83/3130/25000).