Impact of ureido/carboxypenicillin resistance on the prognosis of ventilator-associated pneumonia due to Pseudomonas aeruginosa

Introduction

Although Pseudomonas aeruginosa is a leading pathogen responsible for ventilator-associated pneumonia (VAP), the excess in mortality associated with multi-resistance in patients with P. aeruginosa VAP (PA-VAP), taking into account confounders such as treatment adequacy and prior length of stay in the ICU, has not yet been adequately estimated.

Methods

A total of 223 episodes of PA-VAP recorded into the Outcomerea database were evaluated. Patients with ureido/carboxy-resistant P. aeruginosa (PRPA) were compared with those with ureido/carboxy-sensitive P. aeruginosa (PSPA) after matching on duration of ICU stay at VAP onset and adjustment for confounders.

Results

Factors associated with onset of PRPA-VAP were as follows: admission to the ICU with septic shock, broad-spectrum antimicrobials at admission, prior use of ureido/carboxypenicillin, and colonization with PRPA before infection. Adequate antimicrobial therapy was more often delayed in the PRPA group. The crude ICU mortality rate and the hospital mortality rate were not different between the PRPA and the PSPA groups. In multivariate analysis, after controlling for time in the ICU before VAP diagnosis, neither ICU death (odds ratio (OR) = 0.73; 95% confidence interval (CI): 0.32 to 1.69; P = 0.46) nor hospital death (OR = 0.87; 95% CI: 0.38 to 1.99; P = 0.74) were increased in the presence of PRPA infection. This result remained unchanged in the subgroup of 87 patients who received adequate antimicrobial treatment on the day of VAP diagnosis.

Conclusions

After adjustment, and despite the more frequent delay in the initiation of an adequate antimicrobial therapy in these patients, resistance to ureido/carboxypenicillin was not associated with ICU or hospital death in patients with PA-VAP.     

A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia

Introduction

The aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria.

Methods

This was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011).

Results

The study was stopped prematurely at the recommendation of the Independent Data Monitoring Committee that was blinded to treatment arm assignment and performed a scheduled review of data which showed signals that were close to the pre-specified stopping limits. The final analyses included 274 randomized patients. The clinical cure rate at the end of therapy (EOT) in the microbiological intent-to-treat (MITT) population was numerically lower for patients in the doripenem arm compared to the imipenem-cilastatin arm (45.6% versus 56.8%; 95% CI, -26.3% to 3.8%). Similarly, the clinical cure rate at EOT was numerically lower for patients with Pseudomonas aeruginosa VAP, the most common Gram-negative pathogen, in the doripenem arm compared to the imipenem-cilastatin arm (41.2% versus 60.0%; 95% CI, -57.2 to 19.5). All cause 28-day mortality in the MITT group was numerically greater for patients in the doripenem arm compared to the imipenem-cilastatin arm (21.5% versus 14.8%; 95% CI, -5.0 to 18.5) and for patients with P. aeruginosa VAP (35.3% versus 0.0%; 95% CI, 12.6 to 58.0).

Conclusions

Among patients with microbiologically confirmed late-onset VAP, a fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin. Consideration should be given to treating patients with VAP for more than seven days to optimize clinical outcome.

Trial Registration

ClinicalTrials.gov: NCT00589693     

Antimicrobial treatment for ventilator-associated tracheobronchitis: a randomized, controlled, multicenter study

Introduction

Ventilator-associated tracheobronchitis (VAT) is associated with increased duration of mechanical ventilation. We hypothesized that, in patients with VAT, antibiotic treatment would be associated with reduced duration of mechanical ventilation.

Methods

We conducted a prospective, randomized, controlled, unblinded, multicenter study. Patients were randomly assigned (1:1) to receive or not receive intravenous antibiotics for 8 days. Patients with ventilator-associated pneumonia (VAP) prior to VAT and those with severe immunosuppression were not eligible. The trial was stopped early because a planned interim analysis found a significant difference in intensive care unit (ICU) mortality.

Results

Fifty-eight patients were randomly assigned. Patient characteristics were similar in the antibiotic (n = 22) and no antibiotic (n = 36) groups. Pseudomonas aeruginosa was identified in 32% of VAT episodes. Although no difference was found in mechanical ventilation duration and length of ICU stay, mechanical ventilation-free days were significantly higher (median [interquartile range], 12 [8 to 24] versus 2 [0 to 6] days, P < 0.001) in the antibiotic group than in the no antibiotic group. In addition, subsequent VAP (13% versus 47%, P = 0.011, odds ratio [OR] 0.17, 95% confidence interval [CI] 0.04 to 0.70) and ICU mortality (18% versus 47%, P = 0.047, OR 0.24, 95% CI 0.07 to 0.88) rates were significantly lower in the antibiotic group than in the no antibiotic group. Similar results were found after exclusion of patients with do-not-resuscitate orders and those randomly assigned to the no antibiotic group but who received antibiotics for infections other than VAT or subsequent VAP.

Conclusion

In patients with VAT, antimicrobial treatment is associated with a greater number of days free of mechanical ventilation and lower rates of VAP and ICU mortality. However, antibiotic treatment has no significant impact on total duration of mechanical ventilation.

Trial registration

ClinicalTrials.gov, number NCT00122057.     

Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial

Purpose

Anti-virulence strategies have not been evaluated for the prevention of bacterial infections. Prolonged colonization of intubated patients with Pseudomonas aeruginosa isolates producing high-levels of the quorum sensing (QS)-regulated virulence factor rhamnolipids has been associated with ventilator-associated pneumonia (VAP). In this pathogen, azithromycin reduces QS-regulated virulence. We aimed to assess whether azithromycin could prevent VAP in patients colonized by rhamnolipids producing isolates.

Methods

In a randomized, double-blind, multicenter trial, intubated colonized patients received either 300?mg/day azithromycin or placebo. Primary endpoint was the occurrence of P. aeruginosa VAP. We further identified those patients persistently colonized by isolates producing high-levels of rhamnolipids and therefore at the highest risk to develop VAP linked to this QS-dependent virulence factor.

Results

Ninety-two patients were enrolled; 43 azithromycin-treated and 42 placebo patients were eligible for the per-protocol analysis. In the per-protocol population, the occurrence of P. aeruginosa VAP was reduced in the azithromycin group but without reaching statistical significance (4.7 vs. 14.3?% VAP, p?=?0.156). QS-dependent virulence of colonizing isolates was similarly low in both study groups, and only five patients in each arm were persistently colonized by high-level rhamnolipids producing isolates. In this high-risk subgroup, the incidence of VAP was reduced fivefold in azithromycin versus placebo patients (1/5 vs. 5/5 VAP, p?=?0.048).

Conclusions

There was a trend towards reduced incidence of VAP in colonized azithromycin-treated patients. In addition, azithromycin significantly prevented VAP in those patients at high risk of rhamnolipid-dependent VAP, suggesting that virulence inhibition is a promising anti-microbial strategy.     

Candida spp. airway colonization could promote antibiotic-resistant bacteria selection in patients with suspected ventilator-associated pneumonia

Objective

Candida spp. airway colonization could promote development of ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa, a potentially multidrug-resistant (MDR) bacteria, and worsen the outcome of VAP regardless of pathogen. We therefore address the question of the risk of MDR bacteria isolation within the airway of patients with suspected VAP, whether Candida spp. is present or not.

Design and setting

Prospective observational study in a teaching hospital.

Patients and methods

Consecutive patients with suspected VAP were included. Respiratory tract secretions were seeded on specific medium for yeast isolation in addition to standard culture. Outcome as well as presence of MDR bacteria were assessed according to fungal colonization.

Results

323 suspected VAP were analysed. Among these, 181 (56?%) cases presented with Candida spp. airway colonization. Colonized and noncolonized patients were similar regarding baseline characteristics, prior exposure to antibiotics and VAP severity. However, mortality rate was greater in patients with fungal airway colonization than in those without (44.2 versus 31.0?%, respectively; p?=?0.02). In addition, MDR bacteria isolation was 31.5?% in patients with Candida spp. colonization versus 23.2?% in those without (p?=?0.13). Moreover, Candida spp. airway colonization was one independent risk factor for MDR bacteria isolation [odds ratio (OR)?=?1.79, 95?% confidence interval 1.05–3.05; p?=?0.03], in addition to the time elapsed between intensive care unit (ICU) admission and VAP suspicion.

Conclusions

In patients with suspected VAP, Candida spp. airway colonization is frequent and associated with increased risk for MDR bacteria isolation. This could worsen outcome and should therefore be considered when choosing an empiric antibiotic therapy.     

Risk factors for carbapenem-resistant Gram-negative bacteremia in intensive care unit patients

Purpose

Carbapenem-resistant (CR) Gram-negative pathogens have increased substantially. This study was performed to identify the risk factors for development of CR Gram-negative bacteremia (GNB) in intensive care unit (ICU) patients.

Methods

Prospective study; risk factors for development of CR-GNB were investigated using two groups of case patients: the first group consisted of patients who acquired carbapenem susceptible (CS) GNB and the second group included patients with CR-GNB. Both case groups were compared to a shared control group defined as patients without bacteremia, hospitalized in the ICU during the same period.

Results

Eighty-five patients with CR- and 84 patients with CS-GNB were compared to 630 control patients, without bacteremia. Presence of VAP (OR 7.59, 95 % CI 4.54–12.69, p < 0.001) and additional intravascular devices (OR 3.69, 95 % CI 2.20–6.20, p < 0.001) were independently associated with CR-GNB. Presence of VAP (OR 2.93, 95 % CI 1.74–4.93, p < 0.001), presence of additional intravascular devices (OR 2.10, 95 % CI 1.23–3.60, p = 0.007) and SOFA score on ICU admission (OR 1.11, 95 % CI 1.03–1.20, p = 0.006) were independently associated with CS-GNB. The duration of exposure to carbapenems (OR 1.079, 95 % CI 1.022–1.139, p = 0.006) and colistin (OR 1.113, 95 % CI 1.046–1.184, p = 0.001) were independent risk factors for acquisition of CR-GNB. When the source of bacteremia was other than VAP, previous administration of carbapenems was the only factor related with the development of CR-GNB (OR 1.086, 95 % CI 1.003–1.177, p = 0.042).

Conclusions

Among ICU patients, VAP development and the presence of additional intravascular devices were the major risk factors for CR-GNB. In the absence of VAP, prior use of carbapenems was the only factor independently related to carbapenem resistance.     

Pseudomonas aeruginosa acquisition on an intensive care unit: relationship between antibiotic selective pressure and patients' environment

Introduction

The purpose of this study was to investigate the relationship among Pseudomonas aeruginosa acquisition on the intensive care unit (ICU), environmental contamination and antibiotic selective pressure against P. aeruginosa.

Methods

An open, prospective cohort study was carried out in a 16-bed medical ICU where P. aeruginosa was endemic. Over a six-month period, all patients without P. aeruginosa on admission and with a length of stay >72 h were included. Throat, nasal, rectal, sputum and urine samples were taken on admission and at weekly intervals and screened for P. aeruginosa. All antibiotic treatments were recorded daily. Environmental analysis included weekly tap water specimen culture and the presence of other patients colonized with P. aeruginosa.

Results

A total of 126 patients were included, comprising 1,345 patient-days. Antibiotics were given to 106 patients (antibiotic selective pressure for P. aeruginosa in 39). P. aeruginosa was acquired by 20 patients (16%) and was isolated from 164/536 environmental samples (31%). Two conditions were independently associated with P. aeruginosa acquisition by multivariate analysis: (i) patients receiving ≥3 days of antibiotic selective pressure together with at least one colonized patient on the same ward on the previous day (odds ratio (OR) = 10.3 ((% confidence interval (CI): 1.8 to 57.4); P = 0.01); and (ii) presence of an invasive device (OR = 7.7 (95% CI: 2.3 to 25.7); P = 0.001).

Conclusions

Specific interaction between both patient colonization pressure and selective antibiotic pressure is the most relevant factor for P. aeruginosa acquisition on an ICU. This suggests that combined efforts are needed against both factors to decrease colonization with P. aeruginosa.     

Impact of a multifaceted prevention program on ventilator-associated pneumonia including selective oropharyngeal decontamination

Purpose

We describe the impact of a multifaceted program for decreasing ventilator-associated pneumonia (VAP) after implementing nine preventive measures, including selective oropharyngeal decontamination (SOD).

Methods

We compared VAP rates during an 8-month pre-intervention period, a 12-month intervention period, and an 11-month post-intervention period in a cohort of patients who received mechanical ventilation (MV) for?>?48 h. The primary objective was to assess the effect on first VAP occurrence, using a Cox cause-specific proportional hazards model. Secondary objectives included the impact on emergence of antimicrobial resistance, antibiotic consumption, duration of MV, and ICU mortality.

Results

Pre-intervention, intervention and post-intervention VAP rates were 24.0, 11.0 and 3.9 VAP episodes per 1000 ventilation-days, respectively. VAP rates decreased by 56% [hazard ratio (HR) 0.44, 95% CI 0.29–0.65; P?<?0.001] in the intervention and by 85% (HR 0.15, 95% CI 0.08–0.27; P?<?0.001) in the post-intervention periods. During the intervention period, VAP rates decreased by 42% (HR 0.58, 95% CI 0.38–0.87; P?<?0.001) after implementation of eight preventive measures without SOD, and by 70% after adding SOD (HR 0.30, 95% CI 0.13–0.72; P?<?0.001) compared to the pre-intervention period. The incidence density of intrinsically resistant bacteria (to colistin or tobramycin) did not increase. We documented a significant reduction of days of therapy per 1000 patient-days of broad-spectrum antibiotic used to treat lower respiratory tract infection (P?<?0.028), median duration of MV (from 7.1 to 6.4 days; P?<?0.003) and ICU mortality (from 16.2 to 13.5%; P?<?0.049) for patients ventilated?>?48 h between the pre- and post-intervention periods.

Conclusions

Our preventive program produced a sustained decrease in VAP incidence. SOD provides an additive value.

     

Non-adherence to guidelines: an avoidable cause of failure of empirical antimicrobial therapy in the presence of difficult-to-treat bacteria

Purpose

To identify the risk factors of ventilator-associated pneumonia (VAP) due to difficult-to-treat (DTT) bacteria (i.e., Pseudomonas aeruginosa, Acinetobacter baumannii and oxacillin-resistant Staphylococcus aureus), and to assess the rate and the causes of inappropriateness of empirical antimicrobial therapy.

Methods

In an intensive care unit of a university hospital, patients with VAP were empirically treated with antibiotics without activity against DTT bacteria if the patients had no prior hospitalization or prior administration of antibiotics, according to local guidelines.

Results

Overall, the empirical antimicrobial therapy was appropriate in 190 (87%) out of 218 patients with VAP. Fifty (23%) patients developed problems due to DTT bacteria. The risk factors for VAP due to DTT bacteria were shock state, prior antimicrobial therapy, prior stay in long-term care facilities and late-onset VAP. Empirical antimicrobial therapy was inappropriate in 20 (40%) patients with VAP due to DTT bacteria and 8 (5%) patients with VAP due to non-DTT (P?=?0.001). Guidelines violations (nine patients), bacteria not included in antibiotic spectrum (eight patients) and bacterial resistance (three patients) were the causes of inappropriateness in case of DTT bacteria.

Conclusion

Despite the abundant information for the treatment of VAP and the establishment of guidelines, too many patients with DTT bacteria received inappropriate antimicrobial therapy. Since 45% of the cases are related to non-adherence to the local protocol, there is room for improvement by implementing educational programs. Also, since DTT bacteria are found in 23% of late-onset VAP, empirical antibiotic treatment should be directed against these pathogens.     

Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis

Background

Prone position ventilation for acute hypoxemic respiratory failure (AHRF) improves oxygenation but not survival, except possibly when AHRF is severe.

Objective

To determine effects of prone versus supine ventilation in AHRF and severe hypoxemia [partial pressure of arterial oxygen (PaO₂)/inspired fraction of oxygen (FiO₂) <100 mmHg] compared with moderate hypoxemia (100 mmHg ≤ PaO₂/FiO₂ ≤ 300 mmHg).

Design

Systematic review and meta-analysis.

Data Sources

Electronic databases (to November 2009) and conference proceedings.

Methods

Two authors independently selected and extracted data from parallel-group randomized controlled trials comparing prone with supine ventilation in mechanically ventilated adults or children with AHRF. Trialists provided subgroup data. The primary outcome was hospital mortality in patients with AHRF and PaO₂/FiO₂ <100 mmHg. Meta-analyses used study-level random-effects models.

Results

Ten trials (N = 1,867 patients) met inclusion criteria; most patients had acute lung injury. Methodological quality was relatively high. Prone ventilation reduced mortality in patients with PaO₂/FiO₂ <100 mmHg [risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74–0.96; p = 0.01; seven trials, N = 555] but not in patients with PaO₂/FiO₂ ≥100 mmHg (RR 1.07, 95% CI 0.93–1.22; p = 0.36; seven trials, N = 1,169). Risk ratios differed significantly between subgroups (interaction p = 0.012). Post hoc analysis demonstrated statistically significant improved mortality in the more hypoxemic subgroup and significant differences between subgroups using a range of PaO₂/FiO₂ thresholds up to approximately 140 mmHg. Prone ventilation improved oxygenation by 27–39% over the first 3 days of therapy but increased the risks of pressure ulcers (RR 1.29, 95% CI 1.16–1.44), endotracheal tube obstruction (RR 1.58, 95% CI 1.24–2.01), and chest tube dislodgement (RR 3.14, 95% CI 1.02–9.69). There was no statistical between-trial heterogeneity for most clinical outcomes.

Conclusions

Prone ventilation reduces mortality in patients with severe hypoxemia. Given associated risks, this approach should not be routine in all patients with AHRF, but may be considered for severely hypoxemic patients.     

Bacteremia is an independent risk factor for mortality in nosocomial pneumonia: a prospective and observational multicenter study

Introduction

Since positive blood cultures are uncommon in patients with nosocomial pneumonia (NP), the responsible pathogens are usually isolated from respiratory samples. Studies on bacteremia associated with hospital-acquired pneumonia (HAP) have reported fatality rates of up to 50%. The purpose of the study is to compare risk factors, pathogens and outcomes between bacteremic nosocomial pneumonia (B-NP) and nonbacteremic nosocomial pneumonia (NB-NP) episodes.

Methods

This is a prospective, observational and multicenter study (27 intensive care units in nine European countries). Consecutive patients requiring invasive mechanical ventilation for an admission diagnosis of pneumonia or on mechanical ventilation for > 48 hours irrespective of admission diagnosis were recruited.

Results

A total of 2,436 patients were evaluated; 689 intubated patients presented with NP, 224 of them developed HAP and 465 developed ventilation-acquired pneumonia. Blood samples were extracted in 479 (69.5%) patients, 70 (14.6%) being positive. B-NP patients had higher Simplified Acute Physiology Score (SAPS) II score (51.5 ± 19.8 vs. 46.6 ± 17.5, P = 0.03) and were more frequently medical patients (77.1% vs. 60.4%, P = 0.01). Mortality in the intensive care unit was higher in B-NP patients compared with NB-NP patients (57.1% vs. 33%, P < 0.001). B-NP patients had a more prolonged mean intensive care unit length of stay after pneumonia onset than NB-NP patients (28.5 ± 30.6 vs. 20.5 ± 17.1 days, P = 0.03). Logistic regression analysis confirmed that medical patients (odds ratio (OR) = 5.72, 95% confidence interval (CI) = 1.93 to 16.99, P = 0.002), methicillin-resistant Staphylococcus aureus (MRSA) etiology (OR = 3.42, 95% CI = 1.57 to 5.81, P = 0.01), Acinetobacter baumannii etiology (OR = 4.78, 95% CI = 2.46 to 9.29, P < 0.001) and days of mechanical ventilation (OR = 1.02, 95% CI = 1.01 to 1.03, P < 0.001) were independently associated with B-NP episodes. Bacteremia (OR = 2.01, 95% CI = 1.22 to 3.55, P = 0.008), diagnostic category (medical patients (OR = 3.71, 95% CI = 2.01 to 6.95, P = 0.02) and surgical patients (OR = 2.32, 95% CI = 1.10 to 4.97, P = 0.03)) and higher SAPS II score (OR = 1.02, 95% CI = 1.01 to 1.03, P = 0.008) were independent risk factors for mortality.

Conclusions

B-NP episodes are more frequent in patients with medical admission, MRSA and A. baumannii etiology and prolonged mechanical ventilation, and are independently associated with higher mortality rates.     

Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death

Background

Venous thromboembolism (VTE) and thromboembolic arterial diseases are usually considered to be distinct entities, but there is evidence to suggest that these disorders may be linked. The aim of this study was to determine whether a diagnosis of VTE increases the long-term risk of myocardial infarction (MI).

Methods

The incidence rate (IR) and relative risk (RR) of MI in a cohort of patients with a diagnosis of VTE (n = 4890) compared with that of a control cohort without prior VTE (n = 43 382) were evaluated in the UK General Practice Research Database (GPRD). Death during follow-up was also determined. Patients were followed for up to 8 years (mean of 3 years).

Results

The IR of MI per 1000 person-years was 4.1 (95% CI: 3.1–5.3) for the VTE cohort and 3.5 (95% CI: 3.2–3.8) for the control cohort. The IR of MI was highest in the first year after the VTE episode, but overall differences between the two cohorts were not significant (RR of MI associated with VTE: 1.2; 95% CI: 0.9–1.6). The risk of death was higher in the VTE cohort than the control cohort, even after adjustment for cancer, heart failure and ischaemic heart disease (RR: 2.4; 95% CI: 2.2–2.6), particularly during the first year after VTE (RR: 3.8; 95% CI: 3.4–4.3).

Conclusion

A VTE episode does not significantly increase the risk of MI, but does increase the risk of death, particularly in the first year following VTE diagnosis.     

Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: a multicenter observational study

Introduction

The intent of this study was to determine whether serum procalcitonin (PCT) levels are associated with prognosis, measured as organ dysfunctions and 28-day mortality, in patients with severe pneumonia.

Methods

This was a multicenter, observational study of critically ill adult patients with pneumonia requiring mechanical ventilation conducted in 10 academic hospitals in Canada, the United States, and Central Europe. PCT was measured daily for 14 days using an immuno-luminometric assay.

Results

We included 175 patients, 57 with community acquired pneumonia (CAP), 61 with ventilator associated pneumonia (VAP) and 57 with hospital acquired pneumonia (HAP). Initial PCT levels were higher in CAP than VAP patients (median (interquartile range: IQR); 2.4 (0.95 to 15.8) vs. 0.7 (0.3 to 2.15), ng/ml, P < 0.001) but not significantly different to HAP (2.2 (0.4 to 8.0) ng/ml). The 28-day ICU mortality rate for all patients was 18.3% with a median ICU length of stay of 16 days (range 1 to 142 days). PCT levels were higher in non-survivors than in survivors. Initial and maximum PCT levels correlated with maximum Sequential Organ Failure Assessment (SOFA) score r² = 0.50 (95% CI: 0.38 to 0.61) and r² = 0.57 (0.46 to 0.66), respectively. Receiver operating curve (ROC) analysis on discrimination of 28-day mortality showed areas under the curve (AUC) of 0.74, 0.70, and 0.69 for maximum PCT, initial PCT, and Acute Physiology and Chronic Health Evaluation (APACHE) II score, respectively. The optimal cut-off to predict mortality for initial PCT was 1.1 ng/ml (odds ratio: OD 7.0 (95% CI 2.6 to 25.2)) and that for maximum PCT was 7.8 ng/ml (odds ratio 5.7 (95% CI 2.5 to 13.1)).

Conclusions

PCT is associated with the severity of illness in patients with severe pneumonia and appears to be a prognostic marker of morbidity and mortality comparable to the APACHE II score.     

Value of lower respiratory tract surveillance cultures to predict bacterial pathogens in ventilator-associated pneumonia: systematic review and diagnostic test accuracy meta-analysis

Purpose

In ventilator-associated pneumonia (VAP), early appropriate antimicrobial therapy may be hampered by involvement of multidrug-resistant (MDR) pathogens.

Methods

A systematic review and diagnostic test accuracy meta-analysis were performed to analyse whether lower respiratory tract surveillance cultures accurately predict the causative pathogens of subsequent VAP in adult patients. Selection and assessment of eligibility were performed by three investigators by mutual consideration. Of the 525 studies retrieved, 14 were eligible for inclusion (all in English; published since 1994), accounting for 791 VAP episodes. The following data were collected: study and population characteristics; in- and exclusion criteria; diagnostic criteria for VAP; microbiological workup of surveillance and diagnostic VAP cultures. Sub-analyses were conducted for VAP caused by Staphylococcus aureus, Pseudomonas spp., and Acinetobacter spp., MDR microorganisms, frequency of sampling, and consideration of all versus the most recent surveillance cultures.

Results

The meta-analysis showed a high accuracy of surveillance cultures, with pooled sensitivities up to 0.75 and specificities up to 0.92 in culture-positive VAP. The area under the curve (AUC) of the hierarchical summary receiver-operating characteristic curve demonstrates moderate accuracy (AUC: 0.90) in predicting multidrug resistance. A sampling frequency of >2/week (sensitivity 0.79; specificity 0.96) and consideration of only the most recent surveillance culture (sensitivity 0.78; specificity 0.96) are associated with a higher accuracy of prediction.

Conclusions

This study provides evidence for the benefit of surveillance cultures in predicting MDR bacterial pathogens in VAP. However, clinical and statistical heterogeneity, limited samples sizes, and bias remain important limitations of this meta-analysis.     

Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients

Purpose

To assess the effects of stress ulcer prophylaxis (SUP) versus placebo or no prophylaxis on all-cause mortality, gastrointestinal (GI) bleeding and hospital-acquired pneumonia in adult critically ill patients in the intensive care unit (ICU).

Methods

We performed a systematic review using meta-analysis and trial sequential analysis (TSA). Eligible trials were randomised clinical trials comparing proton pump inhibitors or histamine 2 receptor antagonists with either placebo or no prophylaxis. Two reviewers independently assessed studies for inclusion and extracted data. The Cochrane Collaboration methodology was used. Risk ratios/relative risks (RR) with 95 % confidence intervals (CI) were estimated. The predefined outcome measures were all-cause mortality, GI bleeding, and hospital-acquired pneumonia.

Results

Twenty trials (n = 1,971) were included; all were judged as having a high risk of bias. There was no statistically significant difference in mortality (fixed effect: RR 1.00, 95 % CI 0.84–1.20; P = 0.87; I ² = 0 %) or hospital-acquired pneumonia (random effects: RR 1.23, 95 % CI 0.86–1.78; P = 0.28; I ² = 19 %) between SUP patients and the no prophylaxis/placebo patients. These findings were confirmed in the TSA. With respect to GI bleeding, a statistically significant difference was found in the conventional meta-analysis (random effects: RR 0.44, 95 % CI 0.28–0.68; P = 0.01; I ² = 48 %); however, TSA (TSA adjusted 95 % CI 0.18–1.11) and subgroup analyses could not confirm this finding.

Conclusions

This systematic review using meta-analysis and TSA demonstrated that both the quality and the quantity of evidence supporting the use of SUP in adult ICU patients is low. Consequently, large randomised clinical trials are warranted.     

A systematic review and meta-analysis on the use of traditional Chinese medicine compound kushen injection for bone cancer pain

Purpose

Bone cancer pain presents a clinical challenge with limitations of current treatments. Compound kushen injection (CKI) is a well-known traditional Chinese medicine (TCM) formulation in treatment of patients with bone cancer pain. The objective of this study is to assess the efficacy and safety of CKI for bone cancer pain.

Methods

A systematic literature search was conducted in nine databases until December 2012 to identify randomized controlled trials (RCTs) of CKI versus current western therapies for bone cancer pain. The primary outcome was total pain relief rate. The secondary outcomes were the quality of life and adverse events at the end of treatment course. The methodological quality of RCTs was assessed independently using six-item criteria according to the Cochrane Collaboration, and the level of evidence was assessed by the GRADE approach. All data were analyzed using Review Manager 5.1.0.

Results

Seven RCTs with 521 patients from 2010 to 2012 were identified. Compared with radiotherapy or bisphosphonates, seven RCTs showed significant effects of CKI for improving pain relief in patients with bone cancer pain (n?=?521, risk ratio (RR)?=?1.25, 95 % CI (95 % confidence intervals (CI)), 1.13 to 1.38, p?<?0.0001)), three RCTs for improving Karnofsky scoring (KPS) increase rate (n?=?305, RR?=?1.62, 95 % CI, 1.32 to 1.99, p?<?0.00001), 1 RCT for increasing KPS scores (n?=?78, mean difference (MD)?=?10.43, 95 % CI 4.76 to 16.10, p?=?0.0003). 4 RCTs reported adverse effects in both the treatment and control groups. The patients treated with CKI achieved statistically significant reductions of incidences of leukopenia (n?=?276, RR?=?0.32, 95 % CI, 0.21 to 0.47, p?<?0.00001) and nausea (n?=?78, RR?=?0.15, 95 % CI, 0.06 to 0.34, p?<?0.00001). No severe adverse events were found and no treatment was stopped because of adverse events of CKI in the treatment groups. However, the studies were deemed to have a high risk of bias.

Conclusion

This systematic review showed positive but weak evidence of CKI for bone cancer pain because of the poor methodological quality and the small quantity of the included trials. Future rigorously designed RCTs are required.     

Topical agent therapy for prevention and treatment of radiodermatitis: a meta-analysis

Background

Radiodermatitis (RD) is a common side effect during radiotherapy. Various topical agents have been tried to be applied on RD. However, the efficiency of topical agents applied on radiotherapy is still uncertain.

Objective

This study aims to assess the efficiency of the topical agents in the prevention and treatment of RD.

Methods

The Cochrane Central Register of Controlled Trials, Pubmed, and Medline were searched for relevant reports. Quantitative analysis was carried out to evaluate the efficiency of topical agents in the prevention and treatment of RD.

Results

Twenty reports involving 3,098 patients were included: 2,406 patients for prophylactic trials and 692 for treatment trials, respectively. For prophylactic trials, primary meta-analysis indicated that using topical agents could not reduce the incidence of grade 2 and higher RD (P?=?0.128, RR?=?0.90, 95 % CI?=?0.78–1.03) with a high heterogeneity (P?=?0.000, I ²?=?71.5 %). In subgroup analyses, heterogeneity disappeared by excluding reports with low Jadad score (≤3) (P?=?0.292, I ²?=?15.2 %), and still no significant difference was found between the topical agent group and control group (P?=?0.625, RR?=?0.98, 95 % CI?=?0.89–1.07). In addition, for treatment trials, topical agents failed to increase the incidence of wound healing (P?=?0.784, RR?=?1.01, 95 % CI?=?0.92–1.12) with a high heterogeneity (P?=?0.067, I ²?=?51.5 %).

Conclusions

Topical agents could not prevent or treat RD effectively. New type of agents should be developed to improve the efficiency based on the pathophysiology of RD.     

Bleeding and risk of death with hydroxyethyl starch in severe sepsis: post hoc analyses of a randomized clinical trial

Purpose

We aimed to characterize the degree and clinical importance of bleeding in patients treated with hydroxyethyl starch (HES).

Methods

In post hoc analyses, we examined the associations between fluid assignment, hemostatic variables, bleeding events, transfusions, and death among 798 patients with severe sepsis randomized to fluid resuscitation with HES 130/0.42 versus Ringer’s acetate. We used Cox regression analysis adjusted for fluid assignment and baseline characteristics.

Results

Overall, 93 (23 %) patients assigned to HES versus 60 (15 %) patients assigned to Ringer’s acetate bled in the ICU (relative risk (RR) 1.55; 95 % CI 1.16–2.08; P = 0.003). Of these, 38 and 25 (RR 1.52; 95 % CI 0.94–2.48; P = 0.09), respectively, had severe bleeding (intracranial or concomitant transfusion with three units of red blood cells). Most patients bled in the first days after randomization when most trial fluid was given. The hazards ratios for occurrence of any bleeding and severe bleeding in patients treated with HES versus Ringer’s acetate were 1.70 (95 % CI 1.23–2.36; P = 0.001) and 1.55 (95 % CI 0.93–2.56; P = 0.09), respectively. The adjusted hazard ratios for death among patients with any bleeding and severe bleeding compared to those without bleeding were 1.36 (95 % CI 1.04–1.79; P = 0.03) and 1.74 (95 % CI 1.20–2.53; P = 0.004), respectively.

Conclusions

In post hoc analyses of patient with severe sepsis, treatment with HES increased the risk of bleeding which was associated with increased risk of death. HES-induced bleeding complications may negatively affect outcome in patients with severe sepsis.     

Steroid use in PROWESS severe sepsis patients treated with drotrecogin alfa (activated)

Introduction

In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC).

Methods

Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC (all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure <90 mmHg on vasopressors; mechanical ventilation; and one of urine <0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/inspired fractional oxygen <280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window.

Results

Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and drotrecogin alfa (activated) groups was 38% (19/50) and 28% (13/47), respectively (relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41–1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset (n = 612), placebo mortality was 38% (118/313) and drotrecogin alfa (activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62–0.98). Using AEC but excluding the 8-hour window and with steroids initiated at baseline and/or infusion (n = 228) resulted in mortality for placebo and drotrecogin alfa (activated) groups of 43% (51/118) and 33% (36/110), respectively (RR = 0.76, 95% CI 0.54–1.06).

Conclusion

Patients with severe sepsis from the PROWESS trial who were likely to respond to low-dose steroids according to the AEC were those patients at a high risk for death. However, when using the AEC, regardless of steroid use, patients exhibited a survival benefit from treatment with drotrecogin alfa (activated).     

Unerwünschte Nebenwirkungen von Tapentadol im Vergleich zu Oxycodon

Objective

Tapentadol is a new centrally acting analgesic with a dual mode of action as an agonist of the ??-opioid receptor and as a norepinephrine reuptake inhibitor. The aim of the present study was to evaluate the results from randomized controlled trials investigating the relative amount of adverse effects using tapentadol or oxycodone for the treatment of pain.

Methods

A quantitative systematic review was carried out according to the PRISMA recommendations on randomized controlled trials comparing tapentadol and oxycodone in pain treatment. The incidences of typical adverse side effects of opioid-based analgesic therapy (e.g. nausea, vomiting, obstipation or pruritus) were extracted and the pooled relative risks (RR) with corresponding 95% confidence intervals (CI) were calculated.

Results

A total of 9 trials involving 7,948 patients were included and of these 2,810 patients were treated with oxycodone and 5,138 were treated with tapentadol in equivalent analgesic dosages as documented by an equivalent analgesic effect. The risk of typical opioid-based adverse effects, such as nausea (RR 0.61; 95% CI 0.57?C0.66), vomiting (RR 0.50, 95% CI: 0.41?C0.60), obstipation (RR 0.47, 95%-CI 0.40?C0.56), dizziness (RR 0.86, 95% CI 0.78?C0.95), somnolence (RR 0.76, 95% CI 0.67?C0.86) and pruritus (RR 0.46, 95% CI 0.37?C0.58) was reduced when tapentadol was used for analgesic treatment. These adverse effects were investigated in all nine trials. The risk for dryness of the mouth (6 trials, 6,218 patients, RR 1.79, 95% CI 1.40?C2.29) and dyspepsia (1 trial, 646 patients, RR 2.75, 95% CI 1.09?C6.94) was increased when tapentadol was used instead of oxycodone. There were no significant differences in the relative risk for any other investigated adverse effect such as dysentery, headache or fatigue.

Conclusion

The results show that using tapentadol significantly reduces the risk of the typical opioid-based adverse effects compared with oxycodone while providing equivalent analgesic treatment.