The association of polypharmacy with functional decline in elderly patients undergoing cardiac surgery.

AIMS: Identifying preoperative risk factors in older patients becomes more important to reduce adverse functional outcome. This study investigated the association between preoperative medication use and functional decline in elderly cardiac surgery patients and compared polypharmacy as a preoperative screening tool to a clinical frailty assessment. METHODS: This sub-study of the Anaesthesia Geriatric Evaluation study included 518 patients aged ≥70 years undergoing elective cardiac surgery. The primary outcome was functional decline, defined as a worse health-related quality of life or disability 1 year after surgery. The association between polypharmacy (i.e. ≥5 prescriptions and <10 prescriptions) or excessive polypharmacy (i.e. ≥10 prescriptions) and functional decline was investigated using multivariable Poisson regression. Discrimination, calibration and reclassification indices were used to compare preoperative screening tools for patient selection. RESULTS: Functional decline was reported in 284 patients (55%) and preoperative polypharmacy and excessive polypharmacy showed higher risks (adjusted relative risk 1.57, 95% confidence interval [CI] 1.23-1.98 and 1.93, 95% CI 1.48-2.50, respectively). Besides cardiovascular medication, proton-pump inhibitors and central nervous system medication were significantly associated with functional decline. Discrimination between models with polypharmacy or frailty was similar (area under the curve 0.67, 95% CI 0.61-0.72). The net reclassification index improved when including polypharmacy to the basic model (17%, 95% CI 0.06-0.27). CONCLUSION: Polypharmacy is associated with functional decline in elderly cardiac surgery patients. A preoperative medication review is easily performed and could be used as screening tool to identify patients at risk for adverse outcome after cardiac surgery.

Extrapulmonary manifestations of a telomere syndrome in patients with idiopathic pulmonary fibrosis are associated with decreased survival.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a heterogenous disease with a median survival of 3-4 years. Patients with mutations in telomere-related genes exhibit extrapulmonary signs and symptoms. These patients represent a distinct phenotype of IPF with worse survival. As genetic analyses are not available for most patients with IPF, we sought to determine the predictive value of extrapulmonary signs and symptoms of a telomere syndrome in patients with IPF. METHODS: We retrospectively studied 409 patients with IPF. Clinical characteristics, laboratory results and family history suggestive of a telomere syndrome were related to leukocyte telomere length measured by quantitative PCR and patient outcomes. RESULTS: The cohort included 293 patients with sporadic IPF and 116 patients with a background of familial pulmonary fibrosis. Any or a combination of a clinical history (haematological disease, liver disease, early greying of hair, nail dystrophy, skin abnormalities), a family history or haematological laboratory abnormalities (macrocytosis, anaemia, thrombopenia or leukopenia) suggestive of a telomere syndrome was present in 27% of IPF patients and associated with shorter leukocyte telomere length and shorter survival (p = 0.002 in a multivariate model). In sporadic IPF, having either a clinical history, family history or haematological laboratory abnormalities was not significantly associated with decreased survival (p = 0.07 in a multivariate model). CONCLUSION: Taking a careful clinical and family history focused on extrapulmonary manifestations of a telomere syndrome can provide important prognostic information in patients with IPF, as this is associated with shorter survival.

Preoperative frailty and chronic pain after cardiac surgery: a prospective observational study.

BACKGROUND: Chronic pain after cardiac surgery, whether or not related to the operation, is common and has negative impact on health related quality of life (HRQL). Frailty is a risk factor for adverse surgical outcomes, but its relationship with chronic pain after cardiac surgery is unknown. This study aimed to address the association between frailty and chronic pain following cardiac surgery. METHODS: This sub-study of the Anesthesia Geriatric Evaluation study included 518 patients ≥ 70 years undergoing elective cardiac surgery. Pain was evaluated with the Short-Form 36 questionnaire prior to and one year after surgery. Associations between chronic postoperative pain and frailty domains, including medication use, nutritional status, mobility, physical functioning, cognition, HRQL, living situation and educational level, were investigated with multivariable regression analysis. RESULTS: Chronic pain one year after cardiac surgery was reported in 182 patients (35%). Medication use, living situation, mobility, gait speed, Nagi's physical functioning and preoperative HRQL were frailty domains associated with chronic pain after surgery. For patients with chronic pain physical HRQL after one year was worse compared to patients without chronic pain (ß -10.37, 99% CI -12.57 - -8.17). CONCLUSIONS: Preoperative polypharmacy, living alone, physical frailty and lower mental HRQL are associated with chronic pain following cardiac surgery. Chronic postoperative pain is related to worse physical HRQL one year after cardiac surgery. These findings may guide future preoperative interventions to reduce chronic pain and poor HRQL after cardiac surgery in older patients. TRIAL REGISTRATION: This trial has been registered before initiation under number NCT02535728 at clinicaltrials.gov.

Five years' experience with value-based quality improvement teams: the key factors to a successful implementation in hospital care.

BACKGROUND: In recent years, value-based healthcare (VBHC) has become one of the most accepted concepts for fixing the 'broken' healthcare systems. Numerous hospitals have embraced VBHC and are trying to implement value-based quality improvement (VBQI) into their practice. However, there is a lack of knowledge on how to practically implement VBHC and organizations differ in their approach. The aim of this study was to explore the main factors that were experienced as hindering and/or supporting in the implementation of VBQI teams in hospital care. METHODS: A qualitative study was performed with semi-structured interviews with 43 members of eight VBQI teams in a large Dutch top-clinical teaching hospital. Participants included physicians, physician assistants, nurses, VBHC project leaders, managers, social workers, researchers and paramedics. Interview grids were structured according to the RE-AIM model (reach, effectiveness, adoption, implementation and maintenance). A thematic content analysis with open coding was used to identify emerging (sub)themes. RESULTS: We identified nine main factors divided over three domains (organization, culture and practice) that determined whether the implementation of VBQI teams was successful or not: 1). Practical organization of value-based quality improvement teams, 2). Organizational structure 3). Integration of VBHC with existing quality improvement approaches and research 4). Adoption and knowledge of the VBHC concept in the hospital 5). Multidisciplinary engagement 6). Medical leadership 7). Goal setting and selecting quality improvement initiatives 8). Long-cycle benchmarking and short-cycle feedback 9). Availability of outcome data. CONCLUSIONS: Overall, this study goes beyond the general VBHC theory and provides healthcare providers with more detailed knowledge on how to practically implement value-based quality improvement in a hospital care setting. Factors in the 'organization' and 'practice' domain were mentioned in the strategic value agenda of Porter and Lee. Though, this study provides more practical insight in these two domains. Factors in the 'culture' domain were not mentioned in the strategic value agenda and have not yet been thoroughly researched before.

External validation of the Memorial Sloan Kettering Cancer Centre and Briganti nomograms for the prediction of lymph node involvement of prostate cancer using clinical stage assessed by magnetic resonance imaging.

OBJECTIVES: To evaluate the impact of using clinical stage assessed by multiparametric magnetic resonance imaging (mpMRI) on the performance of two established nomograms for the prediction of pelvic lymph node involvement (LNI) in patients with prostate cancer. PATIENTS AND METHODS: Patients undergoing robot-assisted extended pelvic lymph node dissection (ePLND) from 2015 to 2019 at three teaching hospitals were retrospectively evaluated. Risk of LNI was calculated four times for each patient, using clinical tumour stage (T-stage) assessed by digital rectal examination (DRE) and by mpMRI, in the Memorial Sloan Kettering Cancer Centre (MSKCC; 2018) and Briganti (2012) nomograms. Discrimination (area under the curve [AUC]), calibration, and the net benefit of these four strategies were assessed and compared. RESULTS: A total of 1062 patients were included, of whom 301 (28%) had histologically proven LNI. Using DRE T-stage resulted in AUCs of 0.71 (95% confidence interval [CI] 0.70-0.72) for the MSKCC and 0.73 (95% CI 0.72-0.74) for the Briganti nomogram. Using mpMRI T-stage, the AUCs were 0.72 (95% CI 0.71-0.73) for the MSKCC and 0.75 (95% CI 0.74-0.76) for the Briganti nomogram. mpMRI T-stage resulted in equivalent calibration compared with DRE T-stage. Combined use of mpMRI T-stage and the Briganti 2012 nomogram was shown to be superior in terms of AUC, calibration, and net benefit. Use of mpMRI T-stage led to increased sensitivity for the detection of LNI for all risk thresholds in both models, countered by a decreased specificity, compared with DRE T-stage. CONCLUSION: T-stage as assessed by mpMRI is an appropriate alternative for T-stage assessed by DRE to determine nomogram-based risk of LNI in patients with prostate cancer, and was associated with improved model performance of both the MSKCC 2018 and Briganti 2012 nomograms.

Increased long-term mortality after open colorectal cancer surgery: A multicentre population-based study.

AIM: Unlike meta-analyses of randomized controlled trials, population-based studies in colorectal cancer (CRC) patients have shown a significant association between open surgery and increased 30- and 90-day mortality compared with laparoscopic surgery. Long-term mortality, however, is scarcely reported. This retrospective population-based study aimed to compare long-term mortality after open and laparoscopic surgery for CRC. METHOD: The Dutch Colorectal Audit and the Dutch Cancer Centre registry were used to identify patients from three large nonacademic teaching hospitals who underwent curative resection for CRC between 2009 and 2018. Patients with relative contraindications for laparoscopic surgery (cT4 or pT4 tumours, distant metastasis requiring additional resection and emergency surgery) were excluded. Multivariable regression was used to assess the effect of laparoscopic surgery on long-term mortality with adjustment for gender, age, American Society of Anesthesiologists score, TNM stage, chemoradiation therapy and other confounders. RESULTS: We included 4531 patients, of whom 1298 (29%) underwent open surgery. The median follow-up was 43 months (interquartile range 23-71 months). Open surgery was associated with an increased risk of long-term mortality (adjusted hazard ratio 1.26, 95% confidence interval 1.10-1.45, p = 0.001). Mixed-effects Cox regression with year of surgery as a random effect also showed an increased risk after open surgery (adjusted hazard ratio 1.33, 95% confidence interval 1.11-1.52, p = 0.004). CONCLUSION: Open surgery seems to be associated with increased long-term mortality in the elective setting for CRC patients. A minimally invasive approach might improve long-term outcomes.

Long-term BMI and growth profiles in offspring of women with gestational diabetes.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is reported to be associated with childhood obesity, however the magnitude of this association and relation to intrauterine growth is uncertain. We, therefore, aimed to assess whether the growth trajectories of large for gestational age (LGA) and non-LGA offspring of mothers with GDM (OGDM) are different until early adolescence. We also aimed to explore whether growth trajectories of OGDM differ from those of offspring of mothers with type 1 or 2 diabetes (ODM1, ODM2). METHODS: We studied height and BMI standard deviation score (SDS) of the OGDM group, up to the age of 14 years, with subgroup analysis comparing LGA with non-LGA at birth as a reflection of the intrauterine environment. All mothers with GDM who delivered at the University Medical Center Utrecht between 1990 and 2006 were contacted to participate; informed consent was received for 104 OGDM of 93 mothers. Offspring data were collected through Dutch infant welfare centres. Recorded height and weight were converted to BMI and age- and sex-specific SDS values for Dutch children. Additionally, we compared the OGDM group with ODM1 and ODM2 groups in order to identify those offspring with the highest risk of becoming overweight. Growth trajectories were compared between non-LGA and LGA OGDM and between OGDM, ODM1 and ODM2, using a random-effects model. In the longitudinal follow-up a mean of 7.4 ± 2 measurements per infant were available. RESULTS: Mothers had a prepregnancy BMI of 25.8 kg/m2 and 24% of their infants were LGA at birth. Heights of OGDM were no different from those of the Dutch Growth Study. Non-LGA OGDM showed a BMI SDS comparable with that of the reference population, with a slight increase in early adolescence. LGA OGDM had a higher BMI SDS trajectory than non-LGA OGDM and the reference population, which plateaued at around 10 years of age. Comparison of growth trajectories of OGDM, ODM1 and ODM2 showed ODM2 to have the highest trajectory followed by ODM1 and OGDM, with the LGA counterparts of all three offspring groups in the highest BMI SDS ranges. CONCLUSIONS/INTERPRETATION: Until early adolescence, OGDM have a BMI that is 0.5 SDS higher than that of the Dutch background population. LGA OGDM appear to be at particularly higher risk of being overweight in adolescence compared with non-LGA OGDM, putting them also at a higher lifetime risk of being overweight and developing obesity. ODM2 showed the highest BMI SDS values and had an average BMI SDS of +1.6 until the age of 14, when it became +2 SD. These results emphasize the importance of adequate recognition and timely treatment of maternal gestational diabetes to prevent fetal macrosomia in obstetrics.

Growth and BMI during the first 14 y of life in offspring from women with type 1 or type 2 diabetes mellitus.

BACKGROUND: Infants of women with pregestational diabetes are at risk for developing obesity in later life. This study aimed to identify subgroups at highest risk, by studying growth profiles of offspring from women with type 1 or 2 diabetes mellitus (ODM1, ODM2) until the age of 14 y. METHODS: Information from infant welfare centers was received for 78 ODM1 and 44 ODM2. Mean BMI SD scores (SDS) (based on 1980 nation-wide references) and height SDS (based on 2009 references) were calculated and included in a random-effects model. Values were compared to the 2009 Dutch growth study. RESULTS: BMI SDS profiles differed between ODM1 and ODM2, with the highest mean BMI SDS profiles in ODM2. Other factors that affected growth profiles in these infants included the presence of maternal obesity, large for gestational age (LGA) at birth and in ODM2 a Dutch-Mediterranean origin. CONCLUSION: Offspring of women with diabetes have higher BMI SDS profiles than observed in the 2009 Dutch growth study, with the highest BMI SDS in ODM2 who are LGA at birth and have obese mothers. Preventive strategies for offspring adiposity may include pursuing lower prepregnancy maternal BMI, prevention of LGA at birth, and prevention of increased weight gain during childhood.

Granzyme A impairs host defense during Streptococcus pneumoniae pneumonia.

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia (CAP). Granzyme A (GzmA) is a serine protease produced by a variety of cell types involved in the immune response. We sought to determine the role of GzmA on the host response during pneumococcal pneumonia. GzmA was measured in bronchoalveolar lavage fluid (BALF) harvested from CAP patients from the infected and contralateral uninfected side and in lung tissue slides from CAP patients and controls. In CAP patients, GzmA levels were increased in BALF obtained from the infected lung. Human lungs showed constitutive GzmA expression by both parenchymal and nonparenchymal cells. In an experimental setting, pneumonia was induced in wild-type (WT) and GzmA-deficient (GzmA(-/-)) mice by intranasal inoculation of S. pneumoniae In separate experiments, WT and GzmA(-/-) mice were treated with natural killer (NK) cell depleting antibodies. Upon infection with S. pneumoniae, GzmA(-/-) mice showed a better survival and lower bacterial counts in BALF and distant body sites compared with WT mice. Although NK cells showed strong GzmA expression, NK cell depletion did not influence bacterial loads in either WT or GzmA(-/-) mice. These results implicate that GzmA plays an unfavorable role in host defense during pneumococcal pneumonia by a mechanism that does not depend on NK cells.

Myeloid-related protein-8/14 facilitates bacterial growth during pneumococcal pneumonia.

BACKGROUND: Streptococcus pneumoniae is the most commonly identified pathogen in community-acquired pneumonia (CAP). Myeloid-related protein (MRP) 8/14 is a major component of neutrophils that is released upon infection or injury. MRP8/14 is essential for protective immunity during infection by a variety of micro-organisms through its capacity to chelate manganese and zinc. Here, we aimed to determine the role of MRP8/14 in pneumococcal pneumonia. METHODS: MRP8/14 was determined in bronchoalveolar lavage fluid (BALF) and serum of CAP patients, in lung tissue of patients who had succumbed to pneumococcal pneumonia, and in BALF of healthy subjects challenged with lipoteichoic acid (a component of the gram-positive bacterial cell wall) via the airways. Pneumonia was induced in MRP14 deficient and normal wildtype mice. The effect of MRP8/14 on S. pneumoniae growth was studied in vitro. RESULTS: CAP patients displayed high MRP8/14 levels in BALF, lung tissue and serum. Healthy subjects challenged with lipoteichoic acid demonstrated elevated MRP8/14 in BALF. Likewise, mice with pneumococcal pneumonia had high MRP8/14 levels in lungs and the circulation. MRP14 deficiency, however, was associated with reduced bacterial growth and lethality, in the absence of notable effects on the inflammatory response. High zinc levels strongly inhibited growth of S. pneumoniae in vitro, which was partially reversed by MRP8/14. CONCLUSIONS: In sharp contrast to its previously reported host-protective role in several infections, the present results reveal that in a model of CAP, MRP8/14 is misused by S. pneumoniae, facilitating bacterial growth by attenuating zinc toxicity toward the pathogen.

Coronary artery calcification in hemophilia A: no evidence for a protective effect of factor VIII deficiency on atherosclerosis.

OBJECTIVE: Ischemic heart disease mortality is lower in hemophilia patients than in the general male population. As coagulation plays a role in the inflammatory pathways involved in atherogenesis, we investigated whether the clotting factor deficiency protects hemophilia patients from developing atherosclerosis. METHODS AND RESULTS: Coronary artery calcification, measured with multidetector-row computed tomography, was compared between 42 men, ≥59 years, with severe or moderate hemophilia A, and 613 nonhemophilic men from the Rotterdam Study, a prospective population-based study. None of the study subjects were HIV infected or had a history of cardiovascular disease. Coronary artery calcification was quantified by calculating the Agatston score and calcification mass. Data were analyzed using linear regression. Mean difference (ß) of the natural log-transformed Agatston score between men with and without hemophilia was 0.141 (95% CI -0.602 to 0.885, P=0.709). Results did not change after adjustment for age, body mass index, hypercholesterolemia, hypertension, and use of antidiabetic medication (ß=0.525, 95% CI -0.202 to 1.252, P=0.157). Comparable results were found for calcification mass. CONCLUSION: The extent of coronary artery atherosclerosis is comparable between elderly men with and without hemophilia. Results from this study underline the importance of screening and treating atherosclerosis risk factors in hemophilia patients.

Outcomes in pulmonary sarcoidosis: results of a newly implemented prednisone protocol.

Background and aim Prednisone is used as first-line therapy for patients with pulmonary sarcoidosis. There is however no clear association between prednisone dose and FVC change in patients with pulmonary sarcoidosis. In order to improve our standard of care we introduced a more conservative prednisone protocol. Methods This study is a single centre observational study, applying value-based healthcare (VBHC) and quality improvement (QI) principles. Prednisone intake was reduced from a starting dose of 40 mg to a starting dose of 20 mg. Primary outcomes evaluated were FVC, FEV1 and DLCO % predicted. The secondary outcome measure was BMI. Results 369 patients were included in the old-cohort and 215 in the new-cohort. In the old-cohort, 182 (49.0%) of the patients were treated with prednisone. In total, 114 patients (62.6%) were treated according to the old protocol with a mean initial prednisone dose of 32.1 ±14.2 mg. In the new-cohort, 93 patients (45.0%) were treated with prednisone of which 53 patients (57.0%) received prednisone according to the new protocol. The mean initial prednisone dose in the new-cohort was 21.4 ±9.8 mg. Changes in FVC and FEV1 % predicted did not vary. Change in % predicted DLCO was 2.4 ±9.3 for the old-cohort and -1.3 ±11.4 for the new-cohort (p = 0.01). No statistically significant changes in BMI were observed. Conclusions Our results indicate that in more than half of the patients the new protocol was followed. Data support the observation that a more conservative prednisone regimen might be equally effective, looking at changes in pulmonary function and BMI.

No effect of danazol treatment in patients with advanced idiopathic pulmonary fibrosis.

Background: Telomere dysfunction can underly the development of idiopathic pulmonary fibrosis (IPF), and recent work suggests that patients with telomere syndromes might benefit from treatment with androgens, such as danazol. Methods: This was a prospective observational cohort study. 50 patients with IPF received off-label treatment with danazol after they showed progressive disease under treatment with pirfenidone or nintedanib. The primary outcome was the difference in yearly decline in forced vital capacity (FVC) prior to (pre) and after (post) start of treatment with danazol. Results: There was no significant difference in FVC-decline between 1 year pre and 1 year post start of danazol treatment (mean decline pre 395 mL (95% confidence interval (CI) 290-500) compared to post 461 mL (95% CI 259-712); p=0.46; paired t-test). 11 patients (22%) were still on danazol after 1 year, and 39 patients had stopped danazol, mainly because of side-effects (56%) or death (33%). In patients who were still using danazol after 1 year, FVC-decline significantly slowed down under danazol treatment (mean pre 512 mL (95% CI 308-716) versus post 198 mL (95% CI 16-380); p=0.04). Median survival post danazol was 14.9 months (95% CI 11.0-18.8). Conclusion: Danazol as a treatment of last resort in patients with IPF did not lead to slowing of lung function decline and was associated with significant side-effects. It remains to be determined if earlier treatment or treatment of specific patient subgroups is beneficial.

How to Use Lean Thinking for the Optimization of Clinical Pathways: A Systematic Review and a Proposed Framework to Analyze Pathways on a System Level.

Lean Thinking and clinical pathways are commonly used concepts to improve healthcare. However, little is known on how to use Lean Thinking for the optimization of pathways or the quantification of both concepts. This study aims to create a framework to analyze pathways with Lean Thinking on a system level, by quantifying the seven wastes, flow and pull. A systematic literature review was performed. Inclusion criteria were the focus of the article on a well-defined group of patients and studied a pathway optimization with Lean Thinking. Data were extracted on measured outcomes, type of intervention and type of researched pathway. Thirty-six articles were included. No articles described the implementation of the Lean Thinking philosophy or studied the development of their people and partners ("4 P" model). Most articles used process optimization tools or problem-solving tools. The majority of the studies focused on process measures. The measures found in the review were used as input for our suggested framework to identify and quantify wastes, flow, and pull in a clinical pathway. The proposed framework can be used to create an overview of the improvement potential of a pathway or to analyze the level of improvement after an enhancement is introduced to a pathway. Further research is needed to study the use of the suggested quantifications.

Addition of vitamin D status to prognostic scores improves the prediction of outcome in community-acquired pneumonia.

BACKGROUND: Vitamin D plays a role in host defense against infection. Vitamin D deficiency is common worldwide. The prognostic value of vitamin D levels in pneumonia is unknown. In this study, we aimed to investigate the impact of vitamin D status on outcome in community-acquired pneumonia (CAP). METHODS: We conducted a prospective cohort study in 272 hospitalized patients with CAP. Levels of 25-hydroxyvitamin D, leukocytes, C-reactive protein, and total cortisol and the Pneumonia Severity Index (PSI) and CURB-65 scores were measured on admission. Major outcome measures were intensive care unit (ICU) admission and 30-day mortality. RESULTS: One hundred forty-three patients (53%) were vitamin D deficient (<50 nmol/L), 79 patients (29%) were vitamin D insufficient (50-75 nmol/L), and 50 patients (18%) were vitamin D sufficient (>75 nmol/L). Vitamin D deficiency was associated with an increased risk of ICU admission and 30-day mortality. Vitamin D status was an independent predictor of 30-day mortality (area under the curve [AUC] =0.69; 95% confidence interval [CI], .57-.80). Multivariate regression analysis including all predictors for outcome resulted in a final model including vitamin D status and the PSI score, with a significantly higher prognostic accuracy compared with the PSI score alone (AUC=0.83; 95% CI, .71-.94). CONCLUSIONS: Vitamin D deficiency is associated with adverse outcome in CAP. Vitamin D status is an independent predictor of 30-day mortality and adds prognostic value to other biomarkers and prognostic scores, in particular the PSI score. CLINICAL TRIALS REGISTRATION: NCT00471640.

Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation. METHODS: In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640. FINDINGS: Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4-5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0-9·0) in the dexamethasone group compared with 7·5 days (5·3-11·5) in the placebo group (95% CI of difference in medians 0-2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001). INTERPRETATION: Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia. FUNDING: None.

Immunomodulatory effects of macrolides during community-acquired pneumonia: a literature review.

Macrolides are known to possess immunomodulatory properties, next to their antimicrobial effects. These immunomodulatory activities have been proven beneficial in chronic pulmonary inflammatory diseases. Whether macrolides also exert favourable immunomodulatory effects during acute inflammation, and therefore can act as adjuvant therapy in community-acquired pneumonia (CAP), is less clear. We aimed to give an overview of the existing evidence from in vitro and in vivo studies on the immunomodulatory effects of macrolides during CAP. A comprehensive search in the PubMed/MEDLINE and Embase databases was performed. Two investigators independently examined the eligible literature. Studies that dealt with the effects of macrolides on the immune response, in terms of cytokine secretion and the number or function of inflammatory and structural cells during acute inflammation, were included. A total of 27 studies were included, of which 15 were in vitro studies, 9 in vivo, 2 both in vivo and in vitro, and 1 was in human subjects. Although the methods and experimental model systems used in these studies are very heterogeneous, macrolides in general tempered inflammation caused by viable and non-viable bacteria or their products. Cytokine secretion decreased, as did inflammatory and structural cell activation and histological inflammatory signs. Not all data, however, are consistent and sometimes pro-inflammatory effects were found. To conclude, the available literature suggests that macrolides can temper the inflammatory response during CAP, independent of their antimicrobial activity. However, because the studies differ in their methodology, no definite conclusions can be drawn.

Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded.

BACKGROUND: D-dimer testing to rule out deep vein thrombosis is less useful in older patients because of a lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut-off combined with clinical probability for the exclusion of deep vein thrombosis. DESIGN AND METHODS: Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability of deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 µg/L) and the age-adjusted D-dimer cut-off (patient's age x 10 µg/L in patients >50 years). RESULTS: In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) patients with the age-adjusted cut-off value versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted cut-off value and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non-high probability. CONCLUSIONS: The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded.