Low-Dose Methoxyflurane versus Standard of Care Analgesics for Emergency Trauma Pain: A Systematic Review and Meta-Analysis of Pooled Data.

PURPOSE: Undertreatment of trauma-related pain is common in the pre-hospital and hospital settings owing to barriers to the use of traditional standard of care analgesics. Low-dose methoxyflurane is an inhaled non-opioid analgesic with a rapid onset of pain relief that is approved for emergency relief of moderate-to-severe trauma-related pain in adults. This analysis was performed to compare the efficacy and safety of low-dose methoxyflurane with standard of care analgesics in adults with trauma-related pain. METHODS: A meta-analysis was performed on pooled data from randomized controlled trials identified via a systematic review. The primary endpoint was the pain intensity difference between baseline and various time intervals (5, 10, 15, 20, and 30 minutes) after initiation of treatment. RESULTS: The pain intensity difference was statistically superior with low-dose methoxyflurane compared with standard of care analgesics (overall estimated treatment effect=11.88, 95% CI=9.75-14.00; P<0.0001). The superiority of low-dose methoxyflurane was demonstrated at 5 minutes after treatment initiation and was maintained across all timepoints. Significantly more patients treated with methoxyflurane achieved response criteria of pain intensity ≤30 mm on a visual analog scale, and relative reductions in pain intensity of ≥30% and ≥50%, compared with patients who received standard of care analgesics. The median time to pain relief was shorter with methoxyflurane than with standard of care analgesics. The findings were consistent in a subgroup of elderly patients (aged ≥65 years). CONCLUSION: Methoxyflurane can be considered as an alternative to standard of care analgesics in pre-hospital and hospital settings for treatment of adult patients with acute trauma-related pain.

Utilization of intravenous or subcutaneous immunoglobulins in secondary immune deficiency (ULTIMATE): A retrospective multicenter study.

INTRODUCTION: We conducted a retrospective multicenter cohort study of patients receiving Immunoglobulin replacement therapy (IgRT) for secondary immune deficiency (SID) during 2012. METHODS: Data were retrospectively collected from the first dose of Ig administered in 2012 to 1 year afterward in terms of the indication for IgRT, as well as efficacy and safety. RESULTS: In total, 16 hospitals participated in the study, and 368 patients were included. Indications for IgRT were non-Hodgkin lymphoma (82 [22.3%] patients), multiple myeloma (76 [20.7%]), chronic lymphocytic leukemia (64 [17.4%]) and other (79 [21.5%]). Only 89 (24.2%) patients received IgRT according to 2011 European Medical Agency (EMA) recommendations; 196 (53.3%) received prophylactic antibiotics and 262 (76.2%) had an IgG level < 4 g/L before IgRT initiation. CONCLUSION: In this study, whatever the criteria, only 24.2% of patients with SID who received IgRT met EMA recommendations, which suggests a misuse of IgRT in SID.

Pathophysiology of dyspnoea in acute pulmonary embolism: A cross-sectional evaluation.

BACKGROUND AND OBJECTIVE: Dyspnoea in pulmonary embolism (PE) remains poorly characterized. Little is known about how to measure intensity or about the underlying mechanisms that may be related to ventilatory abnormalities, alveolar dead space ventilation or modulating factors such as psychological modulate. We hypothesized that dyspnoea would mainly be associated with pulmonary vascular obstruction and its pathophysiological consequences, while the sensory-affective domain of dyspnoea would be influenced by other factors. METHODS: We undertook a prospective study of 90 consecutive non-obese patients (mean ± SD age: 49 ± 16 years, 41 women) without cardiorespiratory disease. All patients were hospitalized with symptoms for <15 days and a confirmed PE (multi-detector computed tomography (MDCT) scan, n = 87 and high-probability ventilation/perfusion scan, n = 3). Patients underwent assessment of dyspnoea using the Borg score, modified Medical Research Council (mMRC) scale, assessment of psychological trait, state of anxiety and depression and chest pain via the Visual Analogical Scale at the time of maximum dyspnoea. Functional evaluations such as the quantitative ventilation-perfusion lung scan, echocardiography, alveolar dead space fraction and tidal ventilation measurements were completed within 48 h of admission. RESULTS: Multivariate analyses demonstrated that dyspnoea was mainly linked to pulmonary vascular obstruction and/or its consequences such as raised pulmonary arterial pressure and chest pain. The sensory-affective domain of dyspnoea showed additional determinants such as age, depression and breathing variability. CONCLUSION: Dyspnoea is mainly related to vascular consequences of PE such as increased pulmonary arterial pressure or chest pain. The sensory-affective domain of dyspnoea also correlates with age, depression and breathing variability.

A meta-analysis of diffusion-weighted and gadoxetic acid-enhanced MR imaging for the detection of liver metastases.

OBJECTIVES: To obtain the diagnostic performance of diffusion-weighted (DW) and gadoxetic-enhanced magnetic resonance (MR) imaging in the detection of liver metastases. METHODS: A comprehensive search (EMBASE, PubMed, Cochrane) was performed to identify relevant articles up to June 2015. Inclusion criteria were: liver metastases, DW-MR imaging and/or gadoxetic acid-enhanced MR imaging, and per-lesion statistics. The reference standard was histopathology, intraoperative observation and/or follow-up. Sources of bias were assessed using the QUADAS-2 tool. A linear mixed-effect regression model was used to obtain sensitivity estimates. RESULTS: Thirty-nine articles were included (1,989 patients, 3,854 metastases). Sensitivity estimates for DW-MR imaging, gadoxetic acid-enhanced MR imaging and the combined sequence for detecting liver metastases on a per-lesion basis was 87.1 %, 90.6 % and 95.5 %, respectively. Sensitivity estimates by gadoxetic acid-enhanced MR imaging and the combined sequence were significantly better than DW-MR imaging (p = 0.0001 and p < 0.0001, respectively), and the combined MR sequence was significantly more sensitive than gadoxetic acid-enhanced MR imaging (p < 0.0001). Similar results were observed in articles that compared the three techniques simultaneously, with only colorectal liver metastases and in liver metastases smaller than 1 cm. CONCLUSIONS: In patients with liver metastases, combined DW-MR and gadoxetic acid-enhanced MR imaging has the highest sensitivity for detecting liver metastases on a per-lesion basis. KEY POINTS: • DW-MRI is less sensitive than gadoxetic acid-enhanced MRI for detecting liver metastases • DW-MRI and gadoxetic acid-enhanced MRI is the best combination • Same results are observed in colorectal liver metastases • Same results are observed in liver metastases smaller than 1 cm • Same results are observed when histopathology alone is the reference standard.

The value of a rapid contrast-enhanced angio-MRI protocol in the detection of head and neck paragangliomas in SDHx mutations carriers: a retrospective study on behalf of the PGL.EVA investigators.

OBJECTIVES: To assess the performance of a simplified MRI protocol consisting of a contrast-enhanced three-dimensional MR angiography (CE-MRA) in association with a post-contrast T1-weighted sequence (T1WIV) for the detection of HNPGLs in SDHx mutation carriers. METHODS: This retrospective sub-study is based on the multicenter PGL.EVA cohort, which prospectively enrolled SDHx mutation carriers from 2005 to 2009; 157 index cases or relatives were included. CE-MRA and the T1WIV images were read solely with knowledge of the clinical data but blind to the diagnosis. Sensitivity, specificity and likelihood ratios for the simplified MRI protocol were compared to the full MRI protocol reading results and to the gold standard status obtained through the consensus of an expert committee. RESULTS: The sensitivity and specificity of the readings of the simplified MRI protocol were, respectively, 88.7 % (95 % CI = 78.1-95.3) and 93.7 % (95 % CI = 86.8-97.7) versus 80.7 % (95 % CI = 68.6-89.6) and 94.7 % (95 % CI = 88.1-98.3) for the readings of the full MRI protocol. CONCLUSIONS: The simplified post-contrast MRI with shorter duration (5 to 10 minutes) showed no performance difference compared to the lengthy standard full MRI and can be proposed for the detection of head and neck paragangliomas (HNPGLs) in SDHx mutation carriers. KEY POINTS: • Rapid angio-MRI protocol and the usual lengthy protocol show equal diagnostic performance. • The CE-MRA is the key sequence for the detection of HNPGLs. • The T1WIV sequence assists in localizing HNPGLs.

Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome.

Patients with Gitelman syndrome (GS), an inherited salt-losing tubulopathy, are usually treated with potassium-sparing diuretics or nonsteroidal anti-inflammatory drugs and oral potassium and magnesium supplementations. However, evidence supporting these treatment options is limited to case series studies. We designed an open-label, randomized, crossover study with blind end point evaluation to compare the efficacy and safety of 6-week treatments with one time daily 75 mg slow-release indomethacin, 150 mg eplerenone, or 20 mg amiloride added to constant potassium and magnesium supplementation in 30 patients with GS (individual participation: 48 weeks). Baseline plasma potassium concentration was 2.8±0.4 mmol/L and increased by 0.38 mmol/L (95% confidence interval [95% CI], 0.23 to 0.53; P<0.001) with indomethacin, 0.15 mmol/L (95% CI, 0.02 to 0.29; P=0.03) with eplerenone, and 0.19 mmol/L (95% CI, 0.05 to 0.33; P<0.01) with amiloride. Fifteen patients became normokalemic: six with indomethacin, three with eplerenone, and six with amiloride. Indomethacin significantly reduced eGFR and plasma renin concentration. Eplerenone and amiloride each increased plasma aldosterone by 3-fold and renin concentration slightly but did not significantly change eGFR. BP did not significantly change. Eight patients discontinued treatment early because of gastrointestinal intolerance to indomethacin (six patients) and hypotension with eplerenone (two patients). In conclusion, each drug increases plasma potassium concentration in patients with GS. Indomethacin was the most effective but can cause gastrointestinal intolerance and decreased eGFR. Amiloride and eplerenone have similar but lower efficacies and increase sodium depletion. The benefit/risk ratio of each drug should be carefully evaluated for each patient.

Endurance-training in healthy men is associated with lesser exertional breathlessness that correlates with circulatory-muscular conditioning markers in a cross-sectional design.

Whether exertional dyspnoea can be attributed to poor circulatory-muscular conditioning is a difficult clinical issue. Because criteria of poor conditioning such as low oxygen pulse, low ventilatory threshold or high heart rate/oxygen consumption slope can be observed in heart or lung diseases and are not specific to conditioning, we assessed the relationships between physical exercise, conditioning and exertional breathlessness in healthy subjects, in whom the aforementioned criteria can confidently be interpreted as reflecting conditioning. To this end, healthy males with either low (inactive men, n = 31) or high (endurance-trained men, n = 31) physical activity evaluated using the International Physical Activity Questionnaire (IPAQ) underwent spirometry and incremental exercise testing with breathlessness assessment using Borg scale. No significant breathlessness was reported before the ventilatory threshold in the two groups. Peak breathlessness was highly variable, did not differ between the two groups, was not related to any conditioning criterion, but correlated with peak respiratory rate. Nevertheless, endurance-trained subjects reported lower breathlessness at the same ventilation levels in comparison with inactive subjects. Significant but weak associations were observed between isoventilation breathlessness and physical activity indices (Borg at 60 L/min and total IPAQ scores, rho = -0.31, p = 0.020), which were mainly attributable to the vigorous domain of physical activity, as well as with conditioning indices (Borg score at 60 L.min(-1) and peak oxygen pulse or heart rate/oxygen consumption slope, rho = -0.31, p = 0.021 and rho = 0.31, p = 0.020; respectively). In conclusion, our data support a weak relationship between exertional breathlessness and circulatory-muscular conditioning, the later being primarily related to vigorous physical activity.

Ageing and endurance training effects on quantity and quality of pulmonary vascular bed in healthy men.

It has recently been demonstrated that in healthy individuals, peak oxygen consumption is associated with a greater pulmonary capillary blood volume and a more distensible pulmonary circulation. Our cross-sectional study suggests that, in healthy men aged 20 to 60 years (n = 63), endurance sport practice (vigorous-intensity domain of the International Physical Activity Questionnaire) is associated with better quantity (pulmonary capillary blood volume) and quality (slope of increase in lung diffusion for carbon monoxide on exercise) of the pulmonary vascular bed, partly counterbalancing the deleterious effects of ageing, which remains to be demonstrated in a prospective longitudinal design.

Plasma soluble (pro)renin receptor is independent of plasma renin, prorenin, and aldosterone concentrations but is affected by ethnicity.

A soluble (pro)renin receptor (sPRR) circulates in plasma and is able to bind renin and prorenin. It is not known whether plasma sPRR concentrations vary with the activity of the renin-angiotensin system. We measured plasma sPRR, renin, prorenin, and aldosterone concentrations in 121 white and 9 black healthy subjects, 40 patients with diabetes mellitus, 41 hypertensive patients with or without renin-angiotensin system blockers, 9 patients with primary aldosteronism, and 10 patients with Gitelman syndrome. Median physiological plasma sPRR concentration was 23.5 ng/mL (interquartile range, 20.9-26.5) under usual uncontrolled sodium diet. sPRR concentration in healthy subjects, unlike renin and prorenin, did not display circadian variation or dependence on age, sex, posture, or hormonal status. sPRR concentrations were ≈25% lower in black than in white subjects, whereas renin concentrations were ≈40% lower. Patients with diabetes mellitus (average renin-high prorenin levels) and with hypertension only (average renin-average prorenin levels) had sPRR concentrations similar to healthy subjects. Renin-angiotensin system blockade was associated with increase of sPRR concentration by ≈12%. sPRR in patients with primary aldosteronism (low renin-low prorenin) and Gitelman syndrome (high renin-high prorenin) were similar and ≈10% higher than in healthy subjects. There was no correlation between sPRR and renin or prorenin. In conclusion, our results show that plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity.

Efficacy of composite versus ceramic inlays and onlays: study protocol for the CECOIA randomized controlled trial.

BACKGROUND: Dental caries is a common disease and affects many adults worldwide. Inlay or onlay restoration is widely used to treat the resulting tooth substance loss. Two esthetic materials can be used to manufacture an inlay/onlay restoration of the tooth: ceramic or composite. Here, we present the protocol of a multicenter randomized controlled trial (RCT) comparing the clinical efficacy of both materials for tooth restoration. Other objectives are analysis of overall quality, wear, restoration survival and prognosis. METHODS: The CEramic and COmposite Inlays Assessment (CECOIA) trial is an open-label, parallel-group, multicenter RCT involving two hospitals and five private practices. In all, 400 patients will be included. Inclusion criteria are adults who need an inlay/onlay restoration for one tooth (that can be isolated with use of a dental dam and has at least one intact cusp), can tolerate restorative procedures and do not have severe bruxism, periodontal or carious disease or poor oral hygiene. The decayed tissue will be evicted, the cavity will be prepared for receiving an inlay/onlay and the patient will be randomized by use of a centralized web-based interface to receive: 1) a ceramic or 2) composite inlay or onlay. Treatment allocation will be balanced (1:1). The inlay/onlay will be adhesively luted. Follow-up will be for 2 years and may be extended; two independent examiners will perform the evaluations. The primary outcome measure will be the score obtained with use of the consensus instrument of the Fédération Dentaire Internationale (FDI) World Dental Federation. Secondary outcomes include this instrument's items, inlay/onlay wear, overall quality and survival of the inlay/onlay. Data will be analyzed by a statistician blinded to treatments and an adjusted ordinal logistic regression model will be used to compare the efficacy of both materials. DISCUSSION: For clinicians, the CECOIA trial results may help with evidence-based recommendations concerning the choice of materials for inlay/onlay restoration. For patients, the results may lead to improvement in long-term restoration. For researchers, the results may provide ideas for further research concerning inlay/onlay materials and prognosis.This trial is funded by a grant from the French Ministry of Health. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01724827.

Imaging work-up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: a multicenter prospective study from the PGL.EVA Investigators.

CONTEXT: Recommendations have not been established concerning imaging to screen SDHx mutation carriers for paraganglioma and pheochromocytoma. OBJECTIVE: Our objective was to compare the performance of gadolinium-enhanced magnetic resonance angiography, contrast-enhanced computed tomography, and [(123)I]metaiodo-benzylguanidine and somatostatin receptor scintigraphies for detecting head and neck and thoracic-abdominal-pelvic paragangliomas in SDHx mutation carriers. DESIGN AND SETTING: We conducted a prospective, multicenter study from June 2005 to December 2009 at 23 French medical centers. PATIENTS: A total of 238 index cases or relatives carrying mutations in SDHD, SDHB, or SDHC genes were included. INTERVENTION: Images obtained by each technique were analyzed blind, without knowledge of results from other tests, first in each local center and then centrally. MAIN OUTCOME MEASURES: We evaluated sensitivity, specificity, and likelihood ratios for individual and combinations of tests, the gold standard being the consensus of an expert committee. RESULTS: Two hundred two tumors were diagnosed in 96 subjects. At local assessment, the sensitivity of anatomical imaging for detecting all tumors was higher (85.7%) than that of both scintigraphic techniques (42.7% for [(123)I]metaiodo-benzylguanidine and 69.5% for somatostatin receptor scintigraphy), except for thoracic localizations where somatostatin receptor scintigraphy was more sensitive (61.5 vs. 46.2% for anatomical imaging and 30.8% for [(123)I]metaiodo-benzylguanidine scintigraphy). The best diagnostic performance during local assessment was obtained by combining anatomical imaging tests and somatostatin receptor scintigraphy (sensitivity 91.7%). Central assessment significantly increased the sensitivity (98.6%) of tests in combination. CONCLUSIONS: In routine practice, the imaging work-up for screening SDHx mutation carriers should include thoraco-abdomino-pelvic computed tomography, head and neck magnetic angiography, and somatostatin receptor scintigraphy. Expert centralized image assessment is recommended.

Relationships between respiratory and airway resistances and activity-related dyspnea in patients with chronic obstructive pulmonary disease.

BACKGROUND: The aims of the study were: (1) to compare numerical parameters of specific airway resistance (total, sRaw(tot), effective, sRaw(eff) and at 0.5 L · s(-1), sRaw(0.5)) and indices obtained from the forced oscillation technique (FOT: resistance extrapolated at 0 Hz [Rrs(0 Hz)], mean resistance [Rrs(mean)], and resistance/frequency slope [Rrs(slope)]) and (2) to assess their relationships with dyspnea in chronic obstructive pulmonary disease (COPD). METHODS: A specific statistical approach, principal component analysis that also allows graphic representation of all correlations between functional parameters was used. A total of 108 patients (mean ± SD age: 65 ± 9 years, 31 women; GOLD stages: I, 14; II, 47; III, 39 and IV, 8) underwent spirometry, body plethysmography, FOT, and Medical Research Council (MRC) scale assessments. RESULTS: Principal component analysis determined that the functional parameters were described by three independent dimensions (airway caliber, lung volumes and their combination, specific resistance) and that resistance parameters of the two techniques were not equivalent, obviously. Correlative analyses further showed that Raw(tot) and Raw(eff) (and their specific resistances) can be considered as equivalent and correlated with indices that are considered to explore peripheral airways (residual volume (RV), RV/ total lung capacity (TLC), Rrs(slope)), while Rrs(mean) and Raw(0.5) explored more central airways. Only specific resistances taking into account the specific resistance loop area (sRaw(tot) and sRaw(eff)) and Rrs(slope) were statistically linked to dyspnea. CONCLUSION: Parameters obtained from both body plethysmography and FOT can explore peripheral airways, and some of these parameters (sRaw(tot), sRaw(eff,) and Rrs(slope)) are linked to activity-related dyspnea in moderate to severe COPD patients.

Activity-related dyspnea is not modified by psychological status in people with COPD, interstitial lung disease or obesity.

Sensory (physiological) and affective (psychological) dimensions of dyspnea have been described but the usefulness of measuring psychological status in addition to ventilatory capacity (spirometry, lung volumes) in the assessment of exertional dyspnea remains controversial. We hypothesized that activity-related dyspnea would not be modified by psychological status. Principal component analysis (PCA) was used to reduce the number of parameters (psychological or functional) to fewer independent dimensions in 328 patients with altered ventilatory capacity: severe obesity (BMI ≥ 35, n = 122), COPD (n = 128) or interstitial lung disease (n = 78). PCA demonstrated that psychological status (Hospital Anxiety-Depression, Fatigue Impact scales) and dyspnea (Medical Research Council [MRC] scale) were independent dimensions. Ventilatory capacity was described by three main dimensions by PCA related to airways, volumes, and their combination (specific airway resistance, FEV(1)/FVC), which were weakly correlated with dyspnea. In conclusion, in patients with COPD, interstitial lung disease or severe obesity, psychological status does not modify activity-related dyspnea rating as evaluated by the MRC scale.