Establishing a link between heart rate and pain in healthy subjects: a gender effect.

Heart rate (HR) is currently used by rehabilitation clinicians as a complementary objective measure of pain. The premise is that, as pain increases, HR should also increase. However, this relationship is not clearly established. The goal of this study was to verify the relationship between HR and pain perception. Thirty-nine healthy volunteers participated in this experimental study. Painful stimuli were induced by a 2-minute immersion of the hand in hot water (47 degrees C). HR was recorded before and during the stimulation and was matched to a pain rating. We observed a rise of 11% in HR after 2 minutes of immersion. There was a significant intrasubject correlation between HR and pain intensity (r = 0.50, P < .001) and pain unpleasantness (r = 0.55, P < .001). Furthermore, there was a strong gender effect in the intersubject correlations. Men presented a strong correlation between mean HR and mean pain perception (intensity: r = 0.77, unpleasantness: r = 0.86), whereas this relationship was absent in women (intensity: r = -0.2, unpleasantness: r = 0.001). In conclusion, results show that, for healthy volunteers, experimental pain can elicit a rise in HR up to 11%. Moreover, the relationship between HR response and pain is gender related. Considering that a positive relationship between HR and pain perception was only found in men, these results do not support a clinical significance of the use of HR for pain evaluation in women. Clinical implications need to be further evaluated with patients before clinicians can use HR as a complementary tool in pain assessment. PERSPECTIVE: A positive correlation between HR and pain was observed for men but not for women. These differences underline the importance of taking into account gender differences in the development of complementary pain assessment. Further research should be conducted to verify the role of sex hormones on heart rate and pain.     

Combined measurements of N-terminal pro-brain natriuretic peptide and cardiac troponins in potential organ donors

Objective Brain death may induce cardiac dysfunction. In potential organ donors measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) and circulating cardiac troponins T and I (cTnT and cTnI), alone or in combination, are performed to investigate the accuracy of these biomarkers for early diagnosis of left ventricular systolic dysfunction. Design and setting Prospective study in a multidisciplinary intensive care unit of an university hospital. Patients 63 brain-dead patients scheduled for multiple organ harvesting. Measurements and results We measured NT-proBNP, cTnT, and cTnI and determined fractional area change (FAC) using transesophageal echocardiography. Forty-five patients had normal FAC, 9 a moderate decrease in FAC (30–50), and 9 a severe decrease in FAC (≤ 30%). NT-proBNP and cTnT concentrations were significantly higher in patients with a severe decrease in FAC than in those with a moderate decrease. Combining measurements of these two biomarkers, the sensitivity of the test to predict severe decrease in FAC increased significantly to reach 1.00 compared with the sensitivities of individual measurements. The ROC curve area of combined measurements of NT-proBNP and cTnT was significantly higher than single measurements: 0.87 vs. 0.82 for NT-proBNP, 0.78 for cTnT, and 0.72 for cTnI. Conclusions In potential organ donors the combined measurement of NT-proBNP and cTnT concentrations is more accurate than individual measurement of NT-proBNP, cTnT, and cTnI in the early diagnosis of severe left ventricular systolic dysfunction. These findings may lead to improve the quality of cardiac care of the potential organ donors.     

Cost-effectiveness of activated protein C in real-life clinical practice

Background

Recombinant human activated protein C (rhAPC) has been reported to be cost-effective in severely ill septic patients in studies using data from a pivotal randomized trial. We evaluated the cost-effectiveness of rhAPC in patients with severe sepsis and multiple organ failure in real-life intensive care practice.

Methods

We conducted a prospective observational study involving adult patients recruited before and after licensure of rhAPC in France. Inclusion criteria were applied according to the label approved in Europe. The expected recruitment bias was controlled by building a sample of patients matched for propensity score. Complete hospitalization costs were quantified using a regression equation involving intensive care units variables. rhAPC acquisition costs were added, assuming that all costs associated with rhAPC were already included in the equation. Cost comparisons were conducted using the nonparametric bootstrap method. Cost-effectiveness quadrants and acceptability curves were used to assess uncertainty of the cost-effectiveness ratio.

Results

In the initial cohort (n = 1096), post-license patients were younger, had less co-morbid conditions and had failure of more organs than did pre-license patients (for all: P < 0.0001). In the matched sample (n = 840) the mean age was 62.4 ± 14.9 years, Simplified Acute Physiology Score II was 56.7 ± 18.5, and the number of organ failures was 3.20 ± 0.83. When rhAPC was used, 28-day mortality tended to be reduced (34.1% post-license versus 37.4% pre-license, P = 0.34), bleeding events were more frequent (21.7% versus 13.6%, P = 0.002) and hospital costs were higher (€47,870 versus €36,717, P < 0.05). The incremental cost-effectiveness ratios gained were as follows: €20,278 per life-year gained and €33,797 per quality-adjusted life-year gained. There was a 74.5% probability that rhAPC would be cost-effective if there were willingness to pay €50,000 per life-year gained. The probability was 64.3% if there were willingness to pay €50,000 per quality-adjusted life-year gained.

Conclusion

This study, conducted in matched patient populations, demonstrated that in real-life clinical practice the probability that rhAPC will be cost-effective if one is willing to pay €50,000 per life-year gained is 74.5%.     

MR imaging,targeting and characterization of pulmonary fibrosis using intra‐tracheal administration of gadolinium‐based nanoparticles

Idiopathic pulmonary fibrosis is a devastating disease. Animal models are critical to develop new diagnostic approaches. We investigate here whether the application of an ultra‐short echo time MRI sequence combined with the intra‐tracheal administration of Gd‐based nanoparticles can help to visualize and characterize pulmonary fibrosis in mice. 21 mice were imaged. Treated mice were administered bleomycin. MRI was used for longitudinal detection of bleomycin‐induced lung injury from Day 1 up to Day 60. On Day 30, all mice received nanoparticles and MR images were acquired. A signal enhancement of 120% and 50% in fibrotic lesions and healthy tissues respectively was obtained. A twofold increase of contrast‐to‐noise ratio between fibrotic and healthy tissue was also observed, leading to a more accurate delineation of the extent of fibrosis. The elimination time constant of the nanoparticles was 54% higher in fibrotic lesions. Bleomycin‐induced lung injury can be monitored using MRI. Intra‐tracheal administration of Gd‐based nanoparticles enabled us to enhance fibrotic tissue in lungs but also to extract imaging biomarkers that quantify elimination and diffusion of contrast agents and can characterize fibrotic tissue. The added value of MRI associated with pulmonary administration of contrast agents is key to better understand the lung fibrotic process and monitor drug response in pre‐clinical studies, which will be valuable for translational applications. Copyright © 2016 John Wiley & Sons, Ltd.     

Process induced transformations during tablet manufacturing: phase transition analysis of caffeine using DSC and low frequency micro-Raman spectroscopy

The phase transition of a model API, caffeine Form I, was studied during tableting process monitored with an instrumented press. The formulation used had a plastic flow behavior according to the Heckel model in the compression pressure range of 70-170 MPa. The quantitative methods of analysis used were Differential Scanning Calorimetry (DSC) and low frequency Micro Raman Spectroscopy (MRS) which was used for the first time for the mapping of polymorphs in tablets. They brought complementary contributions since MRS is a microscopic spectral analysis with a spatial resolution of 5 μm³ and DSC takes into account a macroscopic fraction (10 mg) of the tablet. Phase transitions were present at the surfaces, borders and center of the tablets. Whatever the pressure applied during the compression process, the transition degree of caffeine Form I toward Form II was almost constant. MRS provided higher transition degrees (50-60%) than DSC (20-35%). MRS revealed that caffeine Form I particles were partially transformed in all parts of the tablets at a microscopic scale. Moreover, tablet surfaces showed local higher transition degree compared to the other parts.     

Cytoskeleton as an emerging target of anthrax toxins

Bacillus anthracis, the agent of anthrax, has gained virulence through its exotoxins produced by vegetative bacilli and is composed of three components forming lethal toxin (LT) and edema toxin (ET). So far, little is known about the effects of these toxins on the eukaryotic cytoskeleton. Here, we provide an overview on the general effects of toxin upon the cytoskeleton architecture. Thus, we shall discuss how anthrax toxins interact with their receptors and may disrupt the interface between extracellular matrix and the cytoskeleton. We then analyze what toxin molecular effects on cytoskeleton have been described, before discussing how the cytoskeleton may help the pathogen to corrupt general cell processes such as phagocytosis or vascular integrity.     

The role of the brain renin–angiotensin system in hypertension: Implications for new treatment

Hypertension affects 26% of adults and is in constant progress related to increased incidence of obesity and diabetes. One-third of hypertensive patients may be successfully treated with one antihypertensive agent, one-third may require two agents and in the remaining patients will need three agents for effective blood pressure (BP) control. The development of new classes of antihypertensive agents with different mechanisms of action therefore remains an important goal. Brain renin–angiotensin system (RAS) hyperactivity has been implicated in hypertension development and maintenance in several types of experimental and genetic hypertension animal models. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III have similar affinities for type 1 (AT1) and type 2 (AT2) Ang II receptors. Following intracerebroventricular (i.c.v.) injection, Ang II and Ang III similarly increase arginine–vasopressin (AVP) release and BP. Blocking the brain RAS may be advantageous as it simultaneously (1) decreases sympathetic tone and consequently vascular resistance, (2) decreases AVP release, reducing blood volume and vascular resistance and (3) blocks angiotensin-induced baroreflex inhibition, decreasing both vascular resistance and cardiac output. However, as Ang II is converted to Ang III in vivo, the exact nature of the active peptide is not precisely determined. We summarize here the main findings identifying AngIII as one of the major effector peptides of the brain RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP in hypertensive rats, identifying brain aminopeptidase A (APA), the enzyme generating brain Ang III, as a potentially candidate target for hypertension treatment. This has led to the development of potent orally active APA inhibitors, such as RB150 — the prototype of a new class of centrally acting antihypertensive agents.