Severe asthma: follow-up after one year from the Italian Registry on Severe Asthma (IRSA)

Summary: Background. Asthma affects millions of people worldwide, with a subgroup suffering from severe asthma (SA). Biologics have revolutionized SA treatment, but challenges remain in managing different patient traits. This study analyzed data from the Italian Registry on Severe Asthma (IRSA) to investigate changes in SA characteristics and effectiveness of treatments after one year of follow-up, and to identify factors associated with response to treatments in a real-world setting. Methods. Data on SA patients with one year of follow-up were extracted from IRSA. Asthma control, exacerbations, lung function, and treatments, were assessed at follow-up and analyzed against baseline characteristics. Results. After one year of follow-up, notable improvements were observed in all the outcomes of SA of the included patients (n = 570). The effectiveness of biologic therapies was particularly evident, as they contributed significantly to these positive outcomes. Additionally, certain factors were found to be associated with improvement, namely T2 phenotype, baseline eosinophil count (BEC), and area of residence. On the other hand, comorbidities (obesity, gastro-esophageal reflux disease) and poor lung function were risk factors. Notably, poor-responders to biologics exhibited lower level of education, BEC, and exacerbations, and higher frequency of atopy and ACT score ≥ 20. Conclusions. The findings demonstrate the effectiveness of biologics in asthma management, when implemented as part of a planned follow-up strategy aimed at optimizing and fine-tuning the therapy. Moreover, the study highlights the importance of considering key traits such as the T2 phenotype, BEC, education, and comorbidities when tailoring SA treatment. Overall, this study contributes to enhancing our understanding of SA management and guiding the development of personalized treatment approaches for patients with SA.

Taste and smell in aquatic and terrestrial environments.

Covering: up to 2017The review summarizes results up to 2017 on chemosensory cues occurring in both aquatic and terrestrial environments. The chemicals are grouped by their physicochemical properties to compare their potential mobility in the different media. In contrast to what is widely asserted in the literature, the report emphasizes that living organisms encounter and sense molecules of various degrees of solubility and volatility both on land and in aquatic environments. The picture that emerges from the review suggests a substantial revision of the traditional definitions of the chemical senses based on their spatial range, which is currently orienting the literature on chemosensory signaling, in favor of a new vision based on the natural products that are the actual mediators of the chemosensory perceptions. According to this perspective, natural product chemistry is a powerful tool with which to explore the evolutionary history of the chemical senses.

Non-invasive proportional assist and pressure support ventilation in patients with cystic fibrosis and chronic respiratory failure.

BACKGROUND: Patients with advanced cystic fibrosis can benefit from non-invasive positive pressure ventilation (NPPV) for the treatment of acute decompensation as well as for the management of chronic respiratory failure. This study was undertaken to compare the physiological effects of non-invasive proportional assist ventilation (PAV) and pressure support ventilation (PSV) on ventilatory pattern, transcutaneous blood gas tensions, and diaphragmatic effort in stable patients with cystic fibrosis and chronic CO2 retention. METHODS: In 12 patients two periods of spontaneous breathing were followed randomly by PSV (12 (3) cm H2O) and PAV (flow assist 4.9 (1.3) cm H2O/l.s, volume assist 18.9 (5.1) cm H2O/l) set for the patient's comfort and administered for 40 minutes with 2 cm H2O continuous positive airway pressure. Ventilatory pattern, transcutaneous blood gas tensions, and surface diaphragmatic electromyography were measured in the last 10 minutes of each application. RESULTS: On average, both PSV and PAV improved ventilation (+30%), tidal volume (+30%), and transcutaneous CO2 (-7%) while reducing diaphragmatic activity (-30% with PSV, -20% with PAV). Mean inspiratory airway pressure was lower during PAV than during PSV (9.7 (1.9) and 12.9 (2.7) cm H2O, respectively; p<0.05). The mean coefficient of variation of tidal volume was about 20% (range 11-39%) during spontaneous breathing and did not change with either PAV or PSV. CONCLUSIONS: These results show that short term administration of nasal PAV and PSV to patients with stable cystic fibrosis with chronic respiratory insufficiency is well tolerated, improves ventilation and blood gas tensions, and unloads the diaphragm.

Nasal proportional assist ventilation unloads the inspiratory muscles of stable patients with hypercapnia due to COPD.

This study was undertaken to assess the physiological effects of proportional assist ventilation (PAV), administered noninvasively through a nose mask, on ventilatory pattern, arterial blood gases, lung mechanics, and inspiratory muscle effort in stable, hypercapnic patients with chronic obstructive pulmonary disease. In 15 patients, PAV was set by adjusting volume assist (VA) and flow assist (FA) according to the "run-away" technique and the patient's comfort respectively. The level of support was fixed at 80% of the total possible assistance and averaged 13.9+/-4.1 cmH2O x L(-1) and 4.1+/-1.3 cmH2O x L(-1) x s for VA and FA, respectively. Continuous positive airway pressure (CPAP) was established at 2 cmH2O and then increased to 5 cmH2O. Physiological measurements were made during spontaneous breathing (SB), after more than 40 min of PAV, and 20 min after the rise in CPAP. On average, PAV improved ventilation (10.3+/-2.1 to 12.5+/-2.0 L x m(-1)), tidal volume (0.60+/-0.11 to 0.76+/-0.24 L), arterial oxygen tension and arterial carbon dioxide pressure (from 6.7+/-0.7 to 7.1+/-0.9 and from 7.6+/-1.0 to 7.2+/-1.2 kPa, respectively). During SB, pulmonary resistance and dynamic lung elastance averaged 15.0+/-7.6 cmH2O x L(-1) s and 15.8+/-8.0 cmH2O x L(-1), respectively. Assuming a normal chest wall elastance (5 cmH2O x L(-1)), VA and FA relieved respectively approximately 70% of the elastic and 30% of the resistive burden, with PAV set with the procedure of this study. The overall magnitude of the patients' inspiratory effort, measured by means of the oesophageal and diaphragmatic pressure time product in 10 patients was significantly reduced by PAV, on average, 328+/-122 to 226+/-118 (-31%) and 361+/-119 to 254+/-126 (-30%) cmH2O x min(-1), respectively. In 10 patients the electrical activity of the diaphragm (Edi) was also reduced by PAV to approximately 70%, on average, of the SB activity. The rise of CPAP 25 cmH2O did not cause any further significant change in the physiological variables. In all instances there was a good patient-ventilator interaction, the ventilatory breath never entering into the patient's neural expiratory time. These data show that nasal proportional assist ventilation can provide physiological benefits to the stable hypercapnic chronic obstructive pulmonary disease patients. In fact, proportional assist ventilation, which was well tolerated by all patients, unloaded the inspiratory muscles and improved arterial blood gases. Further studies can clarify whether these beneficial physiological effects of nasal proportional assist ventilation can bear profitable consequences in the overall clinical management of chronic obstructive pulmonary disease patients with chronic carbon dioxide retention.

On-line monitoring of intrinsic PEEP in ventilator-dependent patients.

Measurement of the intrinsic positive end-expiratory pressure (PEEP(i)) is important in planning the management of ventilated patients. Here, a new recursive least squares method for on-line monitoring of PEEP(i) is proposed for mechanically ventilated patients. The procedure is based on the first-order model of respiratory mechanics applied to experimental measurements obtained from eight ventilator-dependent patients ventilated with four different ventilatory modes. The model PEEP(i) (PEEP(i,mod)) was recursively constructed on an inspiration-by-inspiration basis. The results were compared with two well-established techniques to assess PEEP(i): end-expiratory occlusion to measure static PEEP(i) (PEEP(i, st)) and change in airway pressure preceding the onset of inspiratory airflow to measure dynamic PEEP(i) (PEEP(i,dyn)). PEEP(i, mod) was significantly correlated with both PEEP(i,dyn) (r = 0.77) and PEEP(i,st) (r = 0.90). PEEP(i,mod) (5.6 +/- 3.4 cmH(2)O) was systematically >PEEP(i,dyn) and PEEP(i,st) (2.7 +/- 1.9 and 8.1 +/- 5.5 cmH(2)O, respectively), in all the models without external PEEP. Focusing on the five patients with chronic obstructive pulmonary disease, PEEP(i,mod) was significantly correlated with PEEP(i,st) (r = 0.71), whereas PEEP(i,dyn) (r = 0.22) was not. When PEEP was set 5 cmH(2)O above PEEP(i,st), all the methods correctly estimated total PEEP, i.e., 11.8 +/- 5.3, 12.5 +/- 5.0, and 12.0 +/- 4.7 cmH(2)O for PEEP(i,mod), PEEP(i,st), and PEEP(i,dyn), respectively, and were highly correlated (0.97-0.99). We interpreted PEEP(i,mod) as the lower bound of PEEP(i,st) and concluded that our method is suitable for on-line monitoring of PEEP(i) in mechanically ventilated patients.

Effects of open heart surgery on respiratory mechanics.

OBJECTIVE: To investigate the changes in respiratory mechanics in patients undergoing cardiac surgery before and after the operation. DESIGN: Prospective physiological study. SETTING: Operating theatre of the Institute of Cardiac Surgery, Verona, Italy. PATIENTS: 8 patients needing heart surgery because of a coronary bypass or mitral valve replacement. MEASUREMENTS AND RESULTS: We measured respiratory mechanics before and immediately after the surgical procedure with two techniques: (1) the rapid airway occlusion technique during constant flow inflation at different lung volumes, and (2) the negative expiratory pressure (NEP) technique. We found that static and dynamic elastance (15.3 +/- 3.3 and 19.0 +/- 5.5 cmH(2)O/l, respectively) and respiratory resistance, both airway and total flow resistance (5.8 +/- 2.5 and 10.3 +/- 4 cmH(2)O. l(-1). s, respectively) before surgery were slightly higher than in normal anaesthetised subjects. In all patients, the static inflation V-P curves fitted the power function and exhibited a slight upward concavity towards the volume axis (a = 16.9 +/- 3.5, b = 0.74 +/- 0. 07), indicating that elastance decreased with inflating volume. Whereas elastance increased by 30 %, neither intrinsic positive end-expiratory pressure, which was small, averaging 1.5 +/- 1.2 cmH(2)O, nor flow resistance changed after surgery. With the NEP technique, four patients exhibited expiratory flow limitation during the tidal expiration, for about 67 % of the exhaled volume, without changes after surgery. Arterial carbon dioxide tension (32 +/- 4 mm Hg) and pH (7.46 +/- 0.07) did not change, whereas arterial oxygen tension (PaO(2)) (242 +/- 34 mm Hg) decreased significantly by about 70 mm Hg, on average, with a constant fractional inspired oxygen (0. 50). CONCLUSIONS: This study shows that (1) respiratory mechanics can be abnormal in patients undergoing cardiac surgery, including expiratory flow limitation; (2) elastance increases and PaO(2) decreases after surgery; (3) simple, noninvasive techniques are available to measure respiratory mechanics in the operating theatre.

Effect of inspiratory flow waveform on work on endotracheal tubes: a model analysis.

OBJECTIVE: This model analysis aimed to predict the impact of different inspiratory flow wave-forms, i. e., constant, sinusoidal, and two linearly decreasing flows, on the resistive work (Wres) performed on endotracheal tubes. DESIGN: Model analysis. RESULTS: Model analysis predicts that: (i) minimal Wres is obtained with the constant flow; (ii) for any given tidal volume/inspiratory duration (V(T)/T(I), mean inspiratory flow), Wres increases with decreasing tube size; (iii) for any given inspiratory flow waveform, Wres increases with increasing V(T)/T(I), being lowest with constant flow. CONCLUSIONS: These findings have major clinical implications: at any given ventilator setting, not only the size of the endotracheal tube but also the inspiratory flow waveform must be taken into account to interpret the values of Wres and hence of the total work of breathing.

Effect of inverse I:E ratio ventilation on pulmonary gas exchange in acute respiratory distress syndrome.

BACKGROUND: It is not known whether inverse I:E ratio ventilation (IRV) offers any real benefit over conventional mechanical ventilation with positive end-expiratory pressure (CMV-PEEP) at similar levels of end-expiratory pressure. METHODS: The effects of volume-controlled and pressure-controlled IRV (VC-IRV and PC-IRV, respectively) on VA/Q inequality were compared with those of CMV-PEEP at a similar level of end-expiratory pressure and with CMV without PEEP (CMV) in eight patients in the early stages of acute respiratory distress syndrome (ARDS). Respiratory blood gases, inert gases, lung mechanics, and hemodynamics were measured 30 min after the onset of each ventilatory mode. RESULTS: Recruitment of nonventilated, poorly ventilated (or both) but well-perfused alveoli increased the partial pressure of oxygen (PaO2) during CMV-PEEP (+13 mmHg) and IRV-VC (+10 mmHg; P < 0.05) compared with CMV. In contrast, PC-IRV did not affect PaO2 but caused a decrease in PaCO2 (-7 mmHg; P < 0.05). The latter was due to a concomitant decrease in dead space (P < 0.01) and shift to the right of VA/Q distributions. During PC-IRV, the increase in the mean of blood flow distribution (mean Q; P < 0.01) without a change in the dispersion (log SD Q) did not result in an increase in PaO2, probably because it reflected redistribution of blood flow within well-ventilated areas. CONCLUSIONS: Short-term PC-IRV improved carbon dioxide clearance, but the lung became less efficient as an oxygen exchanger. Furthermore, based on mean airway and plateau pressures, the risk of barotrauma was not reduced with this type of ventilation.

Pulmonary hyperinflation and ventilator-dependent patients.

Pulmonary hyperinflation is a major medical problem in patients with advanced chronic obstructive pulmonary disease (COPD) or acute asthma. The apparent beneficial effects of pulmonary hyperinflation on lung mechanics, such as an increased airway patency and lung elastic recoil, are by far overwhelmed by the deleterious effects on the pressure generating capacity of the respiratory muscles. Moreover, the ventilatory workload can be remarkably increased: 1) by the displacement of the respiratory system toward the upper, flat portion of the pressure-volume curve; 2) by the need to expand the chest wall and not only the lungs; and 3) by the intrinsic positive end-expiratory pressure (PEEPi) systematically associated with dynamic hyperinflation. In mechanically ventilated patients, the mechanisms underlying pulmonary hyperinflation as well as its pathophysiological consequences do not differ from those described in spontaneously breathing patients. However, there are some specific issues that should be taken into account, namely the effect of the endotracheal tube and the mode and setting of the ventilator. In mechanically ventilated patients, pulmonary hyperinflation increases the risk of barotrauma and may hamper weaning due to the excessive burden of PEEPi, which can even lead to ineffective inspiratory efforts. Because of its harmful consequences, pulmonary hyperinflation must be treated aggressively by pharmacological therapy and, when needed, by ventilatory treatment. The setting of the ventilator must be predetermined to ensure the longest possible time for expiration, and positive end-expiratory pressure can be applied to prevent an excessive workload for the patient and ineffective inspiratory efforts.

Effects of inspiratory flow waveforms on arterial blood gases and respiratory mechanics after open heart surgery.

The clinical usefulness of inspiratory flow pattern manipulation during mechanical ventilation remains unclear. The aim of this study was to investigate the effects of different inspiratory flow waveforms, i.e. constant, sinusoidal and decelerating, on arterial blood gases and respiratory mechanics, in mechanically ventilated patients. Eight patients recovering after open heart surgery for valvular replacement and/or coronary bypass were studied. The ventilator inspiratory flow waveform was changed according to a randomized sequence, keeping constant the other variables of the ventilator settings. We measured arterial blood gases, flow, volume and pressure at the proximal (airway opening pressure (Pao)) and distal (Ptr) ends of the endotracheal tubes before and after 30 min of mechanical ventilation with each inspiratory flow waveform. We computed breathing pattern, respiratory mechanics (pressures and dynamic elastance) and inspiratory work, which was then partitioned into its elastic and resistive components. We found that: 1) arterial oxygen tension (Pa,O2) and arterial carbon dioxide tension (Pa,CO2) were not affected by changes in the inspiratory flow waveform; and 2) peak Pao and Ptr were highest with sinusoidal inspiratory flow, whilst mean Pao and Ptr and total work of breathing were least with constant inspiratory flow, mainly because of a concomitant decrease in resistive work during constant flow inflation. The effects of the inspiratory flow profile on Pao, Ptr and total inspiratory work performed by the ventilator were mainly due to the resistive properties of the endotracheal tubes. We conclude that the ventilator inspiratory flow waveform can influence patients' respiratory mechanics, but has no impact on arterial oxygen and arterial carbon dioxide tension.

Short-term effects of nasal proportional assist ventilation in patients with chronic hypercapnic respiratory insufficiency.

Proportional assist ventilation (PAV) has recently been proposed as a mode of synchronized partial ventilatory support. This study evaluates the short-term effects of nasal PAV on arterial blood gases in stable patients with chronic hypercapnia. Forty two patients (30 with chronic obstructive pulmonary disease (COPD) and 12 with restrictive chest wall disease (RCWD) due to kyphoscoliosis) underwent a 1 h run of nasal PAV. Randomly, two levels of assistance were performed: 1) PAV was set at a level corresponding to volume assist (VA) and flow assist (FA) at 80% of the individual values of elastance (Ers) and resistance (Rrs) obtained with the "runaway" method; and 2) VA and FA were set at a value corresponding to the difference between the patients' individual Ers and Rrs and normal values of Ers and Rrs. Arterial blood gases and dyspnoea (by visual analogue scale (VAS)) were evaluated in all patients during unsupported ventilation and 60 min of PAV. PAV was well tolerated and resulted in significant improvement in arterial oxygen tension (Pa,O2), arterial carbon dioxide tension (Pa,CO2) (6.8+/-0.8 to 7.4+/-1.4 and 7.2/-0.9 to 6.8+/-0.9 kPa, respectively) and VAS (29+/-23 to 20+/-18%). The effects of PAV were not different in the two groups of diseases nor in the two groups of settings. Different settings of nasal proportional assist ventilation are well tolerated and may improve gas exchange and dyspnoea in patients with stable hypercapnic respiratory insufficiency.

Flow-triggering reduces inspiratory effort during weaning from mechanical ventilation.

OBJECTIVE: To investigate whether a new flow-triggered (FT) system can reduce the patient's inspiratory effort compared to a traditional pressure-triggered (PT) system during weaning from mechanical ventilation. DESIGN: Prospective study. SETTING: Intensive care unit of a General Hospital. PATIENTS AND PARTICIPANTS: 10 mechanically ventilated patients, without chronic airway disease, ready to wean. MEASUREMENTS: Minute ventilation, breathing pattern, lung mechanics, inspiratory work of breathing (WI) and pressure time product (PTP) of Ppl were obtained in two conditions: 1) unsupported spontaneous breathing through the ventilator circuit (SB); 2) spontaneous breathing with continuous positive airway pressure set at 5 cmH2O (CPAP). Two triggering systems, namely PT and FT, were used in each condition. RESULTS: Though there was no change in breathing pattern, minute ventilation, and lung mechanics, the magnitude of the inspiratory effort decreased significantly with FT compared to PT in both instances. The added resistance (total flow resistance minus pulmonary resistance) decreased by 37% on average when FT replaced PT. PTP decreased, on average, 27% and 15% during SB and CPAP, respectively, with FT compared to PT (p < 0.05). A similar significant decrease was observed in WI. CONCLUSION: The new FT system, i.e. flow-by system, reduces the unintentional ventilatory workload upon the patients' inspiratory muscles compared to traditional PT system during weaning from mechanical ventilation.

Determinants of maximal transdiaphragmatic pressure in adults with cystic fibrosis.

To investigate whether diaphragmatic strength could be reduced in cystic fibrosis (CF), and to examine possible mechanisms leading to diaphragmatic weakness, we measured transdiaphragmatic pressure (Pdi), together with lung mechanics, including dynamic "intrinsic" positive end-expiratory pressure (PEEPi,dyn), ventilation, lung volumes, and nutritional status in 15 adult patients with CF in stable clinical condition. Diaphragmatic strength was assessed as the maximum Pdi (Pdimax). Nutritional assessment included the calculation of weight as a percentage of ideal weight for height (Wt/Ht). On average, our 15 CF patients had airway obstruction (FEV1 = 59 +/- 28% predicted) and a small PEEPi,dyn (1 +/- 0.7 cm H2O). Functional residual capacity average 52 +/- 9% of the predicted total lung capacity. The Wt/Ht was normal on average (95%), but with a large range from malnutrition to a good nutritional status (76 to 109%). We found that Pdimax decreased with increasing FRC/TLC percent predicted (r = 0.55, p < 0.05), but more significantly with decreasing Wt/Ht (r = 0.76, p < 0.001). The multiple linear regression analysis for these factors was significant (R2 = 0.70, p < 0.05); however, the partial regression coefficient was significant only for Wt/Ht (p < 0.01). These results suggest that in CF patients, diaphragmatic strength decreases with the progression of the disease, increasing lung volume and worsening nutritional status, and that malnutrition is the strongest determinant of diaphragmatic weakness.

COPD patients and mechanical ventilation with positive end expiratory pressure (PEEP).

Application of positive and expiratory pressure (PEEP) is widely used in mechanically ventilated patients with acute respiratory failure (ARF) due to adult respiratory distress syndrome. Recent studies have suggested that application of PEEP can be useful in patients with chronic obstructive pulmonary disease (COPD) to reduce the mechanical inspiratory load due to intrinsic positive and expiratory pressure (PEEPi). In any ventilatory mode (controlled mechanical ventilation, assisted mechanical ventilation) and during weaning, application of moderate levels of PEEP replace in part PEEPi without adding to it and without significantly increasing lung volume.

Effects of intrinsic PEEP on pulmonary gas exchange in mechanically-ventilated patients.

The aim of the study was to assess the impact of the intrinsic positive end-expiratory pressure (PEEPi) on pulmonary gas exchange in mechanically-ventilated patients, by comparing the effects of similar levels (0.8-0.9 kPa) of positive end-expiratory pressure (PEEP) and PEEPi. Ten patients with acute respiratory failure, without chronic airway disease, were studied with three ventilatory modes: 1) intermittent positive pressure ventilation with zero end-expiratory pressure (ZEEP mode); 2) continuous positive pressure ventilation with PEEP set by the ventilator (PEEP mode); and 3) intrinsic PEEP elicited by adequate shortening of the expiratory time (PEEPi mode). Cardiorespiratory variables (e.g. respiratory compliance and resistance, arterial and mixed venous blood gases, cardiac output, pulmonary capillary pressure, oxygen delivery) were measured during each ventilatory mode. Compared to ZEEP, both PEEP and PEEPi decreased cardiac output while increasing arterial oxygen tension (PaO2). However, the improvement of PaO2 was more consistent (8 out of 10 patients), and larger (+2.1 kPa, on average, p < 0.05) with PEEP than with PEEPi (5 out of 10 patients, and +1.4 kPa, on average, NS). Since the effects of PEEP and PEEPi on ventilation, lung volume, compliance, cardiac output (QT), mixed venous oxygen tension (PvO2) and oxygen consumption (VO2) were similar, we attributed the less favourable impact of PEEPi on PaO2 to a less homogeneous distribution of PEEPi between lung units with different time constant, and hence to a more uneven distribution of the inspired gas.