Tracheostomy decannulation in severe acquired brain injury patients: The role of flexible bronchoscopy.

INTRODUCTION AND OBJECTIVES: Subjects with severe acquired brain injury (sABI) require long-term mechanical ventilation and, as a consequence, the tracheostomy tube stays in place for a long time. In this observational study, we investigated to what extent the identification of late tracheostomy complications by flexible bronchoscopy (FBS) might guide clinicians in the treatment of tracheal lesions throughout the weaning process and lead to successful decannulation. SUBJECTS AND METHODS: One hundred and ninety-four subjects with sABI admitted to our rehabilitation unit were enrolled in the study. All subjects received FBS and tracheal lesions were treated either by choosing a more suitable tracheostomy tube, or by laser therapy, or by steroid therapy, or by a combination of the above treatments. RESULTS: Overall, 122 subjects (63%) were decannulated successfully. Our subjects received 495 FBSs (2.55 per subject) and as many as 270 late tracheostomy complications were identified. At least one complication was found in 160 subjects (82%). In only 11 subjects, late tracheostomy complications did not respond to the treatment and were the cause of decannulation failure. CONCLUSIONS: In conclusion, in sABI patients FBS is able to guide successful tracheostomy weaning in the presence of late tracheostomy complications that could get in the way decannulation.

Breathing pattern and chest wall kinematics during phonation in chronic obstructive pulmonary disease patients.

BACKGROUND: Breathing pattern description and chest wall kinematics during phonation have not been studied in male and female patients with chronic obstructive pulmonary disease. OBJECTIVES: We used optoelectronic plethysmography to provide a quantitative description of breathing pattern and chest wall kinematics. METHODS: Volumes of chest wall compartments (rib cage and abdomen) were assessed in 15 patients while reading aloud (R), singing (SI) and during high-effort whispering (HW). RESULTS: Relative to quiet breathing, tidal volume and expiratory time increased while inspiratory time decreased. The expiratory flow decreased during R and SI, but was unchanged during HW. In males, the end-expiratory volume decreased as a result of a decreased volume of rib cage during R, SI and HW and due to a decreased volume of abdomen during HW. In females, a decrease in end-expiratory volume was accomplished by a decrease in abdominal volume during R and HW. During R, the chest wall end-expiratory volume of the last expiration in females was to the left of the maximal expiratory flow volume curve (MEFV), with still substantial expiratory reserve volume available. In contrast, during SI and HW in females and during all types of phonation in males, chest wall end-expiratory volume of the last expiration was well to the right of the MEFV curve and associated with respiratory discomfort. Gender had a greater importance than physical characteristics in determining more costal breathing in females than in males under all conditions studied. CONCLUSIONS: Phonation imposes more abdominal breathing pattern changes in males and costal changes in females. Expiratory flow encroaches upon the MEFV curve with higher phonatory efforts and respiratory discomfort.

Chest wall kinematics during cough in healthy subjects.

AIM: The study of kinematics of the chest wall (CW) could allow us to define the relative deflationary contribution of its compartments during fits of coughing. We hypothesized that if forces applied to the lung apposed rib cage are not commensurate with those applied to the abdomen-apposed rib cage, cough could result in rib cage distortion. METHODS: In 12 (five women) healthy subjects we evaluated the volumes of CW (Vcw) and its compartments: the lung apposed rib cage, the abdomen apposed rib cage and the abdomen, by optoelectronic plethysmography. The loop of volume of the lung apposed rib cage/volume of the abdomen apposed rib cage allowed the calculation of mean rib cage distortion, resulting in a dimensionless number which, when multiplied by 100, gives percentage distortion. Each subject performed voluntary single and prolonged coughing efforts at functional residual capacity (FRC) and after maximal inspiration (max). The normal level of mean distortion was set at <0.5%. RESULTS: The three compartments contributed to reducing end-expiratory Vcw during cough at FRC and prolonged maximum cough, with the latter resulting in the greatest CW deflation. Mean rib cage distortion did not differ between men and women (P > 0.1), but tended to significantly increase from single to prolonged Cough Max (1.3% +/- 1.0 vs. 2.3% +/- 1.6, respectively; P = 0.06). CONCLUSION: Rib cage distortion may ensue during coughing, probably as a result of uneven distribution of forces applied to the rib cage.

Chest wall kinematics, respiratory muscle action and dyspnoea during arm vs. leg exercise in humans.

AIM: We hypothesize that different patterns of chest wall (CW) kinematics and respiratory muscle coordination contribute to sensation of dyspnoea during unsupported arm exercise (UAE) and leg exercise (LE). METHODS: In six volunteer healthy subjects, we evaluated the volumes of chest wall (V(cw)) and its compartments, the pulmonary apposed rib cage (V(rc,p)), the diaphragm-abdomen apposed rib cage (V(rc,a)) and the abdomen (V(ab)), by optoelectronic plethysmography. Oesophageal, gastric and trans-diaphragmatic pressures were simultaneously measured. Chest wall relaxation line allowed the measure of peak rib cage inspiratory muscle, expiratory muscle and abdominal muscle pressures. The loop V(rc,p)/V(rc,a) allowed the calculation of rib cage distortion. Dyspnoea was assessed by a modified Borg scale. RESULTS: There were some differences and similarities between UAE and LE. Unlike LE with UAE: (i) V(cw) and V(rc,p) at end inspiration did not increase, whereas a decrease in V(rc,p) contributed to decreasing CW end expiratory volume; (ii) pressure production of inspiratory rib cage muscles did not significantly increase from quiet breathing. Not unlike LE, the diaphragm limited its inspiratory contribution to ventilation with UAE with no consistent difference in rib cage distortion between UAE and LE. Finally, changes in abdominal muscle pressure, and inspiratory rib cage muscle pressure predicted 62% and 41.4% of the variability in Borg score with UAE and LE, respectively (P < 0.01). CONCLUSION: Leg exercise and UAE are associated with different patterns of CW kinematics, respiratory muscle coordination, and production of dyspnoea.

Breathing pattern and kinematics in normal subjects during speech, singing and loud whispering.

AIMS: We used for the first time a non-invasive optoelectronic plethysmography to assess breathing movements and to provide a quantitative description of chest wall kinematics during phonation. METHODS: Volumes of different chest wall compartments (abdomen and lung apposed to rib cage and abdomen) were assessed using optoelectronic plethysmography in 16 normal Italians (eight men) during reading, singing and high-effort whispering (HW). RESULTS: During phonation the breathing pattern was different from quiet breathing and exercise. (1) During phonation, tidal volume and expiratory time increased while inspiratory time decreased. The expiratory volume changes and flows during HW were considerably greater than during vocalization. During HW, the overall end-expiratory thoracic volume significantly decreased as a result of decreased volume of all compartments and essentially impinged on the maximal expiratory flow-volume curve. (2) While, as previously shown, during exercise the expired volume is due entirely to the abdomen, during phonation all three chest wall compartments contribute to it. Under all conditions studied breathing was, on average, more costal in females than in males but this was mainly related to different size rather than gender per se. CONCLUSIONS: Physical characteristics have a greater importance than gender in determining breathing pattern and chest wall kinematics during phonation. The activity of the control of expiration during phonation is more complex than during exercise.

Inspiratory muscle workload due to dynamic intrinsic PEEP in stable COPD patients: effects of two different settings of non-invasive pressure-support ventilation.

BACKGROUND: In severe stable hypercapnic COPD patients the amount of pressure time product (PTP) spent to counterbalance their dynamic intrinsic positive end expiratory pressure (PEEPi,dyn) is high: no data are available on the best setting of non invasive pressure support ventilation (NPSV) to reduce the inspiratory muscle workload due to PEEPi,dyn. METHODS: The objectives of this randomised controlled physiological study were: 1. To measure the inspiratory muscle workload due to PEEPi,dyn 2. To measure the effects on this parameter of two settings of NPSV in stable COPD patients with chronic hypercapnia admitted in a Pulmonary Division of two Rehabilitation Centers. Twenty-three stable COPD patients with chronic hypercapnia on domiciliary nocturnal NPSV for 30 +/- 20 months were submitted to an evaluation of breathing pattern, PEEPi,dyn, inspiratory muscle workload and its partitioning during both assisted and unassisted ventilation. Two settings of NPSV were randomly applied for 30 minutes each: i- "at patient's comfort" (C): Inspiratory pressure support (IPS) was the maximal tolerated pressure able to reduce awake PaCO2 with the addition of a pre-set level of external PEEP (PEEPe); ii- "physiological setting" (PH): the level of IPS able to achieve a > 40% and < 90% decrease in transdiaphragmatic pressure in comparison to spontaneous breathing (SB). A PEEPe level able to reduce PEEPi,dyn by at least 50% was added. RESULTS: During SB the tidal diaphragmatic pressure-time product (PTPdi/b) was 17.62 +/- 7.22 cmH2O*sec, the component due to PEEPi,dyn (PTPdiPEEPi,dyn) being 38 +/- 17% (range: 16-65%). Compared to SB,PTPdiPEEPi,dyn was reduced significantly with both settings, the reduction being greater with PH compared to C. CONCLUSIONS: In conclusion in severe COPD patients with chronic hypercapnia the inspiratory muscle workload due to PEEPidyn is high and is reduced by NPSV at a greater extent when ventilator setting is tailored to patient's mechanics.

Chest wall kinematics and respiratory muscle action in ankylosing spondylitis patients.

No direct measurements of the pressures produced by the ribcage muscles, the diaphragm and the abdominal muscles during hyperventilation have been reported in patients with ankylosing spondylitis. Based on recent evidence indicating that abdominal muscles are important contributors to stimulation of ventilation, it was hypothesised that, in ankylosing spondylitis patients with limited ribcage expansion, a respiratory centre strategy to help the diaphragm function may involve coordinated action of this muscle with abdominal muscles. In order to validate this hypothesis, the chest wall response to a hypercapnic/hyperoxic rebreathing test was assessed in six ankylosing spondylitis patients and seven controls by combined analysis of: 1) chest wall kinematics, using optoelectronic plethysmography, this system is accurate in partitioning chest wall expansion into the contributions of the ribcage and the abdomen; and 2) respiratory muscle pressures, oesophageal, gastric and transdiaphragmatic (Pdi); the pressure/volume relaxation characteristics of both the ribcage and the abdomen allowed assessment of the peak pressure of both inspiratory and expiratory ribcage muscles, and of the abdominal muscles. During rebreathing, chest wall expansion increased to a similar extent in patients to that in controls; however, the abdominal component increased more and the ribcage component less in patients. Peak inspiratory ribcage, but not abdominal, muscle pressure was significantly lower in patients than in controls. End-inspiratory Pdi increased similarly in both groups, whereas inspiratory swings in Pdi increased significantly only in patients. No pressure or volume signals correlated with disease severity. The diaphragm and abdominal muscles help to expand the chest wall in ankylosing spondylitis patients, regardless of the severity of their disease. This finding supports the starting hypothesis that a coordinated response of respiratory muscle activity optimises the efficiency of the thoracoabdominal compartment in conditions of limited ribcage expansion.

Assessing respiratory drive and central motor pathway in humans: clinical implications.

Feedback from sensory elements as well as projection from higher Central Nervous System structures modify the level and pattern of motor outflow to the respiratory muscles and hence ventilation. In this review we describe the different methods to evaluate the degree to which higher centers determine the level and pattern of ventilation and coordinate use of the respiratory muscles in healthy humans and in patients with a number of respiratory disorders.

Chest wall kinematics and respiratory muscle coordinated action during hypercapnia in healthy males.

The present study was designed to verify whether during hypercapnic stimulation, as we had previously found during exercise or walking, the partitioning of the respiratory motor output is equally distributed to the muscles of chest wall compartments to assist diaphragm function. We studied chest wall kinematics and respiratory muscle recruitment in seven healthy men during rebreathing of a hypercapnic-hyperoxic gas mixture (CO(2) RT). Data were compared with those previously obtained during either cycling exercise or walking. The chest wall volume ( Vcw), assessed by optoelectronic plethysmography (OEP), was modeled as the sum of the volumes of the lung-apposed rib cage ( Vrc,p), diaphragm-apposed rib cage ( Vrc,a) and abdomen ( Vab). Esophageal ( Pes), gastric ( Pga) and transdiaphragmatic ( Pdi= Pga- Pes) pressures were simultaneously recorded. Velocity of shortening ( V') and power ( W'= Px V') of the diaphragm ( W'di), rib cage muscles ( W'rcm) and abdominal muscles ( W'abm) were also calculated. During CO(2) RT the progressive increase in end-inspiratory Vcw resulted from an increase in both end-inspiratory Vrc,p and Vrc,a, while the progressive decrease in end-expiratory Vcw was entirely due to the decrease in end-expiratory Vab. The increase in Vrc,p was proportionally slightly greater than that in Vrc,a. The end-inspiratory increase and end-expiratory decrease in Vcw were accounted for by inspiratory rib cage (RCM,i) and abdominal (ABM) muscle recruitment, respectively. W'di, W'rcm and W'abm progressively increased. However, while most of W'di was expressed in terms of velocity of shortening, most of W'rcm and W'abm was expressed as force or pressure. A comparison of CO(2) results with data obtained during exercise revealed: (1). a gradual vs. an immediate response, (2). a similar decrease in Vab,e and Pabm, (3). an apparent lack of any difference in ABM recruitment, (4). less gradual ABM relaxation, (5). no drop in Pdi but a similar Wdi change and decrease in pressure-to-velocity ratio of the diaphragm. We have found that in healthy humans: (1). the increased motor output with hypercapnia is equally distributed between RCM and ABM to minimize transdiaphragmatic pressure and (2). data on chest wall kinematics and respiratory muscle recruitment are only partly in line with those obtained during walking or cycling exercise.

Dyspnea, respiratory function and sputum profile in asthmatic patients during exacerbations.

Dyspnea is often used as a marker of asthma severity although a wide variation in dyspnea perception associated with bronchoconstriction (PB) has been described in asthmatic patients. Our hypothesis is that changes of airway inflammation, airway narrowing and hyperinflation may account for a part of the variability of breathlessness in spontaneous asthma attack. In asthmatic patients with exacerbation of the disease, we evaluated respiratory function, dyspnea (using visual Analogue Scale--VAS) and peak expiratory flow (PEF) values and variability (amplitude % mean), and sputum cellular and biochemical profile before (day I) and after (day II) therapy with i.v. corticosteroids and inhaled beta2-agonists, as appropriate. By day II, forced expiratory volume in 1 s (FEV1), inspiratory capacity (IC), PEF or VAS values and variability, sputum eosinophils and eosinophilic cationic protein (ECP) had improved. Improvement of dyspnea expressed as a decrease in VAS and reduction in variability of dyspnea sensation significantly correlated with increase in FEV1 %predicted value (%pv) (P=0.03; p=0.72 and P=0.02; p=0.74, respectively). No significant correlation was found between IC and VAS either in absolute values or as changes from days I and II, nor between sputum outcomes and PEF or VAS, regardless of how they were measured. We conclude that in acute asthmatic patients, dyspnea measurement, functional measurements and sputum analysis may be useful in monitoring disease activity, response to therapy and can provide different information on the state of the disease.

Chest wall kinematics during chemically stimulated breathing in healthy man.

Chest wall compartment kinematics and respiratory muscle coordinate activity, during either hypercapnia or hypoxia, have not been comparatively assessed in healthy humans. We assessed the displacement volume of the chest wall (Vcw) in 5 normal subjects during hypoxic-normocapnic and hypercapnic-hyperoxic rebreathing by using linearized magnetometers. Vcw was divided into displacement volumes of the rib cage (Vrc) and the abdomen (Vab). Esophageal (Pes) and gastric (Pga) pressures were simultaneously recorded and transdiaphragmatic pressure (Pdi) was calculated by subtracting Pes from Pga. Pressure swings (sw) from end expiration (EE) to end inspiration (EI) were also calculated. During both hypoxia and hypercapnia, from quiet breathing to 40 L/min VE, Vrc,EI increased consistently but Vrc,EE, and Vab,EI did not. Moreover, Vab,EE decreased significantly during hypercapnia and remained unchanged during hypoxia. PesEI decreased (more negative values) and PesEE increased (less negative values) during either stimulus, while PgaEE increased with hypercapnia. Pdisw, calculated as the difference between PdiEE and PdiEI, increased significantly with both hypercapnia and hypoxia ( p = 0.002 for both). On the plot of Pes vs Pga, the slope of a line from end expiratory to end inspiratory lung volume between 20 and 40 L/min VE progressively increased during hypercapnia indicating increasing rib cage muscle (RCM) contribution to inspiratory pressure swings relative to the diaphragm. From these results we conclude that in healthy man: (i) with both chemical stimuli RCM contribution accounts for increase in Vrc displacement; (ii) with hypercapnia, the decrease in Vab,EE displacement indicates abdominal muscle (ABM) contribution to tidal volume; (iii) RCM and ABM assist the diaphragmatic function during hypercapnic stimulation.

Perception of bronchoconstriction in smokers with airflow limitation.

To our knowledge, no data have been provided as to whether and to what extent dynamic hyperinflation, through its deleterious effect on inspiratory muscle function, affects the perception of dyspnoea during induced bronchoconstriction in patients with chronic airflow obstruction. We hypothesized that dynamic hyperinflation accounts in part for the variability in dyspnoea during acute bronchoconstriction. We therefore studied 39 consecutive clinically stable patients whose pulmonary function data were as follows (% of predicted value): vital capacity (VC), 97.8% (S.D. 16.0%); functional residual capacity, 105.0% (18.8%); actual forced expiratory volume in 1 s (FEV(1))/VC ratio, 56.1% (6.3%). Perception of dyspnoea using the Borg scale was assessed during a methacholine-induced fall in FEV(1). The clinical score and the treatment score, the level of bronchial hyper-responsiveness and the cytological sputum differential count were also assessed. In each patient, the percentage fall in FEV(1) and the concurrent Borg rating were linearly related, with the mean slope (PD slope) being 0.09 (0.06). The percentage fall in FEV(1) accounted for between 41% and 94% of the variation in the Borg score. At a 20% fall in FEV(1), the decrease in inspiratory capacity (Delta IC) was 0.156 (0.050) litres. Patients were divided into three subgroups according to the PD slope (arbitrary units/% fall in FEV(1)): subgroup I [eight hypoperceivers; PD slope 0.026 (0.005)], subgroup II [26 moderate perceivers; 0.090 (0.037)] and subgroup III [five hyperperceivers; 0.200 (0.044)]. By applying stepwise multiple regression analysis with the PD slope as the dependent variable, and other characteristics (demographic, clinical and functional characteristics, smoking history, level of bronchial hyper-responsiveness and sputum cytological profile) as independent variables, Delta IC (r(2)=45%, P<0.00001) and to a lesser extent treatment score (r(2)=17.3%, P<0.0006), and to an even lesser extent age (r(2)=3%, P<0.05), independently predicted a substantial amount (r(2)=65.27%, P<0.00001) of the variability in the Borg slope. Thus acute hyperinflation, and to a lesser extent treatment score and age, account in part for the variability in the perception of dyspnoea after accounting for changes in FEV(1) during bronchoconstriction in patients with chronic airflow obstruction.

Perception of dyspnea in patients with neuromuscular disease.

BACKGROUND: The perception of dyspnea is not a prominent complaint of resting patients with neuromuscular disease (NMD). To our knowledge, no study has been addressed at evaluating the interrelationships among lung mechanics, respiratory motor output, and the perception of dyspnea in patients with NMD receiving ventilatory stimulation. MATERIAL: Eleven patients with NMD (mean +/- SD age, 44 +/- 11.8 years; 5 men) of different etiology and a group of normal subjects matched for age and sex (control subjects). METHODS: While patients were breathing room air, lung volumes, arterial blood gases, the pattern of breathing (minute ventilation [E], tidal volume [VT], respiratory frequency, inspiratory time), and maximal (less negative) esophageal pressure during a sniff maneuver (Pessn), as an index of inspiratory muscle strength, were measured. Then we evaluated the response to hypercapnic-hyperoxic stimulation (hypercapnic-hyperoxic rebreathing test [RT]) in terms of breathing pattern, inspiratory swing of pleural pressure (Pessw), and inspiratory effort (Pessw[%Pessn]). During the RT, dyspnea was assessed every 30 s using a modified Borg scale (0 to 10). RESULTS: Pulmonary volumes were reduced in seven patients, and PCO(2) was out of proportion to E in four patients. Group Pessn was 42.8 +/- 23.6 cm H(2)O in patients and 107 +/- 20.4 cm H(2)O in control subjects (p < 0.001). Dynamic elastance (Eldyn) [p = 0.0016] and Pessw(%Pessn) [p < 0.0005] were higher in patients. During the RT, Borg/CO(2), Pessw(%Pessn)/CO(2), and Borg/Pessw(%Pessn) were similar in the two groups, while E/CO(2) and VT/CO(2) were lower in patients (p < 0.0002 for both). As a consequence, for unit change in VT (percentage of predicted vital capacity [%VC]), greater changes in Pessw(%Pessn) were associated with greater Borg scores in patients. Baseline Eldyn related to Pessw(%Pessn)/VT(%VC) during hypercapnia (r(2) = 0.85), an index of neuroventilatory coupling of the ventilatory pump (NVC). NVC predicted a good amount of the variability in Borg/E (r(2) = 0.46, p < 0.02). CONCLUSIONS: In this subset of NMD patients during hypercapnic stimulation, a normal inspiratory motor output per unit change in PCO(2) results in a shallow breathing pattern. The consequent impairment of NVC underlies the higher scoring of dyspnea in these patients.

Physiological response to pressure support ventilation delivered before and after extubation in patients not capable of totally spontaneous autonomous breathing.

We designed a prospective, physiological study in 12 patients affected by chronic respiratory disorders. The study was aimed at assessing the diaphragm energy expenditure (PTPdi), lung resistance (RL) and elastance (EL), arterial blood gases (ABG), breathing pattern, and dyspnea measured by a visual analog scale during invasive pressure support ventilation (i-PSV) and noninvasive PSV (n-PSV). The ventilator settings were kept the same. Both i-PSV and n-PSV significantly reduced the PTPdi per minute, compared with that during a T-piece trial (204.4 +/- 93.8 cm H(2)O x s/min [i-PSV]; 197.5 +/- 119.8 [n-PSV]; 393.8 +/- 129.0 [T-piece]). Expired tidal volume (VTe) was significantly higher (p < 0.05) during n-PSV (615 +/- 166 ml) than during i-PSV (519 +/- 140 ml). The respiratory pump (PTPdi/VTe) was more effective (p < 0.05) with noninvasive ventilation (22.3 +/- 2.3 cm H(2)O x s/L for i-PSV versus 17.2 +/- 3.3 for n-PSV). RL and EL were similar with the two modes of ventilation. Overall dyspnea was significantly (p < 0.05) better during n-PSV than i-PSV, whereas ABG were similar. We have shown, in patients affected by stable chronic respiratory disorders not ready to sustain totally spontaneous breathing, that i-PSV and n-PSV are equally effective in reducing the PTPdi and in improving ABG, but that n-PSV seems to be better tolerated.

The diaphragm and dyspnea during chemically stimulated breathing in a subset of patients with diabetes.

In patients with insulin-dependent diabetes mellitus (IDDM) isolated peripheral airway involvement may give rise to inspiratory threshold load (ITL) contributing to dyspnea. Based on the reported evidence of a greater increase in end-expiratory lung volume (EELV) with hypoxia than with hypercapnia in IDDM, we wondered whether, and to what extent in the two conditions, EELV contribute to perception of dyspnea (PD). We studied five nonsmokers aged between 19 and 45, with IDDM under good metabolic control and five normal control subjects matched for age. In each patient, we evaluated the electromyographic activity of the diaphragm (Edi), the swings of esophageal (Pessw), gastric (Pgsw), and transdiaphragmatic (Pdisw = Pgsw-Pessw) pressures; PD was assessed by a modified Borg scale during hypercapnic-hyperoxic (HCH) and hypoxic-isocapnic (HIC) stimulation. Change in inspiratory capacity (IC) was considered the mirror image of increase in EELV, that is, dynamic hyperinflation (DH), while intrinsic positive end inspiratory pressure (PEEPi) was measured as an index of inspiratory threshold load (ITL). In controls, Edi and Pdi but not their ratio (Edi/Pdi) related to Borg. In patients the following was found: (1) with each of the two stimuli, for any given Edi, Pdi, and Edi/Pdi ratio, there was greater Borg than in controls, (2) a similar increase in ITL and DH with HCH and HIC, (3) Edi/Pdi related to Borg similarly with HCH as with HIC. In conclusion, in controls, Edi and Pdi were associated with the perception of dyspnea similarly with the two chemical stimuli. In this subset of patients with IDDM, Edi/Pdi ratio throughout increase in EELV and ITL was found to affect the perception of dyspnea in hypoxia to a similar extent as in hypercapnia.

Perception of bronchoconstriction and bronchial hyper-responsiveness in asthma.

The inter-relationship between the perception of bronchoconstriction, bronchial hyper-responsiveness and temporal adaptation in asthma is still a matter of debate. In a total of 52 stable asthmatic patients, 32 without airway obstruction ¿forced expiratory volume in 1 s (FEV(1))/vital capacity (VC) 84.1% (S.D. 7.9%), and 20 with airway obstruction [FEV(1)/VC 60% (4%)], we assessed the perception of bronchoconstriction during methacholine inhalation by using: (i) the slope and intercept of the Borg and VAS (Visual Analog Scale) scores against the decrease in FEV(1), expressed as a percentage of the predicted value; and (ii) the Borg and VAS scores at a 20% decrease in FEV(1) from the lowest post-saline level (PB(20)). Bronchial hyper-responsiveness was assessed as the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)FEV(1)). The reduction in FEV(1) was significantly related to the Borg and VAS scores, with values for the group mean slope and intercept of this relationship of 0.13 (S.D. 0.08) and -1.1 (3.02) for Borg, and 1.5 (1.19) and -12.01 (35) for VAS. PB(20) was 3 (1.75) with Borg scores and 34.6 (20.5) with VAS scores. Compared with the subgroup without airway obstruction, the obstructed subgroup exhibited similar slopes, but lower Borg and VAS intercepts. For similar decreases in FEV(1) (5-20% decreases from the lowest post-saline values), the Borg and VAS scores were lower in the non-obstructed than in the obstructed subgroup. PC(20)FEV(1) was significantly related to both Borg PB(20) and VAS PB(20) when considering all patients. When assessing the subgroups, PC(20)FEV(1) was related to Borg PB(20) and VAS PB(20) in the non-obstructed subjects, but not in the obstructed subjects. In neither subgroup was the log of the cumulative dose related to the Borg and VAS scores at the end of the test. We conclude that, unlike in previous studies, the ability to perceive acute bronchoconstriction may be reduced as background airflow obstruction increases in asthma. Bronchial hyper-responsiveness did not play a major role in perceived breathlessness in patients without airway obstruction, and even less of a role in patients with obstruction. The cumulative dose of agonist did not appear to influence the perception of bronchoconstriction.

Mechanism of CO(2) retention in patients with neuromuscular disease.

BACKGROUND: In many studies of patients with muscle weakness, chronic hypercapnia has appeared to be out of proportion to the severity of muscle disease, indicating that factors other than muscle weakness are involved in CO(2) retention. In patients with COPD, the unbalanced inspiratory muscle loading-to-strength ratio is thought to trigger the signal for the integrated response that leads to rapid and shallow breathing and eventually to chronic hypercapnia. This mechanism, although postulated, has not yet been assessed in patients with muscular dystrophy. SUBJECTS: Twenty consecutive patients (mean age, 47.6 years; range, 23 to 67 years) were studied: 11 patients with limb-girdle dystrophy, 3 with Duchenne muscular dystrophy, 1 with Charcot-Marie-Tooth syndrome, 1 with Becker muscular dystrophy, 1 with myotonic dystrophy, 1 with facioscapulohumeral dystrophy, and 2 with amyotrophic lateral sclerosis, without any respiratory complaints. Seventeen normal subjects matched for age and sex were studied as a control group. METHODS: Routine spirometry and arterial blood gases, maximal inspiratory and expiratory muscle pressures (MIP and MEP, respectively), and pleural pressure during maximal sniff test (Pplsn), were measured. Mechanical characteristics of the lung were assessed by evaluating lung resistance (RL) and dynamic elastance (Eldyn). Eldyn was assessed as absolute value and as percent of Pplsn; Eldyn (%Pplsn) indicates the elastic load per unit of inspiratory muscle force. Breathing pattern was assessed in terms of time (inspiratory time [TI]; respiratory frequency [Rf]) and volume (tidal volume [VT]) components of the respiratory cycle. RESULTS: A rapid shallow breathing pattern, as indicated by a greater Rf/VT ratio and a lower TI, was found in study patients compared to control subjects. Eldyn was greater in study patients, while MIP, MEP, and Pplsn were lower. PaCO(2) inversely related to VT, TI, and Pplsn (p = 0.012, p = 0.019, and p = 0.002, respectively), whereas it was directly related to Rf, Rf/VT, Eldyn, and Eldyn (%Pplsn) (p < 0.004 to p < 0.0001). Also Eldyn (%Pplsn) inversely related to TI, and the latter positively related to VT. In other words, increase in Eldyn (%Pplsn) was associated with decrease in TI, and the latter was associated with lower VT and greater PaCO(2). Mechanical and breathing pattern variables were introduced in a stepwise multiple regression that selected Eldyn (%Pplsn) (p < 0.0001; r(2) = 0.62) as a unique independent predictor of PaCO(2). CONCLUSIONS: The present study shows that in patients with neuromuscular disease, elastic load and respiratory muscle weakness are responsible for a rapid and shallow breathing pattern leading to chronic CO(2) retention.

Sexual hybridization of Lycopersicon esculentum and Solanum rickii by means of a sesquidiploid bridging hybrid.

A sesquidiploid hybrid having two genomes of Lycopersicon esculentum and one of Solanum lycopersicoides served as a pistillate bridging parent in crosses with Solanum rickii to produce L. esculentum x S. rickii hybrid progeny. Of the four progeny obtained, one (GH2754) was diploid and three were aneuploid with extra S. lycopersicoides chromosomes. The hybrids had morphological features of both parents, but attributes of the wild parent dominated. The hybrid nature of the four progeny was confirmed by isozyme, restriction fragment length polymorphism, and cytological analyses. A mean of 9.15 bivalents was observed in pollen mother cells of GH2754. A high level of pollen abortion was seen in all hybrids. Crosses of the hybrids with staminate S. rickii yielded one backcross individual, revealing a very low, but certain level of female fertility. Colchicine treatment of GH2754 generated one promising amphidiploid hybrid, which exhibited strong preferential chromosome pairing (94% of the examined cells had 24 bivalents) and appreciable pollen fertility (43% stainable). Chromosome pairing, isozyme, and restriction fragment length polymorphism data support a very close relationship between the two Solanum spp. and a much greater distance between them and L. esculentum, but the data do not discriminate between them in respect to their distances from the latter. The cytological and molecular observations, previous reports of successful transfer of traits from S. lycopersicoides to L. esculentum, and our hybridization of L. esculentum x S. rickii suggest good prospects for gene transfer from S. rickii to L. esculentum.

Fine mapping of quantitative trait loci using selected overlapping recombinant chromosomes, in an interspecies cross of tomato.

Quantitative trait loci (QTLs) have been mapped to small intervals along the chromosomes of tomato (Lycopersicon esculentum), by a method we call substitution mapping. The size of the interval to which a QTL can be mapped is determined primarily by the number and spacing of previously mapped genetic markers in the region surrounding the QTL. We demonstrate the method using tomato genotypes carrying chromosomal segments from Lycopersicon chmielewskii, a wild relative of tomato with high soluble solids concentration but small fruit and low yield. Different L. chmielewskii chromosomal segments carrying a common restriction fragment length polymorphism were identified, and their regions of overlap determined using all available genetic markers. The effect of these chromosomal segments on soluble solids concentration, fruit mass, yield, and pH, was determined in the field. Many overlapping chromosomal segments had very different phenotypic effects, indicating QTLs affecting the phenotype(s) to lie in intervals of as little as 3 cM by which the segments differed. Some associations between different traits were attributed to close linkage between two or more QTLs, rather than pleiotropic effects of a single QTL: in such cases, recombination should separate desirable QTLs from genes with undesirable effects. The prominence of such trait associations in wide crosses appears partly due to infrequent reciprocal recombination between heterozygous chromosomal segments flanked by homozygous regions. Substitution mapping is particularly applicable to gene introgression from wild to domestic species, and generally useful in narrowing the gap between linkage mapping and physical mapping of QTLs.