Early ventilation-heart rate breakpoint during incremental cycling exercise.

Previous observations having reported a transient hypoxia at the onset of incremental exercise, we investigated the existence of concomitant ventilatory and heart rate (HR) breakpoints.33 subjects executed a maximal cycling exercise with averaging for successive 5-s periods of HR, ventilation, tidal volume (VT), mean inspiratory flow rate (VT/Ti), and end-tidal partial pressures of O2 (PETO2) and CO2. In 10 subjects, the transcutaneous partial pressure of O2 (PtcO2) was recorded and the venous blood lactic acid (LA) concentration measured.At the beginning of exercise, PETO2 decreased, reaching a nadir, then progressively increased until the exercise ended. PtcO2 varied in parallel. Whether or not a 0-W cycling period preceded the incremental exercise, the rate of changes in VE, VT, VT/Ti and HR significantly increased when the nadir PO2 was reached. The ventilatory/ HR breakpoint was measured at 33±4% of VO2max, whereas the ventilatory threshold (VTh) was detected at 67±4% of VO2max and LA began to increase at 45 to 50% of VO2max.During incremental cycling exercise, we identified the existence of HR and ventilatory breakpoints in advance of both lactate and ventilatory thresholds which coincided with modest hypoxia and hypercapnia.

Evaluation of visual recognition memory for the early diagnosis of Alzheimer's disease in patients over 75 years.

INTRODUCTION: Current diagnostic criteria of Alzheimer Disease (AD) are mainly based on clinical definition. In France, the Delayed Matching Sample (DMS48) test, a recently introduced test that explores visual object recognition, is recommended for the early diagnosis of AD. However, little is known on the DMS48 performances of older subjects over 75 years. Therefore, our aim was to assess its specific clinical value for early detection of AD in older patients. METHOD: We studied 93 consecutive patients over 75 years from an expert memory clinic in a geriatric hospital. This population included 31 patients with single domain amnestic Mild Cognitive Impairment (aMCI), 31 AD patients and 31 controls subjects. RESULTS AND DISCUSSION: The aMCI and AD performances on the DMS48 were significantly lower than those of the control subjects (set 1 and set 2, P<10(-7)). The DMS48 performances in the healthy group appeared closely related to the previously published normative data. However, the DMS48 performances appeared unexpectedly high in these older patients, especially in the AD subgroup (set 1, 82.2±12.1 and set 2, 75.2±16.2). Moreover, there was an unexpected frequent discordance between the results on the DMS48 and the Free and Cued Selective Reminding tests (FCSR). The DMS test appears useful for highlighting the heterogeneity of the syndromes of aMCI and AD in old-old people aged 75+: our results also underline the need for further characterization of cognitive impairment in this fastest growing subgroup of patients.

Pulmonary function changes 100 days and one year after bone marrow transplantation.

The pulmonary function of patients receiving autologous or allogeneic bone marrow transplantation (BMT) was studied before, 100 days after and 1 year after BMT. The 117 patients studied before transplantation showed a slight reduction in average total lung capacity (TLC) and transfer coefficient (KCO). These reductions were related to haematological disease, previous pulmonary disease or irradiation, or use of toxic lung chemotherapy. Studies 100 days after BMT showed TLC and KCO decreases of 5% and 8%, respectively. These decreases were related to different factors in autologous and allogeneic BMT. The results were influenced by previous pulmonary status in autologous BMT patients and the occurrence of GVHD in allogeneic BMT patients. Seventy patients underwent pulmonary function testing 1 year after BMT. The decrease in TLC values was greater in autologous BMT than in allogeneic BMT patients (107 +/- 3% to 100 +/- 3% versus 113 +/- 3% to 112 +/- 2%, respectively) although TLC remained normal in both groups. KCO values dropped significantly in both populations. Relapse of the initial disease was an important factor impairing lung function in the autologous group. TLC and KCO changes were strongly related to mortality in both groups. These results emphasise the need for frequent pulmonary function tests after BMT to detect and quantify lung function changes.

Cholinergic responsiveness of respiratory and vascular tissues in two different rat strains.

The airway and systemic arterial smooth muscle responsiveness to cholinergic agents of two strains of rats, Rat Albino (RA) and Brown Norway (BN), was compared in vivo and in vitro. In vivo, we measured the doses of carbachol that induced a 100% increase in lung resistance (PD100 RL), a 50% decrease in dynamic lung compliance (PD50 Cdyn), and the value of systolic blood pressure at the carbachol dose of 10 micrograms (Pa 10 micrograms). In vitro airway smooth muscle and systemic arterial smooth muscle responsiveness was assessed by measuring the maximal response to acetylcholine, the slope of the linear portion of the dose-response curve, and the negative logarithm of the molar concentration of acetylcholine producing 50% of the maximal response (pD2). PD100 and PD50 were about four times greater in BN rats than in RA rats. In contrast, Pa 10 micrograms was 1.5 lower in the BN rats. These differences persisted after bivagotomy. Tracheal pD2 was 25% greater in the RA than in the BN strain. The mean dose-response curve of parenchymal strips of RA rats was situated upward and to the left of the BN curve, but the reverse was observed for aortic smooth muscle dose-response curves. Thus 1) airway smooth muscle responsiveness to cholinergic agents is greater in RA strain than in BN, but the reverse is true for systemic arterial smooth muscle responsiveness; and 2) these differences are not due to factors extrinsic to the smooth muscle, since they occurred in vitro and may depend on different densities of muscarinic receptors.

Role of vagal and spinal sensory pathways on eupneic diaphragmatic activity.

The interactions between vagal and spinal afferents in the control of eupneic diaphragmatic activity were studied in two groups of cats anesthetized either with pentobarbital sodium (SPB) or with ethyl carbamate-alpha-chloralose (ECC), which enhanced spinal reflexes. Under both conditions of anesthesia two experimental protocols were performed: 1) bilateral cervical vagotomy followed by spinal section at C8 level or 2) spinal section followed by vagotomy. Changes in integrated diaphragmatic activity (Edi) were studied during eupneic ventilation and tracheal occlusion at end expiration. Vagotomy always significantly increased the amplitude of Edi during eupnea (SPB + 30%; ECC + 15%) and prolonged its duration (Tdi) (SPB + 110%; ECC + 75%) but did not modify the overall shape of the Edi vs. time relationship. Spinal section induced reverse changes in the amplitude of Edi, whether vagal afferents were present or suppressed and modified the shape of the Edi wave, but did not significantly modify Tdi. These results indicate that both vagal and spinal afferents may participate in the control of eupneic inspiration but exert different and interdependent influences on the recruitment and firing time of phrenic motoneurons. In addition, Tdi measured during tracheal occlusion (Todi) was markedly prolonged under ECC anesthesia. In this situation spinal section reduced Todi, which became close to the values obtained in intact or spinal cats under SPB anesthesia. Thus the response to tracheal occlusion at end expiration cannot be interpreted as resulting from the sole suppression of volume related vagal information.

Phrenic afferents and their role in inspiratory control.

In anesthetized cats, with vagi cut and the spinal cord severed at the C8 level, phrenic motor and/or sensory discharge was recorded. Small afferent phrenic fibers were identified through their activation by lactic acid, hyperosmotic NaCl solution, or phenyl diguanide. They exhibited a spontaneous but irregular low-frequency discharge. Block of their conduction by procaine had no effect on eupneic motor phrenic activity. Large afferent phrenic fibers showed a spontaneous rhythmic discharge, and cold block (6 degrees C) of these fibers significantly prolonged the phrenic discharge time (Tphr) and total breath duration (TT) during eupnea. The stimulation of all afferent phrenic fibers lowered the impulse frequency of phrenic motoneurons (f impulses) and shortened both Tphr and TT. When the stimulation was performed during cold block all of the effects on phrenic output persisted, but changes in timing were less pronounced. Under procaine block, only the effects of phrenic nerve stimulation on Tphr persisted. These results suggest that both large and small afferent phrenic fibers control the inspiratory activity with a prominent role of small fibers on phrenic motoneuron impulse frequency.

GABA(B) receptor blockade reduces resistive loading-induced hypoventilation in anesthetized rabbits.

We hypothesized that hypoventilation induced by resistive loaded breathing may result in part from the inhibition of central respiratory-related structures by gamma-aminobutyric acid (GABA), through the stimulation of GABA(B) receptors. In that case, ventilatory depression should be minimized by GABA(B) receptor blockade. To test this assumption, the ventilatory effects of a GABA(B) receptor antagonist (CGP 35348) were evaluated in two groups of urethane anesthetized rabbits, breathing either through an inspiratory resistive load (IRL group) or not (Control group). CGP 35348 did not modify baseline ventilation in the Control group. On the other hand, it partially reversed IRL-induced hypoventilation through a higher respiratory rate and central inspiratory drive. These data suggest that, unlike GABA(A) receptors, GABA(B) receptors would not play a part in eupneic breathing, but that they could participate in the hypoventilation resulting from an acute increase in the work of breathing.

Resistive loading reduces ventilatory response to strychnine in anesthetized rabbits.

Breathing through an inspiratory resistance induces a hypoventilation in mammals despite an increased diaphragmatic activity. We showed in previous works that an increase in GABA and endogenous opioid release in the central respiratory network could explain in part the inadequate increase in the inspiratory drive during inspiratory loading. In the present experiment, we speculated about an additional role of glycine, another inhibitory neurotransmitter. The ventilatory effects of the glycine antagonist strychnine were evaluated in two groups of anesthetized rabbits, breathing either through an inspiratory resistive load (IRL) or not (control group). In the control group, strychnine raised (+7%, P < 0.05) the minute ventilation, V, and the rate of increase in integrated diaphragmatic discharge (Edi peak/T peak: +29%, P < 0.01). In the IRL group, strychnine did not change V and produced a lesser increase in Edi peak/T peak (+9%, P < 0.05). In both groups, strychnine induced a tonic diaphragmatic discharge. These data show that there is a weak inhibition of inspiration by glycine during resistive loading, but the effect is modest compared with that observed during unloaded ventilation. Thus, it seems that IRL breathing reduces the efficacy and/or the release of this neurotransmitter in the central nervous system, in this experimental situation.

Effects of serotonin receptor blockade by methysergide on loaded breathing in the rabbit.

Previous works demonstrated that the excitatory role of serotonin (5-hydroxytryptamine, 5-HT) on ventilation is mediated by 5-HT1,2 receptors stimulation. We hypothesized that load-induced hypoventilation could be minimized by a central release of 5-HT. Conversely, blockade of 5-HT receptors should accentuate hypoventilation. We compared the ventilatory effects of methysergide (MS), a 5-HT1,2 receptors antagonist, in 3 groups of anesthetized, spontaneously breathing rabbits: (1) a group of animals breathing for 60 min through a 370 cm H2O.liter-1.s inspiratory resistive load (IRL group), whose paCO2 increased with IRL; (2) a Control group; (3) a Control + CO2 group, made hypercapnic to assess the possible effect of this stimulus on the ventilatory responses to MS. In the 3 groups, i.v. injection of MS induced the same ventilatory changes, characterized by a rapid shallow breathing with a shorter integrated diaphragmatic activity. This confirms the tonic facilitatory effect of 5-HT on ventilation and suggests that IRL would not increase 5-HT release in the sites close to the respiratory nuclei.

Cardiorespiratory response to bicuculline during resistive loaded breathing in anesthetized rabbits.

We hypothesized that hypoventilation induced by resistive loaded breathing may result in part from an increase in gamma-aminobutyric acid (GABA) concentration in the central nervous system. Accordingly, ventilatory depression should be minimized by GABA receptor blockade. The effects of subseizure doses of the GABAA receptor antagonist bicuculline on the cardiorespiratory variables and cortical activities were evaluated in two groups of urethane anesthetized rabbits, breathing either through an inspiratory resistive load (IRL) or not. Bicuculline induced cardiorespiratory changes which consisted mainly of an augmented respiratory rate, through shortening of expiratory duration, and of bradycardia. Bicuculline effects did not significantly differ between both groups and were accompanied by high amplitude delta rhythmic cortical activities. These data show that GABAA receptors may exert a tonic depressive effect on the respiratory circuit and suggest that endogenous GABA release is not augmented by an acute increase in the work of breathing.

Role of vagal afferents in the ventilatory response to naloxone during loaded breathing in the rabbit.

It was previously shown that inspiratory resistive loading (IRL) increases the cerebrospinal fluid (CSF) level of beta endorphin in awake goats, and also that the slower ventilation induced by injection of this substance into the CSF of anesthetized dogs is suppressed after vagotomy. In the present study, performed on anesthetized rabbits, we evaluated the part played by vagal afferents in the ventilatory response to IRL after opioid receptor blockade by naloxone. During unloaded breathing, naloxone injection did not modify baseline ventilation. Conversely, naloxone partially reversed IRL-induced hypoventilation through an increase in respiratory rate. This effect was abolished after either vagotomy or cold blockade of large vagal fibers, but it persisted after procaine blockade of thin vagal fibers. These results suggest that pulmonary stretch receptors, which are connected to some large vagal afferent fibers, would play a major role in the ventilatory response to IRL under opioid receptor inhibition.

The effects of ischemia, lactic acid and hypertonic sodium chloride on phrenic afferent discharge during spontaneous diaphragmatic contraction.

In 9 sodium pentobarbital anaesthetized cats, 50 single-unit phrenic afferent recordings were determined during spontaneous ventilation, retrograde carotid arterial injection of lactic acid (LA, 0.1 N) and NaCl (5%), and a 2-min occlusion of the superior thoracic aorta. Fifty percent of the units had tonic low-frequency spontaneous discharge; 50% had phasic high-frequency discharge. Tonic fiber activity increased significantly with LA, NaCl and occlusion, while phasic fiber activity decreased in all 3 conditions. These results suggest that the diaphragm contains sensory endings sensitive to ischemia and extracellular metabolic changes.

Exercise-induced inflammatory reaction affects electromyographic changes in skeletal muscle during dynamic contractions in humans.

In order to assess the role of exercise-induced inflammatory reactions on electromyographic (EMG) changes in humans, we have recorded, during a 3-min dynamic handgrip exercise at a high strength (112 w), the surface EMG and the compound evoked muscle action potential (M-wave) in control conditions, and this after ingestion of a well known cyclooxygenase blocker i.e. acetylsalicylic acid (ASA), either as a single dose treatment (10 mg/kg) and as a 3-day treatment (30 mg/kg per day). The power spectrum density function of EMG allowed us to compute both the median frequency (MF) and the energies in a low- and a high-frequency band. We estimated the lactic acid concentration from blood samples drawn from an antecubital vein and we noted that its production was not affected by ASA (single dose or 3-day treatment). We observed at the end of exercise that no change in M-wave duration and conduction time occurred though the median frequency always fell. However, we noted that the slope of the MF vs. time regression line was halved after the 3-day ASA treatment which may indicate that inflammatory reactions are elicited by exhausting contractions and affect the EMG changes.

Impairment of muscle energy metabolism in patients with sleep apnoea syndrome.

Impairment of muscle energy metabolism has been demonstrated in normal subjects with chronic hypoxaemia (altitude chronic respiratory failure). The purpose of this study was to verify the hypothesis that a comparable condition could develop in patients with sleep apnoea syndrome (SAS), considering that they are exposed to prolonged and repeated hypoxaemia periods. Muscle metabolism was assessed in 11 patients with SAS performing a maximal effort on cycloergometer. In comparison with normal subjects, SAS patients reached lower maximal loads [144 +/- 7 vs. 182 +/- 10 W (P < 0.005)] and lower peak oxygen uptakes [26.4 +/- 1.2 vs 33.2 +/- 1.4 ml kg-1 min-1 (P < 0.005)]. Abnormal metabolic features were found: maximal blood lactate concentration was significantly lower than in normal subjects [0.034 +/- 0.004 vs. 0.044 +/- 0.002 mmol l-1 W-1 (P < 0.05)]; and lactate elimination rate, calculated during a 30-min recovery period, was reduced [0.127 +/- 0.017 vs, 0.175 +/- 0.014 mmol l-1 min-1 (P < 0.025)]. The extent of these anomalies correlated with the severity of SAS. The patients also showed higher maximal diastolic blood pressures than normal subjects [104 +/- 5 vs. 92 +/- 4 mmHg (P < 0.05)]. These results can be interpreted as indications of an impairment of muscle energy metabolism in patients with SAS. Decrease in maximum blood lactate concentration suggests an impairment of glycolytic metabolism, while decrease in the rate of lactate elimination indicates a defect in oxidative metabolism. Since no respiratory pathology apart from SAS was found in this group of patients, it seems legitimate to link the genesis of these impairments to repeated bouts of nocturnal hypoxaemia.

Blood ammonia and ventilation at maximal exercise.

This study, intended to evaluate the role of ammonia (NH3) as a ventilatory stimulus, was conducted in three groups of subjects: 14 sedentary individuals, 12 triathletes, 5 patients with a glycolytic deficiency (Mc Ardle disease). All subjects performed maximal exercise tests on a cycle ergometer. Ventilation measured at maximal oxygen consumption (VE 100%) was correlated with lactatemia (lactate 100%) and ammonemia (NH3 100%) in the sedentary group, but only with ammonemia in triathletes, although NH3 100% and lactate 100% were correlated in both groups, which suggests that correlation between VE 100% and NH3 100% is not a false correlation. In patients with Mc Ardle disease, unable to produce lactate during exercise, VE 100% was correlated with NH3 100%. NH3 may act indirectly by increasing the production of lactate in cereberal tissue. Another hypothesis rests on the fact that the catabolism of ammonia leads to an increase in intracerebral glutamate which may act as a ventilatory stimulus.

Long-term exposure of adults to outdoor air pollution is associated with increased airway obstruction and higher prevalence of bronchial hyperresponsiveness.

The authors studied the association between long-term exposure (i.e., > 10 y) to outdoor air pollution and the severity of obstructive pulmonary disease and prevalence of bronchial hyperreactivity to beta2 agonists in two groups of adult patients who were of similar ages and who had similar smoking habits. The subjects lived in downtown districts or in the outer suburbs of Marseilles, the neighborhood that contained air samplers. The regions were similar with respect to sulfur dioxide levels, but levels of nitric oxides and particulate matter (10 millimeters or less) were higher in the downtown area than the suburbs. The authors assessed airway obstruction, as determined by a decrease in forced expiratory volume in 1 s, mean forced expiratory flow measured between 25% and 75% of vital capacity, and an elevated value of central airway resistance. The authors tested the changes in these variables induced by inhalation of a beta2 agonist. Baseline lung function was altered more significantly in both male and female patients who lived in downtown Marseilles than in those who resided in the suburbs, and the differences persisted regardless of the season during which the study occurred. Prevalence of bronchial hyperreactivity and symptoms of asthma (but not of rhinitis) were higher in the downtown than suburban male subjects. The results of this study suggest that an association exists between actual environmental exposure to outdoor air pollution (i.e., nitrogen oxides and/or particulate matter of 10 millimeters or less) and respiratory effects in sensitive adults represented by patients with chronic obstructive pulmonary disease or asthma.

[Bronchial provocation tests. Comparison of 2 inhalation methods]. / Tests de provocation bronchique. Comparaison de deux méthodes d'inhalation.

This study was performed to compare two methods of aerosols delivery and inhalation in a bronchial provocation test with carbachol : the stocked method (S) where the aerosol is previously stocked in a spirometer bell before inhalation and the dosimeter method (D) where the aerosol is directly inhaled after nebulization. Fourteen subjects (seven normal and seven asthmatic) underwent bronchial challenges with the two techniques. Bronchial sensitivity was calculated on SRaw-dose response curves to carbachol. SGaw-dose response curves were also constructed and the slopes of these curves were used to measure bronchial reactivity. Within subjects sensitivity values were lower with the D method than with the S method (40 +/- 5 micrograms (S E) versus 450 +/- 50 micrograms respectively in asthmatics, 340 +/- 30 micrograms versus 2350 +/- 130 micrograms respectively in healthy subjects). Reactivity values were higher with the dosimeter method (2,7 +/- 0,7 x 10(-5) versus 27 +/- 4 x 10(-5) in healthy and 10 +/- 1 x 10(-5) versus 106 +/- 16 x 10(-5) in asthmatics). The dosimeter method had greater efficacy, was less time consuming and appeared to be a useful method for carrying out standardised non-specific bronchoprovocation test.

[Experimental study of the pleural effects of the pulverization, under thoracoscopic control, of a fibrin glue (Tissucol)]. / Etude expérimentale des effets pleuraux de la pulvérisation, sous contrôle thoracoscopique, d'une colle de fibrine (Tissucol).

The instillation of a fibrin sealant (Tissucol) has been proposed in the treatment of recurrent spontaneous pneumothorax. The present work is devoted to an experimental study in the dog of the effects of this substance on the pleural cavity one and two weeks after instillation under thoracoscopic control. Its action is compared to that of placebo (methylene blue). The instillation of a placebo (n = 5) did not alter the ventilatory mechanics or the structure of the pleura. On the other hand Tissucol (n = 6) led to a fall in the thoraco-pulmonary compliance (-14%), corresponding to that of the vital capacity (-10%). In these animals, no pleural symphysis was noted, but the histological analysis gave evidence of changes in the layers of the parietal and visceral pleura: an inflammatory mononuclear reaction (71% of cases) and/or polymorphonuclear (54%), recent fibrosis (67%) and more rarely a mesothelial hyperplasia (21%). The maintenance of the integrity of the mesothelial cellular layer would explain the absence of pleural symphysis after instillation of Tissucol. These results as well as those recently obtained in the human situation prompt us to advise other methods of pleural symphysis which have been tried and tested, such as talcage or surgery.

[The contribution of effort tests in the evaluation of factors related to dyspnea in pneumonology]. / Apport de l'épreuve d'effort dans l'appréciation des facteurs de la dyspnée en pneumologie.

Forty nine patients suffering from respiratory disorders underwent an exercise test carried out on a bicycle ergometer (n = 45) or by walking rapidly on flat or inclined ground (n = 4). The respiratory restrictions on effort were correlated with a degree of dyspnoea (stages 1 to 4) established by a questionnaire. The analysis of the effort test had consequences of practical importance: in effect, in this study, nearly half the patients benefited from advice orientated in particular towards the level of activity which would be suitable for them, and to reduction in their weight.

Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.

In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.