Biomedical subjects
Publications and source records attributed to M Aubier.
Respiratory muscle failure may be due to excessive respiratory load, electrolyte disturbances, acidosis and loss of muscle mass or failure. Acidosis and electrolyte disorders need recognition and correction. Pharmacotherapy with theophylline, sympathomimetic amines and perhaps digitalis have potential for improving respiratory muscle performance.
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The effects of extracellular Ca2+ withdrawal were studied on isolated diaphragmatic muscle fibers and compared with the effects on the papillary, soleus, and extensor digitorum longus (EDL) contractility, using the same in vitro model. Diaphragmatic fibers were obtained from 15 rats, and papillary muscles, soleus, and EDL were obtained from 10 animals. Isometric force generated in response to 1-Hz supramaximal electrical stimulation was measured with a highly sensitive photoelectric transducer. After control measurements, perfusion with a Krebs solution depleted of calcium (0 Ca2+) was started while the fibers were continuously stimulated (4 times/min) and twitches recorded. For the papillary fibers, perfusion with zero Ca2+ was followed by an immediate decrease in twitch tension, complete twitch abolition occurring within 3 +/- 1 min after zero-Ca2+ exposure. Diaphragmatic fibers behaved similarly, although twitch abolition was delayed (10 +/- 3 min after 0-Ca2+ exposure). For the soleus fibers, the twitch amplitude amounted to 38 +/- 10% of control (62% decrease on the average) after 30 min of zero-Ca2+ exposure, no twitch abolition being noted even after 1 h of Ca2+-free exposure. The twitch amplitude of the EDL fibers amounted to 75 +/- 7% of control (25% decrease) after 30 min of zero-Ca2+ exposure. The recovery kinetics for the four fiber types after reexposure to Ca2+-containing solution were also different, with papillary and diaphragmatic fibers recovering completely within 2.5 +/- 0.5 and 4 +/- 0.5 min, respectively. By contrast, neither the soleus nor the EDL showed complete recovery after 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of a 3-day pneumococcal infection on diaphragmatic strength and endurance capacity were studied in an in vivo rat model. Thirty-four rats were divided into a control (C) (n = 17) or a septic (S) group (n = 17). Animals were inoculated subcutaneously with 10(11) Streptococcus pneumoniae (S), or sterile culture media (C). All rats were studied 3 days after inoculation. Diaphragmatic strength and endurance capacity were studied in 11 animals of each group. Diaphragmatic strength was assessed by measuring transdiaphragmatic pressure (Pdi) generated during electrical stimulation of the phrenic nerves at different frequencies (0.5, 10, 20, 30, 50, and 100 Hz). Endurance index was calculated as the ratio of Pdi generated after 30 s of phrenic nerve stimulation at 10 Hz divided by the initial force. Measurements of lung weights and lung histologic examinations were performed in the 6 remaining rats from each group. S animals were hyperthermic (39 to 40 degrees C rectal temperature). There was no evidence of pneumonia at histologic examination in Group S. No differences in wet weight of the lung and in the dry-to-wet weight ratio were noted in Group S as compared with Group C. However, S. pneumoniae was isolated from blood and lungs of S animals. Diaphragmatic weight was not different between S and C groups, whereas the weights of the extensor digitorium longus (EDL), tibialis anterior (TA), and soleus muscles were significantly reduced in Group S as compared to Group C.(ABSTRACT TRUNCATED AT 250 WORDS)
STUDY OBJECTIVE: To assess respiratory muscle fatigue in acute respiratory failure in patients with chronic obstructive pulmonary disease and evaluate its influence on weaning patients from mechanical ventilation. DESIGN AND PATIENTS: We studied the time course of tracheal occlusion pressure (P0.1) and high-to-low ratio of the diaphragmatic electromyogram in 16 patients in acute respiratory failure with chronic obstructive pulmonary disease. METHODS: All patients were intubated and studied during a 15-minute weaning period from ventilation. Minute ventilation (VE), arterial blood gases, P0.1 and high-to-low ratio of the diaphragm were measured every day from the onset to the end of acute failure (before extubation) at 5 and 15 minutes into the weaning period. The diaphragmatic electromyogram was recorded with an esophageal electrode and the high-to-low ratio of the electrical signal analyzed to assess diaphragmatic fatigue. MEASUREMENTS AND MAIN RESULTS: In all patients P0.1 was markedly increased (7.1 +/- 2.4 cm H2O, mean +/- SE) on the first day of acute failure and did not change during weaning. In 11 patients, P0.1 had decreased to 4.7 +/- 1.8 cm H2O (P less than or equal to 0.002) before extubation (which was done after 5 to 9 days). In these patients, the high-to-low ratio of the diaphragm decreased rapidly-during the first minutes of weaning on the first day of acute failure and remained low throughout weaning, whereas before extubation no decrease in high-to-low ratio was seen during weaning. In 5 patients, P0.1 did not change significantly from the onset of acute failure and the high-to-low ratio remained low before extubation. These 5 patients had to be reintubated within 2 to 6 days. In both groups of patients, VE did not change significantly from the first to last day of acute failure (10.3 +/- 3 compared with 10.7 +/- 2.1 min-1), whereas blood gases during room air breathing improved significantly from the first to last day of acute failure, respectively, in each group (arterial oxygen pressure [PaO2], 33.5 +/- 1.5 compared with 44 +/- 9 mm Hg (P less than or equal to 0.05) and PaO2 56 +/- 2.3 compared with 49 +/- 2 mm Hg (P less than 0.005). CONCLUSIONS: Extubation should not be done in patients with respiratory muscle fatigue despite improvement in arterial blood gases and clinical status; and P0.1 provides a valid and simple index to assess the likelihood of respiratory muscle fatigue.
This article assesses the role of pharmacotherapy in the management of respiratory muscle dysfunction. It focuses on two classes of drugs, the methylxanthines and the sympathomimetic agents. A prospective section focuses also on the particularities of the diaphragm among the skeletal striated muscles. In addition, a new approach to respiratory pharmacotherapy, which may be beneficial in patients with respiratory muscle dysfunction, is suggested.
The effect of a sustained-release aminophylline preparation on diaphragmatic contractility was investigated in patients with stable chronic obstructive lung disease (FEV1 = 22.6% of predicted value). Ten such patients were tested before (control) and after a week's course of oral aminophylline. Diaphragmatic contractility was evaluated by measuring the transdiaphragmatic pressure generated at residual functional capacity by bilateral electrical stimulation of the phrenic nerves. The nerves were stimulated supramaximally at 1 Hz, using needle electrodes. Plasma aminophylline levels (12.5 +/- 0.9 mg/l) were within therapeutic range in all patients. After treatment with aminophylline, for each stimulation the transdiaphragmatic pressure increased significantly from 14 +/- 1.3 to 17 +/- 1.3 cm H2O (+21%; P less than 0.005). These results confirm that aminophylline increases the force of contraction of the diaphragmatic fibres electively tested by the technique used. Long-term treatment with theophylline in therapeutic doses may be of interest in such patients, as it might improve their diaphragmatic contractility and result in better control of both respiratory muscle fatigue and episodes of acute respiratory failure.
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Experimental data suggest that theophylline (T) enhances diaphragmatic contractility by increasing the influx of calcium at the cell membrane level through an inhibition of adenosine receptors (Aubier et al., J. Appl. Physiol. 54: 460-4, 1983). Enprofylline (E) is a xanthine drug that has poor ability to antagonize physiological actions of adenosine. The aim of this study was to compare the effects on diaphragmatic contractility of T and E in order to determine whether antagonism of adenosine receptors was the underlying mechanism of the inotropic effect of T on diaphragmatic contractility. Ten normal subjects were studied in the sitting position. The contractile properties of the diaphragm were assessed by measuring the transdiaphragmatic pressure (Pdi) generated at functional residual capacity during bilateral electrical stimulation of the phrenic nerves. The subjects were randomized, and after control measurements were performed, they received T or E. This was a double-blind crossover study, the measurements being repeated with the second drug after one week. Both drugs were administered intravenously with a loading dose of 6 and 2 mg/kg administered in 30 min for T and E and a maintenance dose of 0.9 and 0.075 mg.kg-1 X h-1 for T and E, respectively. Measurements were performed before and 60 min after T or E administration. Plasmatic levels of both drugs were also analyzed. In all the subjects, therapeutic levels of T or E were reached (14.8 +/- 0.6 and 3.9 +/- 0.42 mg/l for T and E, respectively, at 30 min).(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of halothane administration on diaphragm and tibialis anterior (TA) muscle were investigated in 30 anesthetized mechanically ventilated rats. Diaphragmatic strength was assessed in 17 rats by measuring the abdominal pressure (Pab) generated during supramaximal stimulation of the intramuscular phrenic nerve endings at frequencies of 0.5, 30, and 100 Hz. Halothane was administered during 30 min at a constant minimum alveolar concentration (MAC): 0.5, 1, and 1.5 MAC in three groups of five rats. For each MAC, Pab was significantly reduced for all frequencies of stimulation except at 100 Hz during 0.5 MAC halothane exposure. The effects of halothane (0.5, 1, and 1.5 MAC) on diaphragmatic neuromuscular transmission were assessed in five other rats by measuring the integrated electrical activity of the diaphragm (Edi) during electrical stimulation of the phrenic nerve. No change in Edi was observed during halothane exposure. In five other rats TA contraction was studied by measuring the strength of isometric contraction of the muscle during electrical stimulation of its nerve supply at different frequencies (0.5, 30, and 100 Hz). Muscle function was unchanged during administration of halothane in a cumulative fashion from 0.5 to 1.5 MAC. These results demonstrate that halothane does not affect hindlimb muscle function, whereas it had a direct negative inotropic effect on rat diaphragmatic muscle.
The effects of phrenic nerve cooling at 0 degrees C on the nerve and diaphragmatic function were evaluated in dogs. Eleven dogs, anesthetized and mechanically ventilated, were studied. Left diaphragmatic function was assessed by recording the transdiaphragmatic pressure (Pdi) generated during electrical stimulation of the left phrenic nerve at different frequencies (0.5, 30, and 100 Hz). Phrenic nerve stimulations were achieved either directly by electrodes placed around the phrenic nerve above its pericardial course or by intramuscular electrodes placed close to the phrenic nerve endings. Electrical activity of the hemidiaphragm (Edi) was recorded and phrenic nerve conduction time (PNCT) was measured during direct phrenic stimulation. A transpericardial cooling of the nerve, at 0 degrees C, on a length of 1 cm, was performed during 30 min (group A, n = 7) or 5 min (group B, n = 4). After the cooling period, phrenic and diaphragmatic functions were assessed hourly for 4 h (H1-H4). Cooling the phrenic nerve produced a complete phrenic nerve conduction block in all dogs, 100 +/- 10 s after the onset of cold exposure. Conduction recovery time was longer in group A (11 +/- 7 min) than in group B (2 +/- 0.5 min) and PNCT remained increased throughout the study in group A. Furthermore, in group A, Pdi and Edi during direct phrenic stimulation were markedly depressed from H1 to H4. No change in these parameters was noted until H3 during intramuscular stimulation, time at which a significant decrease occurred. By contrast, Pdi and Edi from direct and intramuscular stimulations remained unchanged throughout the study in group B.(ABSTRACT TRUNCATED AT 250 WORDS)
We studied the effects of digoxin, a compound that has an inotropic effect on the myocardium, on diaphragmatic function in 8 patients with chronic obstructive pulmonary disease. All the patients were in acute respiratory failure and were artificially ventilated. Diaphragmatic strength was assessed by measuring the transdiaphragmatic pressure generated at functional residual capacity during bilateral supramaximal electrical stimulation of the phrenic nerves. The latter were stimulated before and at 45 and 90 min after administration of digoxin (0.02 mg/kg infused for 10 min). In all the patients, cardiac output was measured by the thermodilution technique using a Swan-Ganz catheter placed in the pulmonary artery. Arterial blood gases and pH were maintained within normal range by mechanical ventilation. In all the patients, digoxin plasma levels reached the therapeutic range (mean values, 2.82 +/- 0.17 and 2.90 +/- 0.20 nmol/L at 45 and 90 min, respectively) after digoxin administration. Diaphragmatic strength improves significantly after digoxin administration, the transdiaphragmatic pressure for an identical phrenic stimulation increasing by 19.5% (p less than 0.001) on the average. This increase was noted 45 and 90 min after digoxin administration. We conclude that digoxin has a potent effect on diaphragmatic strength generation that may be beneficial in patients with chronic obstructive pulmonary disease during acute respiratory failure. Furthermore, this inotropic positive effect of digoxin on the diaphragm, as previously observed for the myocardium, emphasizes the similarities between these 2 contractile tissues.
Recent investigations have shown that theophylline improves diaphragmatic contractility of the respiratory muscles in isolated muscle preparations in animals and in normal human subjects. It has also been demonstrated that theophylline can reverse diaphragmatic fatigue and prevent fatigue of the diaphragm when given prophylactically. These effects have also been demonstrated in patients with severe chronic obstructive pulmonary disease, all of whom retained CO2 (PaCO2 53 +/- 3 mm Hg) and had hypoxia (PaO2 57 +/- 8 mm Hg). Theophylline, which increases respiratory muscle strength and delays the onset of diaphragmatic fatigue therefore could be a very useful agent in the treatment of patients with chronic airway obstruction.
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Methylxanthines and particularly caffeine are known to increase skeletal muscle contractility. Recently, it has been shown that theophylline improves diaphragmatic contractility of the respiratory muscles both in isolated muscle preparations and in animals and normal human beings. Furthermore, it has been demonstrated that theophylline reverses diaphragmatic fatigue and prevents fatigue of the diaphragm when it is given prophylactically. Finally, recent evidence indicates that theophylline improves diaphragmatic function in patients with chronic obstructive pulmonary disease, all of whom retained CO2 (PaCO2 43 +/- 3 mm Hg) and had hypoxia (PaO2 57 +/- 8 mm Hg). Patients both improved transdiaphragmatic pressure and were less susceptible to fatigue. These data strongly suggest that theophylline, which increases respiratory muscle strength and delays the onset of diaphragmatic fatigue, could be a very useful agent in the treatment of patients with chronic airway obstruction.
The mechanism underlying the decrease in minute ventilation (VE) observed under halothane anesthesia was investigated in nine spontaneously breathing dogs. Anesthesia was induced with pentobarbital sodium and was maintained with halothane. Inspired fraction of halothane (FIhal) was increased every 30 min, from 0.005 to 0.02. VE decreased from 8.1 +/- 0.9 to 4.8 +/- 0.4 l . min-1 (P less than 0.001), as FIhal increased from 0 to 0.02. This resulted from a decrease in both mean inspiratory flow (VT/TI) and the duty ratio (TI/TTOT). Transdiaphragmatic pressure (Pdi) and the integrated electrical activity of both hemidiaphragms (Edi) were measured during normal breathing, and during breathing against closed airways (P0di, E0di), in order to obtain an index of the inspiratory neuromuscular output of the diaphragm. With increasing FIhal, there was a significant decrease in Pdi, P0di, Edi, and E0di. The authors measured Pdi and Edi generated during supramaximal stimulation of the two phrenic nerves (PSdi, Esdi) at frequencies of 10, 20, 50, and 100 Hz, in order to eliminate in this decrease the role played by a decrease in the neural drive to breathing. PSdi and ESdi decreased significantly with increasing FIhal, and had not returned to the control values 30 min after discontinuation of halothane administration. The authors conclude that, in pentobarbital-anesthetized dogs, halothane is responsible for a diaphragmatic dysfunction, which may be located either at the neuromuscular junction, on the contractile processes of the muscle, or on both, and for a decrease in the activation time of the inspiratory muscles. Both of these effects contribute to the decrease in VE observed under halothane anesthesia.