Respiratory muscle failure: fatigue or weakness? The role of theophylline.
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Humans↗
Biomedical subjects
C Roussos
Publications and source records attributed to C Roussos.
Effects of neostigmine and salbutamol on diaphragmatic fatigue.
We studied the effects of neostigmine and salbutamol on the force generated by the fatigued diaphragm in anesthetized dogs. Mechanically ventilated animals were prepared with an open thorax. A thin-walled latex balloon was positioned beneath the diaphragm to measure transdiaphragmatic pressure (Pdi) and a rigid cast was fixed around the abdomen to limit changes in diaphragmatic length and geometry during contractions. Pdi was the index of force generated by the diaphragm. We measured Pdi during supramaximal phrenic stimulation at different frequencies and during spontaneous inspiratory efforts. The diaphragm was fatigued by repeated phrenic stimulation. Fatigue significantly reduced Pdi at all frequencies of stimulation and during spontaneous contractions (P less than 0.05). The reduction in Pdi was associated with a decrease in peak twitch tension (PTT) to 50% of control (P less than 0.05). Infusion of neostigmine restored PTT to values equivalent with or greater than control (P less than 0.05) and improved Pdi at low stimulation frequencies (P less than 0.05) and during spontaneous inspiratory efforts (P less than 0.05). Infusion of salbutamol had no effect on PTT, but did significantly shortened twitch half relaxation time (P less than 0.05). Salbutamol also had no effect on Pdi during stimulated and spontaneous contractions. We conclude that neostigmine improves force generated by the fatigued diaphragm by increasing twitch amplitude while salbutamol did not have a positive inotropic effect.
Albuterol↗
Effects of contraction frequency and duty cycle on diaphragmatic blood flow.
The effects of diaphragmatic contraction frequency (no. of intermittent tetanic contractions/min) at a given tension-time index and of duty cycle (contraction time/total cycle time) on diaphragmatic blood flow were measured in anesthetized mongrel dogs during bilateral supramaximal phrenic nerve stimulation. Diaphragmatic blood flow was measured by the radionuclide-labeled microsphere method. Contraction frequency was varied between 10 and 160/min at duty cycles of 0.25 and 0.75. Diaphragmatic blood flow increased with contraction frequency from 1.47 +/- 0.13 ml X min-1 X g-1 (mean +/- SE) at an average of 18/min to 2.65 +/- 0.16 ml X min-1 X g-1 at 74/min (P less than 0.01) with a duty cycle of 0.25 and from 1.32 +/- 0.19 ml X min-1 X g-1 at an average of 15/min to 1.96 +/- 0.15 ml X min-1 X g-1 at 80/min (P less than 0.02) with a duty cycle of 0.75. At higher contraction frequencies diaphragmatic blood flow did not increase further at both duty cycles. In addition, diaphragmatic blood flow was higher with a duty cycle of 0.25 than 0.75 at all contraction frequencies. We conclude that frequency of contraction is a major determinant of diaphragmatic blood flow and that high duty cycle impedes diaphragmatic blood flow.
Abdomen↗
Effects of pleural pressure and abdominal pressure on diaphragmatic blood flow.
The aim of this experiment was to determine if blood flow to the diaphragm is affected by generating the transdiaphragmatic pressure mainly with positive abdominal pressure or mainly with negative pleural pressure, during both sustained and intermittent diaphragmatic contractions. Diaphragmatic blood flow was measured in anesthetized mongrel dogs by the radionuclide-labeled microsphere method. Sustained and intermittent tetanic diaphragmatic contractions were produced with 1) free abdomen and closed chest (high negative pleural pressure) and 2) bound abdomen and open chest (high positive abdominal pressure). During sustained contractions, diaphragmatic blood flow at maximum levels of activation was significantly higher with negative pleural pressure (P less than 0.05). In contrast with this, intermittent diaphragmatic contractions did not yield a significant difference between diaphragmatic blood flow with negative pleural pressure and with positive abdominal pressure at maximal levels of transdiaphragmatic pressure. During both sustained and intermittent contractions, blood pressure, as measured from the carotid artery, did not vary significantly between negative pleural pressure and positive abdominal pressure. We conclude that during sustained tetanic diaphragmatic contractions, diaphragmatic blood flow is obstructed by high positive abdominal pressures, but during intermittent diaphragmatic contractions, high positive abdominal pressures do not affect total blood flow, since any inhibition of blood flow during the contractile period can be compensated for during the relaxation period between contractions.
Abdomen↗
Arterial CO2 partial pressure affects diaphragmatic function.
The purpose of this study was to examine in an in vivo preparation acute variations of PCO2 on diaphragmatic contractility. Plaster casts were snugly fit around the abdomen of six open-chested dogs, moving the abdominal contents rostrally. Diaphragmatic contractions against this very fixed load in response to phrenic nerve stimulation (supramaximal voltage at 1, 20, 50, and 80 Hz) or during spontaneous inspiratory efforts were virtually isometric (quasi-isometric). Transdiaphragmatic pressure (Pdi) measured by an abdominal balloon was used as an index of diaphragmatic contractility. Arterial PCO2 (PaCO2) was reduced by hyperventilation and raised by increasing PICO2. Pdi values in response to stimulation at 1, 20, 50, and 80 Hz in ranges I (PaCO2 = 0-19 Torr) and II (PaCO2 = 20-34 Torr) did not differ statistically from the control Pdi values (range III; PaCO2 = 35-45 Torr). In range IV (PaCO2 = 46-70 Torr) Pdi values for stimulations of 20, 50, and 80 Hz were significantly lower than control. In range V (PaCO2 = 71-90 Torr), VI (PaCO2 = 91-101 Torr), and VII (PaCO2 greater than or equal to 102 Torr) Pdi values were significantly less than those in range IV at all frequencies of stimulation. In the four dogs measured during spontaneous inspiratory efforts the integrated diaphragmatic electromyogram (Edi) was correlated with the Pdi. As PaCO2 rose (range III to VII), the Pdi values observed at 25, 50, 75, 100% of the maximum Edi (of range III) were significantly lower than the Pdi value of range III.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkalosis, Respiratory↗
Respiratory muscle and organ blood flow with inspiratory elastic loading and shock.
Since respiratory muscles fail when blood flow is inadequate, we asked whether their blood flow would be maintained in severe hypotensive states at the expense of other vital organs (brain, heart, kidney, gut, spleen). We measured blood flow (radiolabeled microspheres) to respiratory muscles and vital organs in 11 dogs breathing against an inspiratory elastic load, first with normal blood pressure (BP) and then hypotension produced by cardiac tamponade. With the elastic load alone, there was no change in BP or cardiac output; diaphragmatic blood flow (Qdi) increased from 12.8 +/- 7.0 to 34.1 +/- 15.6 ml/100 g, and total respiratory muscle flow (QTR) increased from 56.5 +/- 19.1 to 97.4 +/- 36.5 ml/100 g, but except for the brain, there was no change in blood flow to other organs. With tamponade (mean BP = 79 +/- 16 mmHg), flow decreased to all organs, whereas Qdi (39.0 +/- 19.4) did not change. QTR decreased, but not significantly, to 88.6 +/- 49.5. With more tamponade (mean BP = 53 +/- 13 mmHg), flow to all vital organs decreased as well as QTR (57.9 +/- 47.18), but Qdi did not significantly decrease and had the same relationship to respiratory force as with normal BP. Thus, with severe inspiratory elastic loading and severe hypotension, the diaphragm and external intercostal muscles did most of the respiratory work, and their flow was maintained at the expense of other vital organs.
Animals↗
Respiratory muscle fatigue: a cause of ventilatory failure in septic shock.
The effect of endotoxic shock on the respiratory muscle performance was studied in spontaneously breathing dogs given Escherichia coli endotoxin (Difco Laboratories, 10 mg/kg). Diaphragmatic (Edi) and parasternal intercostal (Eic) electromyograms were recorded using fishhook electrodes. The recorded signals were then rectified and electrically integrated. Pleural, abdominal, and transdiaphragmatic (Pdi) pressures were recorded by a balloon-catheter system. After a short control period, the endotoxin was administered slowly intravenously (within 5 min). Death was secondary to respiratory arrest in all animals. All animals died within 150-270 min after the onset of endotoxic shock. Within 45-80 min of the endotoxin administration, mean blood pressure and cardiac output dropped to 42.1 +/- 4.1 and 40.1 +/- 6.0% (mean +/- SE) of control values, respectively, with little change afterward. Mean inspiratory flow rate and Pdi increased from control values of 0.27 +/- 0.03 l X s-1 and 5.75 +/- 0.7 cmH2O to mean values of 0.44 +/- 0.3 l X s-1 and 8.70 +/- 1.05 cmH2O and then decreased to 0.17 +/- 0.03 l X s-1 and 3.90 +/- 0.30 cmH2O before the death of the animals. There were no major changes in the mechanics of the respiratory system. Edi and Eic increased progressively to mean values of 360 +/- 21 and 263 +/- 22% of control, respectively, before the death of the animals. None of the dogs were hypoxic. Arterial PCO2 decreased from a control value of 42.9 +/- 1.7 Torr to a mean value of 29.9 +/- 2.8 Torr and then increased to 51 +/- 4.3 Torr before the death of the animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Collateral sources of costal and crural diaphragmatic blood flow.
We measured the contribution of aortic, internal mammary, and intercostal arteries to the blood flow to the costal and crural segments of the diaphragm and other respiratory muscles in seven dogs breathing against a fixed inspiratory elastic load. We used radiolabeled microspheres to measure the blood flow with control circulation, occlusion of the aorta distal to the left subclavian artery, combined occlusion of the aorta and both internal mammary arteries, and occlusion of internal mammary arteries alone. With occlusion of the aorta distal to the left subclavian artery, blood flow to the crural diaphragm decreased from 40.3 to 23.5 ml . min-1 X 100 g-1, whereas costal flow did not change significantly (from 41.7 to 38.1 ml . min-1 . 100 g-1). Blood flows to the sternomastoid and scalene muscles (above the occlusion) increased by 200 and 340%, respectively, whereas flows to the other respiratory muscles did not change significantly. Blood flows to organs above the occlusion either remained unchanged or increased, whereas flows to those below the occlusion all decreased. When the internal mammary artery was also occluded, flows to the crural segment decreased further to 12.1 and costal flow decreased to 20.4 ml X min-1 X 100 g-1. Internal mammary arterial occlusion alone in two dogs had no effect on diaphragmatic flow. In conclusion, intercostal collateral vessels are capable of supplying a significant proportion of blood flow to both segments of the diaphragm but the costal segment is better served than the crural segment.
Airway Resistance↗
Effects of uncompensated and compensated metabolic acidosis on canine diaphragm.
We investigated the effects of metabolic acidosis and compensated metabolic acidosis on force of contraction of the diaphragm in anesthetized dogs. Mechanically ventilated animals were prepared with an open thorax. A balloon was positioned beneath the diaphragm to measure transdiaphragmatic pressure (Pdi), and a plaster cast was placed around the abdomen to maintain length and geometry of the diaphragm. The force of contraction was evaluated by measuring Pdi during supramaximal phrenic stimulation at different frequencies and also during spontaneous inspiratory efforts. In 13 dogs with an arterial pH (pHa) of 7.38 and arterial PCO2 (PaCO2) of 36.5 Torr, metabolic acidosis was produced by infusion of HCl until pHa equaled 6.98 and PaCO2 equaled 36.4 Torr. Pdi at all frequencies greater than 10 Hz was significantly reduced (P less than 0.05). The dogs were then hyperventilated until pHa was 7.34 and PaCO2 was 12.8 Torr. Pdi was significantly reduced again at all frequencies (P less than 0.05) except 5 Hz. The percent reduction in Pdi by compensated acidosis was significantly greater at low-frequency stimulation than at high (P less than 0.05). Similar qualitative results were observed during spontaneous inspiratory efforts where Pdi was compared at constant magnitudes of diaphragmatic electromyograms. Twitch characteristics revealed that metabolic acidosis led to a significant shortening of twitch relaxation time (P less than 0.05), and compensated metabolic acidosis added to this effect a significant decrease in twitch amplitude (P less than 0.05).
Acidosis↗
Distribution of respiratory muscle and organ blood flow during endotoxic shock in dogs.
Respiratory muscle blood flow and organ blood flow during endotoxic shock were studied in spontaneously breathing dogs (SB, n = 6) and mechanically ventilated dogs (MV, n = 5) with radiolabeled microspheres. Shock was produced by a 5-min intravenous injection of Escherichia coli endotoxin (0.55:B5, Difco, 10 mg/kg) suspended in saline. Mean arterial blood pressure and cardiac output in the SB group dropped to 59 and 45% of control values, respectively. There was a similar reduction in arterial blood pressure and cardiac output in the MV group. Total respiratory muscle blood flow in the SB group increased significantly from the control value of 51 +/- 4 ml/min (mean +/- SE) to 101 +/- 22 ml/min at 60 min of shock. In the MV group, respiratory muscle perfusion fell from control values of 43 +/- 12 ml/min to 25 +/- 3 ml/min at 60 min of shock. In the SB group, 8.8% of the cardiac output was received by the respiratory muscle during shock in comparison with 1.9% in the MV group. In both groups of dogs, blood flow to most organs was compromised during shock; however, blood flow to the brain, gut, and skeletal muscles was higher in the MV group than in the SB group. Thus by mechanical ventilation a fraction of the cardiac output used by the working respiratory muscles can be made available for perfusion of other organs during endotoxic shock.
Animals↗
Effects of aminophylline, isoproterenol, and neostigmine on hypercapnic depression of diaphragmatic contractility.
We investigated the effects of aminophylline, isoproterenol, and neostigmine on decreased diaphragmatic contractility induced by hypercapnia. With the thorax open, the animal receiving mechanical ventilation, and a plaster cast around the abdomen, constant length and geometry of the diaphragm were maintained. Contractility was assessed by analysis of transdiaphragmatic pressure (Pdi) generated during supramaximal phrenic stimulation at different frequencies. Bilateral phrenectomy was performed to prevent spontaneous diaphragm movement. Hypercapnia (PaCO2, 85 mmHg) reduced Pdi by 10% at low and high frequencies of stimulation. Subsequently, aminophylline (20 mg/kg) restored Pdi to the control value at every frequency of stimulation (p less than 0.05), whereas neostigmine (0.25 and 1.0 mg) restored Pdi at low frequencies only (p less than 0.05). Isoproterenol did not improve Pdi at any frequency. Analysis of twitch characteristics revealed that hypercapnia reduced peak twitch amplitude by 17%, this being the underlying cause of the decrease in Pdi. Low and high doses of all 3 drugs significantly reversed this effect by improving peak twitch tension to values equal with or greater than control values (p less than 0.05). In addition, aminophylline (40 mg/kg) and neostigmine (0.25 and 1.0 mg) significantly increased time to peak tension of the twitch (p less than 0.05) and isoproterenol (5 and 20 micrograms/min) significantly decreased twitch half relaxation time (p less than 0.05). We conclude that aminophylline and neostigmine improve diaphragmatic contractility during hypercapnia by virtue of their potentiating effect on twitch amplitude, whereas isoproterenol does not increase contractility because the process underlying the decrease in twitch duration masks the effect of an improved twitch amplitude.
Aminophylline↗
Function and fatigue of respiratory muscles.
The functional anatomy of the respiratory muscles and their actions and interactions are presented, particularly of the diaphragm. The large amount of blood flow to respiratory muscles and the determination of blood flow are reviewed, while the role these muscles play in the overall economy of the body in health and disease are discussed. Finally the failure of the respiratory muscles in the context of the development of hypercapnic respiratory failure is examined. It is argued that as the respiratory muscles become fatigued, afferent information from the respiratory muscles modifies the breathing pattern, which might be beneficial to respiratory muscle function, but it might compromise alveolar ventilation.
Abdominal Muscles↗
Effect of theophylline on respiratory muscle function.
Theophylline improves diaphragmatic contractility of the respiratory muscles both in isolated muscle preparations, as well as in animals and normal human beings. Furthermore, theophylline restores diaphragmatic fatigue and prevents fatigue of the diaphragm when given prophylactically. Finally, it was recently shown that theophylline improves diaphragmatic function in COPD patients, all of whom were CO2 retainers (PaCO2 53 +/- 3 mm Hg) and hypoxemic (PaO2 57 +/- 8 mm Hg). Patients improved transdiaphragmatic pressure and were less susceptible to fatigue. Presently the mechanisms of action of theophylline regarding its effects on diaphragmatic function are not fully elucidated. Experimental evidence, however, suggests that theophylline may have an effect on transmembrane calcium movements by blocking adenosine receptors.
Aminophylline↗
Effect of carbon dioxide on diaphragmatic function in human beings.
We studied the effects of acute changes in the partial pressure of arterial carbon dioxide on diaphragmatic contractility and performance in four normal men. To study contractility we measured the ability of the diaphragm to generate pressure at a given level of excitation by determining the relation between the electrical activity of the diaphragm and transdiaphragmatic pressure during a voluntary quasi-isometric inspiratory effort carried out at different levels of end-tidal carbon dioxide. Our results show that contractility was reduced with hypercapnia (when end-tidal carbon dioxide was 7.5 per cent or higher), although hypocapnia (end-tidal carbon dioxide, 3 per cent) had no effect on diaphragmatic contractility. We also studied the development of diaphragmatic fatigue before and during carbon dioxide breathing. Subjects were studied at the same diaphragmatic tension-time index, a value analogous to the more familiar myocardial tension-time index, while the same inspiratory flow was maintained. Electromyographic signs of fatigue appeared at a lower tension-time index during hypercapnia than during normocapnia, indicating that endurance is diminished during hypercapnia. These findings show that acute respiratory acidosis equivalent to an arterial carbon dioxide tension of about 54 mm Hg decreases the contractility and endurance time of the diaphragm in human beings.
Carbon Dioxide↗
Isoproterenol and aminophylline improve contractility of fatigued canine diaphragm.
We investigated the effects of aminophylline and isoproterenol on diaphragmatic fatigue produced by phrenic stimulation in dogs. With a cast around the abdomen, the diaphragm contracted quasi-isometrically while the thorax was open and the animal was ventilated. We assessed contractility by measuring transdiaphragmatic pressure during supramaximal stimulation of the phrenic nerves at different frequencies and also during spontaneous inspiratory efforts. At doses of 20, 40, and 80 mg/kg, aminophylline significantly improved contractility (p less than 0.01) in a dose-dependent manner during low, but not during high frequency stimulation. The maximal improvement (24%) was observed with 80 mg/kg. With intravenously administered doses of 5 and 10 micrograms/min of isoproterenol, contractility was also significantly enhanced (p less than 0.05) during low frequency stimulation. Maximal improvement (12%) occurred with 5 micrograms/min. Similar results were obtained when spontaneous inspiratory efforts were recorded and transdiaphragmatic pressure was compared at a given diaphragmatic electrical activity before and after administration of each drug. Maximal improvement was 23% with aminophylline and 11% with isoproterenol. Analysis of twitch characteristics revealed that peak tension was increased significantly (p less than 0.025) by both drugs. In addition, isoproterenol caused a marked decrease in the time course of relaxation. We conclude that aminophylline and isoproterenol improve contractility of the fatigued diaphragm by increasing the amplitude of the underlying small twitch. Furthermore, the smaller effect of isoproterenol may be the result of reduced relaxation time of the twitch.
Aminophylline↗
Acute diaphragmatic shortening: in vitro mechanics and fatigue.
In acute hyperinflation, the occurrence of diaphragmatic shortening may alter the contractile characteristics and function of the diaphragm. The aim of this study was to investigate the effects of acute passive diaphragmatic shortening on in vitro mechanical properties and fatigability. Optimal diaphragmatic length (Lo) was defined as being that length at which peak twitch-tension occurred. Acute shortening (85% Lo, 70% Lo) altered the twitch characteristics. At shorter lengths, the time-to-peak tension and the half-relaxation time were significantly reduced (p less than 0.05). These alterations led to marked alterations in the shape of the force-frequency curve at shorter lengths and in the length-tension properties when assessed at different stimulation frequencies. When normalized with respect to maximal tension, a disproportionate decrease in the generated tension was observed at shorter lengths. Fatigability was assessed by repeatedly stimulating the diaphragmatic bundles and observing the drop in tension with respect to time. For a given fatigue regimen, i.e., same stimulation frequency, the shorter diaphragm (70% Lo) generated more absolute force at any given time period. When the initial tensions were matched at Lo and 70% Lo by increasing the stimulation frequency used to fatigue the shorter muscle, the acutely shortened diaphragm generated less absolute force following 60 s of the fatigue regimen. We conclude that alterations in the contractile characteristics of the diaphragm during acute passive shortening are such that a disproportionately greater excitability is required in order to reach a given submaximal tension as at Lo. This factor may partly account for increased diaphragmatic fatiguability in the acutely shortened state.
Animals↗
Histochemical and biochemical correlates of ventilatory muscle fatigue in emphysematous hamsters.
Histochemical and biochemical characteristics of the ventilatory muscles were evaluated in control and elastase-induced emphysematous hamsters. The emphysematous group was divided into sedentary and endurance-trained groups. Endurance training consisted of treadmill running, 1 h a day, 7 d a week. The experimental period lasted 24 wk. Histochemically, the diaphragm from the sedentary emphysematous hamsters revealed a selective fast fiber atrophy which was prevented by endurance training. Training also led to a hypertrophy of the slow, high oxidative fibers. The external intercostals from both emphysematous groups revealed an increased proportion of fast oxidative fibers at the expense of a decreased number of fast glycolytic fibers. However, the fast fibers in both emphysematous groups were significantly atrophied as compared with controls. The internal intercostals revealed no adaptive changes in either size or proportion distribution of the various fiber types. Biochemically, the diaphragm of the emphysematous animals had a significantly improved oxidative potential as measured by citrate synthase, and a reduced glycolytic capacity as indicated by phosphofructokinase activity, compared with controls. The magnitudes of the biochemical changes were similar in both emphysematous groups and were consistent for diaphragmatic samples taken from the costal and crural segments. The combined internal and external intercostals also underwent significant biochemical increases in their oxidative capacity. In addition, training of the emphysematous group led to an increased glycolytic potential of the intercostals.
Animals↗
The geometry of the microvascular bed of the diaphragm: comparison to intercostals and triceps.
The diaphragm may differ from other skeletal muscles in certain blood flow characteristics. We attempted to determine if this could be accounted for by structural differences in the microvasculature. We compared coded specimens of the diaphragm to the intercostals and triceps in rats by a cast corrosion, scanning electron microscopic study. For the comparison we first quantitatively described the vasculature by measuring the angles, distances, and diameters. We also tabulated subjective, descriptive, recurring patterns. We then performed frequency analysis by vessel diameter, correlation, and factor analysis to obtain the description. Arteries and veins of greater than 50 microns diameter have structural characteristics of a conducting system, namely, infrequent, single branching at obtuse angles whereas the vessels from about 15 to 50 microns in diameter have greater branching and frequently splay into many smaller streams. The capillaries form arcades and dichotomize with Y- and psi-shaped branches. The best predictor of branching (distance, angle, and pattern) is the trunk diameter. Individual and combinations of measurements and patterns comparing the diaphragm to the triceps and intercostals pointed out no convincing difference in these structural aspects of microvasculature of these muscles.
Animals↗