Recovery of costal and crural diaphragmatic contractility from partial paralysis

Since the two muscles (costal and crural) that constitute the diaphragm are separate and histologically different, their individual recovery pattern from neuromuscular blockade also may be different. Therefore, we studied the recovery of force and shortening in the in vivo diaphragm from atracurium-induced neuromuscular blockade in seven pentobarbital anesthetized dogs to assess segmental differences. Transdiaphragmatic pressure (Pdi), shortening of costal and crural segments, integrated electromyogram (EMG), and tidal volume (VT) were measured during spontaneous breathing. After atracurium had reduced VT to 30% of control, breathing parameters were followed until recovered to 90% of control values. In addition, force-frequency curves generated by supramaximal tetanic stimuli of the phrenic nerve were measured. Recovery times for tidal Pdi, tidal EMG, tidal shortening, low-frequency shortening, and twitch Pdi were twice as fast as for VT (40 +/- 4 min), reflecting a slower rate of recovery of accessory inspiratory muscles. High-frequency recovery was typically slower than that of VT. During tidal breathing and tetanic stimulation, costal and crural shortening recovered simultaneously. On the other hand, comparison between costal and crural by analysis of pressure-shortening relationships showed a segmental difference (crural shortened 30% more than costal at the same Pdi), which implied reduced afterload on the crural segment. However, since shortening and pressure were linearly related during paralysis and recovery, measurements of Pdi alone can accurately reflect changes in contractile mass when heterogeneity and afterload are controlled.     

Effect of sevoflurane on diaphragmatic contractility in dogs.

The effect of sevoflurane on diaphragmatic contractility was investigated in 12 anesthetized, mechanically ventilated dogs with the thorax opened. Animals were divided into two groups of six each: the sevoflurane and time control groups. We assessed contractility by the transdiaphragmatic pressure (Pdi) during supramaximal stimulation of the phrenic nerve at frequencies of 0.5, 10, 20, 50, and 100 Hz under quasiisometric conditions. The integrated electrical activity (Edi) of the crural and costal parts of the diaphragm (Edi cru, Edi cost) was also measured. In the sevoflurane group, diaphragmatic contractility was determined during three levels of anesthesia, specifically 0, 1.0, and 1.5 minimum alveolar anesthetic concentration (MAC). Measurements were made at the start of the stimulation (initial) and at the end of the 2-s period (2-s). Increasing the depth of sevoflurane anesthesia did not cause any significant differences in Pdi and Edi at 0.5-, 10-, and 20-Hz stimulation. By contrast, at 50- and 100-Hz stimulation, initial Pdi during 1.0 and 1.5 MAC sevoflurane exposure decreased significantly compared with the 0 MAC value (P less than 0.05). In addition, there was a statistical difference in 2-s Pdi between 1.0 and 1.5 MAC at 100-Hz stimulation (P less than 0.05). The Edi cru showed similar changes in Pdi at both measurements, whereas there was no remarkable change in Edi cost. There was no significant change either in Pdi or in Edi with respect to time in the time control group. We conclude from these results that sevoflurane impairs diaphragmatic contractility through its inhibitory effect on neuromuscular transmission, predominantly of the crural part.     

Effects of diaphragm plication for phrenic nerve paralysis on respiratory mechanics and diaphragm function

The purpose of this study is to examine the effects of unilateral diaphragm plication for phrenic nerve paralysis on the respiratory mechanics and diaphragm function. Study 1: We performed thoracotomy (BASELINE), left phrenicotomy (INJURY) and left diaphragm plication (PLICATION) in ten dogs. After chest was closed in each condition, measured were the tidal volume (TV), respiratory rate (f), esophageal and gastric pressure swing (delta Pes, delta Pga), dynamic compliance (Cdyn) the ratio of gastric to esophageal pressure swing (delta Pga/delta Pes) and the work of breathing per liter (WOB/L) under stable spontaneous breathing. Study 2: In eight other left-phrenicotomized dogs, Pdi and fractional shortening of the costal diaphragm during contralateral electrophrenic stimulation were measured before and after plication. After plication TV, delta Pga/delta Pes, Cdyn, Pdi and fractional shortening during stimulation increased significantly, whereas Pes and WOB/L decreased significantly compared with INJURY condition. In conclusion unilateral diaphragm plication after paralysis improves the intact hemidiaphragm contractility and diaphragmatic contribution to breathing.     

Effect of anesthesia on canine diaphragm length

General anesthesia has been shown to induce a cephalad shift of the end-expiratory position of the diaphragm in recumbent human subjects. The authors used the technique of sonomicrometry in chronically instrumented dogs to measure the length changes occurring in the costal and crural diaphragm during anesthesia. Seven dogs were studied in lateral decubitus; first awake, and then during pentobarbital anesthesia. The end-expiratory length (LFRC) of the crural segment increased gradually and reached a plateau after 30 min of anesthesia. Costal LFRC did not change. The results were similar when the hemidiaphragm under study was placed in a gravity-dependent or in a non-dependent position. In the awake state, variable levels of post-inspiratory or tonic diaphragmatic EMG activity were observed, which disappeared during anesthesia. The authors conclude that anesthesia induces a 7-8% increase in end-expiratory length of the crural, but not of the costal, diaphragm. This selective adjustment is not due to a pressure gradient effect, but is compatible with a loss of tone in the crural diaphragm.     

Effects of diltiazem on contractility and electromyographic activity of non-fatigued diaphragm in dogs

BACKGROUND: No data are available for diltiazem on muscle function (contractility and electomyographic activity) of non-fatigued diaphragm. METHODS: Eighteen pentobarbital-anesthetized dogs were divided into 3 groups of 6 each: Group I received no drug; Group II received small-dose of diltiazem (0.1 mg.kg-1.h-1); Group III received large-dose of diltiazem (0.5 mg.kg-1.h-1). Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi), the difference between esophageal and gastric pressures. Diaphragmatic electromyographic activity (Edi) was measured by means of electrodes placed at the anterior portion of the crural and costal parts of the diaphragm. After measuring baseline values of Pdi and Edi at 20 Hz and 100 Hz stimulation, the study drug was administered for 30 min. RESULTS: With infusion of diltiazem, Pdi and Edi to each stimulus did not change in Groups II and III. In Group I, these variables also showed no change. CONCLUSIONS: Diltiazem, at doses below 0.5 mg.kg-1.h-1, does not affect contractility and electromyographic activity of non-fatigued canine diaphragm.     

Impairment of neuromuscular transmission in fatigued canine diaphragm

The role of impairment of neuromuscular transmission in fatigued canine diaphragm was investigated by comparing the function of fatigued diaphragm with that of neuromuscular junction (NMJ)-blocked diaphragm. Diaphragmatic fatigue was produced by intermittent supramaximal stimulation of bilateral phrenic nerves. Partial NMJ blockade was obtained by vecuronium bromide administered intravenously. During control study, no fade was observed either in integrated diaphragmatic electric activity (Edi) or transdiaphragmatic pressure (Pdi). In fatigued diaphragm, Edi generated by 100 Hz showed a remarkable fade. The fade was prominent in high frequency fatigue. In NMJ-blocked diaphragm, fade was observed in Pdi as well as in Edi produced by 100 Hz. The fade of Edi by 100 Hz was prominent. In low frequency fatigue, both Pdi and Edi produced by 20 Hz test stimulation were significantly lower than control values. These results show that in addition to impairment of excitation-contraction coupling, neuromuscular blockade is involved, at least in part, in low frequency diaphragmatic fatigue.     

Dose-response characteristics of midazolam for reducing diaphragmatic contractility

A sedative dose of midazolam decreases contractility of the diaphragm, but no data are available concerning the relationship between dose and diaphragmatic contractility. We studied the dose-response characteristics of midazolam for reducing the diaphragmatic contractility in dogs. Animals were divided into three groups of eight each: Group 1 received no study drug, Group 2 was infused with a sedative dose of midazolam (0.1 mg/kg initial dose plus 0.1 mg x kg(-1) x h(-1) maintenance dose), and Group 3 was infused with an anesthetic dose of midazolam (0.1 mg/kg initial dose plus 0.5 mg x kg(-1) x h(-1) maintenance dose). We assessed the diaphragmatic contractility by transdiaphragmatic pressure (Pdi). With an infusion of midazolam in Groups 2 and 3, Pdi at low-frequency (20 Hz) and high-frequency (100 Hz) stimulation decreased from the baseline values (P < 0.05), and the integrated electrical activity of diaphragm (Edi) at 100-Hz stimulation decreased from the baseline values, whereas Edi at 20-Hz stimulation did not change. Compared with Group 1, Pdi and Edi for each stimulus decreased during midazolam infusion in Groups 2 and 3 (P < 0.05). The decrease in Pdi and Edi was more in Group 3 than in Group 2 (P < 0.05). We conclude that midazolam decreases, in a dose-dependent manner, contractility of the diaphragm in dogs.     

Dobutamine increases diaphragmatic contractility in dogs

The effects of dobutamine on diaphragmatic contractility were studied in 24 dogs anaesthetized with secobarbital and receiving mechanical lung ventilation. The phrenic nerves were stimulated supramaximally for two seconds with electrodes placed around the fifth and sixth cervical roots when the airway was closed at the level of FRC. The stimulating frequency ranged from 10 to 100 Hz. Transdiaphragmatic pressure gradient (Pdi) generated by the electrophrenic stimulation was used as an index of diaphragmatic contractility. The electrical activity of the diaphragm during the stimulation (Edi) was also measured with needle electrodes inserted in the right hemidiaphragm percutaneously. During an infusion of dobutamine (10 micrograms.kg-1.min-1 for 20 min), Pdi increased by 15 +/- 2.1% of control value at 20 Hz stimulation (P less than 0.01), and by 13 +/- 1.2% at 100 Hz stimulation (P less than 0.01). The Edi was not altered by dobutamine infusion. This enhancement of Pdi by dobutamine was abolished by simultaneous infusion of nicardipine, a Ca-channel blocker, but was not affected by prostaglandin E1. These results suggest that dobutamine has a stimulating effect on canine diaphragmatic contraction, and this action may be related to the increased inward movement of extracellular calcium.     

Midazolam-induced muscle dysfunction and its recovery in fatigued diaphragm in dogs

Midazolam, widely used for sedation and anesthesia, decreases contractility in nonfatigued diaphragm; however, its effects on contractility in fatigued diaphragm that are implicated as a cause of respiratory failure have not been established. We therefore studied the effects of midazolam on diaphragm muscle function and recovery in fatigued diaphragm. Dogs were divided into three groups of eight each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20-Hz stimulation for 30 min. When fatigue was established, Group I received no study drug; Group II was infused with a sedative dose (0.1 mg x kg(-1) x h(-1)) of midazolam; and Group III was infused with an anesthetic dose (0.5 mg x kg(-1) x h(-1)) of midazolam. We assessed diaphragm muscle function (contractility and electrical activity) by transdiaphragmatic pressure (Pdi) and integrated electrical activity of the diaphragm (Edi). In the presence of fatigue, Pdi at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), Pdi at high-frequency (100-Hz) stimulation did not change, and Edi to each stimulus did not change. With an infusion of midazolam, in Groups II and III, Pdi at both stimuli and Edi at 100-Hz stimulation decreased from fatigued values (P < 0.05). The decrease in Pdi and Edi was more in Group III than in Group II (P < 0.05). At 60 min after the cessation of midazolam administration, in Group II, Pdi and Edi recovered from midazolam-induced values (P < 0.05) and returned to fatigued values. In Group III, Pdi and Edi did not change from midazolam-induced values. We conclude that midazolam causes, in a dose-related manner, diaphragm muscle dysfunction in fatigued canine diaphragm and that at a sedative dose, but not at an anesthetic dose, midazolam does not delay its recovery.     

Experimental study on diaphragm fatigue during diaphragm pacing

An experimental study was performed to determine the main site of fatigue associated with diaphragm pacing. Using 24 mature mongrel dogs, weighing 7.5 to 12.7 kg, direct phrenic nerve pacing was conducted from the right cervical area at three different respiration rates, 37 (Group 1, n = 6), 25 (Group 2, n = 6) and 12 (Group 3, n = 6) times per minute, under fixed stimulation conditions (pulse duration, 200 microseconds; frequency, 25 Hz; pulse train repetition time, 1.2 sec). Diaphragm fatigue was defined as the reduction in transdiaphragmatic pressure (Pdi) to less than or equal to 60% of the initial value. In each animal, tidal volume (Vt), induced muscle action potential (Edi), conduction time (CT) and electrical current (E) between two electrodes were examined at various periods until fatigue. In addition, after fatigue, aminophylline (10 mg/kg) was injected and each parameter was observed for an additional 45 min. In 10 animals, the polarity of stimulation was changed from anodal to cathodal current after fatigue and changes in Pdi and Edi were examined. The time to fatigue was 70 +/- 20 min for Group 1, 149 +/- 48 min for Group 2, and 371 +/- 97 min for Group 3, showing a significant stimulation rate dependency (P less than 0.05). Vt and Edi showed a significant decrease (P less than 0.05) at fatigue in all of the groups. However, no significant differences of CT and E were seen between pre- and postfatigue values. Pdi and Edi did not change even when polarity was changed after fatigue. Following administration of aminophylline, Pdi showed a significant (P less than 0.05) increase over time in all groups: 19.8 +/- 13.5% at 5 min, 23.0 +/- 13.5% at 15 min, and 16.2 +/- 14.9% at 30 min for Group 1; 23.6 +/- 11.6% at 5 min, 27.3 +/- 15.5% at 15 min, and 19.0 +/- 16.1% at 30 min for Group 2; and 29.9 +/- 21.1% at 5 min, 29.5 +/- 18.6% at 15 min, 22.3 +/- 13.8% at 30 min, and 15.5 +/- 13.4% at 45 min for Group 3. In contrast, administration of aminophylline caused no significant changes in Edi. Based upon the finding that aminophylline was significantly effective at the time of diaphragm fatigue, it is concluded that fatigue of the muscle itself constitutes one of the contributing factors for the fatigue phenomenon associated with diaphragm pacing.     

Effect of aminophylline on the human diaphragm.

The effect of intravenous aminophylline on the contractile function of the diaphragm was studied in four normal subjects. The contractility of the diaphragm was assessed by the measurement of transdiaphragmatic pressure (Pdi) after right phrenic nerve stimulation at 1 Hz. Pdi was measured before and during aminophylline infusion (6 mg/kg over 30 minutes), during which therapeutic concentrations of theophylline were attained (mean 13.8 mg/l, range 8.5-20.2). The Pdi achieved was not affected by aminophylline. This result suggests that theophylline at therapeutic concentrations has little effect on the contractility of the normal human diaphragm.     

Effects of aminophylline on diaphragmatic dysfunction after upper abdominal surgery

The effects of upper abdominal surgery on diaphragmatic function were studied in eight supine patients before and after administration of aminophylline. Changes in pleural (delta Ppl) and gastric pressure (delta Pga) swings were measured with balloon catheter systems. Transdiaphragmatic pressure change (delta Pdi) was calculated as the difference delta Pga-delta Ppl. The ratio delta Pga/delta Pdi, used as an index of the diaphragmatic contribution to the quiet breathing process, decreased significantly as early as 1 h after operation without any further change throughout the 6-h period studied. Administration of aminophylline (6 mg/kg), six hours postoperatively, produced a significant increase in this diaphragmatic index. These data indicate that the early reduced diaphragmatic activity, after upper abdominal surgery, partially may be reversed by administration of aminophylline. The mechanism of its action may involve central nervous stimulation and/or a direct inotropic effect on diaphragmatic muscle. Further studies are needed to evaluate if the correction of altered diaphragmatic motion by aminophylline improves postoperative lung function.     

Comparative effects of xenon and nitrous oxide on diaphragmatic contractility in dogs

BACKGROUND: Xenon at two different concentrations (30%, 60%) has no effect on diaphragmatic contractility. This study was undertaken to compare the effects of xenon and nitrous oxide (N2O), a commonly used and well-established gas anesthetic, on diaphragmatic contractility in dogs. METHODS: Twenty-one pentobarbitone-anesthetized dogs were randomly divided into three groups of seven each: group 1 received xenon 30% (0.25 MAC) in oxygen; group 2 received N2O 47% (0.25 MAC) in oxygen; and group 3 received N2O 60% (0.32 MAC) in oxygen. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi) at low- (20-Hz) and high-frequency (100-Hz) stimulation, after maintaining 60 min of stable condition. The integrated electrical activity of diaphragm (Edi) to each stimulus was measured. RESULTS: With an inhalation of xenon 30%, N2O 47%, or N2O 60%, Pdi and Edi at both stimuli did not change. No difference in Pdi or Edi was observed among the groups. CONCLUSION: When used at clinical concentration, xenon or N2O does not affect contractility and electrical activity of the diaphragm in dogs.     

Effects of isoflurane on contractile properties of diaphragm

Isoflurane has been shown to depress skeletal muscle force in vitro, but data are not available regarding the effects of isoflurane on diaphragmatic muscle function in vivo. To answer this question, 15 rats anesthetized with pentobarbital and mechanically ventilated were studied. They were divided into three groups of five animals each, according to the administered concentration of isoflurane. Diaphragmatic function was assessed by measuring the transdiaphragmatic pressure (Pdi) generated during bilateral supramaximal phrenic nerve stimulation at 0.5 Hz, 20 Hz, 50 Hz, and 100 Hz under quasi-isometric conditions. After a control measurement (C), isoflurane was administered at a constant concentration (0.5, 1, or 1.5 MAC) and Pdi measurements were repeated after 30 min of isoflurane exposure (T1) and 30 min after discontinuing isoflurane (T2). In the group breathing 1.5 MAC isoflurane, the time constant of diaphragmatic relaxation (tau) and integrated electrical activity of the diaphragm (Edi) were also assessed. The Pdi amplitude generated by single twitch (0.5 Hz) was unchanged at the three isoflurane concentrations. A significant increase in Pdi at 20 Hz was observed at T1, which returned to control after 30 min recovery (T2). No change in Pdi during 50 Hz stimulation was noted during 0.5 and 1 MAC isoflurane exposure, whereas it was reduced at T1 during 1.5 MAC. For 100 Hz stimulation, a significant decrease in Pdi was noted for all groups at T1, which returned toward control values at T2. Edi was markedly reduced for 50 and 100 Hz stimulation, but this reduction was also transient, since Edi returned toward control values at T2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Flumazenil recovers diaphragm muscle dysfunction caused by midazolam in dogs

We studied the effects of flumazenil on diaphragm muscle dysfunction caused by midazolam in dogs. Animals were divided into three groups of eight each. In each group, anesthetic doses (0.1 mg/kg initial dose plus 0.5 mg. kg(-1). h(-1) maintenance dose) of midazolam were administered for 60 min. Immediately after the end of midazolam administration, Group 1 received no study drug; Group 2 was infused small-dose (0.004 mg. kg(-1). h(-1)) flumazenil; Group 3 was infused with large-dose (0.02 mg. kg(-1). h(-1)) flumazenil. We assessed diaphragm muscle function (contractility and electrical activity) by transdiaphragmatic pressure (Pdi) and integrated electrical activity of the diaphragm (Edi). After midazolam was administered in each group, Pdi at low-frequency (20-Hz) and high-frequency (100-Hz) stimulation decreased from baseline values (P < 0.05), and values of Edi at 100-Hz stimulation were less than those obtained during baseline (P < 0.05). In Group 1, Pdi and Edi to each stimulus did not change from midazolam-induced values. In Groups 2 and 3, with an infusion of flumazenil, Pdi at both stimuli and Edi at 100-Hz stimulation increased from midazolam-induced values (P < 0.05). The increase in Pdi and Edi was more in Group 3 than in Group 2 (P < 0.05). We conclude that flumazenil recovers the diaphragm muscle dysfunction (reduced contractility and inhibited electrical activity) caused by anesthetic doses of midazolam in dogs. IMPLICATIONS: In dogs, flumazenil recovers diaphragm muscle dysfunction (reduced contractility and inhibited electrical activity) caused by midazolam in a dose-related manner.     

RETRACTED ARTICLE: Contractility of fatigued diaphragm is improved by dobutamine

The effects of dobutamine (DOB) on diaphragmatic fatigue were examined in 20 anaesthetized, mechanically ventilated dogs. Animals were divided into two groups: the DOB group (n = 10) and the control group (n = 10). Diaphragmatic fatigue was induced by intermittent supramaximal electric stimulation applied to bilateral phrenic nerves at a frequency of 20 Hz for 30 min. Diaphragmatic contractility was assessed with transdiaphragmatic pressure (Pdi). After diaphragmatic fatigue, Pdi decreased at low-frequency (20 Hz) stimulation (P < 0.05), whereas the decrease was minimal at high-frequency (100 Hz) stimulation. In the DOB group, after producing fatigue, the continuous administration of 10 μg · kg^?1 · min^?1 dobutamine iv for 30 min produced an increased Pdi at both frequencies of stimulation (P < 0.05). The Pdi returned to pre-fatigue values after cessation of dobutamine administration. In the control group, the speed of recovery from fatigue was much slower at low-frequency stimulation. The integrated diaphragmatic electric activity (Edi) in the two groups did not change throughout the experiment at any frequency of stimulation. We conclude that dobutamine improves contractility in fatigued diaphragm.     

Position and motion of the human diaphragm during anesthesia-paralysis

Regional motion of the human diaphragm was determined by high-speed, three-dimensional x-ray computed tomography. Six healthy volunteers were studied first while awake and breathing spontaneously and again while anesthetized-paralyzed and their lungs ventilated mechanically. Tidal volume (VT) and respiratory frequency were similar during both conditions. Three subjects were studied while they were supine and three while they were prone. During spontaneous breathing, movement of dependent diaphragm regions was greater than that of nondependent regions in four of six subjects. In five of the six subjects, dorsal diaphragm movement exceeded ventral movement regardless of body position. The volume displaced by the diaphragm (delta Vdi) was similar to VT in supine subjects but tended to be less than VT in prone subjects. After induction of anesthesia-paralysis, the end-expiratory position of the diaphragm did not change consistently in supine subjects, whereas a consistent cephalad volume shift occurred in prone subjects. During anesthesia-paralysis and mechanical ventilation, delta Vdi was reduced to approximately 50% of VT in both body positions. In the supine position, the pattern of diaphragm motion during mechanical inflation was nearly uniform. By contrast, in the prone position, the motion was nonuniform, with most motion occurring in the dorsal (nondependent) regions. It is concluded that the dominant influence on diaphragm motion may be some anatomical difference between the crural and costal diaphragm regions rather than the abdominal hydrostatic pressure gradient.     

Effect of halothane on diaphragmatic muscle function in pentobarbital-anesthetized dogs

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.     

RETRACTED ARTICLE: Amrinone improves contractility of fatigued diaphragm in dogs

The effects of amrinone, a bipyridine derivative, on diaphragmatic contractility and fatigue were examined in 36 anaesthetized, mechanically ventilated dogs divided into four groups. In Group Ia (n = 8), dogs without diaphragmatic fatigue were given a bolus injection (0.75 mg · kg^?1) followed by continuous infusion (10 μg · kg^?1 · min^?1) of amrinone iv. In Group Ib (n = 8), animals without fatigue received infusion only of maintenance fluid. In Group IIa (n = 10) and Group IIb (n = 10), diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After producing fatigue, amrinone (0.75 mg · kg^?1 loading dose plus 10 μg · kg^?1 · min^?1 maintenance dose) iv were administered in Group IIa. Only maintenance fluids were administered in Group IIb during this period. Diaphragmatic contractility was assessed in each group by measuring transdiaphragmatic pressure (Pdi). Compared with Group Ib, Pdi at any stimuli in Group Ia did not differ. After producing fatigue, in Group IIa and Group IIb, Pdi decreased at low-frequency (10–30 Hz) stimulation (P < 0.05), whereas no change in Pdi was observed at high-frequency (50–100 Hz) stimulation. In Group IIa, Pdi to each stimulus increased during amrinone infusion compared with Group IIb (P < 0.05). In Group IIb, the speed of recovery from fatigue was relatively slower at low-frequency stimulation. The integrated diaphragmatic electric activity (Edi) did not change throughout the experiment. These results indicate that amrinone improves contractility in the fatigued diaphragm.     

Colforsin daropate improves contractility in fatigued canine diaphragm

We studied the effects of colforsin daropate, a water-soluble forskoline derivative, on contractility in fatigued canine diaphragm. Dogs were randomly divided into 4 groups of 8 each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. Immediately after the end of a fatigue-producing period, Group 1 received no study drug, Group 2 was infused with small-dose colforsin daropate (0.2 microg. kg(-1). min(-1)), Group 3 was infused with large-dose colforsin daropate (0.5 microg. kg(-1). min(-1)), and Group 4 was infused with nicardipne (5 microg. kg(-1). min(-1)) during colforsin daropate (0.5 microg. kg(-1). min(-1)) administration. After the fatigue-producing period, in each group transdiaphragmatic pressure (Pdi) at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups 2 and 3, during colforsin daropate administration, Pdi to each stimulus increased from fatigued values (P < 0.05). The increase in Pdi was larger in Group 3 than in Group 2 (P < 0.05). In Group 4, the augmentation of Pdi by colforsin daropate was abolished in fatigued diaphragm with an infusion of nicardipine. The integrated diaphragmatic electric activity did not change in any of the groups. We conclude that colforsin daropate improves, in a dose-dependent manner, contractility in fatigued canine diaphragm via its effect on transmembrane calcium movement. IMPLICATIONS: Diaphragmatic fatigue is implicated as a cause of respiratory failure in normal subjects and in patients with chronic obstructive lung disease. Colforsin daropate improves contractile properties during diaphragmatic fatigue.