Fatigue-producing Period Research Articles

Olprinone/dopamine combination for improving diaphragmatic fatigue in pentobarbital-anesthetized dogs

Background: Diaphragmatic fatigue might contribute to the development of respiratory failure. In particular, the spontaneous, natural rate of phrenic nerve discharge occurs mainly in low-frequency ranges making low-frequency fatigue clinically important in both humans and animals. Olprinone, a phosphodiesterase 3 inhibitor, improves contractility in fatigued diaphragm, but is also associated with hypotension. Dopamine might be used concomitantly for treating related hypotension. Objective: The purpose of the study was to assess the effect of olprinoneplus dopamine on diaphragmatic fatigue in pentobarbital-anesthetized dogs. Methods: This nonblinded study was conducted at the Department ofAnesthesiology, Institute of Clinical Medicine, Tsukuba, Japan. Diaphragmatic fatigue (assessed by a decrease in diaphragmatic contractility) was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 minutes. Immediately after the fatigue-producing period, groups 2, 3, and 4 received an initial 10 μg/kg dose of olprinone. Group 2 then received maintenance olprinone of 0.3 μg/kg · min; group 3 received maintenance olprinone 0.3 μg/kg · min plus dopamine 2 μg/kg · min; and group 4 received maintenance olprinone 0.3 μg/kg · min plus dopamine 5 μg/kg · min. Group 1 received no study drug. Olprinone and dopamine were administered IV for 30 minutes. Diaphragmatic contractility was assessed by measuring the maximal transdiaphragmatic pressure (Pdi) generated by test stimuli after airway occlusion at functional residual capacity. Hypotension induced by the study drugs was defined as a >10 mm Hg decrease in mean arterial pressure (MAP), calculated by diastolic pressure plus ⅓ pulse pressure, from baseline. Results: Twenty-eight mongrel dogs (18 males and 10 females, weighing 10-15 kg)were used in the study; 7 dogs were randomly assigned to each treatment group. When fatigue was established in each group, mean (SD) Pdi at low-frequency (20 Hz) stimulation decreased significantly from baseline in all groups (group 1: 15.6 [2.2] vs 11.7 [2.4] cm H 2O, P = 0.008; group 2: 15.4 [1.5] vs 11.6 [1.3] cm H 2O, P= 0.005; group 3:15.5 [2.0] vs 11.6 [1.8] cm H 2O, P= 0.006; group 4: 15.7 [1.4] vs 12.0 [1.4] cm H 2O, P= 0.008), while no significant change existed in Pdi at high-frequency (100 Hz) stimulation ( P = NS). After study drug administration, Pdi in groups 2, 3, and 4 increased significantly from fatigued values at both 20 Hz stimulation (group 2: 11.6 [1.3] vs 21.8 [2.0] cm H 2O, P = 0.001; group 3: 11.6 [1.8] vs 22.2 [1.8] cm H 2O, P = 0.001; group 4: 12.0 [1.4] vs 25.9 [1.9 ] cm H 2O, P = 0.001) and 100 Hz stimulation (group 2: 22.0 [2.2] vs 29.0 [1.9] cm H 2O, P = 0.002; group 3: 22.1 [2.0] vs 29.3 [2.2] cm H 2O, P = 0.002; group 4: 21.8 [2.2] vs 31.7 [2.4] cm H 2O, P= 0.001). The increase in Pdi was significantly larger in group 4 compared with the other 3 groups (all, P < 0.05). Hypotension was not observed in group 4. MAP did not change significantly in group 1 or group 4 compared with baseline or fatigued MAP values ( P = NS). Groups 2 and 3 had significant decreases in MAP with treatment compared with values in group 1 and with baseline and fatigued MAP values (all, P < 0.05). The MAP of group 4 was significantly greater than the MAP of groups 2 and 3 with treatment (both, P < 0.05). Conclusions: Olprinone 0.3 μg/kg sd min plus dopamine 5 μg/kg · min improved contractility in fatigued diaphragms and was not associated with hypotension in these pentobarbital-anesthetized dogs. Olprinone monotherapy and olprinone 0.3 μg/kg · min plus dopamine 2 μg/kg · min might improve contractility significantly. However, it was also associated with significant decreases in MAP.

Inhaled milrinone for the improvement of contractility of fatigued diaphragm in dogs: a dose-ranging study

The present study was undertaken to evaluate the efficacy of inhaled milrinone on contractility of fatigued diaphragm in dogs. Animals were divided into four groups of seven 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 I received inhaled vehicle; Group II received inhaled milrinone 0.1 mg/ml (1 mg); Group III received inhaled milrinone 0.2 mg/ml (2 mg); Group IV received 0.5 mg/ml (5 mg). Study drug was administered for 30 min. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi). After the fatigue-producing period, in each group, Pdi at low-frequency (20 Hz) decreased from baseline values ( P<0.05), and Pdi at high-frequency (100 Hz) stimulation did not change. In Groups III and IV, during milrinone inhalation, Pdi at both stimuli increased from fatigued values ( P<0.05). The increase in Pdi was more in Group IV than in Group III ( P<0.05). Compared with Group I, Pdi to each stimulus did not change in Group II. In conclusion, inhaled milrinone, in doses more than 0.2 mg/ml, is effective for improving contractility of fatigued diaphragm in dogs.

Treatment of diaphragmatic fatigue with inhaled aminophylline therapy in an experimental canine model: an open-label, dose-ranging, pharmacologic study

Background Diaphragmatic fatigue may contribute to the development of respiratory failure. Although aminophylline administered IV has been widely used to treat diaphragmatic fatigue, to date it has not been used in aerosol formulation for this purpose. Objective The aim of this study was to assess the efficacy of inhaled aminophylline on contractility of fatigued diaphragm in an experimental canine model. Methods This open-label, dose-ranging, pharmacologic study was conducted at the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba (Ibaraki, Japan). Diaphragmatic fatigue was induced in healthy, male, mongrel dogs by intermittent supramaximal bilateral electrophrenic stimulation at a low frequency (20 Hz) applied for 30 minutes. Immediately after the end of the fatigue-producing period, group 1 received inhaled vehicle only, group 2 received inhaled aminophylline 12.5 mg/mL, group 3 received inhaled aminophylline 25 mg/mL, and group 4 was infused with verapamil 0.1 mg/kg·min during inhalation of aminophylline 25 mg/mL. Diaphragmatic contractility was assessed using transdiaphragmatic pressure (Pdi). Results Twenty-eight dogs were used in the study (7 dogs were assigned to each treatment group). When fatigue was established, Pdi at low-frequency stimulation decreased significantly from baseline in all groups (all P<0.05), and no significant change in Pdi was found at high-frequency stimulation. In groups 2 and 3, during aminophylline inhalation, Pdi at 20-Hz stimulation increased significantly from fatigued values (both P<0.05). Pdi increased significantly more in group 3 than in group 2 ( P<0.05). In group 4, infusion of verapamil offset the increase in Pdi seen with aerosolized aminophylline in fatigued diaphragm. The integrated electrical activity of the diaphragm did not change significantly in any group. Conclusions Inhaled aminophylline significantly improved contractility of fatigued diaphragm in a dose-related manner in this experimental canine model ( P<0.05). Its potent effect may be caused by transmembrane calcium movement.

Olprinone for the treatment, but not prevention, of fatigue-induced changes in guinea-pig diaphragmatic contractility.

Olprinone, a phosphodiesterase III inhibitor, improves the contractility in fatigued diaphragm in vivo, but no data are available for the treatment and prevention of fatigue-induced changes in vitro. We therefore examined the efficacy of Olprinone for the treatment and prevention of fatigue-induced changes in guinea-pig diaphragmatic contractility. The guinea-pig diaphragm strips were randomly allocated according to dose of Olprinone (0, 10(-6), 10(-5), and 10(-4) M) (n = 7 each) and were stimulated directly in an organ bath. Diaphragmatic contractility was measured by assessing twitch tension and force at 20-Hz and 100-Hz stimulation. Diaphragmatic fatigue was induced by generating rhythmic, repetitive contractions produced by 20-Hz stimulation for 5 min. In the first experiment, after the fatigue-producing period, Olprinone was administered to the organ bath for 5 min. In the second experiment, Olprinone was pretreated for 5 min, and then diaphragmatic fatigue was produced. In Experiment 1, after a fatigue-producing period, tetanic force to each stimulus decreased from baseline values (P < 0.05). Olprinone 10(-5)-10(-4) M caused an increase in force at both stimuli from fatigued values (P < 0.05). In Experiment 2, no change in tetanic force was observed by pretreatment with Olprinone (0-10(-4) M). After producing fatigue, tetanic force to each stimulus decreased from baseline values (P < 0.05). These results suggest that Olprinone 10(-5)-10(-4) M improves the fatigue-induced changes in guinea-pig diaphragmatic contractility and that pretreatment with Olprinone does not prevent diaphragmatic fatigability. Olprinone is effective for the treatment, but not prevention, of fatigue-induced changes in guinea-pig diaphragmatic contractility.

The Effect of Inhaled Colforsin Daropate on Contractility of Fatigued Diaphragm in Dogs

We studied the effect of inhaled colforsin daropate, a water-soluble forskolin derivative, on the contractility of fatigued diaphragm in dogs. Animals were divided into 3 groups of 8. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20-Hz stimulation applied for 30 min. Immediately after the end of the fatigue-producing period, Group 1 received inhaled vehicle, Group 2 received inhaled colforsin daropate 0.1 mg/mL, and Group 3 received inhaled colforsin daropate 0.2 mg/mL. We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). After fatigue was produced, in each group, Pdi at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), and there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups 2 and 3, during colforsin daropate inhalation, Pdi at both stimuli increased from fatigued values (P < 0.05). The increase in Pdi was significantly larger in Group 3 than in Group 2. The integrated electrical activity of the diaphragm did not change in any group. We conclude that inhaled colforsin daropate causes an increase in contractility of fatigued canine diaphragm in a dose-related fashion. Diaphragmatic fatigue may contribute to the development of respiratory failure. Inhaled colforsin daropate improves, in a dose-dependent manner, the contractility of fatigued diaphragm in dogs.

The Dose-Related Efficacy of Diltiazem for Enhancing Diaphragmatic Fatigability in Dogs

Nicardipine, a calcium channel blockade, enhances the production of diaphragmatic fatigue. We studied the dose-related effects of diltiazem, another calcium channel blockade, on diaphragmatic fatigability in dogs. Animals 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 applied for 30 min. During this fatigue-producing period, Group I received no study drug, Group II was infused with diltiazem 0.1 mg. kg(-1). h(-1), and Group III was infused with diltiazem 0.5 mg. kg(-1). h(-1). We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). After the fatigue-producing period, in Group I, 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 II and III, with an infusion of diltiazem, Pdi at both stimuli decreased from baseline values (P < 0.05). The decrease in Pdi to each stimulus was more in Group III than in Group II (P < 0.05). We conclude that diltiazem causes a dose-related augmentation of fatigability in the diaphragm of dogs. Diaphragmatic muscle fatigue is implicated as a cause of respiratory failure. Diltiazem, a calcium channel blockade, enhances diaphragmatic fatigability in dogs in a dose-related manner.

The dose-range effects of propofol on the contractility of fatigued diaphragm in dogs.

Diaphragmatic fatigue may contribute to the development of respiratory failure. We studied the dose-range effects of propofol on the contractility of fatigued diaphragm in dogs. Animals 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. Immediately after the end of a fatigue-producing period, Group 1 received no study drug; Group 2 was infused with small-dose propofol (0.1 mg/kg initial dose plus 1.5 mg x kg(-1) x h(-1) maintenance dose); Group 3 was infused with large-dose propofol (0.1 mg/kg initial dose plus 6.0 mg x kg(-1) x h(-1) maintenance dose). We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). After the fatigue-producing period, in each group, 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, with an infusion of propofol, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05). Compared with Group 1, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05) during propofol administration in Groups 2 and 3. The decrease in Pdi was more in Group 3 than in Group 2 (P < 0.05). We conclude that propofol decreases the contractility of fatigued canine diaphragm in a dose-related fashion. Propofol is a widely used IV anesthetic for the induction and maintenance of general anesthesia and sedation. It decreases, in a dose-related fashion, the contractility of fatigued diaphragm in dogs.

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. 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.

Milrinone enhances the contractility of fatigued diaphragm in dogs: a dose-ranging study.

The dose-related effects of milrinone, a phosphodiesterase (PDE) III inhibitor, on the contractility of fatigued diaphragm were studied in dogs. Animals were divided into three groups of eight each. Diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After the production of fatigue, Group I received no study drug; Group II was infused with milrinone (50 mg kg-1 loading dose plus 0.2 mg kg-1 min-1 maintenance dose); Group III was infused with milrinone (50 mg kg-1 loading dose plus 0.5 mg kg-1 min-1 maintenance dose). Diaphragmatic contractility was assessed by measurement of transdiaphragmatic pressure. After the fatigue-producing period, transdiaphragmatic pressure at low-frequency stimulation (20-Hz) decreased from the prefatigued values in all groups (P < 0.05), whereas transdiaphragmatic pressure at high-frequency (100-Hz) stimulation did not change. Compared with Group I, transdiaphragmatic pressure to each stimulus increased during milrinone infusion in Groups II and III (P < 0.05). The increase in trans-diaphragmatic pressure was greater in Group III than in Group II (P < 0.05). It is concluded that milrinone is associated with a dose-related effect on the contractility of fatigued diaphragm in dogs.

The effects of milrinone and its mechanism in the fatigued diaphragm in dogs.

We studied the effects of milrinone and its mechanism in nonfatigued and fatigued diaphragms in dogs. In Group Ia (n = 5), animals without fatigue, defined as the inability to sustain muscle force, received only maintenance fluids. In Group Ib (n = 5), dogs without fatigue were given a bolus injection (50 microg/kg) followed by continuous infusion (0.5 microg x kg(-1) x min(-1)) of milrinone. In Groups IIa, IIb, and IIc (n = 8 in each), diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After producing fatigue, only maintenance fluids were administered (Group IIa); milrinone (50 microg/kg loading dose plus 0.5 microg x kg(-1) x min(-1) maintenance dose) was administered (Group IIb); or nicardipine 5 microg x kg(-1) x min(-1) was infused simultaneously with milrinone (Group IIc). Diaphragmatic contractility was assessed with transdiaphragmatic pressure (Pdi). No differences in Pdi were observed in Groups Ia and Ib. After the fatigue-producing period, Pdi at low-frequency (20-Hz) stimulation decreased from the prefatigued values in Groups IIa, IIb, and IIc (P < 0.05), whereas the decrease was minimal at high-frequency (100-Hz) stimulation. Compared with Group IIa, Pdi to each stimulus increased during milrinone infusion in Group IIb (P < 0.05). In Group IIc, the augmentation of Pdi in the fatigued diaphragm by milrinone was not abolished with an administration of nicardipine. In conclusion, milrinone improves contractility in the fatigued canine diaphragm but not via its effect on transmembrane calcium movement. Diaphragmatic fatigue may contribute to the development of respiratory failure. Milrinone increases contractility in the fatigued diaphragm and thereby may have an inotropic action on the improvement of diaphragmatic fatigue.

RETRACTED ARTICLE: Effects of nicardipine on diaphragmatic fatigue in the dog: The relationship between dosage and fatigability

We examined the dose-related effects of nicardipine on the diaphragmatic fatigability in 24 anesthetized, mechanically ventilated dogs. Animals were divided into three groups of eight each: the control group (group C), the nicardipine 3 μg·kg(-1) I.V. group (group N1) and the nicardipine 5 μg·kg(-1)·min(-1) I.V. group (group N2). Diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. In groups N1 and N2, nicardipine was continuoulsy infused intravenously during this fatigueproducing period. Diaphragmatic contractility was assessed by changes in transdiaphragmatic pressure (Pdi). After induction of diaphragmatic stimulation at low-frequency (20 Hz), Pdi decreased significantly in all groups compared with the prefatigue value (P<0.05), whereas no change was observed in Pdi at high-frequency (100 Hz) stimulation. The Pdi at 20 Hz stimulation was significantly lower in groups N1 and N2 compared with that in group C (P<0.05). The decrease in Pdi at 20 Hz stimulation was significantly larger in group N2 than in group N1 (P<0.05). The speed of recovery of Pdi at 20 Hz stimulation was dose dependent. The integrated diaphragmatic electric activity (Edi) in each group did not change at any frequency of stimulation throughout the study. Our results demonstrate that nicardipine causes a dose-dependent reduction of the contractility of the fatigued diaphragm.

Nicardipine enhances diaphragmatic fatigue

The effects of nicardipine, a calcium channel blocker, on diaphragmatic fatigue were studied in 20 anaesthetized, mechanically ventilated dogs divided into two groups: control group (Group C, n = 10) and nicardipine group (Group N, n = 10). Diaphragmatic fatigue was induced by intermittent supramaximal electric stimulation to bilateral phrenic nerves at a frequency of 20 Hz for 30 min. In Group N, 5 micrograms.kg-1.min-1 nicardipine iv was infused continuously during this fatigue-producing period. Transdiaphragmatic pressure (Pdi) produced by electrical stimulation (10-100 Hz) of the phrenic nerves was used as an index of diaphragmatic contractility. After a fatigue-producing period, the Pdi in both groups decreased at low frequency (10-30 Hz) stimulation compared with pre-fatigue values (P < 0.05), whereas no change in Pdi was observed at high-frequency (50-100 Hz) stimulation. The decrease of Pdi at low-frequency stimulation was larger in Group N (P < 0.05). The integrated diaphragmatic electric activity (Edi) in both groups did not change at any frequency of stimulation throughout the experiment. We conclude that nicardipine enhances diaphragmatic fatigue.