Department of Anaesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki 305-8576, Japan *Corresponding author
Accepted for publication: October 29, 2001
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Abstract |
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Methods. Diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz stimulation applied for 30 min. When fatigue was established, group I (n=8) received inhaled vehicle; group II (n=8) received inhaled olprinone 1 mg; group III (n=8) received inhaled olprinone 2 mg. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi, cm H2O).
Results. In the presence of fatigue, in each group, Pdi at low-frequency (20 Hz) stimulation decreased from baseline values (P<0.05), whereas Pdi at high-frequency (100 Hz) stimulation did not change. In groups II and III, during olprinone administration, Pdi at both stimuli increased from fatigued values (20 Hz stimulation: group II (mean (SD)) 10.8 (1.0) to 12.5 (1.3), group III 10.9 (1.7) to 15.0 (3.0); 100 Hz stimulation: group II 20.1 (1.9) to 22.6 (1.3), group III 20.6 (2.0) to 24.5 (2.0), P<0.05). The increase in Pdi was larger in group III than in group II (P<0.05).
Conclusions. Inhaled olprinone produces a dose-dependent improvement in contractility of fatigued canine diaphragm.
Br J Anaesth 2002; 88: 40811
Keywords: ventilation, diaphragm, fatigue; pharmacology, phosphodiesterase III inhibitor, olprinone; dog
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Introduction |
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Methods |
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The phrenic nerves were exposed bilaterally at the neck, and stimulating electrodes were placed around them. Transdiaphragmatic pressure (Pdi) was measured using two thin-walled latex balloons: one positioned in the stomach, the other in the middle third of the oesphagus. Balloons were connected to a differential pressure transducer and an amplifier. Supramaximal electrical stimuli (1015 V) of 0.1 ms duration were applied for 2 s at low-frequency (20 Hz) and high-frequency (100 Hz) stimulation with an electrical stimulator. The isometric contractility of the diaphragm was evaluated by measuring maximal Pdi after airway occlusion at FRC. Transpulmonary pressure (Ptp), the difference between airway and oesophageal pressures, was maintained by maintaining same lung volume before each phrenic stimulation. End-expiratory diaphragmatic geometry and muscle fibre length during contraction were kept constant by placing a close-fitting plaster cast around the abdomen and lower one-third of the rib cage. Electrical activity of crural (Edi-cru) and costal (Edi-cost) parts of the diaphragm was recorded by two pairs of fishhook electrodes placed through a midline laparotomy: electrodes were positioned into the anterior portion of crural part near the central tendon and the anterior portion of costal part (away from the zone of apposition) in the left hemidiaphragm. Each pair was placed in parallel fibres 56 mm apart. The abdomen was then sutured in layers. The signal was rectified and integrated with a leaky integrator with a time constant of 0.1 s, and was regarded as the integrated diaphragmatic electrical activity (Edi-cru, Edi-cost).
Twenty-four dogs were randomly divided into three groups of eight each. After measuring the pre-fatigued (baseline) values of Pdi, Edi-cru, Edi-cost, and haemodynamic variables, in each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation applied for 30 min at a frequency of 20 Hz, an entire cycle of 4 s, and a duty cycle of 0.5 (i.e. low-frequency fatigue).7 Olprinone 1 mg (group II), olprinone 2 mg (group III), or vehicle (group I) was inhaled from DeVilbiss 646 nebulizer (DeVilbiss Co., Somerset, PA, USA) operated by compressed air at 5 litre1 min1. The nebulizer output was 0.14 ml min1. The dose of olprinone chosen in this experiment was based on the study of Myou and colleagues.6 Thirty minutes after the start of inhalation, in each group, Pdi, Edi-cru, Edi-cost, heart rate, and mean arterial pressure (MAP) were measured.
Values are mean (SD). Statistical analysis was performed by ANOVA for repeated measurements with Bonferronis adjustment for multiple comparison and Students t-test, where appropriate. A P value of <0.05 was considered significant.
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Results |
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Discussion |
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Hypoxaemia, hypercapnia, and metabolic acidosis decrease contractility of the diaphragm.9 10 The PaO2, PaCO2, pHa, and HCO3 concentration were controlled within normal ranges in this study. Therefore, these factors that could have affected diaphragmatic contractility were excluded. In addition, it has been reported that pentobarbitone, at the dose used in this experiment, does not affect diaphragmatic contractility.11 This was also in accordance with our results in group I showing no change in Pdi.
Low-frequency fatigue is of particular clinical importance because the spontaneous, natural rate of phrenic nerve discharge is mainly in the low-frequency ranges (i.e. 530 Hz).12 Therefore, the effect of inhaled olprinone on contractility in fatigued diaphragm induced by 20 Hz stimulation (i.e. low-frequency fatigue) was examined. Following a fatigue-producing period, in each group, Pdi at 20 Hz stimulation decreased from baseline values (P<0.05), whereas Pdi at 100 Hz stmulation did not change. The results of group I, in which Pdi was observed without inhalation of olprinone in fatigued diaphragm, showed that the speed of recovery from fatigue was relatively slower at 20 Hz stimulation than at 100 Hz stimulation, and also showed that Edi to each stimulus did not change. This was in agreement with previous studies by us.35
PDE III inhibitorsincluding amrinone, milrinone, and olprinoneadministered i.v. at doses used clinically have been shown previously to increase contractility of fatigued diaphragm.35 Amrinone (10 µg kg1 min1) increases Pdi by 55% at 20 Hz stimulation and by 9% at 100 Hz stimulation; milrinone (0.5 µg kg1 min1) increases Pdi by 69% and by 23% at each stimulus; olprinone (0.3 µg kg1 min1) increases Pdi by 85% and by 35% at each stimulus.35 Thus, PDE III inhibitors affect Pdi at 20 Hz stimulation more when compared with Pdi at 100 Hz stimulation. We have no explanation for this difference, but olprinone is more effective than amrinone or milrinone for the augmentation of contractility in fatigued diaphragm. In the present study, Pdi at 20 and 100 Hz stimulation increased from fatigued values (P<0.05) when olprinone was administered by inhalation in groups II and III. The increase in Pdi at both stimuli was also larger in group III than in group II (P<0.05). These observations suggest that inhaled olprinone, in addition to i.v. olprinone, improves contractility of fatigued diaphragm, in a dose-related manner.
Diaphragmatic blood flow is an important determinant factor in diaphragm muscle function12 and is also maintained relatively constant within a certain limit of perfusion pressure.13 When MAP increases to >9.3 kPa, diaphragmatic blood flow is not reduced.14 In this study, however, MAP <9.3 kPa was not observed with an inhlation of olprinone in groups II and III. Therefore, the decrease in MAP during olprinone inhalation would not affect diaphragmatic contractility. Additionally, cardiovascular effects were not evident in group II (no changes in heart rate and MAP) during olprinone inhalation while the effects on Pdi at both stimuli were significant. This suggests that the action of inhaled olprinone on heart rate and MAP are not important for its effects on contractility in the fatigued diaphragm.
Olprinone, administered i.v., increases contractility of cardiac muscle by selectively inhibiting PDE III and accumulating cyclic AMP intracellularly, which, in turn, induces the activation of Ca2+ transport from the sarcoplasmic reticulum.14 In a previous report by us,5 to clarify the mechanism responsible for the effects of olprinone administered i.v. on contractility of fatigued diaphragm, combined olprinone and nicardipine, a calcium antagonist which inhibits Ca2+ influx into diaphragmatic muscle,15 was administered. Augmentation of Pdi by olprinone was abolished by administation nicardipine, suggesting that olprinone may increase contractility of fatigued diaphragm by influencing Ca2+ transport across the cell membrane. Why the fatigued diaphragmatic contractility was enhanced during olprinone inhalation is not known. The mechanisms of action of inhaled olprinone in the improvement of contractility in fatigued diaphragm may be similar to that of i.v. olprinone. However, further studies with inhaled olprinone and nicardipine are required.
In summary, inhaled olprinone produced a dose-dependent improvement, in contractility of fatigued canine diaphragm.
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Acknowledgement |
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References |
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2 Karlsberg RP, DeWood MA, DeMaria AN, et al. Comparative efficacy of short-term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Clin Cardiol 1996; 19: 2130[ISI][Medline]
3 Fujii Y, Toyooka H, Amaha K. Amrinone improves contractility of fatigued diaphragm in dogs. Can J Anaesth 1995; 42: 806[Abstract]
4 Fujii Y, Takahashi S, Toyooka H. The effects of milrinone and its mechanism in fatigued diaphragm in dogs. Anesth Analg 1998; 87: 107782[Abstract]
5
Fujii Y, Takahashi S, Toyooka H. The effect of olprinone compared with milrinone on diaphragmatic muscle function in dogs. Anesth Analg 1999; 89: 7815
6
Myou S, Fujimura M, Kamio Y, et al. Bronchodilater effect of inhaled olprinone, a phosphodiesterase 3 inhibitor, in asthmatic patients. Am J Respir Crit Care Med 1999; 160: 81720
7
Aubier M, Farkas G, DeTroyer A, et al. Detection of diaphragmatic fatigue in man by phrenic nerve stimulation. J Appl Physiol 1981; 50: 53844
8
Grassino A, Goldman MD, Mead J, Sears TA. Mechanics of the human diaphragm during voluntary contraction: statics. J Appl Physiol 1978; 44: 82939
9 Esau SA. Hypoxic, hypercapnic acidosis decreases tension and increases fatigue in hamster diaphragmatic muscle in vitro. Am Rev Respir Dis 1989; 139: 14107[ISI][Medline]
10
Howell S, Fitzgerald RS, Roussos C. Effect of uncompensated and compensated metabolic acidosis on canine diaphragm. J Appl Physiol 1985; 59: 137682
11 Ide T, Kochi T, Isono S, Mizuguchi T. Effect of sevoflurane on diaphragmatic contractility in dogs. Anesth Analg 1992; 74: 73946[Abstract]
12 Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982; 307: 78697[ISI][Medline]
13
Reid MB, Johnson RT. Efficacy, maximal blood flow, and aerobic work capacity of canine diaphragm. J Appl Physiol 1983; 54: 76372
14
Hussain SNA, Roussos C, Magder S. Autoregulation of diaphragmatic blood flow. J Appl Physiol 1988; 64: 32936
15 Satoh H, Endoh M. Effects of a new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-[imidazol(1,2-a)pyridine-6-yl]-3-pyridine carbonitrile hydrochloride monohydrate (E-1020) on contractile force and cyclic AMP metabolism in canine ventricular muscle. Jpn J Pharmacol 1990; 52: 21524[ISI][Medline]