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Anesth Analg 1999;89:781
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

The Effect of Olprinone Compared with Milrinone on Diaphragmatic Muscle Function in Dogs

Yoshitaka Fujii, MD, Shinji Takahashi, MD, and Hidenori Toyooka, MD

Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba City, Ibaraki, Japan

Address correspondence and reprint requests to Yoshitaka Fujii, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2–1-1, Amakubo, Tsukuba City, Ibaraki 305, Japan.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We compared the effect of olprinone with milrinone on the contractility of fatigued diaphragms in dogs. Animals were divided into four groups of 10 each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After producing fatigue, Group I received only maintenance fluids; Group II was given a bolus injection (50 µg/kg) followed by continuous infusion (0.5 µg · kg-1 · min-1) of milrinone; Group III was infused with olprinone (10 µg/kg initial dose plus 0.3 µg · kg-1 · min-1 maintenance dose); Group IV was infused with nicardipine (5 µg · kg-1 · min-1) during olprinone administration. After the fatigue-producing period in each group, transdiaphragmatic pressure (Pdi) at low-frequency (20 Hz) stimulation decreased from the prefatigued values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups II and III, during study drug infusion, Pdi at both stimuli increased from fatigued values (P < 0.05). The increase in Pdi was larger in Group III than in Group II (P < 0.05). In Group IV, the augmentation of Pdi by olprinone was abolished in the fatigued diaphragm with an infusion of nicardipine. We conclude that olprinone is more effective than milrinone for the improvement of contractility in he fatigued diaphragm and that the potentiating mechanism of olprinone may be closely related to the transmembrane calcium movement.

Implications: Diaphragmatic fatigue may contribute to the development of respiratory failure. Compared with milrinone, olprinone improves the contractility in fatigued diaphragm in dogs.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Milrinone, a phosphodiesterase (PDE) III inhibitor, has both inotropic and vasodilator actions to improve hemodynamics in patients with congestive heart failure (1). It also increases the contractility in fatigued diaphragm, defined as the inability to sustain muscle force (2). Olprinone, a newly developed inhibitor of PDE III, may improve cardiac performance not only through its inotropic effects, but also through its vasodilating effects (3,4). We performed this study to assess the efficacy of olprinone versus milrinone for the improvement of contractility in the fatigued diaphragm in dogs.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The protocol was approved by our animal research committee, and care of the animals was in agreement with guidelines for ethical animal research. Forty healthy mongrel dogs weighing 10–15 kg were anesthetized with pentobarbital (25 mg/kg initial dose plus 2 mg · kg-1 · h-1 maintenance dose) IV to abolish movement spontaneously. Muscle relaxants were not used. Animals were placed in the supine position, their tracheas were intubated with a cuffed tracheal tube, and the lungs were mechanically ventilated with a mixture of O2 and air (fraction of inspired oxygen 0.4) to maintain PaO2 >100 mm Hg, PaCO2 35–40 mm Hg, and pHa 7.35–7.45. The right femoral artery was cannulated to monitor arterial blood pressure and to obtain blood samples for the measurement of arterial blood gas tensions. The right femoral vein was cannulated to administer maintenance fluids (10 mL · kg-1 · h-1 lactated Ringer's solution), pentobarbital, and bicarbonate to keep the plasma HCO3- concentration within normal ranges. The left femoral vein was cannulated to administer the study drugs (milrinone, olprinone). A flow-directed pulmonary artery catheter was advanced via the right external jugular vein into the pulmonary artery for the measurement of cardiac output (CO) by thermodilution technique. Rectal temperature was monitored continuously and maintained at 37 ± 1°C.

The phrenic nerves were exposed bilaterally at the neck, and the stimulating electrodes were placed around them. Transdiaphragmatic pressure (Pdi) was measured by using two thin-walled latex balloons: one positioned in the stomach, the other positioned in the middle third of esophagus. The balloons were connected to a differential pressure transducer (TP-604 T; Nihon Kohden, Tokyo, Japan) and an amplifier (Type 1257; Nihondenki San-ei, Tokyo, Japan). Supramaximal electrical stimuli (10–15 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 (SEN-3301; Nihon Kohden). The isometric contractility of the diaphragm was evaluated by measuring the maximal Pdi after airway occlusion at the functional residual capacity. Transpulmonary pressure, the difference between airway and esophageal pressures, was kept constant by maintaining same lung volume before each phrenic stimulation. End-expiratory diaphragmatic geometry and muscle fiber length during contraction were kept constant by placing a close-fitting plaster cast around the abdomen and lower one third of the ribcage. The electrical activity of the crural (Edi-cru) and costal (Edi-cost) parts of the diaphragm was recorded by using two pairs of fishhook electrodes placed through a midline laparotomy; electrodes were positioned into the anterior portion of the crural part near the central tendon and the anterior portion of the costal part (away from the zone of apposition) in the left hemidiaphragm. Each pair was placed in parallel fibers 5–6 mm apart. The abdomen was then sutured in layers. The signal was rectified and integrated with a leaky integrator (Type 1322; Nihondenki San-ei) with a time constant of 0.1 s and was regarded as the integrated diaphragmatic electrical activity (Edi-cru, Edi-cost).

The dogs were randomly divided into four groups of 10 each. After measuring the prefatigued (baseline) values of Pdi, Edi-cru, and Edi-cost and hemodynamic variables, including heart rate, mean arterial pressure, right atrial pressure, mean pulmonary arterial pressure, pulmonary artery occlusion pressure, and CO, 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) (5). Dogs in Group II were given a bolus injection (50 µg/kg) followed by continuous infusion (0.5 µg · kg-1 · min-1) of milrinone IV with an electrical infusion pump for 30 min after the fatigue-producing period. After milrinone administration, Pdi, Edi-cru, Edi-cost, and hemodynamic variables were measured, and CO was evaluated by the thermodilution technique. In Group III, olprinone (10 µg/kg initial dose plus 0.3 µg · kg-1 · min-1 maintenance dose) was continuously administered IV with an infusion pump for 30 min after the fatigue-producing period. In Group IV, nicardipine 5 µg · kg-1 · min-1 inhibiting calcium influx into diaphragmatic muscle (5) was infused IV continuously during olprinone administration after producing diaphragmatic fatigue. In Group I, only maintenance fluid was administered. The same measurements were performed in all groups.

All values were expressed as mean ± SD. Statistical analysis was performed by using analysis of variance for repeated measurements with the Bonferroni adjustment for multiple comparison and Student's t-test, as appropriate. A P value of < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
No differences in hemodynamic variables during the prefatigued period (baseline) were observed among the groups. With an infusion of milrinone (Group II), olprinone (Group III), or combined olprinone and nicardipine (Group IV), increases in heart rate and CO (P < 0.05) and decreases in mean arterial pressure, mean pulmonary arterial pressure, and pulmonary artery occlusion pressure (P < 0.05) were observed compared with baseline values. In Group I, there were no hemodynamic changes throughout the experiments (Table 1).


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  		Table 1. Hemodynamic Data and Changes
 
The Pdi values at different stages are shown in Table 2. After the fatigue-producing period in each group, Pdi at low-frequency (20 Hz) stimulation decreased from the prefatigued (baseline) values (P < 0.05), but Pdi at high-frequency (100 Hz) stimulation did not change. In Group I, the speed of recovery from fatigue was relatively slower at 20-Hz stimulation than at 100-Hz stimulation. In Groups II and III, Pdi at both stimuli increased from the fatigued values (P < 0.05) with an infusion of milrinone (Group II) or olprinone (Group III). The increase in Pdi response to each stimulus was larger in Group III than in Group II (P < 0.05). In Group IV, the augmentation of Pdi by olprinone in the fatigued diaphragm was abolished with an infusion of nicardipine. No changes in Edi-cru and Edi-cost were observed throughout the experiment in any of the groups. Typical recordings of Pdi, Edi-cru, and Edi-cost are shown in Figure 1.


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  		Table 2. Changes in Transdiaphragmatic Pressure
 


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  		Figure 1. Typical recordings of transdiaphragmatic pressure (Pdi), integrated electrical activity of the crural part of diaphragm (Edi-cru), and integrated electrical activity of the costal part of diaphragm (Edi-cost).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major findings of this study are: (a) contractility (as assessed by Pdi) in the fatigued diaphragm was increased during milrinone or olprinone administration without any change in Edi; (b) the increase in diaphragmatic contractility was larger with an infusion of olprinone compared with milrinone; and (c) the positive inotropic effect of olprinone was abolished by the simultaneous administration of nicardipine.

The pressure generated by the diaphragm for a given electrical stimulation is affected by its length and geometry (6). A major determinant of length and geometry of the diaphragm is lung volume. Conceivably, the change in Pdi may be secondary to changes in the end-expiratory lung volume. In this study, however, the airway was occluded at the end-expiratory lung volume during the measurements, and its constancy was monitored by measuring end-expiratory transpulmonary pressure. Therefore, changes in lung volume throughout the experiment can reasonably be excluded. The plaster cast around the abdomen and lower one third of the ribcage was also placed for the prevention of the deformation of thoracoabdominal structures.

Hypoxemia, hypercapnia, and metabolic acidosis decrease contractility in the fatigued diaphragm (7,8). In this study, however, PaO2, PaCO2, pHa, and HCO3- concentration were maintained within normal ranges. Therefore, these factors that affect diaphragmatic contractility were excluded.

The recommended method of administration of the study drugs, milrinone and olprinone, for the improvement of the myocardial performance is a 50-µg/kg bolus dose followed by a maintenance infusion of 0.5 µg · kg-1 · min-1 and a 10-µg/kg bolus dose followed by a maintenance infusion of 0.3 µg · kg-1 · min-1, respectively (1,9). We previously demonstrated that milrinone (50 µg/kg initial dose plus 0.5 µg · kg-1 · min-1 maintenance dose) is effective for the improvement of contractility in the fatigued diaphragm (2). Therefore, the same doses of these drugs were chosen in this study.

Low-frequency fatigue is of particular clinical importance because the spontaneous, natural rate of phrenic nerve discharge is mainly in the low-frequency ranges (5–30 Hz) (10). Therefore, the effect of olprinone compared with milrinone on the contractile properties was evaluated in the fatigued diaphragm induced by 20-Hz stimulation (i.e., low-frequency fatigue).

The results of Group I, which did not receive an administration of PDE III inhibitors, showed that Pdi had a tendency to recover more slowly at 20-Hz stimulation than at 100-Hz stimulation and that Edi did not change at any frequency of stimulation. This is in agreement with our previous studies (2,11,12). Methylxanthines and sympathomimetic amines produce positive inotropic effects on the fatigued diaphragm (13,14). In addition to these pharmacological agents, we previously demonstrated that milrinone improves contractility in the fatigued diaphragm (2), which is in accordance with our results in Group II.

In this study, we showed that olprinone, as well as milrinone, increased contractility in the fatigued diaphragm (Group III). The precise mechanism by which this inotropic drug enhances diaphragmatic contractility is unclear. This drug is considered to increase the cardiac muscle contractile by selectively inhibiting PDE III and accumulating cyclic AMP intracellularly, which, in turn, stimulates the sarcoplasmic reticulum calcium pump (3,4). To examine the role of transmembrane calcium movement in the potentiation of diaphragmatic contractility by olprinone, a combination of olprinone and nicardipine, a calcium antagonist, was administered. Consequently, as shown in Group IV, the potentiating effect of olprinone on fatigued diaphragm was abolished by nicardipine. This suggests that olprinone may augment force generation of fatigued diaphragm by influencing calcium transport across the cell membrane. The inotropic action of aminophylline and dobutamine on the diaphragm is abolished by calcium channel blockers such as verapamil and nicardipine (13,15). However, the potentiating effect of milrinone on contractility in the fatigued diaphragm is not abolished by nicardipine (2). Therefore, based on our results, the potentiating mechanism of olprinone on the fatigued diaphragm may be different from that of milrinone but may be similar to that of aminophylline and dobutamine.

In this study, we also showed that the administration of olprinone, compared with milrinone, enhanced Pdi in the fatigued diaphragm (P < 0.05). This suggests that olprinone is more effective than milrinone in improving contractility in the fatigued diaphragm. The exact reason for this difference is not known, but it may be attributed to the difference in positive inotropic action and potentiating mechanism of these PDE III inhibitors on the fatigued diaphragm. Although the dose (10 µg/kg initial dose plus 0.3 µg · kg-1 · min-1 maintenance dose) of olprinone used in the current animal study was effective in enhancing Pdi, it is not necessarily the optimal dose. Further studies ranging the dose-response curve for the improvement of contractility in the fatigued diaphragm by olprinone are needed to determine the optimal dose.

Blood flow to the diaphragm is an important determinant of diaphragmatic function (10). Diaphragmatic blood flow is maintained relatively constant within a certain limit of perfusion pressure (16) and is not reduced when MAP increases to >70 mm Hg (17). In this study, however, MAP <70 mm Hg was not observed in any of the groups. Therefore, the decrease in MAP during an infusion of the study drugs (i.e., milrinone, olprinone, olprinone plus nicardipine) would not affect diaphragmatic contractility.

In conclusion, compared with milrinone, olprinone is effective in improving contractility in the fatigued diaphragm in dogs, and the potentiating mechanism of olprinone may be closely related to the transmembrane calcium movement. These findings are suggestive of positive inotropic effects of olprinone on the diaphragmatic muscle function in patients with diaphragmatic fatigue, which may contribute to the development of respiratory failure.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Eichhorn EJ, Konstam MA, Weiland DS, et al. Differential effects of milrinone and dobutamine on right ventricular preload, afterload and systolic performance in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1987;60:1329–33.[ISI][Medline]
  2. Fujii Y, Takahashi S, Toyooka H. The effects of milrinone and its mechanism in the fatigued diaphragm in dogs. Anesth Analg 1998;87:1077–82.[Abstract/Free Full Text]
  3. Ogawa T, Ohhara H, Tsunoda H, et al. Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 1st communication. Studies on isolated gunia pig cardiac muscles. Res 1989;39:33–7.
  4. Ohhara H, Ogawa T, Takeda M, et al. Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate studies in dogs. Arzeim Forsch Drug Res 1989;39:38–45.
  5. Grassino A, Goldman MD, Mead J, Sears TA. Mechanics of the human diaphragm during voluntary contractions statistics. J Appl Physiol 1978;44:829–39.[Abstract/Free Full Text]
  6. Fujii Y, Toyooka H, Amaha K. Nicardipine enhances diaphragmatic fatigue. Can J Anaesth 1994;41:435–9.[Abstract/Free Full Text]
  7. Esau SA. Hypoxic, hypercapnic acidosis decreases tension and increases fatigue in hamster diaphragmatic muscle in vitro. Am Rev Respir Dis 1989;139:1410–7.[ISI][Medline]
  8. Howell S, Fitzgerald RS, Roussos C. Effect of uncompensated and compensated metabolic acidosis on canine diaphragm. J Appl Physiol 1985;59:1376–82.[Abstract/Free Full Text]
  9. Kimata S, Hirosawa K, Kasanuki H, et al. Clinical effects of olprinone on acute heart failure evaluation of acute hemodynamic effects of bolus injection and continuous infusion. Jpn J Clin Exp Med 1992;69:2260–74.
  10. Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982;307:786–97.[ISI][Medline]
  11. Fujii Y, Toyooka H, Ebata T, Amaha K. Contractility of fatigued diaphragm is improved by dobutamine. Anaesth 1993;40:453–8.
  12. Fujii Y, Toyooka H, Amaha K. Amrinone improves contractility of fatigued diaphragm in dogs. Can J Anaesth 1995;42:80–6.[Abstract/Free Full Text]
  13. Aubier M, DeTroyer A, Sampson M, et al. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981;305:249–52.[Abstract]
  14. Howell S, Roussos C. Isoproterenol and aminophylline improve contractility of fatigued diaphragm. Am Rev Respir Dis 1984;129:118–24.[ISI][Medline]
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Accepted for publication May 10, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press