Anesth Analg 2002;95:129-132
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Dose-Related Efficacy of Diltiazem for Enhancing Diaphragmatic Fatigability in Dogs
Yoshitaka Fujii, MD,
Aki Uemura, 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, MD, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki 305-8576, Japan. Address e-mail to yfujii{at}igaku.md.tsukuba.ac.jp
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Abstract
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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.
IMPLICATIONS: 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.
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Introduction
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Respiratory muscle fatigue, especially that of the diaphragm, has been implicated as a cause of respiratory failure in normal subjects and in patients with chronic obstructive lung disease (1,2). The exact mechanism of diaphragmatic fatigue is not known, but diaphragmatic fatigue may be closely related to the impairment of excitation-contraction coupling (3). This impairment is thought to be the result of the alteration in movement of Ca2+ from the sarcoplasmic reticulum (4). Thus, the potential cause of diaphragmatic fatigue reflects an alteration in transmembrane Ca2+ transport, suggesting that the calcium channel blockade that inhibits Ca2+ influx into diaphragm muscle may predispose diaphragmatic fatigability. In our previous report (5), we found that nicardipine enhances the production of diaphragmatic fatigue. There have been no reports investigating the effects of diltiazem, another calcium channel blockade, on contractility during a fatigue-producing period. The purpose of the present study was therefore to examine the dose-related effects of diltiazem on diaphragmatic fatigability in dogs.
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Methods
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The protocol was approved by our animal research committee, and the care of animals was in agreement with guidelines for ethical animal research. Twenty-four healthy adult mongrel dogs weighing 10–15 kg (12.5 ± 2.0 kg, mean ± SD) were anesthetized with pentobarbital (25 mg/kg initial dose plus 2 mg · kg-1 · h-1 maintenance dose) IV to abolish spontaneous movement. No muscle relaxants were used. The 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 gas samples for blood gas analysis. 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 drug (diltiazem). Rectal temperature was continuously monitored and maintained at 37° ± 1°C by using a heating pad.
The phrenic nerves were bilaterally exposed at the neck, and the stimulating electrodes were placed around them. Transdiaphragmatic pressure (Pdi) was measured by means of two thin-walled latex balloons; one positioned in the stomach, the other positioned in the middle third of the esophagus. The balloons were connected to a differential pressure transducer and an amplifier. 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. 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 measuring the 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 rib cage. The electrical activity of the crural and costal parts of diaphragm (Edi-cru and Edi-cost, respectively) was recorded by 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 the parallel fibers 5–6 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 and Edi-cost, respectively).
Twenty-four dogs were randomly divided into three groups of eight each. After the baseline measurements of Pdi, Edi-cru, Edi-cost, heart rate (HR), and mean arterial blood pressure (MAP) 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) (4). 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. Diltiazem was administered IV continuously with an electrical infusion pump. The dose of diltiazem chosen in this experiment was in accordance with information on clinical use (6). Immediately after the end of fatigue-producing stimuli, Pdi, HR, and MAP were measured. The changes of Edi-cru and Edi-cost (%Edi-cru and %Edi-cost, respectively) from baseline values were also measured.
Values were expressed as mean ± SD. Statistical analysis was performed by using analysis of variance for repeated measurements with Bonferroni adjustment for multiple comparison and the Student’s t-test, where appropriate. P < 0.05 was considered significant.
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Results
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No differences in hemodynamic variables and Pdi during the baseline period were observed among the groups. With an infusion of diltiazem, in Groups II and III, HR and MAP decreased from the baseline values (P < 0.05). In Group I, there were no hemodynamic changes throughout the experiment. After a fatigue-producing period, in Group I, 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. With an infusion of diltiazem, in Groups II and III, 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). No changes in %Edi-cru and %Edi-cost were observed in Group I. In Groups II and III, both %Edi-cru and %Edi-cost values at 100-Hz stimulation during diltiazem administration were less than those obtained during baseline (P < 0.05) (Table 1).
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Discussion
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The contractility of the diaphragm is assessed by force-frequency characteristics (1,2), and is often evaluated by measuring Pdi, which is affected by the length and geometry of the diaphragm during a precontracted condition (7). A major determinant of diaphragmatic length and geometry 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 measurements, and its constancy was monitored by the measurement of 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 rib cage was also placed for preventing the deformation of thoracoabdominal structures. Hypoxemia, hypercapnia, and metabolic acidosis decrease diaphragmatic contractility (8,9). In this experiment, however, PaO2, PaCO2, pHa, and HCO3- concentration were maintained within normal ranges. Therefore, these factors that could have affected diaphragmatic contractility were excluded. As the dogs were basically anesthetized with pentobarbital, the combined effects of diltiazem and pentobarbital on contractility of the diaphragm were examined. However, pentobarbital, at the doses (2 mg · kg-1 · h-1) used in this experiment, does not affect diaphragmatic contractility (10).
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., 5–30 Hz) (11). In this study, therefore, diaphragmatic fatigue was induced by 20-Hz stimulation. Consequently, Group I, which received no study drug, showed that Pdi at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05) and that Pdi at high-frequency (100-Hz) stimulation and Edi to each stimulus did not change. This was in agreement with our previous study (5), indicating that diaphragmatic fatigue may contribute to the development of respiratory failure (1,2). The exact mechanism of diaphragmatic fatigue is not known, but there is a possibility that it may be closely related to the impairment of excitation-contraction coupling (3). This impairment is supposed to be the result of an alteration in movement of Ca2+ from the sarcoplasmic reticulum (7).
The results of Groups II and III, which received diltiazem in the fatigue-producing period, showed that Pdi to each stimulus decreased from baseline values (P < 0.05) and that Edi values at 100-Hz stimulation were less than those obtained at baseline (P < 0.05). In addition, a decrease in Pdi at both stimuli and Edi at 100-Hz stimulation was greater in Group III than in Group II (P < 0.05). These findings suggest that diltiazem enhances diaphragmatic fatigability in a dose-related manner. The precise mechanism by which diltiazem decreases diaphragmatic contractility (as assessed by Pdi) with a reduced electromyographic activity (as assessed by Edi) is unknown. Selective loss of force at low-frequency stimulation is closely related to the impairment of excitation-contraction coupling (7), whereas selective loss of force and electromyographic activity at high-frequency stimulation indicates the failure of neuromuscular transmission (11,12). Therefore, the decrease in Pdi at both stimuli at Edi at 100-Hz stimulation observed in Groups II and III, which received diltiazem in the fatigue-producing period, is presumably associated with the impairment of excitation-contraction coupling and the failure of neuromuscular transmission.
In our previous study (5), after producing diaphragmatic fatigue simultaneously with an infusion of nicardipine, Pdi at 20-Hz stimulation decreased from baseline values (P < 0.05), whereas Pdi at 100-Hz stimulation and Edi to each stimulus did not change. Consequently, diaphragmatic fatigue is enhanced by nicardipine, based on the fact that nicardipine inhibits calcium release from the sarcoplasmic reticulum and Ca2+ transport across the cell membrane (3,4). Our results showed that diltiazem causes the potentiating effects on diaphragmatic fatigability. Thus, the mechanism of the calcium channel blockades, diltiazem and nicardipine, on diaphragmatic fatigability may be different. However, the exact reason for this difference is not known.
Volatile anesthetics, including halothane, enflurane, isoflurane, and sevoflurane, impair contractile properties of the diaphragm (10,13–15). Halothane depresses both Pdi and Edi at stimulation frequencies ranging from 10 to 100 Hz, which suggests that impaired excitation-contraction coupling and/or impaired neuromuscular transmission exists during halothane administration (13). Enflurane, isoflurane, or sevoflurane impairs diaphragmatic contractility through its inhibitory effect on neuromuscular transmission, based on the fact that a decrease in Pdi at high-frequency stimulation is associated with a parallel reduction of Edi (10,14,15). Our results showed that diltiazem reduced Pdi and Edi during a fatigue-producing period. Thus, like volatile anesthetics, diltiazem may be related to the failure of neuromuscular transmission.
Blood flow to the diaphragm is an important determinant of diaphragm muscle function (16). In this experiment, diaphragmatic blood flow was not directly measured. However, it is maintained relatively constant within a certain limit of perfusion pressure (17), and is autoregulated at a MAP >70 mm Hg (18). Moreover, a MAP <70 mm Hg was not observed in any group in the current study. Therefore, the decrease in MAP during diltiazem administration in the fatigue-producing period would not affect diaphragmatic contractility. Further studies are needed to elucidate the relationship between diltiazem administration and diaphragmatic blood flow.
Calcium channel blockades have been recommended for the prevention and treatment of hypertension (6). However, our results demonstrated that diltiazem enhances diaphragmatic fatigability in a dose-related manner. The clinical importance of this phenomenon remains to be shown in subjects with diaphragm muscle dysfunction when administered diltiazem.
In conclusion, diltiazem causes a dose-related augmentation of fatigability in the diaphragm of dogs. The potentiating mechanism of diltiazem for enhancing diaphragmatic fatigability may be closely related to the direct effect on diaphragmatic contractility.
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References
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Accepted for publication February 21, 2002.
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Abstract
Introduction
