Anesth Analg 2003;97:755-758
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Midazolam-Induced Muscle Dysfunction and Its Recovery in Fatigued Diaphragm 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}md.tsukuba.ac.jp
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Abstract
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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 · kg-1 · h-1) of midazolam; and Group III was infused with an anesthetic dose (0.5 mg · kg-1 · 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.
IMPLICATIONS: Midazolam, widely used for sedation and anesthesia, inhibits diaphragm muscle function in fatigued diaphragm in dogs in a dose-dependent manner.
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Introduction
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The importance of diaphragmatic fatigue as a potential cause of respiratory failure has been recognized (1,2). When fatigue was established, critically ill patients receiving mechanical ventilation were difficult to wean. (3). These ventilated patients usually require sedation. Sedation improves tolerance of the tracheal tube and of invasive procedures, facilitates mechanical ventilation, blunts excessive hemodynamic and metabolic responses, and allays anxiety (4). Midazolam is a potent benzodiazepine with hypnotic, sedative, anxiolytic, amnesic, anticonvulsant, and muscle relaxant properties. It is often used for sedation in patients requiring ventilatory support and for induction and maintenance in patients undergoing general anesthesia (5). In our recent report (6), midazolam decreased contractility with a reduction of electromyographic activity in nonfatigued diaphragm. However, there have been no reports examining the effects of midazolam on contractility in fatigued diaphragm that are implicated as a cause of respiratory failure. We therefore studied the effects of midazolam at two different doses (sedative and anesthetic) on diaphragm muscle function (contractile properties and electrical activity) and its recovery in fatigued diaphragm 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 ± 1.8 kg, mean ± SD) were anesthetized with pentobarbital 2 mg · kg-1 · h-1 IV, supplemented as necessary to abolish spontaneous movement. The dose of pentobarbital used in this experiment has shown no effects on diaphragmatic contractility (7). 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 oxygen 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 the measurements. The right femoral vein was cannulated to administer maintenance fluids (lactated Ringer’s solution 10 mL · kg-1 · h-1) and pentobarbital. The left femoral vein was cannulated for the administration of midazolam. Rectal temperature was continuously monitored and maintained at 37° ± 1° with a heating pad.
Both phrenic nerves were 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 was positioned in the stomach and the other was in the middle-third of the esophagus. Balloons were connected to a differential pressure transducer and an amplifier. One balloon catheter was open to atmosphere, and the position of the other was changed to obtain appropriate pressure. The positions of balloons in the stomach and the esophagus were then confirmed. 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 the measurement of maximal Pdi after airway occlusion at the functional residual capacity. Transpulmonary pressure, the difference between airway and esophageal pressures, was kept constant by maintaining 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 the lower one-third of the ribcage. The electrical activity (Edi) of the crural part (Edi-cru) and the costal part (Edi-cost) of the diaphragm was recorded by two pairs of fishhook electrodes, which 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 an integrator with a time constant of 0.1 s and was regarded as the integrated electrical activity of the diaphragm (Edi-cru, Edi-cost). As mentioned above, animal preparation was similar to that described previously (6).
Dogs were randomly divided into three groups of eight each. Baseline measurements of Pdi, Edi-cru, Edi-cost, and hemodynamic variables, including heart rate (HR) and mean arterial blood pressure (MAP), were recorded 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) (8). In other words, 2 s of 20-Hz stimulation, followed by a 2-s rest, which was continued for 30 min, and thus diaphragmatic fatigue was produced. When fatigue was established, in Groups II (sedative dose, 0.1 mg/kg initial loading dose plus 0.1 mg · kg-1 · h-1 maintenance dose) and III (anesthetic dose, 0.1 mg/kg initial loading dose plus 0.5 mg · kg-1 · h-1 maintenance dose), midazolam was continuously administered IV with an electrical infusion pump for 60 min. Immediately and at 60 min after the cessation of midazolam administration, Pdi, Edi-cru, Edi-cost, HR, and MAP were measured. In Group I, no study drug was administered IV, and the same measurements were performed as those in the other groups. The changes of Edi-cru and Edi-cost (%Edi-cru and %Edi-cost, respectively) from baseline values were also measured.
Values were mean ± SD. Statistical analyses within groups and among the treatment groups were performed by using two-way analysis of variance for repeated measurements followed by the Bonferroni-Dunn test. P < 0.05 was considered significant.
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Results
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No differences in baseline hemodynamic variables were observed among the groups. With an infusion of midazolam, in Groups II and III, HR and MAP decreased from baseline values (P < 0.05). At 60 min after the end of midazolam administration, HR and MAP increased from midazolam-induced values (P < 0.05) and returned to baseline values. In Group I, no hemodynamic changes were observed. After the fatigue-producing period, in each group, Pdi at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05) and Pdi at high-frequency (100-Hz) stimulation did not change. With an infusion of midazolam, in Groups II and III, Pdi at both stimuli decreased from fatigued values (P < 0.05). The values in %Edi-cru and %Edi-cost at 100-Hz stimulation during midazolam administration were less than those obtained during baseline (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. In Group I, Pdi and %Edi did not change from fatigued values throughout the experiment (Table 1).
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Discussion
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The contractility of diaphragm is assessed by force-frequency characteristics (1,2), and is often evaluated by the measurement of Pdi, which is affected by the length and geometry of diaphragm during the precontracted condition (9). 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 measuring the 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 ribcage was also placed for preventing the deformation of thoracoabdominal structures.
Low-frequency fatigue is of particular clinical importance because the spontaneous, natural rate of phrenic nerve discharge is mainly within the low-frequency ranges (i.e., 5–30 Hz) (10). In this study, therefore, the effect of midazolam on the contractility during diaphragmatic fatigue induced by 20-Hz stimulation (i.e., low-frequency fatigue) was examined. The results of Group I, in which Pdi and Edi were obtained without an administration of midazolam, showed that Pdi at both stimuli had no tendency to recover in fatigued diaphragm and that Edi did not change at any frequency of stimulation. This was in accordance with our previous study (11).
We showed that Pdi at 20- and 100-Hz stimulation decreased from baseline values (P < 0.05) with an infusion of midazolam and %Edi-cru and %Edi-cost values at 100-Hz stimulation were less than those obtained during baseline (P < 0.05) in Groups II and III, and also demonstrated that a decrease in Pdi and %Edi was more in Group III than in Group II (P < 0.05). These findings suggest that midazolam decreases, in a dose-dependent manner, contractility of fatigued diaphragm. The exact mechanism by which midazolam depresses contractility of fatigued diaphragm with a reduction of electromyographic activity of the diaphragm (as assessed by Edi) remains unclear. Selective loss of force (Pdi) at 20-Hz stimulation is closely related to the impairment of excitation-contraction coupling (12) and selective loss of force (Pdi) and electromyographic activity (Edi) at 100-Hz stimulation indicates the failure of neuromuscular transmission (13,14). Therefore, the decrease in Pdi at both stimuli and %Edi at 100-Hz stimulation observed in Groups II and III, which received midazolam, is presumably attributed to the impairment of excitation-contraction coupling and the failure of neuromuscular transmission.
The results of Group II receiving a sedative dose of midazolam showed that HR, MAP, Pdi, %Edi-cru, and %Edi-cost decreased from midazolam-induced values (P < 0.05) and returned to baseline values at 60 minutes after the end of midazolam administration. In Group III receiving an anesthetic dose of midazolam, Pdi, %Edi-cru, and %Edi-cost did not change from midazolam-induced values. As the pharmacokinetic properties (i.e., rapid metabolism) (5), the hemodynamic changes by midazolam were abolished at 60 min after the cessation of its administration (recovery period). Also, sedative-dose midazolam-induced diaphragm muscle dysfunction recovered. However, when administered midazolam at anesthetic doses, a decrease in diaphragmatic contractility with a reduction of electromyographic activity did not recover from midazolam-induced values. The reason for this difference is unknown, but may be attributed to the difference in dosage. There is a possibility that anesthetic-dose midazolam may have different effects on hemodynamics and diaphragm muscle function.
When midazolam is administered in repeated boluses or as a continuous IV infusion in critically ill patients, its pharmacokinetic properties change and its half-life (1–4 hours) may be prolonged, possibly causing a longer duration of action after discontinuation (15). Thus, when midazolam is administered at an anesthetic dose during a fatigued condition, its inhibitory effect on diaphragmatic contractility would be prolonged.
Blood flow to the diaphragm is an important determinant factor of diaphragm muscle function (10). Diaphragmatic blood flow was maintained relatively constant within a certain limit of perfusion pressure (16), and it was not reduced when MAP increased to >70 mm Hg (17). In this study, diaphragmatic blood flow was not directly measured. However, MAP <70 mm Hg was not observed in any group throughout the experiment, and thereby a decrease in MAP during midazolam administration would not affect diaphragm muscle function.
Midazolam is often used for sedation and anesthesia induction and maintenance (5). The data described from the current experiment may provide important information on diaphragm muscle function in patients with chronic obstructive pulmonary disease related to the fatigue of respiratory muscle, especially diaphragm and/or in critically ill patients receiving mechanical ventilation. On the basis of our results, diaphragm muscle dysfunction caused by sedative-dose midazolam recovered after the cessation of midazolam administration. Further studies are needed to determine the margin of safety for midazolam regarding diaphragm muscle function in this clinical setting.
In conclusion, midazolam causes, in a dose-related manner, diaphragm muscle dysfunction in fatigued diaphragm in dogs. Sedative-dose, but not anesthetic-dose, midazolam does not delay its recovery.
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References
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Accepted for publication April 24, 2003.
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Abstract
Introduction
