Anesth Analg 2002;95:944-947
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Flumazenil Recovers Diaphragm Muscle Dysfunction Caused by Midazolam 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, 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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We studied the effects of flumazenil on diaphragm muscle dysfunction caused by midazolam in dogs. Animals were divided into three groups of eight each. In each group, anesthetic doses (0.1 mg/kg initial dose plus 0.5 mg · kg-1 · h-1 maintenance dose) of midazolam were administered for 60 min. Immediately after the end of midazolam administration, Group 1 received no study drug; Group 2 was infused small-dose (0.004 mg · kg-1 · h-1) flumazenil; Group 3 was infused with large-dose (0.02 mg · kg-1 · h-1) flumazenil. We assessed diaphragm muscle function (contractility and electrical activity) by transdiaphragmatic pressure (Pdi) and integrated electrical activity of the diaphragm (Edi). After midazolam was administered in each group, Pdi at low-frequency (20-Hz) and high-frequency (100-Hz) stimulation decreased from baseline values (P < 0.05), and values of Edi at 100-Hz stimulation were less than those obtained during baseline (P < 0.05). In Group 1, Pdi and Edi to each stimulus did not change from midazolam-induced values. In Groups 2 and 3, with an infusion of flumazenil, Pdi at both stimuli and Edi at 100-Hz stimulation increased from midazolam-induced values (P < 0.05). The increase in Pdi and Edi was more in Group 3 than in Group 2 (P < 0.05). We conclude that flumazenil recovers the diaphragm muscle dysfunction (reduced contractility and inhibited electrical activity) caused by anesthetic doses of midazolam in dogs.
IMPLICATIONS: In dogs, flumazenil recovers diaphragm muscle dysfunction (reduced contractility and inhibited electrical activity) caused by midazolam in a dose-related manner.
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Introduction
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Midazolam is used as a premedicant, a sedative, and an anesthetic (1). It also has a relatively rapid onset of action and a rapid metabolic clearance, but it occasionally causes unpredictable hypnotic effects (1). Residual depressant effects of benzodiazepines are antagonized by the benzodiazepine antagonist flumazenil (2). Like volatile anesthetics (3–6), midazolam impairs the contractile properties of the diaphragm (7). There have been no reports to support that a reduction of diaphragmatic contractility during midazolam administration is implicated as a cause of respiratory failure. However, reduced contractility of the diaphragm causes an inability to continue to generate sufficient pressure to maintain alveolar ventilation and thereby may contribute to the development of respiratory failure (8). The purpose of this study was to examine the efficacy of flumazenil for the recovery from diaphragm muscle dysfunction caused by midazolam 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, 15 males and 8 females, weighing 10–15 kg (12.8 ± 1.4 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 relaxant was 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 arterial pH 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 (10 mL · kg-1 · h-1 of lactated Ringer’s solution), pentobarbital, and bicarbonate to keep the plasma HCO3- concentration within normal ranges. The left femoral vein was cannulated for the administration of midazolam or flumazenil. Rectal temperature was continuously monitored and maintained at 37°C ± 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 was positioned in the stomach, and the other was positioned 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 the maximal Pdi after airway occlusion at the functional residual capacity. Transpulmonary pressure, the difference between airway and esophageal pressures, was kept constant (nearly -5 cm H2O) 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 rib cage. 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 in 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 with a time constant of 0.1 s and was regarded as the integrated electrical activity of the diaphragm (Edi-cru, Edi-cost).
The dogs were allowed to stabilize for at least 30 min before the study. The dogs were randomly divided into three groups of eight each. Baseline measurements of Pdi, Edi-cru, Edi-cost, heart rate (HR), and mean arterial blood pressure (MAP) were recorded in each group. Anesthetic doses (0.1 mg/kg initial dose plus 0.5 mg · kg-1 · h-1 maintenance dose) of midazolam were administered IV for 60 min with an electrical infusion pump. Immediately after the end of midazolam administration, Group 2 was infused small-dose (0.004 mg · kg-1 · h-1) flumazenil; Group 3 was infused with large-dose (0.02 mg · kg-1 · h-1) flumazenil. The dose of flumazenil chosen in this experiment referred to information on clinical use (2). The study drug was continuously administered IV via an electrical infusion pump for 60 min. At 60 min after the onset of flumazenil administration, Pdi, Edi-cru, Edi-cost, HR, and MAP were measured. In Group 1, 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 expressed as mean ± SD. Statistical analysis was performed by analysis of variance with Bonferroni’s adjustment for multiple comparison and Student’s t-test, where appropriate. 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. After administering anesthetic doses of midazolam, in each group, HR and MAP decreased from baseline values (P < 0.05). With an infusion of flumazenil, in Groups 2 and 3, HR and MAP increased from midazolam-induced values (P < 0.05). At 60 min after the cessation of midazolam administration, in Group 1, HR and MAP increased from midazolam-induced values (P < 0.05) and returned to baseline values. With an infusion of midazolam at anesthetic doses, in each group, Pdi at both stimuli decreased from baseline values (P < 0.05), and both %Edi-cru and %Edi-cost values at 100-Hz stimulation were less than those obtained during baseline (P < 0.05). In Group 1, Pdi and %Edi to each stimulus did not change from midazolam-induced values. In Groups 2 and 3, with an infusion of flumazenil, Pdi at both stimuli and Edi at 100-Hz stimulation increased from midazolam-induced values (P < 0.05). The increase in Pdi and Edi was more in Group 3 than in Group 2 (P < 0.05) (Table 1).
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Discussion
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Diaphragmatic contractility is assessed by force-frequency characteristics (8,9) and is often evaluated by the measurement of Pdi, which is affected by the length and geometry of the diaphragm during the precontracted condition (10). A major determinant of diaphragmatic length and geometry is lung volume. Conceivably, the change in Pdi may be secondary to changes in end-expiratory lung volume. In this experiment, however, the airway was occluded at the end-expiratory lung volume during measurements, and its constancy was monitored by the measurement of the end-expiratory transpulmonary pressure. Therefore, changes in lung volume during the experimental procedures can reasonably be excluded. Furthermore, the plaster cast around the abdomen and lower third of the rib cage was also placed for the prevention of deformation of thoracoabdominal structures.
Hypoxemia, hypercapnea, and metabolic acidosis decrease diaphragmatic contractility (11,12). The PaO2, PaCO2, arterial pH, and plasma HCO3- concentration were controlled within normal ranges in this study. Therefore, these factors, which could have affected diaphragmatic contractility, were eliminated. Because the dogs were anesthetized with pentobarbital, the combined effects of pentobarbital and either midazolam or flumazenil on the contractility of the diaphragm were examined. However, it has been reported that pentobarbital, at the dose (2 mg · kg-1 · h-1) used in this experiment, does not affect diaphragmatic contractility (6). This was also in accordance with a previous study, which found that pentobarbital-anesthetized dogs receiving no study drug showed no change in Pdi (7).
We found that Pdi at 20- and 100-Hz stimulation decreased from baseline values (P < 0.05) with an infusion of midazolam at anesthetic doses and that Edi-cru and Edi-cost values at 100-Hz stimulation during midazolam administration were less than those obtained during baseline (P < 0.05) in each group. This was in agreement with our previous study (7). The exact mechanism by which midazolam decreases diaphragmatic contractility with a reduction of electromyographic activity (as assessed by Edi) is not known. Selective loss of force at 20 Hz is closely related to the impairment of excitation-contraction coupling (13), and selective loss of force and electromyographic activity at 100-Hz stimulation indicate the failure of neurotransmission (14,15). Therefore, the decrease in Pdi at both stimuli with a reduction of Edi at 100-Hz stimulation during midazolam administration is probably associated with the impairment of excitation-contraction coupling and the failure of neurotransmission.
The results of Group 1, in which HR, MAP, Pdi, and Edi were obtained without an administration of flumazenil, the benzodiazepine antagonist, showed that HR and MAP increased from midazolam-induced values (P < 0.05) and returned to baseline values and that Pdi and Edi to each stimulus did not change from midazolam-induced values at 60 minutes after the cessation of midazolam administration. Thus, as with the pharmacokinetic properties (i.e., rapid metabolism) (1), the cardiovascular effects of midazolam were abolished at 60 minutes after the cessation of midazolam administration. However, the inhibitory effects of midazolam on the contractility and electromyographic activity of the diaphragm were prolonged. The exact reason for this difference was not known, but there is a possibility that midazolam may have different effects on hemodynamics and diaphragm muscle function.
The results of Groups 2 and 3 with an infusion of flumazenil showed that Pdi at both stimuli and Edi at 100-Hz stimulation increased from midazolam-induced values (P < 0.05) and that the increase in Pdi and Edi was larger in Group 3 than in Group 2 (P < 0.05). These findings suggest that flumazenil recovers diaphragm muscle dysfunction (reduced contractility and inhibited electrical activity) caused by midazolam in a dose-related manner.
Diaphragmatic contractility depends on the energy supply to the diaphragm, which is related to the diaphragmatic blood flow (16). In a previous study of ours (7), the inhibitory effect of midazolam on diaphragmatic contractility may have been related to the decrease in diaphragmatic blood flow. Blood flow to the diaphragm is maintained relatively constant within a certain limit of perfusion pressure (17), and it is autoregulated at MAP >70 mm Hg (18). In this experiment, diaphragmatic blood flow was not directly measured. However, MAP <70 mm Hg was not observed in any group in this study, and thereby decreases in MAP during midazolam or flumazenil administration would not affect diaphragmatic contractility. Further studies are needed to elucidate the relationship between midazolam or flumazenil administration and diaphragmatic blood flow.
Midazolam is the commonly used benzodiazepine for preoperative medication, sedation, induction of anesthesia, and maintenance of anesthesia in combination with other drugs (1). Our results demonstrated that the cardiovascular effects of midazolam were abolished at 60 minutes after the cessation of midazolam administration and that the inhibitory effects of midazolam on the contractility and electromyographic activity of the diaphragm were prolonged. There have been no reports to evaluate the effects of flumazenil alone on diaphragm muscle function. To clarify the flumazenil-induced changes in contractility and electromyographic activity of the diaphragm, further studies are needed. However, on the basis of our results, clinicians should pay attention to this clinical risk posed by midazolam.
In conclusion, flumazenil recovers, in a dose-related manner, the diaphragm muscle dysfunction (reduced contractility and inhibited electrical activity) caused by anesthetic doses of midazolam in dogs.
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References
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Accepted for publication June 20, 2002.
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Abstract
Introduction
