Anesth Analg 2000;91:1035-1037
© 2000 International Anesthesia Research Society
BRIEF COMMUNICATION
The Effect of Sedative Drugs on Diaphragmatic Contractility in Dogs: Propofol Versus Midazolam
Yoshitaka Fujii, MD,
Takuo Hoshi, 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.
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Abstract
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Implications: A sedative dose (0.1 mg · kg-1 · h-1) of midazolam, compared with a subhypnotic dose (1.5 mg · kg-1 · h-1) of propofol, decreases the contractility of the diaphragm in dogs.
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Introduction
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Asubhypnotic dose of propofol decreases the contractility of the diaphragm (1). This depression could be accounted for by the inhibitory effect of propofol on diaphragmatic muscle function, which may be related to the impairment of excitation-contraction coupling and/or the decrease in blood flow to the diaphragm (1). Midazolam, as well as propofol, is widely used for equivalent sedation (2). We performed this study to assess the effect of a sedative dose of midazolam compared with a subhypnotic dose of propofol on the diaphragmatic contractility in dogs.
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Methods
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The protocol was approved by our animal research committee, and care of the animals was in agreement with guidelines for ethical animal research. We studied 30 healthy mongrel dogs (10–15 kg); the dogs were anesthetized with pentobarbital and their lungs mechanically ventilated. Animal preparation was similar to that described previously (1). Briefly, anesthesia was maintained with pentobarbital 2 mg · kg-1 · h-1 IV. No muscle relaxant was used. The animal’s trachea was intubated, and ventilation was mechanically controlled with a mixture of O2 and air (fraction of inspired oxygen 0.4) to maintain PaO2, PaCO2, and pHa within normal ranges. The femoral artery for monitoring arterial blood pressure and vein for administering the study drug (propofol, midazolam) were cannulated. Transdiaphragmatic pressure (Pdi) was measured by using two thin-walled latex balloons: one positioned in the stomach, the other in the middle third of the esophagus. Balloons were connected to a differential pressure transducer and an amplifier. Bilateral phrenic nerves were exposed at the neck, and the stimulating electrodes were placed around them. 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. The electrical activity of the diaphragm was recorded by two pairs of electrodes, and it was rectified and was integrated with a leaky integrator with a time constant of 0.1 s. This was regarded as the integrated electrical activity of the crural (Edi-cru) and costal (Edi-cost) parts of the diaphragm.
The dogs were randomly divided into three groups of 10 each. After the baseline measurements of Pdi, Edi-cru, Edi-cost, and hemodynamic variables, including heart rate, and mean arterial pressure in each group, Group II was given a bolus injection (0.1 mg/kg) followed by a continuous infusion (1.5 mg · kg-1 · h-1) of propofol IV via an electrical infusion pump for 60 min; Group III was administered IV midazolam (0.1 mg/kg initial dose plus 0.1 mg · kg-1 · h-1) continuously via an infusion pump for 60 min. After administering the study drug, Pdi, Edi-cru, Edi-cost, and hemodynamic variables were measured. The doses of these drugs to evaluate the diaphragmatic muscle function are based on the fact that propofol (1.5 mg · kg-1 · h-1) and midazolam (0.1 mg · kg-1 · h-1) are widely used for equivalent sedation (3,4). In Group I, only maintenance fluids were administered, and the same measurements were performed. The changes of Edi-cru and Edi-cost (%Edi-cru and %Edi-cost, respectively) from baseline values were measured.
All values were expressed as mean ± SD. Statistical analysis was performed by using analysis of variance with Bonferroni’s adjustment for multiple comparison and Student’s t-tests, where appropriate. A P value of <0.05 was considered significant.
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Results
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No differences in baseline values were observed among the groups. In Groups II and III, heart rate and mean arterial pressure decreased from baseline values (P < 0.05) during the study drug administration. With an infusion of propofol, in Group II, Pdi at low-frequency (20-Hz) stimulation decreased from the baseline values (P < 0.05), whereas Pdi at high-frequency (100-Hz) stimulation did not change. With an infusion of midazolam, in Group III, Pdi at both stimuli decreased from the baseline values (P < 0.05). The decrease in Pdi at both stimuli was greater in Group III than in Group II (P < 0.05). No changes in Edi-cru and Edi-cost were observed in Groups I and II. In Group III, both Edi-cru and Edi-cost values at 100-Hz stimulation during midazolam administration were less than those obtained at baseline (P < 0.05) (Table 1).
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Discussion
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The results of Group II, with an infusion of propofol, 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 accordance with the characteristics of low-frequency fatigue that is closely related to the impairment of excitation-contraction coupling (ECC) (5,6). The exact mechanism by which propofol decreases diaphragmatic contractility is unknown, but it is suggested that this inhibitory effect of propofol on diaphragmatic muscle function may be related to the impairment of ECC (1). This impairment is thought to result from the alteration in movement of Ca2+ from sarcoplasmic reticulum (7).
The results in Group III showed that midazolam decreased Pdi at both stimuli compared with baseline values (P < 0.05) and that Edi-cru and Edi-cost values at 100-Hz stimulation during midazolam administration were less than those obtained at baseline (P < 0.05). The exact mechanism by which midazolam depresses the diaphragmatic contractility with a reduced electromyographic activity (as assessed by using Edi) remains unclear. Selective loss of force at low-frequency stimulation is closely related to the impairment of ECC (5), whereas selective loss of force and electromyographic activity at high-frequency stimulation indicates the failure of neuromuscular transmission (8,9). Therefore, the reduction of Pdi at low-frequency (20-Hz) and high-frequency (100-Hz) stimulation is presumably a result of the impairment of ECC and the failure of neuromuscular transmission. Thus, the potentiating mechanism of midazolam on diaphragmatic contractility may be different from that of propofol.
Our results showed that a sedative dose of midazolam, compared with a subhypnotic dose of propofol, decreased Pdi at both stimuli (P < 0.05), which suggests that midazolam causes more inhibitory effect on diaphragmatic contractility than propofol. The exact reason for this difference is not known, but it may be attributed to the difference in the impediment to diaphragmatic muscle function and the potentiating mechanism of these two drugs on the diaphragmatic contractility.
In conclusion, a sedative dose (0.1 mg · kg-1 · h-1) of midazolam, compared with a subhypnotic dose (1.5 mg · kg-1 · h-1) of propofol, decreases the contractility of the diaphragm in dogs.
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References
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Accepted for publication June 9, 2000.
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Abstract
Introduction
