British Journal of Anaesthesia, 2001, Vol. 86, No. 6 879-881
© 2001 The Board of Management and Trustees of the British Journal of Anaesthesia
Midazolam versus propofol for reducing contractility of fatigued canine diaphragm
Department of Anaesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1 Amakubo, Tsukuba City, Ibaraki, Japan*Corresponding author
Accepted for publication: December 4, 2000
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Abstract |
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The effects of midazolam and propofol on the contractility of fatigued canine diaphragm were examined. Diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After fatigue had been induced, group I (n=10) received no study drug, group II (n=10) was given a propofol infusion (0.1 mg kg–1 loading dose plus 1.5 mg kg–1 h–1 maintenance dose) and group III (n=10) was given a midazolam infusion (0.1 mg kg–1 loading dose plus 0.1 mg kg–1 h–1 maintenance dose). Diaphragmatic contractility was assessed by measuring transdiaphragmatic pressure (Pdi). After the fatigue-inducing period in each group, Pdi at low-frequency (20 Hz) stimulation was lower than the baseline values (P<0.05), whereas no change in Pdi at high-frequency (100 Hz) stimulation was observed. In group II, Pdi at 20 Hz stimulation was lower than fatigued values (P<0.05); Pdi at 100 Hz stimulation did not change. In group III, Pdi at both stimulation frequencies was lower than fatigued values (P<0.05). Compared with group I, Pdi at 20 Hz stimulation was lower than fatigued values (P<0.05) during administration of the study drug in groups II and III. The decrease in Pdi was greater in group III than in group II (P<0.05). In conclusion, midazolam compared with propofol is associated with an inhibitory effect on contractility in the fatigued canine diaphragm.
Br J Anaesth 2001; 86: 879–81
Keywords: muscle skeletal, diaphragm; anaesthetics i.v., midazolam; anaesthetics i.v., propofol
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Introduction |
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Fatigue of the respiratory muscles, especially diaphragm, may cause respiratory failure.1 Like volatile anaesthetics, propofol reduces diaphragmatic contractility.2 Midazolam and propofol are widely used for equivalent sedation.3 However, little is known about the effects of these drugs on the contractility of fatigued diaphragm. The purpose of this study was to examine the efficacy of midazolam compared with propofol on the contractility of fatigued canine diaphragm.
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Methods and results |
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Institutional approval for the study was obtained from the animal care and uses committee of the University of Tsukuba School of Medicine. Thirty healthy adult mongrel dogs, weighing 10–15 kg (mean (SD) 12.6 (1.6) kg), were anaesthetized and mechanically ventilated. Animals were prepared as described previously.2 Anaesthesia was maintained with pentobarbital 2 mg kg–1 h–1 i.v., supplemented as necessary to sustain adquate anaesthesia. Muscle relaxants and analgesics were not used. Tracheas were intubated. Ventilation was mechanically controlled with a mixture of oxygen and air (FIO2 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 drugs, propofol and midazolam) were cannulated. Transdiaphragmatic pressure (Pdi) was measured by means of two thin-walled latex balloons, one positioned in the stomach and the other in the middle third of the oesophagus. Balloons were connected to a differential pressure transducer and an amplifier. Both 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 or high frequency (20 and 100 Hz, respectively) with an electrical stimulator. The isometric contractility of the diaphragm was evaluated by measuring the maximal Pdi after airway occlusion at functional residual capacity. The electrical activity of the diaphragm was recorded by two pairs of electrodes and was rectified and 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.
Dogs were randomly divided into three groups of 10. After measuring baseline values of Pdi, Edi-cru, Edi-cost and haemodynamic variables, including heart rate and mean arterial 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 After the fatigue-inducing period, group II was given a bolus injection of propofol 0.1 mg kg–1 followed by a continuous infusion (1.5 mg kg–1 h–1) i.v. with an electrical infusion pump for 60 min; group III received i.v. midazolam (0.1 mg kg–1 loading dose plus 0.1 mg kg–1 h–1 maintenance dose) continuously with an infusion pump for 60 min. After administration of the study drug, Pdi, Edi-cru, Edi-cost and haemodynamic variables were measured. The doses used in the current study were based on the observation that a subhypnotic dose (1.5 mg kg–1 h–1) of propofol and a sedative dose (0.1 mg kg–1 h–1) of midazolam were widely used for equivalent sedation.3 5 In group I, only maintenance fluids were administered, and the same measurements were performed. The changes in Edi-cru and Edi-cost (%Edi-cru and %Edi-cost, respectively) from baseline were measured. At the end of the experiment, animals were killed with an overdose of pentobarbital.
Values are expressed as mean (SD). Statistical analysis was performed by ANOVA with Bonferroni correction for multiple comparison and Student’s t-test, as appropriate. P values of <0.05 were considered significant.
No differences in baseline variables were observed among the groups. In groups II and III, heart rate and MAP decreased below baseline (P<0.05) during administration of the study drug. After the fatigue-inducing period, Pdi at low-frequency (20 Hz) stimulation was lower than baseline (P<0.05) and Pdi at high-frequency (100-Hz) stimulation did not change in each group. In group II, Pdi at 20 Hz stimulation was lower than fatigued values (P<0.05); Pdi at 100 Hz stimulation did not change. In group III, Pdi at both stimuli was lower than fatigued values (P<0.05). The decrease in Pdi was greater in group III than in group II (P<0.05). In group III, both Edi-cru and Edi-cost at 100 Hz stimulation during midazolam administration were less than baseline values (P<0.05) (Table 1).
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Comment |
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Low-frequency fatigue is of particular clinical importance because the spontaneous, natural rate of the phrenic nerve firing is mainly within the low-frequency ranges (i.e. 5–30 Hz).6 In this study, therefore, we examined the effects of midazolam and propofol on the contractility of fatigued diaphragm induced by 20 Hz stimulation (i.e. low-frequency fatigue) were examined. The results of group I, in which Pdi and Edi were observed without an infusion of propofol or midazolam, showed that Pdi at both stimulation frequencies had no tendency to recover in the fatigued diaphragm and that Edi did not change at either stimulation frequency. This was in agreement with a previous study by us.7
In a preliminary study, we examined the effects of propofol on contractility in the non-fatigued diaphragm. With an infusion of propofol at a subhypnotic dose (1.5 mg kg–1 h–1), Pdi at 20 Hz stimulation was lower than baseline; Pdi at 100 Hz stimulation and Edi did not change.3 In group II, Pdi at 20 Hz stimulation was lower than fatigued values (P<0.05); Pdi at 100 Hz stimulation and Edi did not change. These results suggest that propofol may decrease the contractility of both fatigued and non-fatigued diaphragms. The exact mechanism by which propofol decreases the contractility of the diaphragm is unknown. However, these phenomena during propofol administration are similar to the characteristics of low-frequency fatigue, which is also related to impaired coupling of excitation and contraction.4 8 Therefore, it is possible that an inhibitory effect of propofol on diaphragmatic muscle function may be related to an impediment of excitation–contraction coupling.
In group III, midazolam reduced Pdi at both stimulation frequencies compared with fatigued values (P<0.05), and Edi-cru and Edi-cost at 100 Hz stimulation during midazolam administration were less than those obtained in the baseline period (P<0.05). The precise mechanism by which midazolam reduces the contractility of fatigued diaphragm with a reduction of electromyographic activity (as assessed by Edi) is not known. Selective loss of force at low-frequency stimulation is closely related to the impairment of excitation–contraction coupling,8 whereas selective loss of force and electromyographic activity at high-frequency stimulation indicates the failure of neuromuscular transmission.9 10 Therefore, reductions in Pdi at low- (20 Hz) and high-frequency (100 Hz) stimulation and in Edi at high-frequency (100-Hz) stimulation may result from impairment of excitation–contraction coupling and failure of neuromuscular transmission.
In conclusion, we have shown that midazolam, compared with propofol, reduces Pdi at both stimulation frequencies in fatigued diaphragm (P<0.05), suggesting that midazolam causes more contractile inhibition.
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8 Moxham J, Wiles CM, Newham D, Edwards RHT. Contractile function and fatigue of the respiratory muscles in man. In: Porter R, Whelan J, eds. Human Muscle Fatigue. Ciba Foundation Symposium, No. 82. London: Pitman Medical, 1981; 197–205
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