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GENERAL ARTICLES

Propofol Decreases Diaphragmatic Contractility in Dogs

Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba City, Ibaraki, Japan

Address correspondence and reprint requests Yoshitaka Fujii, MD, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki 305, Japan.

	Abstract

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Volatile anesthetics depress diaphragmatic muscle function; however, no data are available regarding the effect of propofol on diaphragmatic contractility. We therefore studied this effect in dogs. Pentobarbital-anesthetized animals were divided into three groups of 10 each. Group I received only maintenance fluid; Group II was infused with a subhypnotic dose of propofol (0.1-mg/kg initial dose plus 1.5-mg · kg^-1 · h^-1 maintenance dose); Group III was infused with an anesthetic dose of propofol (0.1-mg/kg initial dose plus 6.0-mg · kg^-1 · h^-1 maintenance dose). We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). With an infusion of propofol in Groups II and III, 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. Compared with Group I, Pdi at 20-Hz stimulation decreased during propofol administration in Groups II and III (P < 0.05). The decrease in Pdi was more in Group III than in Group II (P < 0.05). We conclude that propofol is associated with a dose-related inhibitory effect on diaphragmatic contractility in dogs.

Implications: Propofol is an effective IV anesthetic for the induction and maintenance of anesthesia. Subhypnotic and anesthetic doses of propofol decrease diaphragmatic contractility in dogs.

	Introduction

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The favorable recovery profile with propofol offers advantages over volatile anesthetics (1). Several investigators have found that halothane, enflurane, isoflurane, and sevoflurane depress diaphragmatic contractility in vivo (2–5). However, no data are available regarding the effect of propofol on diaphragmatic contractility. The purpose of this study was to examine the effect of propofol on contractile properties of the diaphragm.

	Methods

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The protocol was approved by our animal research committee. Thirty healthy mongrel dogs weighing 10–15 kg were anesthetized with pentobarbital (25-mg/kg initial dose plus 2-mg · kg^-1 · h^-1 maintenance dose) IV to abolish spontaneous movement. 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 arterial pH 7.35–7.45. The right femoral artery was cannulated to monitor arterial blood pressure and to obtain blood samples for the measurement of arterial blood gas tensions. 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 plasma HCO₃^- concentration within normal ranges. The left femoral vein was cannulated for the administration of propofol. A flow-directed pulmonary artery catheter was advanced via the right external jugular vein into the pulmonary artery to measure cardiac output (CO) by using the thermodilution technique. Rectal temperature was monitored continuously and maintained at 37° ± 1°C.

The phrenic nerves were exposed bilaterally at the neck, and the stimulating electrodes were placed around them. Transdiaphragmatic pressure (Pdi) was measured by using two thin-walled latex balloons; one was positioned in the stomach, the other was positioned in the middle third of the esophagus. The balloons were connected to a differential pressure transducer (TP-604 T; Nihon Kohden, Tokyo, Japan) and an amplifier (Type 1257; Nihondenki San-ei, Tokyo, Japan). 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 (SEN-3301; Nihon Kohden).

The isometric contractility of the diaphragm was evaluated by using 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 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 lower one-third of the ribcage. The electrical activity (Edi) of the crural (Edi-cru) and costal (Edi-cost) parts of the diaphragm was recorded by two pairs of fishhook electrodes placed through a midline laparotomy; electrodes 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 (Type 1322; Nihondenki San-ei) with a time constant of 0.1 s and was regarded as the integrated diaphragmatic electrical activity (Edi-cru, Edi-cost).

The dogs were randomly divided into three groups of 10 each: Groups I, II, and III. After measuring the baseline values of Pdi, Edi-cru, Edi-cost, and hemodynamic variables, including heart rate, mean arterial pressure (MAP), right atrial pressure, mean pulmonary arterial pressure, pulmonary artery occlusion pressure, and CO in each group dogs in Group II were given a bolus injection (0.1 mg/kg) followed by a continuous infusion (1.5 mg · kg^-1 · h^-1) of propofol IV with an electrical infusion pump for 60 min. After propofol administration, Pdi, Edi-cru, Edi-cost, and hemodynamic variables were measured, and CO was evaluated by using the thermodilution technique. In Group III, propofol (0.1-mg/kg initial dose plus 6.0-mg · kg^-1 · h^-1 maintenance dose) was continuously administered IV with an infusion pump for 60 min. In Group I, only the maintenance fluid was administered. The same measurements were performed in Groups I and III as those in Group II.

All 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, as appropriate. A P value of <0.05 was considered significant.

	Results

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No differences in baseline values were observed among the groups (Table 1). With an infusion of propofol in Groups II and III, heart rate, MAP, mean pulmonary arterial pressure, and CO decreased from baseline values (P < 0.05). In Group I, no hemodynamic changes were observed.

View larger version (12K): [in this window] [in a new window]   Figure 1. Typical recordings of transdiaphragmatic pressure (Pdi), integrated electrical activity of the crural part of the diaphragm (Edi-cru), and integrated electrical activity of the costal part of the diphragm (Edi-cost).

	Discussion

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The pressure generated by the diaphragm after a given electrical stimulation depends on its length and geometry (6), a major determinant of which is lung volume. Conceivably, the change in Pdi may be secondary to changes in the end-expiratory lung volume. However, in this study, the airway was occluded at the end-expiratory lung volume during the measurements, and its constancy was monitored by the measurement of end-expiratory transpulmonary pressure. Therefore, changes in lung volume during the experimental procedures can reasonably be excluded. The plaster cast around the abdomen and the lower one-third of the ribcage was also placed to prevent the deformation of thoracoabdominal structures.

Hypoxemia, hypercapnia, and metabolic acidosis decrease contractility of the diaphragm (7,8). Because PaO₂, PaCO₂, arterial pH, and HCO₃^- concentrations were controlled within normal ranges in this study, the factors that may have affected diaphragmatic contractility were excluded.

Volatile anesthetics, including halothane, enflurane, isoflurane, and sevoflurane impair contractile properties of the diaphragm (2–5). Selective loss of force at low-frequency stimulation is closely related to the impairment of excitation-contraction coupling (9), whereas selective loss of force at high-frequency stimulation indicates failure of neuromuscular transmission (10,11). Halothane depresses both Pdi and electromyographic activity (as assessed by using Edi) of the diaphragm at stimulation frequencies ranging from 10 Hz to 100 Hz, which suggests that impaired excitation-contraction coupling and/or impaired neuromuscular transmission exists during halothane administration (2). 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 (3–5). Thus, the volatile anesthetic depresses diaphragmatic contractility during high-frequency stimulation, and its mechanism may be related to the failure of neuromuscular transmission.

The results of Groups II and III 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 agreement with the characteristic of low-frequency fatigue (6). The precise mechanism by which propofol decreases diaphragmatic contractility is not clear. However, the search for a mechanism underlying the changes in the development of muscle tension during propofol administration may be helped by an analysis of the relationship between Pdi and both stimuli. On the basis of our findings, the potentiating mechanism of propofol on diaphragmatic dysfunction may be different from volatile anesthetics, but it may be similar to low-frequency fatigue that is closely related to the impairment of excitation-contraction coupling (12). This impairment is supposed to be the result of the alteration in movement of Ca²⁺ from the sarcoplasmic reticulum (13).

Blood flow to the diaphragm is an important determinant of diaphragmatic muscle function (14). Diaphragmatic blood flow is maintained relatively constant within a certain limit of perfusion pressure (15) and is autoregulated at MAP above 70 mm Hg (16). However, CO is one of the major factors determining blood flow to the diaphragm, and thereby may have affected diaphragmatic contractility (17). Although MAP < 70 mm Hg was not observed in any of the groups in our study, a decrease in CO, observed in Groups II and III with an infusion of propofol, may have led to a decrease in blood flow to the diaphragm. Consequently, its decrease may have reduced contractility of the diaphragm.

We demonstrated that Pdi at 20-Hz stimulation decreased from baseline values (P < 0.05) during propofol administration in Groups II and III and showed that a decrease in Pdi was greater in Group III than in Group II. This suggests that propofol decreases contractility of the diaphragm in a dose-dependent manner. The difference in Pdi between Groups II and III (P < 0.05) during propofol administration may be attributable to the difference in its direct inhibitory effect on diaphragmatic contractility and/or its indirect effect on it through a decrease in blood flow to the diaphragm, which is related to CO. In this study, CO decreased from baseline values with an infusion of propofol (P < 0.05) in Groups II and III, and a decrease in CO was greater in Group III than in Group II (P < 0.05).

Propofol has become more widely used during general anesthesia, as well as for sedation in the intensive care unit (1). Our results suggest that impaired contractility of the diaphragm associated with propofol may contribute to diaphragmatic dysfunction. The clinical importance of this phenomenon remains to be shown in humans.

We conclude that increasing the dose of propofol produces a progressive decrease in contractility of the diaphragm and that an inhibitory effect of propofol on diaphragmatic muscle function may be related to the impairment of excitation-contraction coupling and/or the decrease in blood flow to the diaphragm.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999