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Anesth Analg 2001;93:1194-1198
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Dose-Range Effects of Propofol on the Contractility of 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, 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


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Diaphragmatic fatigue may contribute to the development of respiratory failure. We studied the dose-range effects of propofol on the contractility of fatigued diaphragm in dogs. Animals 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. Immediately after the end of a fatigue-producing period, Group 1 received no study drug; Group 2 was infused with small-dose propofol (0.1 mg/kg initial dose plus 1.5 mg · kg-1 · h-1 maintenance dose); Group 3 was infused with large-dose 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). After the fatigue-producing period, in each group, Pdi at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups 2 and 3, with an infusion of propofol, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05). Compared with Group 1, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05) during propofol administration in Groups 2 and 3. The decrease in Pdi was more in Group 3 than in Group 2 (P < 0.05). We conclude that propofol decreases the contractility of fatigued canine diaphragm in a dose-related fashion.

IMPLICATIONS: Propofol is a widely used IV anesthetic for the induction and maintenance of general anesthesia and sedation. It decreases, in a dose-related fashion, the contractility of fatigued diaphragm in dogs.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Respiratory muscle fatigue, especially that of the diaphragm, has been implicated as a cause of respiratory failure in normal subjects (1) and in patients with chronic obstructive lung disease (2). Volatile anesthetics, including halothane, enflurane, isoflurane, and sevoflurane, depress contractile properties of the diaphragm (3–6). Like these volatile anesthetics, propofol impairs diaphragm muscle function via an impairment of excitation-contraction coupling, a decrease in blood flow to the diaphragm (7), or both, and it causes less inhibition of contractility during diaphragmatic fatigue than midazolam (8). There have been no reports to evaluate the dose-related effects of propofol on contractility in fatigued diaphragm. The purpose of this study was, therefore, to determine the dose-range effects of propofol on the contractility of fatigued diaphragm in dogs.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The protocol was approved by our animal research committee and care of the animals was in agreement with guidelines for ethical animal research. Twenty-four healthy mongrel dogs, 13 males and 11 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 movement and breathing spontaneously. 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 samples for blood gas analysis. Arterial blood gases were measured every 30 min throughout the experiment. 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 the 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 the thermodilution technique. Rectal temperature was monitored continuously and maintained at 37°C ± 1°C by using a heating pad.

The phrenic nerves were exposed bilaterally at the neck, and stimulating electrodes were placed around them. Transdiaphragmatic pressure (Pdi) was measured by using two thin-walled latex balloons; one was positioned in the stomach, and the other was positioned in the middle third of the esophagus. The balloons were connected to a differential pressure transducer and an amplifier. While one balloon catheter was open to the atmosphere, the position of the other was changed to obtain appropriate pressure. Then the position of the balloons in the esophagus and the stomach was 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. Diaphragmatic contractility was evaluated by measuring the maximal Pdi generated by test stimuli after airway occlusion at functional residual capacity. Transpulmonary pressure, the difference between airway and esophageal pressures, was kept constant by maintaining the same lung volume before each phrenic nerve 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 third of the ribcage. The electrical activity of the crural and costal parts of the diaphragm (Edi-cru and Edi-cost, respectively) was recorded by using two pairs of fishhook electrodes placed through a midline laparotomy; electrodes 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 a leaky integrator with a time constant of 0.1 s and was regarded as the integrated Edi-cru and 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, and hemodynamic variables, including heart rate, mean arterial pressure, right atrial pressure, mean pulmonary arterial pressure, pulmonary artery occlusion pressure, and CO, 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) (9). Immediately after the cessation of a fatigue-producing period, Group 2 was infused with small-dose propofol (0.1 mg/kg initial dose plus 1.5 mg · kg-1 · h-1 maintenance dose), and Group 3 was infused large-dose propofol (0.1 mg/kg initial dose plus 6.0 mg · kg-1 · h-1 maintenance dose). The study drug was continuously administered IV via an electrical infusion pump for 30 min. At 30 min after the onset of propofol administration, Pdi, Edi-cru, Edi-cost, hemodynamic variables, and CO were measured. In Group 1, no study drug was administered IV, and the same measurements were performed as those in the other groups.

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


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
No differences in baseline hemodynamic variables were observed among the groups. With an infusion of propofol, in Groups 2 and 3, heart rate, mean arterial pressure, mean pulmonary arterial pressure, pulmonary artery occlusion pressure, and CO decreased from baseline values (P < 0.05). In Group 1, no hemodynamic changes were observed (Table 1). The Pdi values at different stages and the changes of Edi-cru and Edi-cost (%Edi-cru and %Edi-cost, respectively) from baseline values are shown in Table 2. After the fatigue-producing period, in each group, Pdi at low frequency (20 Hz) decreased from baseline values (P < 0.05), but Pdi at high-frequency (100-Hz) stimulation did not change. With an infusion of propofol, in Groups 2 and 3, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05). The decrease in Pdi was more in Group 3 than in Group 2 (P < 0.05). In Group 1, Pdi to each stimulus did not recover from fatigued values. No changes in %Edi-cru and Edi-cost were observed throughout the experiment in any group.


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  		Table 1. Hemodynamic Data and Changes
 

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  		Table 2. Changes in Pdi, %Edi-cru, and %Edi-cost
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major finding of this study is that propofol decreases contractility in a dose-related fashion (as assessed by Pdi) of fatigued diaphragm, without any change in electromyographic activity (as assessed by Edi). The pressure generated by the diaphragm (Pdi) for a given electrical stimulation is affected by its length and geometry (10). A major determinant of length and geometry of the diaphragm is lung volume. Conceivably, the change in Pdi may be secondary to changes in the end-expiratory lung volume. In this experiment, lung volume was strictly controlled, because the airway was occluded at the end-expiratory lung volume during measurements, and the end-expiratory transpulmonary pressure was monitored and kept constant before each stimulus. The deformation of thoracoabdominal structures was also avoided by placing a cast around the abdomen and lower third of the rib cage. Therefore, the changes in Pdi observed in this study are probably the result of changes in contractility of the diaphragm.

Hypoxemia, hypercapnia, and metabolic acidosis decrease contractility in fatigued diaphragm (11,12). In this study, however, PaO2, PaCO2, arterial pH, and serum bicarbonate were controlled within normal ranges. Therefore, these factors, which may have affected diaphragmatic contractility, were excluded. Because the dogs were basically anesthetized with pentobarbital, the combined effects of propofol and pentobarbital on the contractility of the diaphragm were examined in this experiment. However, pentobarbital at the doses (2 mg · kg-1 · h-1) used in this study does not affect diaphragmatic contractility (6).

Low-frequency fatigue is of particular clinical importance because the spontaneous, natural rate of phrenic nerve discharge is mainly in the low-frequency ranges (i.e., 5 to 30 Hz) (13). Therefore, the effects of propofol on contractility in fatigued diaphragm induced by 20-Hz stimulation (i.e., low-frequency fatigue) were examined. The results of Group 1, in which Pdi was obtained without an administration of propofol in fatigued diaphragm, showed that Pdi to each stimulus did not recover from fatigued values and that Edi did not change at any frequency of stimulation. This was in agreement with our previous study (14).

We found that Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05) with an infusion of propofol and Pdi at 100-Hz stimulation, and Edi (Edi-cru, Edi-cost) at both stimuli did not change during propofol administration in Groups 2 and 3. Also Pdi decreased more in Group 3 than in Group 2 (P < 0.05). Thus, our results suggest that propofol decreases, in a dose-related fashion, contractility in fatigued diaphragm.

The exact mechanism by which propofol depresses contractility in fatigued diaphragm is not known. Selective loss of force at 20 Hz is closely related to the impairment of excitation-contraction coupling (15), and selective loss of force and electromyographic activity at 100-Hz stimulation indicates the failure of neuromuscular transmission (16,17). Therefore, the decrease in Pdi at 20-Hz stimulation without any change of Edi during propofol administration is presumably associated with the impairment of excitation-contraction coupling.

Diaphragmatic contractility depends on the energy supplies to the diaphragm; these are related to its blood supply, and CO is one of the major factors determining blood flow to the diaphragm (18). The decrease in CO observed in Groups 2 and 3 with an infusion of propofol may have led to a decrease in blood flow to the diaphragm and thereby may have reduced contractility of the diaphragm. We showed that CO decreased from fatigued values with an infusion of propofol (P < 0.05) in Groups 2 and 3 and also showed that CO was less in Group 3 than in Group 2 (P < 0.05). Thus, the difference in Pdi between the two groups (P < 0.05) during propofol administration may be attributed to the difference in CO, which is related to blood flow to the diaphragm. In this study, however, the blood flow to the diaphragm was not directly measured. Further studies are needed to clarify the relationship between CO and the contractility of fatigued diaphragm during propofol administration.

We have demonstrated that contractility in nonfatigued diaphragm decreases by 22% (22% ± 7%, mean ± SD) at 20-Hz stimulation and does not decrease when stimulated at 100 Hz with an infusion of an anesthetic dose (6 mg · kg-1 · h-1) of propofol (7). In this experiment, contractility in fatigued diaphragm decreased by 28% (28% ± 4%, mean ± SD) at 20-Hz stimulation and did not change at 100-Hz stimulation during large-dose (6 mg · kg-1 · h-1) propofol administration. Thus, there is a possibility that propofol may cause more inhibition of contractility in fatigued diaphragm, compared with nonfatigued diaphragm. However, when statistically analyzed, no difference in a reduction rate of Pdi at 20-Hz stimulation was observed in nonfatigued and fatigued diaphragm (P = 0.98 with Student’s t-tests). Consequently, propofol decreases diaphragmatic contractility during fatigued as well as nonfatigued conditions.

Propofol has become a widely used IV anesthetic for the induction and maintenance of general anesthesia and sedation. The favorable recovery profile associated with propofol offers advantages over traditional anesthetic and sedative medications in clinical situations (19). Our results demonstrated that diaphragmatic contractility is impaired by administering propofol at sedative and anesthetic doses. Clinicians should pay attention to diaphragmatic muscle function in the clinical setting during propofol administration.

In conclusion, propofol decreases the contractility of fatigued canine diaphragm in a dose-related fashion. The inhibitory effects of propofol on contractility during diaphragmatic fatigue may be related to the impairment of excitation-contraction coupling, the decrease in diaphragmatic blood flow, or both of these.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Macklem PT, Roussos C. Respiratory muscle fatigue: a cause of respiratory failure? Clin Sci Mol Med 1977; 53: 419–22.[ISI][Medline]
  2. Cohen CA, Zagelbaum G, Gross D, et al. Clinical manifestations of inspiratory muscle fatigue. Am J Med 1982; 73: 308–16.[ISI][Medline]
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  9. Aubier M, Farkas G, DeTroyer A, et al. Detection of diaphragmatic fatigue in man by phrenic nerve stimulation. J Appl Physiol 1981; 50: 538–44.[Abstract/Free Full Text]
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Accepted for publication June 28, 2001.




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Lippincott, Williams & Wilkins 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 HighWire Press