Anesth Analg 2004;99:113-116
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000116927.80080.1E
ANESTHETIC PHARMACOLOGY
The Recovery Profile of Reduced Diaphragmatic Contractility Induced by Propofol 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, MD, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2–1–1, Amakubo, Tsukuba City, Ibaraki 305–8576, Japan. Address email to yfujii{at}md.tsukuba.ac.jp
 |
Abstract
|
|---|
Propofol decreases contractility of the diaphragm, but no data are available for its effects on recovery. We studied the recovery profile of reduced diaphragmatic contractility induced by propofol in dogs. Animals were divided into 4 groups of 7 each. Group I, without fatigue, received only maintenance fluid; Group II, without fatigue, was infused with propofol; Group III, with fatigue, received no study drug; Group IV, with fatigue, was infused propofol. Propofol at an anesthetic dose (0.1 mg/kg initial dose plus 6.0 mg · kg–1 · h–1) was administered for 60 min. In Groups III and IV, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at 20-Hz for 30 min. We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). In group II, Pdi at low-frequency (20-Hz) stimulation decreased to less than baseline (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. At 10 min after the end of propofol administration, Pdi at 20-Hz stimulation returned to baseline. When fatigue was established, in Groups III and IV, Pdi at 20-Hz stimulation decreased to less than baseline (P < 0.05), whereas Pdi at 100-Hz stimulation did not change. After administering propofol in Group IV, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05). At 20 min after the end of propofol administration, Pdi at 20-Hz stimulation returned to fatigued values. We conclude that reduced contractility in nonfatigued and fatigued canine diaphragm induced by propofol recovers within 20 min after the cessation of administration.
IMPLICATIONS: Propofol at an anesthetic dose decreases diaphragmatic contractility in dogs, and its recovery is established within 20 min after the cessation of administration. This rapid recovery profile for diaphragm muscle dysfunction is widely accepted in anesthetic practice.
|
Introduction
|
|---|
Propofol has achieved considerable popularity for 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 (1). Like volatile anesthetics (halothane, enflurane, isoflurane, and sevoflurane) (2–5), propofol decreases contractility in nonfatigued and fatigued diaphragm (6,7). No studies have been reported evaluating the recovery from reduced diaphragmatic contractility caused by propofol. The purpose of this study, therefore, was to examine the recovery profile of reduced diaphragmatic contractility induced by propofol in dogs.
|
Methods
|
|---|
The protocol was approved by our animal research committee, and the care of animals was in agreement with guidelines for ethical animal research. Twenty-eight healthy adult mongrel dogs, 18 males and 10 females, weighing 10–15 kg (12.6 ± 1.5 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 ventilated mechanically with a mixture of oxygen and air (fraction of inspired oxygen, 0.4) to maintain PaO2 >100 mm Hg, PaCO235–40 mm Hg, and pHa 7.35–7.45. The right femoral artery was cannulated to monitor arterial blood pressure and to obtain 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) and pentobarbital. The left femoral vein was cannulated for the administration of propofol. Rectal temperature was continuously monitored and maintained at 37°C ± 1°C by using a heating pad.
Both phrenic nerves were exposed at the neck, and the stimulating electrodes were placed around them. Transdiaphragmatic pressure (Pdi) was measured by means of 2 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 one was changed to obtain appropriate pressure. The position of balloons in the esophagus and the stomach was 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. Isometric contractility of the diaphragm was evaluated by measuring 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 the lower one-third of the ribcage.
Electrical activity of the crural part (Edi-cru) and costal part (Edi-cost) of the diaphragm was recorded by using 2 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 an integrator with a time constant of 0.1 s and was recorded as the integrated electrical activity of the diaphragm (Edi-cru, Edi-cost).
Dogs were allowed to stabilize for at least 30 min before the study, and were randomly divided into 4 groups of 7 each. Baseline measurements of Pdi, Edi-cru, Edi-cost, heart rate (HR), and mean arterial blood pressure (MAP) were recorded in each group. Dogs in Group II were given an initial dose of propofol, 0.1 mg/kg followed by a continuous infusion of 6.0 mg · kg–1 · h–1 IV with an electrical infusion pump for 60 min. At 0 min, 10 min, 20 min, and 30 min after the cessation of propofol administration, Pdi, Edi-cru, Edi-cost, HR, and MAP were measured. In Group I, only maintenance fluid was administered and the same measurements were performed as those in Group II. In Groups III and IV, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation applied for 30 min at a frequency of 20-Hz, a cycle length of 4 s, and a duty cycle of 0.5 (i.e., low-frequency fatigue) (8). When fatigue was established, in Group IV, propofol was administered IV as described above for Group II. At 0 min, 10 min, 20 min, and 30 min after the end of propofol administration, Pdi, Edi-cru, Edi-cost, HR, and MAP were measured. In Group III, no study drug was administered IV and the same measurements were performed as those in Group IV. The changes of Edi-cru (%Edi-cru) and Edi-cost (%Edi-cost) from baseline values were also recorded.
Values were reported as mean ± SD. Statistical analysis was performed by analysis of variance for repeated measurements followed by Bonferroni-Dunn test for multiple comparisons and Student’s t-test, where appropriate. P < 0.05 was considered statistically significant. Analyses were performed using the Statistical Package for Social Sciences version 8.0 (SPSS Inc., Chicago, IL).
|
Results
|
|---|
No differences in baseline values were observed among the groups. After administering propofol in Groups II and IV, HR and MAP decreased from baseline values (P < 0.05). At 10 min after the cessation of propofol administration, HR and MAP increased from propofol-induced values (P < 0.05) and returned to baseline values. In Groups I and III, no hemodynamic changes were observed. With an infusion of propofol in Group II, Pdi at low-frequency (20-Hz) stimulation decreased to less than baseline (P < 0.05) and Pdi at high-frequency (100-Hz) stimulation did not change. At 10 min after the end of propofol administration, Pdi at 20-Hz stimulation returned to baseline. In Group I, Pdi to each stimulus did not change. When fatigue was established, in Groups III and IV, Pdi at 20-Hz stimulation decreased to less than baseline whereas Pdi at 100-Hz stimulation did not change. After administering propofol in Group IV, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05). At 20 min after the end of propofol administration, Pdi at 20-Hz stimulation returned to fatigued values. In Group III, Pdi at both stimuli did not recover from fatigued values. No changes in %Edi-cru and %Edi-cost were observed throughout the experiment in any group (Table 1).
|
Discussion
|
|---|
Diaphragmatic contractility is assessed by force-frequency characteristics (9,10) and is often evaluated by measuring Pdi, which is affected by the length and geometry of the diaphragm during the precontracted condition (11). 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 study, however, the airway was occluded at the end-expiratory lung volume during measurements, and its constancy was monitored by measuring the end-expiratory transpulmonary pressure. Therefore, changes in lung volume during the experimental procedures can reasonably be excluded. To avoid the deformation of thoracoabdominal structures, the plaster cast around the abdomen was also placed on the lower one-third of the ribcage. As the dogs were anesthetized with pentobarbital, the combined effect of pentobarbital and propofol on diaphragmatic contractility was examined. However, it has been reported that pentobarbital, at the dose used in this experiment (2 mg · kg–1 · h–1), does not affect contractility of the diaphragm (5). This was in accordance with our results that pentobarbital-anesthetized dogs without an administration of propofol (Groups I and III) showed no change in Pdi.
We found that Pdi at 20-Hz stimulation decreased from baseline values (P < 0.05) (Group II) or fatigued values (P < 0.05) (Group IV) with an infusion of propofol at anesthetic doses and that Pdi at 100-Hz stimulation and Edi (Edi-cru, Edi-cost) at both stimuli did not change. This was in agreement with our previous studies (6,7). The mechanism by which propofol decreases contractility in nonfatigued and fatigued diaphragm remains unclear. Selective loss of force at 20-Hz is closely related to the impairment of excitation-contraction coupling (12), and selective loss of force and electromyographic activity at 100-Hz stimulation indicate the failure of neurotransmission (13,14). Therefore, the decrease in Pdi at 20-Hz stimulation without any change in Pdi at 100-Hz stimulation and Edi to each stimulus during propofol administration is probably associated with the impairment of excitation-contraction coupling.
The results of Groups I and III, in which HR, MAP, Pdi, and Edi were obtained without an administration of propofol, showed that HR and MAP increased from propofol-induced values (P < 0.05) and returned to baseline values at 10 min after the cessation of propofol administration. Thus, as with the pharmacokinetic properties (i.e., rapid metabolic clearance) (1), the hemodynamic effects of propofol were abolished at 10 min after the end of propofol administration. Similarly, the inhibitory effects of propofol on contractility in nonfatigued diaphragm (Group II) were abolished. However, reduced diaphragmatic contractility induced by propofol in fatigued diaphragm (Group IV) recovered at 20 min after the end of propofol administration. The exact reason for this difference is unknown, but it may be attributed to the difference in diaphragm muscle condition (i.e., nonfatigued versus fatigued). Further studies are needed to elucidate the recovery profile associated with propofol in nonfatigued and fatigued diaphragm.
Propofol is an effective IV anesthetic that has been developed for the induction and maintenance of anesthesia and sedation (1). Our results showed that the cardiovascular effects of propofol (i.e., decreases in HR and MAP) were abolished at 10 min after the end of propofol administration and that the inhibitory effects of propofol on contractility in fatigued, but not nonfatigued, diaphragm were prolonged. Thus, when propofol is used at an anesthetic dose, clinicians should pay attention to diaphragm muscle dysfunction caused by propofol in patients with chronic obstructive pulmonary disease related to the fatigue of respiratory muscle, especially the diaphragm (9,10). However, its recovery was established within 20 min after the end of propofol administration. In our preliminary report (6), a sedative dose (1.5 mg · kg–1 · h–1) of propofol administered IV for 60 min decreased diaphragmatic contractility by 10% in dogs. The long-time (>60 min) effects on diaphragm muscle function were not published but reduced diaphragmatic contractility induced by propofol at a sedative dose administered IV for 60 min was not changed at 120 min after the onset of propofol administration (unpublished data). Further studies are needed to determine the possible time-dependent effects of a sedative dose of propofol.
In conclusion, propofol at an anesthetic dose decreases contractility in nonfatigued and fatigued diaphragm in dogs, and this reduced contractility induced by propofol recovers within 20 min after the cessation of administration.
|
References
|
|---|
- Smith I, White PF, Nathanson M, Gouldson R. Propofol: an update on its clinical use. Anesthesiology 1994; 81: 1005–43.[ISI][Medline]
- Dureuil R, Viires N, Nivoche Y, et al. Different effects of halothane on diaphragm and hindlimb muscle in rats. J Appl Physiol 1987; 63: 1757–62.[Abstract/Free Full Text]
- Kochi T, Ide T, Isono S, et al. Different effects of halothane and enflurane on diaphragmatic contractility in vivo. Anesth Analg 1990; 70: 362–8.[Abstract/Free Full Text]
- Veber B, Dureuil R, Viires N, et al. Effects of isoflurane on contractile properties of diaphragm. Anesthesiology 1989; 70: 684–8.[ISI][Medline]
- Ide T, Kochi T, Isono S, Mizuguchi T. Effect of sevoflurane on diaphragmatic contractility in dogs. Anesth Analg 1992; 74: 739–46.[Abstract/Free Full Text]
- Fujii Y, Hoshi T, Takahashi S, Toyooka H. Propofol decreases diaphragmatic contractility in dogs. Anesth Analg 1999; 89: 1557–60.[Abstract/Free Full Text]
- Fujii Y, Uemura A, Toyooka H. The dose-range effects of propofol on the contractility of fatigued diaphragm in dogs. Anesth Analg 2001; 93: 1194–8.[Abstract/Free Full Text]
- 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]
- Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982; 307: 786–97.[ISI][Medline]
- Macklem PT, Roussos C. Respiratory muscle fatigue: a cause of respiratory failure. Clin Sci Mol Med 1977; 53: 419–22.[ISI][Medline]
- Grassino A, Goldman MD, Mead J, Sears TA. Mechanics of the human diaphragm during voluntary contraction: statics. J Appl Physiol 1978; 44: 829–39.[Abstract/Free Full Text]
- 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.
- Edwards RHT. Physiological analysis of skeletal muscle weakness and fatigue. Clin Sci Mol Med 1987; 54: 463–70.
- Jones DA, Bigland-Ritchie B, Edwards RHT. Excitation frequency and muscle fatigue: mechanical responses during voluntary and stimulated contraction. Exp Neurol 1979; 64: 401–13.[ISI][Medline]
Accepted for publication December 17, 2003.
This article has been cited by other articles:
|
|
|
|
 
Y. Fujii and A. Uemura
The Effects of Different Dobutamine Infusion Rates on Hypercapnic Depression of Diaphragmatic Contractility in Pentobarbital-Anesthetized Dogs
Anesth. Analg.,
November 1, 2007;
105(5):
1379 - 1384.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
