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EFFECT OF FENTANYL ON VENTILATORY RESISTANCES DURING BARBITURATE GENERAL ANAESTHESIA
British Journal of Anaesthesia 1992; 69: 595-598
EFFECT OF FENTANYL ON VENTILATORY RESISTANCES DURING BARBITURATE GENERAL ANAESTHESIA R. COHENDY, J. Y. LEFRANT, M. LARACINE, T. REBIERE AND J. J. ELEDJAM
Fentanyl has been shown to increase the overall resistance to inspiratory flow of the ventilatory system (Rmax). Rmax is the sum of the airway resistance (Raw) and of the non-Newtonian resistance (AR) which may result from the viscoe/astic properties of the thoracic tissues, from inequalities of the regional time constants within the lung, or from both. A bronchoconstrictor challenge may increase the magnitude of variation in regional time constants. Thus, in order to describe the effect of fentanyl on the two components of Rmax, this study was performed, with the endinflation occlusion method, during paralysis and mechanical ventilation in 10 normal men undergoing barbiturate anaesthesia for minor urological procedures. The patients were anaesthetized with methohexitone and paralysed with vecuronium. Before administration of fentanyl, A R accounted for 56% of Rmax. Fentanyl 5 fig kg~' elicited a significant increase in Rmax (+34.5%; P = 0.005) and a parallel increase in both Raw (+35.2%, P = 0.0/7; and AR ( + 33.5%, P = 0.005). The increase in Raw, but not in AR, was reversed by atropine, suggesting that the increase in these two components of Rmax was not linked. Thus fentanyl increased both components of Rmax, but the effects of fentanyl on Raw and AR seemed to depend on different mechanisms. (Br. J. Anaesth. 1992; 69: 595-598) KEY WORDS Anaesthesia: general. Analgesics: fentanyl. Lung: respiratory resistance.
Fentanyl increases ventilatory impedance in man. The drug induces truncal muscular rigidity [1] and bronchoconstriction [2] and it increases the overall resistance to inspiratory flow of the ventilatory system (Rmax) [3]. This resistance is the sum of two distinct resistances [4]: airway resistance (.Raw) and non-Newtonian resistance (AR) which varies with the ventilatory pattern [5]. AR may result from either or both of two distinct phenomena [6, 7]—viscoelasticity of the thoracopujmqnary tissues or inhomogeneity of regional time constants within the lungs; the latter is considered to be negligible in the normal subject. However, a bronchoconstrictor challenge may induce or aggravate this phenomenon [8].
The aim of this study was to describe the effects of fentanyl on .Rmax and on its two components, AR and .Raw, in anaesthetized, paralysed man undergoing mechanical ventilation. For this purpose we used the end-inflation occlusion method [7]. The study was completed with the description of the effect of fentanyl on the elastic properties of the ventilatory system: static elastance (Est) and dynamic elastance (jSdyn). Moreover, as atropine decreases .Rmax during general anaesthesia in man [9]j its effects on the fentanyl-induced modifications of the ventilatory mechanics were also described. PATIENTS AND METHODS
After approval from the local Ethics Committee, we studied 10 men undergoing elective surgery for testicular biopsy under general anaesthesia (mean age 30 yr (range 26-34 yr) weights 69.7 (SD 5.9) kg). The exclusion criteria were clinical or radiological abnormality of the ventilatory system; heavy smoking; suspected (history of atopy) or overt (history of wheezes) bronchial hypersensitivity; treatment with a beta blocker [10]. Mechanical ventilation was performed with a Servo Ventilator 900 D (Siemens-Elema, Sweden). This ventilator produces a constant inflation flow (Vi), and an accurate tidal volume (FT) [11, 12]. It allows end-expiratory and end-inspiratory airway occlusions [13]. The ventilatory circuit comprised short tubing (40 cm) without a humidifier, in order to reduce the compressible volume. Each disposable tracheal tube (internal diameter 8 mm) was fitted with a lateral port at its distal end ("Blue Line", ref. 100/196/080 Portex Great Britain), that allowed measurement of the tracheal pressure [14]. The port was connected to a pressure transducer (model SK + 20 cm HjO, EFFA, Le Pre St Gervais, France) and a linear amplifier (MRC 4411, LEIM, Aix en Provence, France). The pressure signal and the flow signal fed by the ventilator were recorded on a Gould TA 550 polygraph, at a paper speed of 15 mm s"1. Ventilatory mechanics were studied using the endinspiratory occlusion method which has already been ROBERT COHENDY, M.D., M.SC. ; JEAN YVES LEFRANT, M.D. ; MICHEL LARACINE, M.D.; THIERRY REBIERE, M.D.; JEAN JACQUES ELEDJAM,
M.D.; Department of Anaesthesia and Intensive Care, Centre Hospitalier Regional et Universitaire de Nimes, 5, rue Hoche, 30029 Nimes Cedex, France. Accepted for Publication: June 19, 1992.
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SUMMARY
596
BRITISH JOURNAL OF ANAESTHESIA TABLE I. Overall resistance of the ventilatory system (Rmax), airway resistance (Raw), non-Newtonian resistance (AR) and contribution of AR to Rmax (AR/Rmax) (mean (SD)) at baseline (To), 6 min after fentanyl 5 fig kg "' (T,) and 6 min after fentanyl 1.75 fig kg'1 (TJ. f Friedman test Resistance (cm H,O litre"1 s) T, i?max Raw AR AR/Rmax (%)
3.62 (0.87) 1.59(0.47) 2.03 (0.56) 56 (0.076)
4.87(1.2) 2.15(0.8) 2.71 (0.5) 56.8 (0.075)
3.95 (0.99) 1.40(0.55) 2.54 (0.59) 64.9(0.071)
0.0002 0.02 0.0002 0.02
TABLE II. Dynamic elastance CEdyri) and static elastance (Ejt) of the venlilalory system (mean (SD)) at baseline (To), 6 min after fentanyl 5 fig kg~' (Tj) and 6 min after fentanyl 1.75 fig kg'1 (jHr). + Friedman test Elastance (cm H,O litre"1)
£dyn Est
14.30(2.6) 12.27(2.36)
15.21(2.67) 12.50(2.41)
15.07(2.63) 12.53(2.41)
0.0001 0 18
baseline values). A first dose of fentanyl 4.9 (0.4) jig kg"1 was given and a second group of occlusions (T t ) was recorded 6 min later. A second dose of fentanyl 1.75 (0.3) fig kg"1 was given together with atropine 1 mg. The last group of occlusions (T2) was performed 6 min later. The duration of the study did not exceed 25 min and recovery was always uneventful. Statistical analysis Data are given as mean (SD). Means were compared with a non-parametric Friedman test and Wilcoxon signed-rank tests. P < 0.05 was considered to be significant. RESULTS
After administration of fentanyl, all the measured resistances increased significantly: .Rmax (P = 0.005), .Raw (P = 0.017) and AR (P = 0.005) (table I). The increase in .Raw paralleled the increase in AR, because the contribution of AR to .Rmax remained stable: 56% at T o and 56.8% at T, (P = 0.87). While £st remained stable during the whole study, £dyn increased slightly ( + 6.4%) (P = 0.005) with fentanyl (table II). When atropine was added to fentanyl, .Raw decreased significantly (P = C.007) and returned to its control value (P = 0.17). However, AR at T 2 remained stable compared with its value at T t (P = 0.14) but was significantly greater than at T o (P = 0.012); its contribution to .Rmax increased significantly (P = 0.028) between T! and T 2 and was significantly greater at T, than at T o (P = 0.01). The decrease in .Rmax at T 2 was significant compared with those at T, (P = 0.005) and T o (P = 0.04). Z?dyn remained stable between T, and T 2 (P = 0.64) (table II). DISCUSSION
We have found that, in anaesthetized, paralysed patients undergoing mechanical ventilation, fentanyl increased all the measured resistances. There was a
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 30, 2015
described extensively [7]. Briefly, at the end of the inflation of a preset tidal volume (FT), an occlusion of about 6 s was performed at the ventilator valves (while pressing the "inspiratory hold" button) to detect any air leak. After airway occlusion, there was an abrupt decrease in tracheal pressure from a maximum pressure Pmax to an inflection point P u and a more gradual decay to a plateau pressure which is the elastic recoil pressure of the ventilatory system (Pel) [12]. Gas exchange during occlusion has a negligible effect on Pel [15], which was measured after 3 s of the end-inspiratory occlusion. The initial decrease in pressure (Pmax —PJ reflects the resistive pressure attributable to the airway resistance (.Raw) during the constant inflation flow preceding occlusion (Fi). Thus .Raw equals (Pmax —PL) Fi"1. Similarly, overall resistance, .Rmax, was calculated as .Rmax = (Pmax —Pel) Vr1; additional resistance (AR) = Rmax —Raw; static elastance (£st) = Pel FT" 1 . [12]; dynamic elastance (£dyn) = Pmax FT" 1 . The possibility of an intrinsic PEEP (PEEPi) was excluded by an end-expiratory occlusion performed at the ventilator valves (while pressing the " expiratory hold" button). It would have been necessary to take account of any PEEPi in calculating resistance and elastance, but it was never seen in our patients. In order to avoid absorption atelectasis, the lungs were ventilated with 30% oxygen in nitrogen [16]. At each experimental time, at least one endexpiratory occlusion followed by at least three endinspiratory occlusions were performed. All the occlusions were separated by five tidal breaths. As the ventilatory mechanics are frequency-, flow- and volume-dependent [5], all the subjects underwent ventilation of the lungs with the same pattern: frequency 15 b.p.m., F T = 0.6 litre, inspiratory time (7i) 1 s, expiratory time ( TE) 3 s. The study was performed in the operating theatre, before the beginning of the surgical procedure. Midazolam 5 mg i.m. was given as premedication. Anaesthesia was induced with methohexitone 2.85 (SD 0.5) mg kg"1 and maintained with a continuous infusion of this drug (0.1 mg kg"1 min"1). Neuromuscular block was produced with vecuronium 0.15 mg kg"1 and monitored with train-of-four stimulation of the adductor pollicis muscle. A surgical level of paralysis was observed in every subject during the duration of the study. The trachea was intubated with the orotracheal tube described above, the lungs were ventilated manually in order to achieve a standard volume history and the patient was connected to the ventilator. Six minutes later, the first group of occlusions were recorded (T o :
T,
VENTILATORY RESISTANCES AND FENTANYL
induction of general anaesthesia [1]. In fact, the observed stability of £st suggests that such a change was negligible during the short duration of our study. Moreover, D'Angelo and colleagues [5] have shown that AR varies in the same direction as lung volume. In our study, AR increased with fentanyl. Thus the increase in .Raw resulted from bronchoconstriction and not a reduction in lung volume. Moreover, the increase in the initial pressure change after occlusion after a bronchoconstrictive challenge reflects an effective increase in .Raw, despite introduction of significant mechanical heterogeneities in the lung, as shown by Ludwig and colleagues [24]. Because Raw decreased with atropine, which blocks all muscarinic responses within the bronchial tree with equal efficacy [25], it is suggested that the observed effect of fentanyl on the bronchial muscle was vagally induced. The second component of .Rmax is the additional resistance, AR, that may result from the viscoelastic properties of the respiratory system, variation in regional time constants, or both. As Est remained stable, the increase in AR was probably not caused by variation in lung volume. Moreover, in spite of the bronchodilatation induced by atropine, AR did not change. This suggests that the bronchoconstrictor effect of fentanyl did not induce significant variations in regional time constants that could have explained the increase in AR observed at T1. Consequently, it can be argued that fentanyl acts directly on pulmonary viscoelastic properties [26]. An effect of thoracic and abdominal muscles is excluded, because of the presence of neuromuscular block. Thus fentanyl increased peripheral resistance, possibly through an effect on peribronchiolar contractile structures [27]. These structures are independent of the parasympathic system and are insensitive to atropine because there are few muscarinic receptors in terminal bronchioles [23]. REFERENCES 1. Gal TJ. Respiratory Physiology in Anesthetic Practice. Baltimore: Williams and Wilkins, 1991. 2. Yasuda I, Hirano T, Yusa T, Satoh M. Tracheal constriction by morphine and fentanyl in man. Anesthesiology 1978; 49: 117-119. 3. Cigarini I, Bonnet F, Lorino AM, Harf A, Desmonts JM. Comparison of the effects of fentanyl on respiratory mechanics under propofol of thiopental anaesthesia. Acta Anaesthesiologica Scandinavica 1990; 34: 253-256. 4. Bates JHT, Rossi A, Milic-Emili J. Analysis of the behavior of the respiratory system with constant inspiratory flow. Journal of Applied Physiology 1985; 58: 1848-1848. 5. D'Angelo E, Calderini E, Torri G, Robatto F, Bono D, Milic-Emili J. Respiratory mechanics in anesthetizedparalyzed humans: effect of flow, volume and time. Journal of Applied Physiology 1990; 67: 2556-2564. 6. Similowski T, Levy P, Corbeil C, Albala M, Pariente R, Derenne JPH, Bates JHT, Johnson B, Milic-Emili J. Viscoelastic behavior of lung and chest wall in dogs determined by flow interruption. Journal of Applied Physiology 1990; 67: 2219-2229. 7. Milic-EmUi ], Robatto FM, Bates JHT. Respiratory mechanics in anaesthesia. British Journal of Anaesthesia 1990; 65: 4-12. 8. Sly PD, Brown KA, Bates JHT, Macklem PT, Milic-Emili J, Martin JG. Effect of lung volume on interrupter resistance in cats challenged with methacholine. Journal of Applied Physiology 1988; 64: 360-366.
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parallel increase in Raw and AR, their respective contribution to Rmax remaining stable. When atropine was given, Raw decreased and returned to the control value, while the contribution of AR to Rmax increased. We have used the end-inspiratory occlusion method [7]; this allows separation of airway resistance (Raw) from the non-Newtonian, peripheral resistance (AR). As AR varies with the ventilatory pattern [5], we maintained the same pattern in all patients, to allow comparison of resistances. The tracheal pressure was measured within the airway, in order to avoid subtraction of the tracheal tube resistance from the resistance values [14]. Any occlusion has a finite time, and allows a residual flow [17]. The volume resulting from this residual flow can be estimated as 2.5 % of FT, according to the calculations of Kochi and colleagues [18], who have studied ventilatory mechanics in cats with the same occlusion method and a very similar ventilator (Servo Ventilator 900 C). This leads to underestimation of the initial pressure change and thus of the values of .Rmax and .Raw. However, each subject acted as his own control and this allowed at least a qualitative comparison. General anaesthesia and paralysis were obtained with methohexitone and vecuronium, respectively. It could be argued that these drugs might have modified bronchial size and reactivity. However, neither of these drugs induces measurable liberation of histamine [19,20], and vecuronium does not interact with the muscarinic receptor of the bronchial autonomic innervation [20]. Moreover, because fentanyl does not induce detectable liberation of histamine in plasma [21] or the tissues [22], we can postulate that the changes in resistance observed during the study were probably caused by the direct effect of fentanyl. A second dose of fentanyl was given before the T 2 measurements in order to avoid an excessive decrease in plasma concentration of fentanyl. After a loading dose, there is a second distribution of fentanyl, with a half-life (Tf) of 10-30 min, but with a wide variability in individual pharmacokinetics [23]. A second dose (1.75 ug kg~')j is then able to maintain a relatively great plasma concentration of the drug [23]. Thus the effect of fentanyl on resistances would not be declining with time, and the observed values at T 2 could be attributed to the antagonism by atropine of the effect of fentanyl. The baseline values of Rmax, Raw, AR and £st were in the range of values calculated from the data of D'Angelo and colleagues [5], who studied adult subjects anaesthetized with enflurane and nitrous oxide and paralysed with pancuronium. In our study, with fentanyl, Rmax and its two components, .Raw and AR, increased. An increase in .Rmax with a similar dose of fentanyl during thiopentone anaesthesia was described by Cigarini and colleagues [3]v In their study, such an^increasenn Rmax with fentanyl did not occur during anaesthesia with propofol. However, these authors did not partition .Rmax. The initial component of Rmax is .Raw. The increase in our study could have been caused by a reduction ir. TkC which is observed commonly after
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BRITISH JOURNAL OF ANAESTHESIA
598
18. Kochi T, Okubo S, Zin WA, Milic-Emili J. Flow and volume dependance of pulmonary mechanics in anesthetized cats. Journal of Applied Physiology 1988; 64: 441-450. 19. Hirshman CA, Edelstein RA, Ebertz JM, Hanifin JM. Thiobarbiturate-induced histamine release in human skin mast cells. Anesthesiology 1985; 63: 353-356. 20. Vctterman J, Beck KC, Lindahl SGE, Brichant JF, Rehder K. Actions of enflurane, isoflurane, vecuronium, atracurium and pancuronium on pulmonary resistance in dogs. Anesthesiology 1988; 69: 688-695. 21. Rosow CE, Moss J, Philbin DM, Savarese JJ. Histamine release* during morphine and fentanyl anesthesia. Anesthesiology 1982; 56: 93-96. 22. Levy JH, Brister NW, Shearin A, Ziegler J, Hug CC, Adelson DM, Walker BF. Wheal and flare responses to opoids in humans. Anesthesiology 1989; 70: 756-760. 23. Bailey PL, Stanley TH. Narcotic intravenous anesthetics. In: Miller RD, ed. Anesthesia, 3rd Edn. New York: Churchill Livingstone, 1990; 281-366. 24. Ludwig MS, Romero PV, Sly PD, Fredberg JJ, Bates JHT. Interpretation of interrupter resistance after histamineinduced constriction in the dog. Journal of Applied Physiology 1990; 68: 1651-1656. 25. Barnes PJ. Muscarinic receptors in lung. Postgraduate Medical Journal 1987; 63: 13-19. 26. D'Angelo E, Robatto FM, Caldenni E, Tavola M, Bono D, Torri G, Milic-Emili J. Pulmonary and chest wall mechanics in anesthetized paralyzed humans. Journal of Applied Physiology 1991; 70: 2602-2610. 27. Staub NC, Albertine KH. The structure of the lung relative to their principal function. In: Murray JF, Nadel JA, eds.
Medical and Biological Engineering and Computing 1987; 25:
Textbook
136-140.
Saunders, 1988; 12-36.
of
Respiratory
Medicine.
Philadelphia:
WB
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9. Don HF, Robson JC. The mechanics of the respiratory system during anesthesia. The effect of atropine and carbon dioxide. Anesthesiology 1965; 26: 168-178. 10. Roering DL, Kotrly KJ, Ahlf SB, Dawson CA, Kampine JP. Effect of propanolol on the first pass uptake of fentanyl in the human and rat lung. Anesthesiology 1989; 71: 62-68. 11. Johnson A, Bengtsson M. Comparison of anaesthesia ventilators using a lung model. Acta Anatsthestologica Scandinavica 1990; 34: 22-226. 12. Levy P, Similowski T, Corbeil C, Albala M, Pariente R, Milic-Emili J, Johnson B. A method for studying the static volume-pressure curves of the respiratory system during mechanical ventilation. Journal of Critical Care 1989; 4: 83-89. 13. Sly PD, Bates JHT, Milic-Emili J. Measurement of respiratory mechanics using the Siemens Servo Ventilator 900C. Pediatric Pulmonology 1987; 3: 400-405. 14. Navajas D, Farre R, Rotger M, Canet J. Recording pressure at the distal end of the endotracheal tube to measure respiratory impedance. European Respiratory Journal 1989; 2: 178-184. 15. Sydow M, Burchardi H, Zinserling J, Ische H, Crozier ThA, Weyland W. Improved determination of static compliance by automated single volume steps in ventilated patients. Intensive Care Medicine 1991; 17: 108-114. 16. Nunn JF. Applied Respiratory Physiology, 3rd Edn. London: Butterworths, 1987. 17. Bates JHT, Hunter IW, Sly PD, Okubo S, Filiatrault S, Milic-Emili J. Effect of valve closure time on the determination of respiratory resistance by flow interruption.
EFFECT OF FENTANYL ON VENTILATORY RESISTANCES DURING BARBITURATE GENERAL ANAESTHESIA R. COHENDY, J. Y. LEFRANT, M. LARACINE, T. REBIERE AND J. J. ELEDJAM
Fentanyl has been shown to increase the overall resistance to inspiratory flow of the ventilatory system (Rmax). Rmax is the sum of the airway resistance (Raw) and of the non-Newtonian resistance (AR) which may result from the viscoe/astic properties of the thoracic tissues, from inequalities of the regional time constants within the lung, or from both. A bronchoconstrictor challenge may increase the magnitude of variation in regional time constants. Thus, in order to describe the effect of fentanyl on the two components of Rmax, this study was performed, with the endinflation occlusion method, during paralysis and mechanical ventilation in 10 normal men undergoing barbiturate anaesthesia for minor urological procedures. The patients were anaesthetized with methohexitone and paralysed with vecuronium. Before administration of fentanyl, A R accounted for 56% of Rmax. Fentanyl 5 fig kg~' elicited a significant increase in Rmax (+34.5%; P = 0.005) and a parallel increase in both Raw (+35.2%, P = 0.0/7; and AR ( + 33.5%, P = 0.005). The increase in Raw, but not in AR, was reversed by atropine, suggesting that the increase in these two components of Rmax was not linked. Thus fentanyl increased both components of Rmax, but the effects of fentanyl on Raw and AR seemed to depend on different mechanisms. (Br. J. Anaesth. 1992; 69: 595-598) KEY WORDS Anaesthesia: general. Analgesics: fentanyl. Lung: respiratory resistance.
Fentanyl increases ventilatory impedance in man. The drug induces truncal muscular rigidity [1] and bronchoconstriction [2] and it increases the overall resistance to inspiratory flow of the ventilatory system (Rmax) [3]. This resistance is the sum of two distinct resistances [4]: airway resistance (.Raw) and non-Newtonian resistance (AR) which varies with the ventilatory pattern [5]. AR may result from either or both of two distinct phenomena [6, 7]—viscoelasticity of the thoracopujmqnary tissues or inhomogeneity of regional time constants within the lungs; the latter is considered to be negligible in the normal subject. However, a bronchoconstrictor challenge may induce or aggravate this phenomenon [8].
The aim of this study was to describe the effects of fentanyl on .Rmax and on its two components, AR and .Raw, in anaesthetized, paralysed man undergoing mechanical ventilation. For this purpose we used the end-inflation occlusion method [7]. The study was completed with the description of the effect of fentanyl on the elastic properties of the ventilatory system: static elastance (Est) and dynamic elastance (jSdyn). Moreover, as atropine decreases .Rmax during general anaesthesia in man [9]j its effects on the fentanyl-induced modifications of the ventilatory mechanics were also described. PATIENTS AND METHODS
After approval from the local Ethics Committee, we studied 10 men undergoing elective surgery for testicular biopsy under general anaesthesia (mean age 30 yr (range 26-34 yr) weights 69.7 (SD 5.9) kg). The exclusion criteria were clinical or radiological abnormality of the ventilatory system; heavy smoking; suspected (history of atopy) or overt (history of wheezes) bronchial hypersensitivity; treatment with a beta blocker [10]. Mechanical ventilation was performed with a Servo Ventilator 900 D (Siemens-Elema, Sweden). This ventilator produces a constant inflation flow (Vi), and an accurate tidal volume (FT) [11, 12]. It allows end-expiratory and end-inspiratory airway occlusions [13]. The ventilatory circuit comprised short tubing (40 cm) without a humidifier, in order to reduce the compressible volume. Each disposable tracheal tube (internal diameter 8 mm) was fitted with a lateral port at its distal end ("Blue Line", ref. 100/196/080 Portex Great Britain), that allowed measurement of the tracheal pressure [14]. The port was connected to a pressure transducer (model SK + 20 cm HjO, EFFA, Le Pre St Gervais, France) and a linear amplifier (MRC 4411, LEIM, Aix en Provence, France). The pressure signal and the flow signal fed by the ventilator were recorded on a Gould TA 550 polygraph, at a paper speed of 15 mm s"1. Ventilatory mechanics were studied using the endinspiratory occlusion method which has already been ROBERT COHENDY, M.D., M.SC. ; JEAN YVES LEFRANT, M.D. ; MICHEL LARACINE, M.D.; THIERRY REBIERE, M.D.; JEAN JACQUES ELEDJAM,
M.D.; Department of Anaesthesia and Intensive Care, Centre Hospitalier Regional et Universitaire de Nimes, 5, rue Hoche, 30029 Nimes Cedex, France. Accepted for Publication: June 19, 1992.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 30, 2015
SUMMARY
596
BRITISH JOURNAL OF ANAESTHESIA TABLE I. Overall resistance of the ventilatory system (Rmax), airway resistance (Raw), non-Newtonian resistance (AR) and contribution of AR to Rmax (AR/Rmax) (mean (SD)) at baseline (To), 6 min after fentanyl 5 fig kg "' (T,) and 6 min after fentanyl 1.75 fig kg'1 (TJ. f Friedman test Resistance (cm H,O litre"1 s) T, i?max Raw AR AR/Rmax (%)
3.62 (0.87) 1.59(0.47) 2.03 (0.56) 56 (0.076)
4.87(1.2) 2.15(0.8) 2.71 (0.5) 56.8 (0.075)
3.95 (0.99) 1.40(0.55) 2.54 (0.59) 64.9(0.071)
0.0002 0.02 0.0002 0.02
TABLE II. Dynamic elastance CEdyri) and static elastance (Ejt) of the venlilalory system (mean (SD)) at baseline (To), 6 min after fentanyl 5 fig kg~' (Tj) and 6 min after fentanyl 1.75 fig kg'1 (jHr). + Friedman test Elastance (cm H,O litre"1)
£dyn Est
14.30(2.6) 12.27(2.36)
15.21(2.67) 12.50(2.41)
15.07(2.63) 12.53(2.41)
0.0001 0 18
baseline values). A first dose of fentanyl 4.9 (0.4) jig kg"1 was given and a second group of occlusions (T t ) was recorded 6 min later. A second dose of fentanyl 1.75 (0.3) fig kg"1 was given together with atropine 1 mg. The last group of occlusions (T2) was performed 6 min later. The duration of the study did not exceed 25 min and recovery was always uneventful. Statistical analysis Data are given as mean (SD). Means were compared with a non-parametric Friedman test and Wilcoxon signed-rank tests. P < 0.05 was considered to be significant. RESULTS
After administration of fentanyl, all the measured resistances increased significantly: .Rmax (P = 0.005), .Raw (P = 0.017) and AR (P = 0.005) (table I). The increase in .Raw paralleled the increase in AR, because the contribution of AR to .Rmax remained stable: 56% at T o and 56.8% at T, (P = 0.87). While £st remained stable during the whole study, £dyn increased slightly ( + 6.4%) (P = 0.005) with fentanyl (table II). When atropine was added to fentanyl, .Raw decreased significantly (P = C.007) and returned to its control value (P = 0.17). However, AR at T 2 remained stable compared with its value at T t (P = 0.14) but was significantly greater than at T o (P = 0.012); its contribution to .Rmax increased significantly (P = 0.028) between T! and T 2 and was significantly greater at T, than at T o (P = 0.01). The decrease in .Rmax at T 2 was significant compared with those at T, (P = 0.005) and T o (P = 0.04). Z?dyn remained stable between T, and T 2 (P = 0.64) (table II). DISCUSSION
We have found that, in anaesthetized, paralysed patients undergoing mechanical ventilation, fentanyl increased all the measured resistances. There was a
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 30, 2015
described extensively [7]. Briefly, at the end of the inflation of a preset tidal volume (FT), an occlusion of about 6 s was performed at the ventilator valves (while pressing the "inspiratory hold" button) to detect any air leak. After airway occlusion, there was an abrupt decrease in tracheal pressure from a maximum pressure Pmax to an inflection point P u and a more gradual decay to a plateau pressure which is the elastic recoil pressure of the ventilatory system (Pel) [12]. Gas exchange during occlusion has a negligible effect on Pel [15], which was measured after 3 s of the end-inspiratory occlusion. The initial decrease in pressure (Pmax —PJ reflects the resistive pressure attributable to the airway resistance (.Raw) during the constant inflation flow preceding occlusion (Fi). Thus .Raw equals (Pmax —PL) Fi"1. Similarly, overall resistance, .Rmax, was calculated as .Rmax = (Pmax —Pel) Vr1; additional resistance (AR) = Rmax —Raw; static elastance (£st) = Pel FT" 1 . [12]; dynamic elastance (£dyn) = Pmax FT" 1 . The possibility of an intrinsic PEEP (PEEPi) was excluded by an end-expiratory occlusion performed at the ventilator valves (while pressing the " expiratory hold" button). It would have been necessary to take account of any PEEPi in calculating resistance and elastance, but it was never seen in our patients. In order to avoid absorption atelectasis, the lungs were ventilated with 30% oxygen in nitrogen [16]. At each experimental time, at least one endexpiratory occlusion followed by at least three endinspiratory occlusions were performed. All the occlusions were separated by five tidal breaths. As the ventilatory mechanics are frequency-, flow- and volume-dependent [5], all the subjects underwent ventilation of the lungs with the same pattern: frequency 15 b.p.m., F T = 0.6 litre, inspiratory time (7i) 1 s, expiratory time ( TE) 3 s. The study was performed in the operating theatre, before the beginning of the surgical procedure. Midazolam 5 mg i.m. was given as premedication. Anaesthesia was induced with methohexitone 2.85 (SD 0.5) mg kg"1 and maintained with a continuous infusion of this drug (0.1 mg kg"1 min"1). Neuromuscular block was produced with vecuronium 0.15 mg kg"1 and monitored with train-of-four stimulation of the adductor pollicis muscle. A surgical level of paralysis was observed in every subject during the duration of the study. The trachea was intubated with the orotracheal tube described above, the lungs were ventilated manually in order to achieve a standard volume history and the patient was connected to the ventilator. Six minutes later, the first group of occlusions were recorded (T o :
T,
VENTILATORY RESISTANCES AND FENTANYL
induction of general anaesthesia [1]. In fact, the observed stability of £st suggests that such a change was negligible during the short duration of our study. Moreover, D'Angelo and colleagues [5] have shown that AR varies in the same direction as lung volume. In our study, AR increased with fentanyl. Thus the increase in .Raw resulted from bronchoconstriction and not a reduction in lung volume. Moreover, the increase in the initial pressure change after occlusion after a bronchoconstrictive challenge reflects an effective increase in .Raw, despite introduction of significant mechanical heterogeneities in the lung, as shown by Ludwig and colleagues [24]. Because Raw decreased with atropine, which blocks all muscarinic responses within the bronchial tree with equal efficacy [25], it is suggested that the observed effect of fentanyl on the bronchial muscle was vagally induced. The second component of .Rmax is the additional resistance, AR, that may result from the viscoelastic properties of the respiratory system, variation in regional time constants, or both. As Est remained stable, the increase in AR was probably not caused by variation in lung volume. Moreover, in spite of the bronchodilatation induced by atropine, AR did not change. This suggests that the bronchoconstrictor effect of fentanyl did not induce significant variations in regional time constants that could have explained the increase in AR observed at T1. Consequently, it can be argued that fentanyl acts directly on pulmonary viscoelastic properties [26]. An effect of thoracic and abdominal muscles is excluded, because of the presence of neuromuscular block. Thus fentanyl increased peripheral resistance, possibly through an effect on peribronchiolar contractile structures [27]. These structures are independent of the parasympathic system and are insensitive to atropine because there are few muscarinic receptors in terminal bronchioles [23]. REFERENCES 1. Gal TJ. Respiratory Physiology in Anesthetic Practice. Baltimore: Williams and Wilkins, 1991. 2. Yasuda I, Hirano T, Yusa T, Satoh M. Tracheal constriction by morphine and fentanyl in man. Anesthesiology 1978; 49: 117-119. 3. Cigarini I, Bonnet F, Lorino AM, Harf A, Desmonts JM. Comparison of the effects of fentanyl on respiratory mechanics under propofol of thiopental anaesthesia. Acta Anaesthesiologica Scandinavica 1990; 34: 253-256. 4. Bates JHT, Rossi A, Milic-Emili J. Analysis of the behavior of the respiratory system with constant inspiratory flow. Journal of Applied Physiology 1985; 58: 1848-1848. 5. D'Angelo E, Calderini E, Torri G, Robatto F, Bono D, Milic-Emili J. Respiratory mechanics in anesthetizedparalyzed humans: effect of flow, volume and time. Journal of Applied Physiology 1990; 67: 2556-2564. 6. Similowski T, Levy P, Corbeil C, Albala M, Pariente R, Derenne JPH, Bates JHT, Johnson B, Milic-Emili J. Viscoelastic behavior of lung and chest wall in dogs determined by flow interruption. Journal of Applied Physiology 1990; 67: 2219-2229. 7. Milic-EmUi ], Robatto FM, Bates JHT. Respiratory mechanics in anaesthesia. British Journal of Anaesthesia 1990; 65: 4-12. 8. Sly PD, Brown KA, Bates JHT, Macklem PT, Milic-Emili J, Martin JG. Effect of lung volume on interrupter resistance in cats challenged with methacholine. Journal of Applied Physiology 1988; 64: 360-366.
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parallel increase in Raw and AR, their respective contribution to Rmax remaining stable. When atropine was given, Raw decreased and returned to the control value, while the contribution of AR to Rmax increased. We have used the end-inspiratory occlusion method [7]; this allows separation of airway resistance (Raw) from the non-Newtonian, peripheral resistance (AR). As AR varies with the ventilatory pattern [5], we maintained the same pattern in all patients, to allow comparison of resistances. The tracheal pressure was measured within the airway, in order to avoid subtraction of the tracheal tube resistance from the resistance values [14]. Any occlusion has a finite time, and allows a residual flow [17]. The volume resulting from this residual flow can be estimated as 2.5 % of FT, according to the calculations of Kochi and colleagues [18], who have studied ventilatory mechanics in cats with the same occlusion method and a very similar ventilator (Servo Ventilator 900 C). This leads to underestimation of the initial pressure change and thus of the values of .Rmax and .Raw. However, each subject acted as his own control and this allowed at least a qualitative comparison. General anaesthesia and paralysis were obtained with methohexitone and vecuronium, respectively. It could be argued that these drugs might have modified bronchial size and reactivity. However, neither of these drugs induces measurable liberation of histamine [19,20], and vecuronium does not interact with the muscarinic receptor of the bronchial autonomic innervation [20]. Moreover, because fentanyl does not induce detectable liberation of histamine in plasma [21] or the tissues [22], we can postulate that the changes in resistance observed during the study were probably caused by the direct effect of fentanyl. A second dose of fentanyl was given before the T 2 measurements in order to avoid an excessive decrease in plasma concentration of fentanyl. After a loading dose, there is a second distribution of fentanyl, with a half-life (Tf) of 10-30 min, but with a wide variability in individual pharmacokinetics [23]. A second dose (1.75 ug kg~')j is then able to maintain a relatively great plasma concentration of the drug [23]. Thus the effect of fentanyl on resistances would not be declining with time, and the observed values at T 2 could be attributed to the antagonism by atropine of the effect of fentanyl. The baseline values of Rmax, Raw, AR and £st were in the range of values calculated from the data of D'Angelo and colleagues [5], who studied adult subjects anaesthetized with enflurane and nitrous oxide and paralysed with pancuronium. In our study, with fentanyl, Rmax and its two components, .Raw and AR, increased. An increase in .Rmax with a similar dose of fentanyl during thiopentone anaesthesia was described by Cigarini and colleagues [3]v In their study, such an^increasenn Rmax with fentanyl did not occur during anaesthesia with propofol. However, these authors did not partition .Rmax. The initial component of Rmax is .Raw. The increase in our study could have been caused by a reduction ir. TkC which is observed commonly after
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18. Kochi T, Okubo S, Zin WA, Milic-Emili J. Flow and volume dependance of pulmonary mechanics in anesthetized cats. Journal of Applied Physiology 1988; 64: 441-450. 19. Hirshman CA, Edelstein RA, Ebertz JM, Hanifin JM. Thiobarbiturate-induced histamine release in human skin mast cells. Anesthesiology 1985; 63: 353-356. 20. Vctterman J, Beck KC, Lindahl SGE, Brichant JF, Rehder K. Actions of enflurane, isoflurane, vecuronium, atracurium and pancuronium on pulmonary resistance in dogs. Anesthesiology 1988; 69: 688-695. 21. Rosow CE, Moss J, Philbin DM, Savarese JJ. Histamine release* during morphine and fentanyl anesthesia. Anesthesiology 1982; 56: 93-96. 22. Levy JH, Brister NW, Shearin A, Ziegler J, Hug CC, Adelson DM, Walker BF. Wheal and flare responses to opoids in humans. Anesthesiology 1989; 70: 756-760. 23. Bailey PL, Stanley TH. Narcotic intravenous anesthetics. In: Miller RD, ed. Anesthesia, 3rd Edn. New York: Churchill Livingstone, 1990; 281-366. 24. Ludwig MS, Romero PV, Sly PD, Fredberg JJ, Bates JHT. Interpretation of interrupter resistance after histamineinduced constriction in the dog. Journal of Applied Physiology 1990; 68: 1651-1656. 25. Barnes PJ. Muscarinic receptors in lung. Postgraduate Medical Journal 1987; 63: 13-19. 26. D'Angelo E, Robatto FM, Caldenni E, Tavola M, Bono D, Torri G, Milic-Emili J. Pulmonary and chest wall mechanics in anesthetized paralyzed humans. Journal of Applied Physiology 1991; 70: 2602-2610. 27. Staub NC, Albertine KH. The structure of the lung relative to their principal function. In: Murray JF, Nadel JA, eds.
Medical and Biological Engineering and Computing 1987; 25:
Textbook
136-140.
Saunders, 1988; 12-36.
of
Respiratory
Medicine.
Philadelphia:
WB
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9. Don HF, Robson JC. The mechanics of the respiratory system during anesthesia. The effect of atropine and carbon dioxide. Anesthesiology 1965; 26: 168-178. 10. Roering DL, Kotrly KJ, Ahlf SB, Dawson CA, Kampine JP. Effect of propanolol on the first pass uptake of fentanyl in the human and rat lung. Anesthesiology 1989; 71: 62-68. 11. Johnson A, Bengtsson M. Comparison of anaesthesia ventilators using a lung model. Acta Anatsthestologica Scandinavica 1990; 34: 22-226. 12. Levy P, Similowski T, Corbeil C, Albala M, Pariente R, Milic-Emili J, Johnson B. A method for studying the static volume-pressure curves of the respiratory system during mechanical ventilation. Journal of Critical Care 1989; 4: 83-89. 13. Sly PD, Bates JHT, Milic-Emili J. Measurement of respiratory mechanics using the Siemens Servo Ventilator 900C. Pediatric Pulmonology 1987; 3: 400-405. 14. Navajas D, Farre R, Rotger M, Canet J. Recording pressure at the distal end of the endotracheal tube to measure respiratory impedance. European Respiratory Journal 1989; 2: 178-184. 15. Sydow M, Burchardi H, Zinserling J, Ische H, Crozier ThA, Weyland W. Improved determination of static compliance by automated single volume steps in ventilated patients. Intensive Care Medicine 1991; 17: 108-114. 16. Nunn JF. Applied Respiratory Physiology, 3rd Edn. London: Butterworths, 1987. 17. Bates JHT, Hunter IW, Sly PD, Okubo S, Filiatrault S, Milic-Emili J. Effect of valve closure time on the determination of respiratory resistance by flow interruption.