1Département dAnesthésieRéanimation Adulte, Groupe Hospitalier de La Timone, F-13385 Marseille Cedex 05, France. 2Département dAnesthésieRéanimation, Hôpital dInstruction des Armées Laveran, F-13998 Marseille, France. 3Département dAnesthésieRéanimation, Hôpital Sainte Marguerite, Marseille Cedex 09, France.*Corresponding author
Accepted for publication: March 15, 2000
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Abstract |
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Br J Anaesth 2000; 85: 4405
Keywords: anaesthetics volatile, sevoflurane; hypoxia; pig
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Introduction |
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Sevoflurane is a recently introduced inhalational anaesthetic. Its effects on hypoxic pulmonary vasoconstriction (HPV) have been the focus of a few studies. In vitro experiments using constant-flow perfused rabbit lung5 confirmed concentration-dependent inhibition of vasoconstriction by sevoflurane. The only available study that we know of in intact chronically instrumented animals showed that sevoflurane did not inhibit hypoxic pulmonary vasoconstriction.7
The present study was designed to assess the effect of sevoflurane at the clinically relevant concentration of 1 MAC on HPV in intact anaesthetized piglets. Piglets were chosen as the study model because of their strong pulmonary vasoconstriction response to hypoxia.9 Pulmonary haemodynamics were evaluated by multipoint P/Q plots, which provide a quantitative measure of the relationship between pulmonary vascular pressure (P) and cardiac index (Q).10 Previous experiments have demonstrated that these plots are linear in intact anaesthetized piglets.11
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Materials and methods |
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Animal preparation
After a 12 h fasting period with free access to water, 10 large white piglets (2231 kg, mean 25 kg) were premedicated with ketamine (20 mg kg1 i.m.), midazolam (0.1 mg kg1 i.m.) and atropine (0.25 mg i.m.) and placed in the supine position. Anaesthesia was induced with midazolam 0.1 mg kg1 i.v., fentanyl 2 µg kg1 i.v. and maintained with intravenous infusions of fentanyl 20 µg kg1 h1 and midazolam 0.1 mg kg1 h1. Muscle paralysis was achieved with vecuronium bromide 1 mg kg1 i.v. and maintained with an infusion of vecuronium bromide 2 mg kg1 h1 after tracheostomy had been performed. Lungs were mechanically ventilated via a no. 6 cuffed tracheostomy tube (Tracheosoft Lanz 101-70 i.d. 6.0; Malindkrodt Medical, Athlone, Ireland) with a servo ventilator B 900 (Siemens, Elema, Sweden) initially set to deliver a FIO2 of 0.4, a tidal volume of approximately 1215 ml kg1 and a respiratory rate adjusted to maintain an arterial PaCO2 between 4.7 and 5.3 kPa. No positive end-expiratory pressure was used. Sevoflurane was administered through a vaporizer adapted to the ventilator. Inspired and expired fractions of oxygen, carbon dioxide and sevoflurane were measured using an Ultima II infrared spectrophotometer (Datex, Helsinki, Finland).
Throughout the experiment, 0.9% sodium chloride was infused in the left internal jugular vein at 4 ml kg1 h1. Temperature was maintained at 3839°C using an electrical heating pad. Metabolic acidosis, when present, was corrected by slow infusion of triaminolacetate (THAM; Roger Bellon Laboratories, Neuilly-sur-Seine, France).
A thermistor-tipped SwanGanz catheter (93A-131-7F; Edwards Laboratories, Santa Anna, CA, USA) was inserted in the right internal jugular vein and positioned with reference to right arterial pressure (RAP), mean pulmonary arterial pressure (PAP) and mean capillary wedge pressure (PCWP). It was used to measure central core temperature and perform mixed venous blood sampling. A polyethylene catheter was placed in the abdominal aorta via the right femoral artery for systemic arterial pressure (SAP) measurements and arterial blood sampling. A balloon catheter (Redigard, 9F 40 ml; St Jude Medical Inc., Chelmsford, MA, USA) was placed in the inferior vena cava through a right femoral venotomy. Inflation of this balloon produced a gradual decrease in cardiac output by reducing venous return. All catheters were inserted through peripheral cut-down.
A left thoracotomy was performed to place a polyethylene catheter (Liddle LAP 17 G 50.6 cm; Research Medical Inc., Salt Lake City, UT, USA) via the atrial appendage into the left atrium to monitor left atrial pressure (LAP). The thoracotomy was hermetically closed and a tube (Argyle 24) was inserted into the pleural space and connected first to a vacuum pump and then to a water seal as soon as vacuum was achieved. Thrombus formation along the catheters was prevented by giving sodium heparin 100 IU kg.1 i.v. just before insertion and 100 IU kg1 h1 continuously.
Measurements
Pulmonary, cardiac and systemic pressures were measured using disposable transducers (pressure monitoring kit; Baxter SA, Maurepas, France) connected to a multichannel monitor (Merlin; Hewlett-Packard Inc., Palo Alto, CA, USA). Zero reference was located at midchest, and readings were taken at the end of expiration. Heart rate was continuously recorded by three electrocardiographic leads connected to the same monitor. Cardiac output was rapidly measured at the end of expiration by the thermodilution technique using injections of 5 ml of 0.9% sodium chloride at 0°C. Results were analysed by a computer. Values correspond to means of at least three measurements after elimination of readings 10% higher or lower than the previous value. Haemodynamic data were sampled every 20 s, digitized and stored on the hard disc of a personal IBM PC/AT (Hewlett Packard Vectra 386 DX 33 with Hewlett Packard software). Arterial and mixed venous pH, PCO2 and PO2 were measured immediately after drawing the samples using an automated analyser (ABL 500; Radiometer, Copenhagen, Denmark), all blood gas values were corrected according to central temperature. Body surface area (m2) was calculated as 0.112xweight2/3 (kg).
Protocol
After ensuring steady-state conditions for 10 min at an FIO2 of 0.4 (stable SAP, PAP, LAP, Q, end-tidal carbon dioxide and heart rate), a first four-point P/Q plot was generated in 20 min: the first point corresponding to basal cardiac output followed by one point for each incremental inflation of the vena cava balloon (three points). Each P/Q point construction took 5 min. A similar plot was constructed at an FIO2 of 0.12 for 30 min when PaO2 reached 5.36.7 kPa. Previously reported stimulusresponse curves for HPV in intact anaesthetized ventilated piglets have shown that the whole-lung hypoxic pressor response is undetectable if FIO2 is >0.3 and maximal when FIO2 is 0.12.11 Similar plots were generated at FIO2 0.4 and at FIO2 0.12 with 2.6% end-tidal sevoflurane. Finally, return to baseline, defined as end-tidal sevoflurane concentration around zero, was tested in hyperoxia and hypoxia. Haemodynamic parameters (SAP, LAP, RAP, PCWP, PAP, heart rate) and arterial and mixed venous blood gases were measured at each phase of the study and Q level. Repeated exposure to hypoxia was performed to make sure that the magnitude of HPV was constant throughout this experiment.
Statistical analysis
Individual PAP/Q, (PAP LAP)/Q and (PAP PCWP)/Q plots appeared to be linear, so a linear regression analysis (least squares method) was used to compute slopes. Q was considered as the independent variable and P as the dependent variable. To obtain composite P/Q plots, pressures interpolated from the regression analysis from individual piglets were averaged at 0.5 litre min1 m2 intervals of Q from 0.5 to 2.5 litre min1 m2. Blood gas and haemodynamic data were analysed by analysis of variance for serial measurements. When the significance of a factor was P<0.05, a Bonferroni post hoc test was performed to compare specific situations. Slopes of composite P/Q plots were compared by Students t-test. Data are expressed as mean (SD). All analyses were performed with Statview 4 software (Abacus concept) on a Macintosh Power PC 6200/75 personal computer.
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Results |
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Sevoflurane in hypoxia
In hypoxia, administration of 2.6% end-tidal sevoflurane increased heart rate at highest Q and reduced SAP compared with baseline. PAP, LAP and PCWP were unchanged (Table 1). No inhibitory effect on hypoxic pressor response was observed (Figure 1). Sevoflurane had no effect on PaO2, pHa, PvO2, PaCO2 at highest Q. At the lowest Q, PvO2 was slightly lower than at the highest Q.
Stability and reproducibility of HPVbaseline return
At constant Q, three sequences of alternating 30 min periods at a FIO2 of 0.4 and 0.12, there was essentially no change in blood gases (Table 3) or in haemodynamics in the successive periods at the same FIO2 (Table 1). No change in PAP occurred at the same FIO2 The hypoxia-induced increase in PAP recurred during the third hypoxic episode (Table 1).
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Discussion |
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One in vitro study has demonstrated that sevoflurane inhibits the HPV response in a dose-related manner, in constant flow-perfused rabbit lung.5 To our knowledge, only one study has assessed the effects of sevoflurane on HPV in chronically instrumented and unsedated animals,7 and no previous experiment has been performed in anaesthetized animals.
The P/Q plots in our piglets were linear under all experimental conditions, in keeping with previous studies in intact anaesthetized5 or unsedated animals.10
The technique we used to assess pharmacological and physiological variations in pulmonary vasomotor tone involved generation of multipoint P/Q plots. This technique was developed by Lodato, Michael and Murray in conscious dogs, at two different inspired oxygen concentrations.10 The inferior vena cava occlusion technique, involving incremental inflation of a balloon catheter, produced a titratable decrease in Q. P/Q plots were then generated. This P/Q relationship allows vasoactive effects on the pulmonary circulation to be distinguished from passive mechanical effects. This technique is more relevant than use of calculated pulmonary vascular resistance, which does not take in consideration how this resistance varies with Q. However, it has a number of limitations, including systemic hypotension, changes in blood gases and changes in zonal conditions of the lung. This technique has already been used in mammals to test anaesthetic effects,6 10 and physiological or metabolic manipulations on HPV.11 14.
HPV varies widely between individuals and species.13 Twelve-week-old piglets were selected for our study since they show a stronger pressor response to hypoxia than most other mammals.9 13
Some factors may alter pulmonary vascular pressor response to hypoxia in animals: First, increasing LAP can reduce HPV in anaesthetized animals. This suggests that the whole pulmonary vasculature does not behave as a Starling resistor in hyperoxia or hypoxia.14 In our piglets, LAP did not change throughout study, and so could not have modified pulmonary vascular response to hypoxia.
Second, alternating hyperoxia and hypoxia and repetition of hypoxic episodes enhance HPV.15 In our study, PAP/Q plots increased between baseline and baseline return in hyperoxia and in hypoxia, but this variation was not significant and probably did not influence the mechanism of HPV.
Third, although pressor response is usually dependent on PaO2, major changes in mixed venous PvO2 can modify the magnitude of HPV.16 In our study, hypoxia and low Q led to a marked decrease in PvO2 in both cases. This decrease could have enhanced HPV.
Fourth, pressor response can be altered by changes in arterial pH and PaCO2.17 In anaesthetized dogs, marked alkalosis induced by artificial hyperventilation during hypoxia reduces PAP.17 This was unlikely to have occurred in our study since arterial pH and PaCO2 were kept constant at all levels of Q.
Finally, reduction of Q, as was performed in our experiment, activates the arterial baroreceptor reflex. Carotid sinus baroreceptor reflex directly controls the entire systemic and pulmonary arterial pressureflow relationships in anaesthetized dogs.18 In intact conscious dogs, circulatory hypotension resulted in active pulmonary vasoconstriction, primarily mediated by sympathetic 1 adrenoreceptor activation.19 In our study, at baseline, activation of baroreceptor reflex by lowering Q was not effective, as suggested by the lower PAP at lowest Q in both hyperoxia and hypoxia.
As in previous data with other inhalational anaesthetics in intact mammals, sevoflurane induced only systemic vasodilation and had no significant effect on HPV, when it was used at 1 MAC. Investigations assessing the effects of halogenated agents on HPV have produced different results, depending on the experimental model. Studies on isolated perfused lungs showed that inhaled agents inhibited HPV.35 Conversely, experiments with intact mammals showed either inhibition20 or no significant effect.7 21
Many factors could account for the conflicting results of in vivo studies.
Associated intravenous anaesthetics. This experiment, including a thoracotomy, the placement of a balloon catheter into the inferior vena cava and several hours of immobilization, required general anaesthesia and mechanical ventilation. These anaesthetic conditions were close to those used in clinical settings, where sevoflurane is administered with fentanyl.22 Neither fentanyl nor midazolam has any recognized effect on pulmonary vascular tone.23 Pentobarbital sodium was not used in this study because a previous report showed that it might have a slight inhibitory effect on HPV in intact piglets.11 Moreover, in isolated perfused sheep lungs, pentobarbital sodium decreased HPV by 1428% when administered at concentrations used in anaesthesia.24
Mechanical ventilation. Intermittent positive pressure ventilation can affect the pulmonary circulation in various ways, such as by directly compressing alveolar vessels and by increasing lung volume.25 This could explain the differences observed between mechanically ventilated and unsedated intact animals. In our experiment, pulmonary vascular pressures were measured at the end of expiration when pleural pressure was presumably lowest. However, effects of mechanical ventilation on pulmonary vascular tone cannot be ruled out.
Site of action of hypoxia. The site of action of hypoxia may vary among species. In dogs, HPV is thought to occur mainly in pulmonary arteries,26 whereas capillaries may be the major site of vasoconstriction in pigs.27
Action of the sympathetic nervous system. In anaesthetized dogs, chemical sympathectomy or chemodenervation increased PAP at all levels of Q studied both in hypoxia and in hyperoxia.28 The effect of the sympathetic nervous system in hyperoxic and hypoxic healthy mammal lungs seems to reduce pulmonary vascular tone. In our study, administration of sevoflurane in hyperoxia probably induced a sympathetic activation as judged by the significant increase of heart rate compared with baseline. This activation was less evident in hypoxia, in which there was a non-significant increase in heart rate. In these conditions, sevoflurane could have partially altered the baroreflex. The effect of sevoflurane on HPV in the intact animal is therefore less evident than in the isolated lung, when the autonomic nervous system is not effective. This could explain the discrepancies between in vitro and in vivo studies on sevoflurane.
In summary, we assessed the effects of sevoflurane on HPV at 1 MAC, in intact anaesthetized mechanically ventilated piglets. This was allowed by generation of pulmonary vascular P/Q relationships which were linear in hyperoxia and hypoxia and with sevoflurane. Hypoxia resulted in a significant increase in pressure gradients (PAPLAP) and (PAPPCWP) because of active pulmonary vasoconstriction. Sevoflurane did not appear to influence hypoxic pulmonary vasoconstriction. These findings are different from those obtained in in vitro experiments, but in agreement with those from a previous in vivo study.7 Therefore this halogenated agent seems not to inhibit HPV in intact animals, whether in the conscious or anaesthetized state.
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Acknowledgements |
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References |
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