Effects of sevoflurane on hypoxic pulmonary vasoconstriction in anaesthetized piglets

F. Kerbaul1, M. Bellezza1, C. Guidon1, L. Roussel2, M. Imbert2, J. P. Carpentier2 and J. P. Auffray3

1Département d’Anesthésie–Réanimation Adulte, Groupe Hospitalier de La Timone, F-13385 Marseille Cedex 05, France. 2Département d’Anesthésie–Réanimation, Hôpital d’Instruction des Armées Laveran, F-13998 Marseille, France. 3Département d’Anesthésie–Réanimation, Hôpital Sainte Marguerite, Marseille Cedex 09, France.*Corresponding author

Accepted for publication: March 15, 2000


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In vitro, halogenated agents reduce the pulmonary vasoconstrictor response to alveolar hypoxia in isolated perfused lungs. However, studies in intact animals have been less convincing. The aim of the present study was to assess the effect of sevoflurane on hypoxic pulmonary vasoconstriction (HPV) in anaesthetized piglets using the pressure/cardiac index relationship (P/Q).Ten large white piglets were anaesthetized and mechanically ventilated, alternately in hyperoxia (FIO2=0.4) and hypoxia (FIO2=0.12). Multipoint plots of pulmonary arterial pressure (PAP) or differences between PAP and left atrial pressure (LAP) against Q were generated by gradual inflation of a balloon introduced into the inferior vena cava. P/Q relationships were established in hyperoxia and hypoxia at baseline, and then with sevoflurane. In hypoxia, pressure gradients (PAP – LAP) increased at every level of Q, thus demonstrating active pulmonary vasoconstriction. Sevoflurane at 1 MAC did not affect these P/Q relationships in hyperoxia or hypoxia as compared with baseline. Sevoflurane at a clinically relevant concentration (1 MAC) has no significant effect on HPV in anaesthetized piglets.

Br J Anaesth 2000; 85: 440–5

Keywords: anaesthetics volatile, sevoflurane; hypoxia; pig


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Pulmonary vasoconstriction in response to acute hypoxia helps to maintain arterial oxygen tension.1 Impairment of this mechanism by inhalational anaesthetic agents has been implicated in hypoxemia during anaesthesia.2 However, this conclusion is controversial since in vitro studies showing inhibition by halothane, enflurane, isoflurane and desflurane3 4 have not been consistently confirmed by in vivo experiments in intact animals.68

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


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study design was reviewed and approved by the animal ethics committee of the La Timone Medical School in Marseille. All procedures were compliant with the Guiding Principles in the Care and Use of Animals of the American Physiological Society.

Animal preparation
After a 12 h fasting period with free access to water, 10 large white piglets (22–31 kg, mean 25 kg) were premedicated with ketamine (20 mg kg–1 i.m.), midazolam (0.1 mg kg–1 i.m.) and atropine (0.25 mg i.m.) and placed in the supine position. Anaesthesia was induced with midazolam 0.1 mg kg–1 i.v., fentanyl 2 µg kg–1 i.v. and maintained with intravenous infusions of fentanyl 20 µg kg–1 h–1 and midazolam 0.1 mg kg–1 h–1. Muscle paralysis was achieved with vecuronium bromide 1 mg kg–1 i.v. and maintained with an infusion of vecuronium bromide 2 mg kg–1 h–1 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 12–15 ml kg–1 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 kg–1 h–1. Temperature was maintained at 38–39°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 Swan–Ganz 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 kg–1 h–1 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 5.3–6.7 kPa. Previously reported stimulus–response 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 min–1 m–2 intervals of Q from 0.5 to 2.5 litre min–1 m–2. 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 Student’s 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.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Induced variations of cardiac index
Stepwise inflation of the balloon catheter in the inferior vena cava induced variations in Q. Mean values ranged from 1 to 2.3 litre min–1 m–2 (Table 1). The PAP/Q, (PAP–LAP)/Q and (PAP–PCWP)/Q relationships were linear in all experimental conditions (Table 2). Blood gases mainly changed by a decrease in mixed venous PO2 at the lowest Q (Table 3).


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Table 1 Effects of sevoflurane on haemodynamic data. Values are means (SD) (n=10 piglets). Abbreviations: H and L, highest and lowest cardiac index (Q), respectively; SAP, mean systemic arterial pressure; PAP, mean pulmonary artery pressure; PCWP, mean capillary wedge pressure; LAP and RAP, mean left and right atrial pressure, respectively. $Significant difference (P<0.05) compared with base line at the same FIO2; #significant difference (P<0.05) compared with the corresponding stage in hyperoxic animals; *significant difference (P<0.05) between highest and lowest Q at the same stage
 

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Table 2 Slopes and correlation coefficients (r2) corresponding to composite P/Q plots made in hyperoxia (FIO2=0.4) and hypoxia (FIO2;=0.12) at baseline, with sevoflurane, and after return to baseline. Values are means (SD) (n=10 piglets). *Significant difference (P<0.01) for comparison between slope at FIO2 0.4 and that at FIO2 0.12 in the same step. #Significant difference (P<0.05) for comparison of slopes at different steps at the same FIO2
 

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Table 3 Effects of sevoflurane on blood gases. Values are means (SD) (n=10 piglets). Abbreviations: H and L, highest and lowest values of Q, respectively. *Significant difference (P<0.05) between highest and lowest Q at the same stage; #significant difference (P<0.05) compared with the corresponding stage in hyperoxic animals
 
Baseline values in hyperoxia and hypoxia
Hypoxia markedly decreased arterial and mixed venous PO2 with no change in pH or PaCO2 (Table 3). SAP, LAP, RAP and PCWP were the same in hypoxic and hyperoxic conditions. Over the full range of Q studied, hypoxia increased PAP (P<0.01) (Figure 1), while it significantly increased heart rate only for the lowest Q. The main sign of hypoxic pressor response was a significant increase in the slopes of PAP/Q, (PAP–LAP)/Q and (PAP–PCWP)/Q relationships.



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Fig 1 Extrapolated plots of (a) PAP, (b) PAP–LAP and (c) PAP–PCWP against cardiac index (Q) at baseline, in hyperoxia ({blacksquare}) and hypoxia ({square}), and with 2.6% sevoflurane end-tidal concentration in hyperoxia (•) and hypoxia ({circ}). *P<0.05 for comparison of slopes between hyperoxia and hypoxia. Values are means±SEM, n=10 piglets.

 
Sevoflurane in hyperoxia
Sevoflurane (2.6% end-tidal) significantly increased heart rate and significantly reduced SAP compared with baseline (P<0.05), whereas PAP, LAP, RAP, PCWP were unchanged. At lowest Q, SAP was significantly lower than at baseline (P<0.05).

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 HPV–baseline 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).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The present study was designed to assess the effect of sevoflurane on HPV in intact piglets. P/Q plots were generated in 10 piglets anaesthetized with midazolam and fentanyl, and mechanically ventilated. Sevoflurane at a clinically relevant dose induced marked systemic vasodilation (decrease in SAP with an unchanged Q), but HPV was unaffected by this anaesthetic. The end-tidal concentration of sevoflurane studied is equivalent to 1 MAC in pigs.12 Higher concentrations are required to induce a relevant effect on HPV in the isolated lung.5 This concentration was chosen because it is equivalent to that used in clinical settings when in combination with opiates.

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 pressure–flow relationships in anaesthetized dogs.18 In intact conscious dogs, circulatory hypotension resulted in active pulmonary vasoconstriction, primarily mediated by sympathetic {alpha}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 14–28% 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 (PAP–LAP) and (PAP–PCWP) 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.


    Acknowledgements
 
We are grateful to Peter MacCavana, Patrick Bartarès and Andy Corsini for their active contribution to this study.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 Cutaia M, Rounds S. Hypoxic pulmonary vasoconstriction. Physiologic significance, mechanism and clinical relevance. Chest 1990; 97: 706–18[ISI][Medline]

2 Pavlin EG. Respiratory pharmacology of inhaled anesthetic agents. In: Miller RD, ed. Anesthesia. New York: Churchill Livingstone, 1981; 349–82

3 Marshall C, Lindgren L, Marshall BE. Effects of halothane, enflurane and isoflurane on hypoxic pulmonary vasoconstriction in rat lungs in vitro. Anesthesiology 1984; 60: 304–8[ISI][Medline]

4 Loer SA., Scheeren TWL, Tarnow J. Desflurane inhibits hypoxic pulmonary vasoconstriction in isolated rabbit lung. Anesthesiology 1995; 83: 552–6[ISI][Medline]

5 Ishibe Y, Gui X, Uno H., Shiokawa Y, Umeda T, Suekane K. Effect of sevoflurane on hypoxic pulmonary vasoconstriction in the perfused rabbit lung. Anesthesiology 1993; 79: 1348–53[ISI][Medline]

6 Ewalenko P, Stephanidis C, Holoye A, Brimioulle S, Naeije R. Pulmonary vascular impedance vs. resistance in hypoxic and hyperoxic dogs: effects of propofol and isoflurane. J Appl Physiol 1993; 74: 2188–93[Abstract]

7 Lesitsky MA, Davis S, Murray PA. Preservation of hypoxic pulmonary vasoconstriction during sevoflurane and desflurane anesthesia compared to the conscious state in chronically instrumented dogs. Anesthesiology 1998; 89: 1501–8[ISI][Medline]

8 Domino KB, Borowec L, Alexander CM et al. Influence of isoflurane on hypoxic pulmonary vasoconstriction in dogs. Anesthesiology 1986; 64: 423–9[ISI][Medline]

9 Tucker A., MacMurtry IF, Reeves JT, Alexander AF, Will DH, Grover RF. Lung vascular smooth muscle as a determinant of pulmonary hypertension at high altitude. Am J Physiol 1975; 228: 762–7[ISI][Medline]

10 Lodato RF, Michael JR, Murray PA. Multipoint pulmonary vascular pressure cardiac output plots in conscious dogs. Am J Physiol 1985; 249: H351–7[ISI][Medline]

11 De Canniere D, Stefanidis C, Hallemans R, Delcroix M, Brimioulle S, Naeije R. Stimulus response curves for hypoxic pulmonary vasoconstriction in piglets. Cardiovasc Res 1992; 26: 944–9[ISI][Medline]

12 Manohar M. Regional brain blood flow and cerebral cortical O2 consumption during sevoflurane anesthesia in healthy isocapnic swine. J Cardiovasc Pharmacol 1986; 8: 1268–75[ISI][Medline]

13 Grover RF, Vogel JHK, Averill KH, Blount SG Jr. Pulmonary hypertension: individual and species variability relative to vascular reactivity. Am Heart J 1963; 66: 1–3[ISI]

14 Lejeune P, De Smet JM, De Francquen P et al. Inhibition of hypoxic pulmonary vasoconstriction by increased left atrial pressure in dogs. Am J Physiol 1990; 259: H93–100[Abstract/Free Full Text]

15 Unger M., Atkins M, Briscoe WA, King TKC. Potentialisation of pulmonary vasoconstriction response with repeated intermittent hypoxia. J Appl Physiol 1977; 43: 662–7[Abstract/Free Full Text]

16 Hughes JD, Rubin LJ. Relation between mixed venous oxygen tension and pulmonary vascular tone during normoxic, hyperoxic and hypoxic ventilation in dogs. Am J Cardiol 1984; 54: 1118–23[ISI][Medline]

17 Loeppky JA, Scotto P, Riedel CE, Roach RC, Chick TW. Effects of acid–base status on acute hypoxic pulmonary vasoconstriction and gas exchange. J Appl Physiol 1992; 72: 1787–97[Abstract/Free Full Text]

18 Shoukas AA, Brunner MJ, Frankle AE, Greene AS, Kallman CH. Carotid sinus baroreceptor reflex control and the role of the autoregulation in the systemic and pulmonary arterial pressure–flow relationships of the dog. Circ Res 1984; 54: 674–82[Abstract]

19 Peterson WP, Trempy GA, Nishiwaki K, Nyhan DP, Murray PA. Neurohumoral regulation of the pulmonary circulation during circulatory hypotension in conscious dogs. J Appl Physiol 1993; 75: 1675–82[Abstract]

20 Lennon PF, Murray PA. Attenuated hypoxic pulmonary vasoconstriction during isoflurane anesthesia is abolished by cyclo-oxygenase inhibition in chronically instrumented dogs. Anesthesiology 1996; 84: 404–14[ISI][Medline]

21 Naeije R, Lejeune P, Leeman M, Melot C, Deloof T. Pulmonary arterial pressure flow plots in dogs: effects of isoflurane and nitroprusside. J Appl Physiol 1987; 63: 969–77[Abstract/Free Full Text]

22 Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology 1998; 88: 18–24[ISI][Medline]

23 Eisenkraft JB. Effects of anaesthetics on the pulmonary circulation. Br J Anaesth 1990; 65: 63–78[ISI][Medline]

24 Wetzel RC, Martin LD. Pentobarbital attenuates pulmonary vasoconstriction in isolated sheep lungs. Am J Physiol 1989; 25: H898–903

25 Pinsky MR. Cardiopulmonary interactions. The effects of negative and positive pleural pressure changes on cardiac output. In: Dantzker DR, ed. Cardiopulmonary Critical Care. Toronto: Grune and Stratton, 1986

26 Hakim TS, Michel RP, Minami H, Chang HK. Site of pulmonary hypoxic vasoconstriction studied with arterial and venous occlusion. J Appl Physiol 1983; 54: 1298–302[Abstract/Free Full Text]

27 Sylvester JT, Mitzner W, Ngeow Y, Permutt S. Hypoxic constriction of alveolar and extra-alveolar vessels in isolated pig lungs. J Appl Physiol 1983; 54: 1660–66[Abstract/Free Full Text]

28 Naeije R, Lejeune P, Leeman M, Melot C, Closset J. Pulmonary vascular response to surgical denervation and chemical sympathectomy in dogs. J Appl Physiol 1989; 66: 42–50[Abstract/Free Full Text]