Cardiovascular Research

Cardiovascular Research 1999 42(1):183-192; doi:10.1016/S0008-6363(98)00301-0
© 1999 by European Society of Cardiology

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Copyright © 1999, European Society of Cardiology

Effects of low flow on pulmonary vascular flow–pressure curves and pulmonary vascular impedance

Serge Brimioulle^*, Marco Maggiorini, Jean Stephanazzi, Françoise Vermeulen, Philippe Lejeune and Robert Naeije

Laboratory of Cardiovascular and Respiratory Physiology, Free University of Brussels, Brussels, Belgium

^* Corresponding author. Department of Intensive Care, Erasme University Hospital, Lennik Road 808, B-1070 Brussels, Belgium. Tel.: +32-2-555-4410; fax: 32-2-555-4698, E-mail address: sbrimi@ulb.ac.be (S. Brimioulle)

Received 2 April 1998; accepted 2 October 1998

	Abstract

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
Objective: Flow–pressure curves and vascular impedance are commonly used to investigate pulmonary circulation, but they may be affected at low flow by reflex neurohumoral activation. We therefore investigated the mechanical effects and the reflex effects of decreased flow on pulmonary vascular resistance and impedance. Methods: In ten anaesthetized dogs, we compared flow–pressure curves generated in less than 10 s to prevent sympathetic activation (fast curves), or generated over 20–30 min to allow neurohumoral equilibration (slow curves), in hyperoxia (inspired oxygen, 40%) and in hypoxia (inspired oxygen, 10%), before and after adrenergic blockade by phentolamine and propranolol. Resistance was assessed from the flow–pressure relationship. Impedance was computed from instantaneous flow and pressure obtained with an ultrasonic flowmeter and a micromanometer-tipped catheter. Results: At baseline, fast flow–pressure curves were steeper and had a lower pressure intercept. Transient low flow did not affect heart rate or pulmonary arterial elastance. Sustained low flow increased heart rate, resistance and elastance, suggesting baroreceptor-induced sympathetic stimulation. After adrenergic blockade, no difference persisted between effects of transient and sustained low flow. In hypoxia, slow and fast flow–pressure curves were similar. Hypoxia increased heart rate and resistance but did not decrease elastance, suggesting chemoreceptor-induced sympathetic stimulation. In hypoxia, differences between transient and sustained low flow were no longer significant, and were completely suppressed by adrenergic blockade. In two additional dogs, epinephrine infusion increased pulmonary vascular resistance and elastance. Conclusions: We conclude that (1) compared to transient low flow, sustained low flow is associated with increases in distal resistance and proximal elastance due to sympathetic stimulation and (2) these differences between the effects of transient and sustained low flow do not persist in hypoxia, because of an already present chemoreceptor-induced sympathetic stimulation.

KEYWORDS Pulmonary circulation; Resistance; Impedance; Elastance; Hypoxia; Baroreceptor; Chemoreceptor; Sympathetic system; Adrenergic blockade

	1 Introduction

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
Pulmonary vascular flow–pressure curves and pulmonary vascular impedance are commonly used to investigate the pulmonary circulation [20]. Flow–pressure curves refer to mean pressure and mean flow, and are mainly used to assess the resistance of small distal vessels [10, 20]. Impedance describes the relationship between pressure oscillations and flow oscillations, and is mainly used to assess the elastance of large proximal vessels and the importance of wave reflections [19–21]. Both approaches are assumed to characterize the pulmonary circulation independently of flow. Low flow, however, causes systemic hypotension and, therefore, neurohumoral reflexes, which in turn can affect pulmonary vessels [7, 10, 15]. In conscious dogs, low flow with hypotension causes pulmonary vasoconstriction due to -adrenergic stimulation [24]. In anaesthetized dogs, low flow increases characteristic impedance, which has been suggested to result from reduced proximal vessel diameter and sympathetic stimulation [9, 17]. Even in the absence of pressure change and adrenergic stimulation, decreasing flow causes proximal and distal pulmonary vasoconstriction, probably by decreasing shear stress-mediated vasodilation [6, 14]. How much direct and reflex mechanisms contribute to the effects of low flow on the pulmonary vasculature effects is unclear. Whether each mechanism remains contributive in pulmonary hypertension and in hypoxia also remains unclear.

We therefore investigated both the direct mechanical effects and the reflex sympathetic effects of low flow on pulmonary vascular resistance and impedance. Global effects of low flow were assessed during ‘slow’ flow–pressure curves, obtained over 20–30 min by reducing venous return progressively and allowing haemodynamic equilibration at each flow value. Direct mechanical effects were assessed during ‘fast’ flow–pressure curves, generated over 6–8 s, i.e. before baroreflex-induced sympathetic stimulation could become effective [16]. Reflex sympathetic effects were evaluated by comparison of slow and fast curves. To determine the time course of the reflex sympathetic effects, we compared fast curves obtained after 6, 15, 30 and 120 s flow reduction. To confirm the role of the adrenergic sympathetic nervous system, we performed these sequential measurements before and after adrenergic receptor blockade. Considering that the effects of low flow could be different at normal and high pulmonary arterial pressure, we made all measurements under baseline conditions (mild hyperoxia) and in the presence of hypoxic pulmonary hypertension. Finally, we verified that exogenous adrenergic stimulation could reproduce the effects attributed to endogenous adrenergic stimulation.

	2 Methods

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
2.1 Preparation
All experiments were performed in accordance with the ‘Guiding Principles in the Care and Use of Animals’, approved by the American Physiological Society. Twelve mongrel dogs (20±1 kg, mean±SE) were anaesthetized with sufentanyl (i.v. 10 mcg/kg) and -chloralose (i.v. 80 mg/kg). Ventilation was provided via a cuffed endotracheal tube (Elema 900 B ventilator, Siemens, Solna, Sweden) with a respiratory rate of 10/min, a tidal volume of 20 ml/kg, a positive end-expiratory pressure of 5 cm H₂O and an inspiratory oxygen fraction (FiO₂) of 0.40. Anaesthesia was maintained with -chloralose (20 mg kg^–1 h^–1 and sufentanyl (1 mcg kg^–1 h^–1). A catheter was placed via the left external jugular vein into the superior vena cava, and Ringer’s lactate solution was infused at about 10 ml/kg/h, to maintain a left atrial pressure (Pla) of 5 to 10 mmHg. A fast response thermistor-tipped pulmonary artery catheter (model 93A-754H-7.5F, Baxter-Edwards, Irvine, CA, USA) was inserted via the right external jugular vein and positioned under pressure monitoring in a branch of the pulmonary artery for measurement of thermodilution cardiac output and for sampling of mixed venous blood. A catheter was placed in the aorta via the right femoral artery for measurement of systemic arterial pressure (Psa) and for sampling of arterial blood. A balloon catheter (Percor catheter, Datascope, Paramus, NJ) was advanced into the inferior vena cava through the right femoral vein, to allow a titratable reduction in cardiac output by inflating the balloon and reducing venous return. A large-bore catheter was inserted into the left femoral artery and left femoral vein to be used as an arterio-venous fistula, in order to increase the cardiac output by opening the fistula and increasing venous return. Temperature was maintained at 36–38°C with an electric heating pad.

2.2 Thoracotomy
Thoracotomy was performed in the fourth left intercostal space for placement of instantaneous flow and pressure measurement catheters. Before and during surgery, sufentanyl was added (1–2 mcg/kg boluses) to prevent any increase in heart rate or systemic pressure. A 16 or 20 mm ultrasonic flow probe (Transonic Systems, Ithaca, NY, USA) was positioned around the root of the pulmonary artery for measurement of instantaneous pulmonary blood flow (Q). Arterial constriction or distortion were carefully avoided, and good ultrasonic contact was ensured by blood clots inserted between the arterial wall and the flow probe. A 5F manometer-tipped catheter (SPC 350, Millar Instruments, Houston, TX, USA) was positioned in the right ventricle for measurement of right ventricular pressure (Prv). Another 5F manometer-tipped catheter was introduced through the right ventricle into the pulmonary artery, and its tip was positioned just distal to the flow probe for measurement of instantaneous pulmonary arterial pressure (Ppa). A fluid-filled catheter was inserted into the left atrium for measurement of left atrial pressure (Pla). The chest was closed but no attempt was made to restore a negative pleural pressure. Lungs were inflated several times with a double tidal volume, to reverse atelectasis. Tidal volume was then adjusted (most often close to 20 ml/kg) to maintain PaCO₂ at 35–40 mmHg at baseline flow. Sodium bicarbonate was infused if needed to correct post-operative metabolic acidosis. Thrombus formation along the catheters was prevented by administering 100 U kg^–1 sodium heparin IV at the end of the surgical procedure. Hypoxic pulmonary vasoconstriction was enhanced by acetylsalicylic acid (50 mg/kg, i.v.) [4], and stabilization was allowed for at least 30 min.

2.3 Measurements
Heart rate was obtained from an ECG lead monitoring. Fluid-filled catheter-derived pressures were zero-referenced at mid-chest level and processed using disposable transducers (Baxter-Bentley, Uden, Netherlands) and a Sirecust 404 monitoring system (Siemens, Erlangen, Germany). Micromanometer-derived pressures were processed using TCB-500 units (Millar), and flow using a T-101 unit with the 100 Hz low-pass filter setting (Transonic). Pressures and flow were recorded continuously on a six-channel recorder (model 2400 S, Gould, Cleveland, OH, USA). Cardiac output was measured with the thermodilution method (REF-1 computer, Edwards, Irvine, CA, USA), using the mean of three determinations. Injections of 10 ml of iced 5% dextrose in 0.45% saline were delivered at the beginning of expiration by a pneumatic injector that was synchronized on the ventilatory cycle. Arterial (a) and mixed venous (v) pH, PCO₂ and PO₂ were measured immediately after drawing the samples (ABL 2 analyzer, Radiometer, Copenhagen, Denmark).

2.4 Protocol
In ten dogs, slow flow–pressure curves were first obtained by decreasing flow (‘downward curves’) in hyperoxia (FiO₂, 0.40) and in hypoxia (FiO₂, 0.10). Hypoxia was used to determine if results would be similar at low pressure (hyperoxia) and at high pressure (hypoxia in animals with a strong hypoxic response). Second, fast flow–pressure curves were obtained while rapidly decreasing flow (‘downward curves’), and obtained again while rapidly restoring flow after a variable time delay (‘upward curves’). The whole fast curves sequence was also performed in hyperoxia and in hypoxia. Third, phentolamine and propranolol were administered to ensure complete - and β-adrenergic receptor blockade. Fourth, the whole sequence of fast flow–pressure curves was obtained again in hyperoxia and in hypoxia. In two additional dogs, haemodynamics were measured before and during infusion of epinephrine at 0.5, 1, 2 and 4 mcg kg^–1 min^–1. Data were collected after stabilization at a given blood flow, and included baseline measurements and a fast downward flow–pressure curve.

2.5 Flow–pressure curves
Slow five-point flow–pressure curves were obtained by decreasing flow progressively and allowing haemodynamics to stabilize at each point before collecting data. The first point was obtained after deflation of the intracaval balloon and opening of the arterio-venous fistula, the second point after clamping the fistula and the third to fifth points after stepwise inflations of the balloon. Haemodynamic variables were collected at each point, and blood gases at the first and last points of the curve (highest flow and lowest flow). Generation of a complete five-point curve required 20–30 min. Fast flow–pressure curves were obtained by filling the caval balloon in order to reduce flow by approximately 50% in a few seconds, while recording flow and pressures for a total of 12 s. The balloon was deflated after 6, 15, 30 or 120 s of inflation, and flow and pressures were recorded again during flow restoration. During 30 and 120 s low flow episodes, some balloon deflation was allowed during the waiting period, in order to maintain Psa at around 50 mmHg. Fast flow–pressure curves were obtained in duplicate, while ventilation was transiently discontinued. Each fast curve manoeuvre was delayed until recovery of baseline heart rate, flow and pressures. Complete haemodynamic variables and blood gases were collected at the beginning of each fast curve sequence (highest flow).

2.6 Adrenergic blockade
Combined - and β-adrenergic blockade was obtained with phentolamine i.v. (bolus of 2 mg/kg and infusion of 50 mcg kg^–1 h^–1) and propranolol i.v. (slow bolus of 2 mg/kg). The effectiveness of the adrenergic blockade was tested using phenylephrine (5 mcg/kg, i.v.) and isoproterenol (1 mcg/kg, i.v.) before and 15 min after blockade. Phenylephrine increased the mean Psa by 41±3 mmHg at baseline, by 1±1 mmHg after phentolamine, and by 0±1 mmHg at the end of the experiment. Isoproterenol increased the heart rate by 105±10 beats/min at baseline, by 4±1 beats/min after propranolol, and by 4±1 beats/min at the end of the experiment.

2.7 Data analysis
Instantaneous flow and pressure signals were digitized at a sampling rate of 200 Hz, displayed on screen for visual inspection, and stored on disk for off-line determination of flow–pressure curves and pulmonary vascular impedance. To compensate for the ultrasonic underestimation of flow in large vessels, the flow signal was scaled to match the thermodilution value. The scaling factor was somewhat different between dogs (1.45±0.07) but was fairly constant for each single animal (coefficient of variation, 5±1%). Flow was indexed to body surface area, estimated as area (m²)=0.112xweight (kg)^2/3 [12]. Slow flow–pressure curves were analyzed using the five available values. Fast flow–pressure curves were analyzed using 6–20 beats from the last baseline beat to the last beat that showed changes in both flow and pressure. Individual curves were found to be essentially linear, and all curves were submitted to least-squares linear regression analysis. To obtain composite curves, pressures were interpolated from the individual equations at intervals of 0.5 l min^–1 m^–2 over the range of flows encountered under each experimental condition (1.7 to 3.2 l min^–1 m^–2 in hyperoxia and 2.0 to 4.0 l min^–1 m^–2 in hypoxia). Pulmonary vascular impedance was calculated from the Fourier series expressions for pressure and flow [19]. At each harmonic, the impedance modulus (amplitude) was computed as the ratio between pressure and flow moduli, and the impedance phase as the difference between the flow and pressure phase [19]. Harmonics with flow values lower than 1% of the first harmonic flow were considered as noise and were discarded. From the impedance spectra were derived the total resistance (Z_o), the characteristic impedance (Z_c), the first harmonic modulus (Z₁) and first harmonic phase angle (Ph₁) and the reflection coefficient (R_c). Z_o was defined as the 0 Hz (mean term) impedance. Z_c was estimated as the average of impedance moduli between 2 and 15 Hz. R_c was estimated as (Z_o–Z_c)/(Z_o+Z_c). Total hydraulic power (W_tot) was calculated as the integral of the pressure–flow product over time. Steady power (W_st) was calculated as the product of mean pressure and mean flow, and oscillatory power (W_osc) as the difference between total and steady power [19]. The maximal rate of right ventricular pressure increase (dP/dt_max) was derived from the instantaneous ventricular pressure signal.

2.8 Statistics
Results are expressed as the mean±SE. Statistical analysis consisted of an analysis of variance for multiple factors (baseline vs. adrenergic blockade and hyperoxia vs. hypoxia) and repeated measurements in the same group of animals [29]. Analysis of contrasts was used to compare specific situations (high vs. low flow, slow vs. fast curve, decreasing vs. increasing flow, 6 s vs. 2 min delay), and to identify a dose-related trend during the epinephrine infusion [29]. P values below 0.05 were accepted as indicating statistical significance.

	3 Results

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
Ten dogs completed the hyperoxic part of the experimental protocol. Seven dogs completed the hypoxic studies before adrenergic blockade, whereas the other three either showed no hypoxic response or poorly tolerated the hypoxia. Five dogs achieved the hypoxic studies after adrenergic blockade. Dogs achieving and not achieving the hypoxic part of the study had similar hyperoxic values. Balloon inflation markedly decreased flow in all dogs, from about 3.1 to 1.7 l min^–1 m^–2 in hyperoxia and from about 4.1 to 1.7 l min^–1 m^–2 in hypoxia. Low flow was associated with a decrease in all intravascular pressures and in PvO₂. Because Pla significantly decreased with flow, pulmonary vascular tone was assessed as the difference between Ppa and Pla (Ppa–Pla) vs. the flow relationship. Hypoxia decreased PaO₂ from about 200 to 40 mmHg and PvO₂ from about 40 to 25 mmHg. Hypoxia was associated with a marked increase in blood flow, heart rate, Ppa and Ppa–Pla difference.

Slow flow–pressure curves were essentially linear in hyperoxia and in hypoxia (correlation coefficients of 0.95±0.01). Fast curves were remarkably linear in hyperoxia and in hypoxia (correlation coefficients of 0.97±0.01 and 0.99±0.01, respectively). Data obtained from duplicate determinations of fast curves showed excellent reproducibility, both when decreasing and when increasing flow. Average values were thus used for further analysis. Fast curves obtained during decreasing flow before 6, 15, 30 and 120 s of balloon inflation were almost superimposable, and were therefore pooled into one single curve to clarify tables and figures.

3.1 Slow vs. fast curves
Haemodynamics during slow and fast flow–pressure curves are compared in Table 1 and Fig. 1. Haemodynamics were similar at baseline, except for the lower heart rate with slow curves. Flow reduction was similar during slow and fast curves. During slow curves, flow reduction was associated with a marked increase in heart rate, a marked decrease in Psa, and a slight decrease in Ppa–Pla. During fast curves, low flow caused no change in heart rate, almost no decrease in Psa, and more decrease in Ppa–Pla. As a result, fast curves are associated with a steeper slope and a lower pressure intercept (Fig. 1). Regarding the changes in Ppa–Pla, the difference between fast and slow curves is not significant in Table 1 because the table results from measured values, which are affected by individual flow variability. The difference between fast and slow curves is significant in Fig. 1 because the figure results from interpolated values that are no longer affected by flow variability.

View this table: [in this window] [in a new window]   Table 1 Haemodynamics and blood gases in hyperoxia, before adrenergic blockade

 

View larger version (20K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Slow vs. fast pulmonary vascular flow–pressure curves in hyperoxia (lower curves, means±SE, n=10) and in hypoxia (upper curves, means±SE, n=7). All curves were obtained while decreasing flow. In hyperoxia, the fast curve shows a steeper slope and a lower pressure intercept. In hypoxia, no significant difference was observed between the two curves.

 
3.2 Effect of time
Fig. 2 shows fast upward flow–pressure curves obtained during balloon deflation after 6–120 s of the low flow state. Upward curves after 6 s of low flow were similar to downward curves. Upward curves after 120 s of low flow were associated with higher heart rate, lower Psa and higher Ppa–Pla. At the same flow, these values are comparable to those obtained at the end of slow curves. As seen in Fig. 2, most of the increase in pulmonary vascular tone is already observed after 15 s of low flow.

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Fast pulmonary vascular flow–pressure curves, in hyperoxia and before adrenergic blockade (means±SE, n=10). The dashed curve was obtained while decreasing flow and the solid curves while restoring flow after 6, 15, 30 and 120 s. Increasing the low flow time progressively shifted the flow–pressure curve upwards.

 
3.3 Effect of adrenergic blockade
Fig. 3 displays upward flow–pressure curves obtained after - and β-adrenergic blockade by phentolamine and propranolol. Again, upward curves after 6 s of low flow were similar to downward curves. After 120 s of low flow, heart rate did not change and the increase in Ppa–Pla noted before adrenergic blockade was significantly but not completely prevented. No difference persisted between curves obtained after 15 and 120 s of low flow.

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Fast pulmonary vascular flow–pressure curves, in hyperoxia and after adrenergic blockade (means±SE, n=10). The dashed curve was obtained while decreasing flow and the solid curves while restoring flow after 6, 15, 30 and 120 s. Adrenergic blockade partially inhibited the upward shift observed in Fig. 2.

 
3.4 Effect of hypoxia
Table 2 and Fig. 1 present data from slow and fast flow–pressure curves obtained during hypoxia. Compared to hyperoxia, hypoxia markedly increased blood flow, heart rate, Ppa and Ppa–Pla difference. Slow curves were associated with an increase in heart rate, a decrease in Psa, and a steep slope. Fast curves showed no change in heart rate, less change in Psa, and a similar steep slope. No significant difference persists between slow and fast curves. In hypoxia, upward curves obtained after 6, 15 and 30 s of a low flow state were comparable to the downward curves. In hypoxia after adrenergic blockade, upward curves obtained after 6, 15 and 30 s of the low flow state remained comparable to the downward curves.

View this table: [in this window] [in a new window]   Table 2 Haemodynamics and blood gases in hypoxia, before adrenergic blockade

 
3.5 Pulmonary vascular impedance
During slow flow–pressure curves, low flow did not affect Z_o but markedly increased Z₁, Z_c and Ph₁ (Table 1). During fast curves, it increased Z₁ and Z_c to a lesser extent and did not affect Ph₁. Upward curves values after 6 s of low flow were similar to fast downward curve values. Upward curve values after 2 min of low flow were comparable to those obtained at the end of slow curves. After adrenergic blockade, Z₁ and Z_c still increased at low flow but were no longer affected by time. Hypoxia increased Z_o but did not affect Z₁ or Z_c. In hypoxia, low flow increased Z_o, Z_c and Ph₁ during slow curves, but not or less during fast curves (Table 2). Upward data after 6 s of low flow were similar to fast downward data. Data after 30 s of low flow were comparable to those obtained at the end of slow curves. After adrenergic blockade, Z_o, Z₁ and Z_c were no longer affected by time.

3.6 Hydraulic work and dP/dt_max
Low flow generally decreased W_st markedly, decreased W_osc to a lesser extent, and thus increased W_osc/W_tot. Hypoxia increased W_st markedly but did not affect W_osc, so that W_osc/W_tot decreased. Adrenergic blockade did not specifically affect work data. Conversely, dP/dt_max decreased at low flow and increased in hypoxia. Adrenergic blockade decreased dP/dt_max and prevented the dP/dt_max increase observed after 2 min or 30 s of low flow.

3.7 Effects of epinephrine infusion
Independently of blood flow, which was stabilized at a similar initial value, exogenous epinephrine increased Psa and heart rate, and progressively shifted flow–pressure curves upwards (Fig. 4). Epinephrine also progressively increased Z_o, Z₁ and Z_c (Table 3).

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Fast pulmonary vascular flow–pressure curves before and during epinephrine infusion at 0.5, 1 and 2 mcg kg–1 min–1 (means±SE, n=2). All curves were generated by decreasing flow. Epinephrine progressively shifted the flow–pressure curve upwards.

 

View this table: [in this window] [in a new window]   Table 3 Haemodynamics during epinephrine infusion

 

	4 Discussion

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
4.1 Critique of the methods
Flow–pressure curve determinations and pulmonary vascular impedance calculations both require methodological precautions. The relationship between mean flow and mean pressure is actually curvilinear, with a concavity towards the flow axis [20]. In physiological ranges of flow, however, pulmonary vascular flow–pressure curves are well described by linear fitting [28]. In the present work, linear correlation coefficients were 0.95±0.01 for slow curves and 0.98±0.01 for fast curves. Interpolated pressure values therefore could be used for graphical presentation and statistical analysis. Flow–pressure curves also must be compared over the same range of flow. Ranges here were similar for all downward curves. Upward curves obtained after prolonged low flow generally extended over a wider range, but they still could be interpreted meaningfully because they were linear and always included the flow range of the other curves. Using the impedance concept implies that the vascular system is linear, i.e. that pressure waves only generate flow waves of the same frequency, and that the pressure/flow ratio at any frequency is independent of the size and shape of the pressure pulse [19]. Accepting some approximation, this condition has been verified for the pulmonary circulation [2]. Fourier transforms should be applied to cyclic events, meaning that flow and pressure values must be the same at the beginning and at the end of the examined cycle. Impedance therefore was only computed at high and low flow, i.e. immediately before and after the flow change. The pulmonary artery must be free to pulse within the flow probe, which is confirmed here by the low Z_c values [19]. Pulmonary vascular impedance spectra obtained in the present study are comparable to those reported previously in dogs and in man [19].

4.2 Effects of flow reduction
The direct mechanical effects of low flow on pulmonary haemodynamics were assessed from data obtained during fast downward curves, assuming that no cardiovascular reflex is effective within such a short period of time (about 6 s) [16, 28]. The absence of sympathetic stimulation was confirmed by the absence of changes in heart rate. Low flow was associated with the expected decrease in Ppa–Pla, but also with an increase in Z₁ and Z_c, an increase in W_osc/W_tot, and a decrease in dP/dt_max. The increases in Z₁ and Z_c indicate an increase in pulsatility. They cannot be attributed to flow changes per se, because the impedance concept implies that the pulmonary vascular system is linear [19], nor to increased vessel wall stiffness with increased wave velocity, because this would have affected Ph₁ and R_c, which actually remained unchanged [21], nor to increased intravascular pressure, since pressure decreased. The increase in Z₁ and Z_c could thus only result from the decreased vessel diameter. The increase in W_osc/W_tot in turn results from the increased pulsatility. An increase in W_osc/W_tot means that a larger proportion of the energy developed by the right ventricle was ‘wasted’ in generating oscillations, rather than used in generating flow [21]. In other words, right ventriculo-vascular matching deteriorated at low flow. This is consistent with the concept that right ventriculo-vascular matching is optimal under normal conditions [26]. The decrease in dP/dt_max confirms previous observations that this index of myocardial contractility is dependent on preload [3]. These results are consistent with those of Grant and Canty [13], who reported that high flow increases pulmonary arterial pressure, pulmonary arterial compliance, energy transmission, and dP/dt_max. In that study, Z_c did not decrease, but high flow was associated with a decrease in systemic arterial pressure, which could have stimulated the sympathetic system. In our study, the upward curves obtained after only 6 s of balloon occlusion were almost superimposable on the downward curves, indicating the absence of hysteresis in the system.

4.3 Effects of sympathetic activation
Hypotension activates the baroreflex, which stimulates the adrenergic sympathetic nervous system [8]. Effects of adrenergic stimulation were thus assessed here by comparing the fast and slow downward curves. At similar low flow levels, slow curves were associated with an increase in heart rate and in Ppa–Pla, an increase in Z_c and Ph₁, and a decrease in R_c and W_osc/W_tot. The marked increase in heart rate suggests a strong adrenergic stimulation. The increase in Ppa–Pla with adrenergic stimulation (Fig. 1) is consistent with the previously reported decrease in Ppa–Pla at low flow after complete adrenergic blockade [5]. Both observations indicate a predominance of -adrenergic vasoconstriction on small resistive vessels at low flow. These results are consistent with previous reports that -adrenergic blockade abolishes hypotension-induced pulmonary vasoconstriction [24]. The pulmonary vasoconstriction observed at low flow also explains why flow–pressure curves are sometimes close to horizontal and extrapolate to positive pressure at zero flow. The increase in Z_c indicates an increased elastance (i.e. an increased stiffness, a decreased compliance) of large proximal vessels. Increased wave velocity and wave reflexion would be expected, whereas we actually observed an increase in Ph₁ and a decrease in R_c. These effects could be due to the higher heart rate and lower stroke volume, the reflected wave being smaller and arriving later with reference to the shorter cardiac cycle. The decrease in W_osc/W_tot is consistent with the decrease in wave reflexion and with the increase in heart rate [18]. Ventriculo-vascular matching thus improved with sympathetic activation, which completely reversed the deterioration due to low flow. dP/dt_max was not higher in slow curves than in fast curves, but it decreased less between high and low flow (P<0.05). This confirms its limitations as an index of contractility.

Effects of adrenergic stimulation can also be assessed by comparing data from fast upward curves obtained after 6 s and after 2 min of balloon inflation. Upward curves obtained after 6 s were similar to downward curves. By comparison, upward curves obtained after 2 min were associated with increased heart rate and Ppa–Pla, and increased Z₁, Z_c and Ph₁. These data confirm that sympathetic stimulation increases both the resistance of small distal vessels and the elastance of large proximal vessels. The comparison of curves obtained after variable durations of balloon inflation (Fig. 2) indicates that effects of adrenergic activation are already close to maximal after 15 s, which is consistent with previous reported values of 15 to 20 s [16].

4.4 Effects of adrenergic blockade
Adrenergic blockade was used to ascertain that the effects associated with sustained low flow actually resulted from an adrenergic stimulation. Phentolamine and propranolol completely blocked the responses to - and β-agonists. Adrenergic blockade decreased dP/dt_max but did not affect the pulmonary circulation at baseline. This absence of effect indicates that baseline adrenergic stimulation was low in our dogs, probably due to the anaesthesia [5]. Effects of adrenergic blockade on slow flow–pressure curves had been investigated in a previous study [5], and were therefore not repeated here. In that study, adrenergic blockade did not affect pulmonary vascular tone significantly, but Ppa–Pla however tended to decrease at low flow and to increase at high flow, resulting in a somewhat steeper flow–pressure curve. Perhaps the effects were blunted by pentobarbital anaesthesia [22]. In conscious dogs, -adrenergic blockade has been reported to abolish hypotension-induced pulmonary vasoconstriction, whereas β-blockade had no effect [24]. In the present study, adrenergic blockade clearly attenuated the upward shift of flow–pressure curves induced by sustained low flow. The shift was not completely prevented, but the remaining response was no longer significant. Some remaining response might result from non-sympathetic mechanisms, involving, for example, vasopressin [24]or reduced nitric oxide synthesis [6], or from sympathetic non-adrenergic mediators such as neuropeptide Y [11]. Adrenergic blockade completely prevented the effects of sustained low flow on pulmonary vascular impedance and on hydraulic work. Compared to transient low flow, the effects of sustained low flow on both distal resistance and proximal elastance can thus be attributed to the adrenergic activation. These findings confirm our previous conclusions [17]that increases in Z_c observed during slow flow–pressure curves result both from mechanical changes and from adrenergic stimulation. They are consistent with previous reports that Z_c is increased by direct sympathetic stimulation [23, 25]and by haemorrhage-induced sympathetic stimulation [9].

4.5 Effects of epinephrine infusion
The data obtained during epinephrine infusion show that, independently of flow, exogenous adrenergic stimulation also increases Ppa–Pla and increases Z_o, Z₁ and Z_c. This further confirms that adrenergic stimulation can increase both the resistance and elastance of the pulmonary vasculature.

4.6 Effects of hypoxia
Hypoxia was used to investigate whether or not the effects of sustained low flow would be similar at low and high pulmonary arterial pressure. Hypoxia caused vigorous pulmonary vasoconstriction, as expected after acetylsalicylic acid administration [4]. Hypoxic vasoconstriction occurs in small distal vessels and results in a passive dilation of proximal vessels [1, 10]. Despite the increase in proximal diameter, Z₁ and Z_c did not decrease. This absence of change is consistent with previous observations [25, 27]. Heart rate increased markedly, suggesting a chemoreceptor-mediated adrenergic stimulation. Chemoreceptor stimulation indeed can override baroreceptor regulation in acute hypoxia [8]. We conclude that adrenergic stimulation prevented the expected Z₁ and Z_c decrease by enhancing the elastance of proximal vessels. As a confirmation of this mechanism, Z₁ and Z_c did decrease after adrenergic blockade in hypoxia. Since hypoxia did not affect Z₁ and Z_c, R_c and W_osc did not change and W_osc/W_tot therefore decreased. Adrenergic stimulation can also explain the other results observed in hypoxia. Slow and fast downward curves were similar, because chemoreceptor-mediated adrenergic stimulation was present in both conditions. Upward curves after 6, 15 and 30 s of low flow were comparable for the same reason. Adrenergic stimulation possibly was more intense after 15 and 30 s, as suggested by the higher heart rate, the slight (nonsignificant) upward shift of flow–pressure curves, and the complete disappearance of these differences after adrenergic blockade. Effects of sustained low flow on impedance spectra were qualitatively comparable to those observed during hyperoxia, but less ample and generally not significant. These limited (nonsignificant) changes all were prevented by adrenergic blockade.

	5 Conclusions

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
In summary, we compared the effects of sustained and transient low flow on pulmonary vascular steady-state and pulsatile flow–pressure relationships in anaesthetized dogs. In hyperoxia, fast flow–pressure curves were steeper and had a lower pressure intercept, due to the absence of adrenergic stimulation. In hypoxia, slow and fast curves were similar, due to the presence of chemoreceptor-induced adrenergic stimulation. Adrenergic stimulation, either caused by sustained low flow, by hypoxia or by epinephrine infusion, increased both the resistance of small distal vessels and the elastance of large proximal vessels. Thereby, it enhanced the Z_c increase associated with low flow and prevented the Z_c decrease associated with hypoxia.

Time for primary review 33 days.

	Acknowledgements

 
S. Brimioulle was supported by the Foundation for Cardiac Surgery (Belgium), M. Maggiorini by the Ettore Balli Foundation and the Hertzog-Egli Foundation (Switzerland), and F. Vermeulen by the Erasme Foundation (Belgium). The study was supported by grant # 9.4513.94 from the Foundation for Medical Scientific Research (Belgium). Phentolamine was kindly supplied by Ciba-Geigy (Groot-Bijgaarden, Belgium) and propranolol by Zeneca (Destelbergen, Belgium).

	References

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 

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