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Differential effects of lumbar and thoracic epidural anaesthesia on the haemodynamic response to acute right ventricular pressure overload
British Journal of Anaesthesia 104 (2): 143–9 (2010)
doi:10.1093/bja/aep354
Advance Access publication December 22, 2009
CARDIOVASCULAR Differential effects of lumbar and thoracic epidural anaesthesia on the haemodynamic response to acute right ventricular pressure overload C. Missant1†, P. Claus2†, S. Rex3 4 and P. F. Wouters5* 1
Centre for Experimental Anaesthesiology, Emergency and Intensive Care Medicine, Department of Acute Medical Sciences and 2Division of Imaging and Cardiovascular Dynamics, Department of Cardiovascular Diseases, Catholic University Leuven, Belgium. 3Department of Anaesthesiology and 4Department of Intensive Care, RWTH Aachen, Germany. 5Department of Anaesthesiology, University of Ghent, Belgium
Background. The safety of epidural anaesthesia in patients at risk for right ventricular pressure overload remains controversial. We compared the haemodynamic effects of vascular and cardiac autonomic nerve block, induced by selective lumbar (LEA) and high thoracic epidural anaesthesia (TEA), respectively, in an animal model subjected to controlled acute right ventricular pressure overload. Methods. Eighteen pigs were instrumented with epidural catheters at the thoracic (T) and lumbar (L) level and received separate injections at T2 (1 ml) and L3 (4 ml) with saline (s) or bupivacaine 0.5% (b). Three groups of six animals were studied: (i) a control group (LsþTs), (ii) LEA group (LbþTs), and (iii) TEA group (LsþTb). Haemodynamic measurements including biventricular pressure-volumetry were performed. Right ventricular afterload was then increased by inflating a pulmonary artery (PA) balloon. Measurements were repeated after 30 min of sustained right ventricular afterload increase. Results. LEA decreased systemic vascular resistance (SVR) and did not affect ventricular function. TEA had minor effects on SVR but decreased left ventricular contractility while baseline right ventricular function was not affected. Control and LEA-treated animals responded similarly to a PA balloon occlusion with an increase in right ventricular contractility and heart rate. Animals pretreated with a TEA did not show this positive inotropic response and developed low cardiac output in the presence of right ventricular pressure overload. Conclusions. In contrast to LEA, TEA reduced the haemodynamic tolerance to PA balloon occlusion by inhibiting the right ventricular positive inotropic response to acute pressure overload. Br J Anaesth 2010; 104: 143–9 Keywords: anaesthetic techniques, epidural; complications, pulmonary hypertension; heart, myocardial function; heart, ventricles; lung, intravascular pressure Accepted for publication: October 7, 2009
Pulmonary hypertension remains an important risk factor in anaesthesia, yet surprisingly little experimental data exist to guide clinicians in selecting a proper anaesthetic technique for such patients.1 2 In particular, the use of epidural anaesthesia continues to evoke controversy.3 Epidural injection of local anaesthetics invariably produces segmental autonomic denervation, causing
vasodilation in systemic arteries and veins.4 Systemic vasodilation is particularly dangerous in the presence of a pressure-overloaded right ventricle because it compromises ventricular interdependence, decreases myocardial perfusion, and reduces venous return, all of which can †
These two authors contributed equally to this study.
# The Author [2009]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
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*Corresponding author: Department of Anaesthesia, University Hospitals Ghent, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: [email protected]
Missant et al.
measured at regular intervals (ABL 520, Radiometer A/S, Bro¨nsho¨j, Denmark) and the ventilation was adjusted to maintain normocapnia and normoxia. A balanced electrolyte solution was administered at a rate of 8 ml kg21 h21. Normothermia was maintained using an infrared heating lamp. Two 18 G epidural catheters (B. Braun Melsungen AG, Melsungen, Germany) were inserted at the height of the lumbar vertebrae L3/4 and L4/5 using the loss-of-resistance technique. Guided by radioscopic control, one catheter was advanced until its tip was situated at the level of L2, whereas the other catheter was advanced to thoracic vertebra T2. Correct position of the catheters was verified by the injection of contrast agent (Iomeron 300, Byk Belga N.V./S.A., Brussels, Belgium), and it was ensured that the contrast agent spread symmetrically in rostral and caudal directions. Haemostatic sheaths (Terumo Europe, Haasrode, Belgium) were inserted in the right and left femoral veins. Under radioscopic guidance, a 6 Fr valvuloplasty balloon was advanced into the main pulmonary artery (PA). In addition, a 10 Fr sizing balloon catheter was positioned in the inferior vena cava (IVC) for controlled alterations of ventricular preload. And finally, a 16 G silicone catheter was advanced through the right femoral artery with its tip in the descending aorta. A lateral cutdown was performed in the cervical region and 8 Fr introducer sheaths were inserted in the left and right carotid arteries and the right external jugular vein. Combined micro-tipped multi-segment pressure –volume catheters (SPC 560, SPC 570, Millar Instruments, Houston, TX, USA) were inserted, under radioscopic guidance, into the left and the right ventricles via the left carotid artery and the right external jugular vein, respectively.
Methods
Experimental protocol
The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and was approved by the institution’s ethics committee for animal research.
After completion of instrumentation and achieving a haemodynamic steady state, baseline measurements were performed with the ventilation suspended at end-expiration. Data were acquired during steady-state conditions and during a brief period of IVC occlusion, for the assessment of the preload-recruitable stroke work (PRSW) and the end-systolic pressure – volume relationship (ESPVR). After baseline measurements, animals were randomly assigned to receive placebo, TEA, or LEA treatment. The investigators were unaware of the treatment modality and received two unlabelled syringes for injection at the lumbar (4 ml) and thoracic (1 ml) level, respectively. The control group (n¼6) received NaCl 0.9% in both syringes, the TEA group (n¼6) received bupivacaine 0.5% for the thoracic and NaCl 0.9% for the lumbar catheter, and the LEA group (n¼6) received NaCl 0.9% for the thoracic and bupivacaine 0.5% for the lumbar catheter. In pilot
Instrumentation Eighteen pigs [mean weight 36 (SD 2) kg] were included in this study. After i.m. premedication with ketamine (20 mg kg21), piritramide (1 mg kg21), and atropine (0.5 mg), anaesthesia was induced with i.v. propofol (2 mg kg21) and tracheal intubation was performed. Anaesthesia was maintained with a continuous i.v. infusion of propofol (5 mg kg21 h21), sufentanil (3 mg kg21 h21), and pancuronium (0.2 mg kg21 h21). The lungs were mechanically ventilated with a mixture of oxygen and room air [mean tidal volume 10 (1) ml kg21]. Arterial blood gases were
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precipitate acute right ventricular failure and haemodynamic collapse.5 – 9 On the basis of experimental data, we recently proposed yet another mechanism through which neuroaxial anaesthesia may interfere with the delicate circulatory balance in a pressure-overloaded right ventricle and pulmonary circulation. We observed that thoracic epidural anaesthesia (TEA) limited the contractile response of the right ventricle to acute pressure overload in an experimental model for hypoxia-induced pulmonary hypertension.9 We hypothesized that this was due to a selective inhibition of the cardiac sympathetic afferent and efferent nerves. However, TEA also had profound systemic vasodilatory effects in this experimental model, probably because the autonomic denervation extended far beyond the targeted area of the cardiac sympathetic nerves. The present study was designed specifically to differentiate between the effects of cardiac autonomic denervation and those produced by vasodilation caused by vascular sympatholysis, in the pressure-overloaded right ventricle. From a clinical perspective, such a differentiation is crucial as well because the extent of vascular and cardiac autonomic block varies with the particular epidural technique used. Local anaesthetic drugs were therefore targeted to primarily block either the cardiac (with high TEA) or the vascular sympathetic nerves (with lumbar epidural anaesthesia; LEA) in distinct groups of animals subjected to a standardized acute right ventricular pressure overload. The extent of autonomic block was verified with thermography. Haemodynamic changes were quantified using load and heart rate (HR) independent indices of contractility based on ventricular pressure – volume loop analysis in an anaesthetized, mechanically ventilated closed chest animal model.
Epidural anaesthesia and acute right ventricular pressure overload
Data acquisition and analysis The conductance catheters were connected to a signalprocessing unit (Sigma 5 DF, CDLeycom, Zoetermeer, The Netherlands). The theory of conductance volumetry has been described extensively previously.12 Parallel conductance was measured by injecting 10 ml hypertonic saline into the right atrium13 and blood resistivity was determined. The correction factor a was re-calculated for each measurement. All variables were digitized at 250 Hz and stored for off-line analysis with custom-made algorithms written in Matlab (The Mathworks Inc., Natick, MA, USA). Ventricular contractility was quantified by the slope (Mw) of the PRSW relationship and the slope (Ees) of the ESPVR.14 15 These load-independent indices of contractility have been validated specifically for the right ventricle16 and were determined according to the standard laboratory practice.12 Ees was calculated by linear fitting through coordinates of successive end-systolic pressure – volume points, obtained during a rapid IVC occlusion. Mw was calculated as the slope of the linear relationship between stroke work (the integrated area of each pressure
volume loop) and the corresponding end-diastolic volume. For both indices, only data showing R 2 values equal to or above 0.95 with linear regression analysis over the full range of volumes were accepted. Right ventricular afterload was determined as PA-Ea, calculated as the ratio of right ventricular end-systolic pressure to stroke volume. CO was measured using the transpulmonary thermodilution technique. Each measurement consisted of three successive injections of a 15 ml ice-cold saline bolus and the mean CO value was recorded for statistical analysis. SVR was calculated as the pressure gradient over mean flow: (MAP – RVEDP)/CO, where MAP is mean arterial pressure and RVEDP the right ventricular end-diastolic pressure.
Statistical analysis Data are presented as mean (SEM). Results were statistically analysed using a commercially available software package (Statistica for Windows version 6.0, Statsoft, Tulsa, OK, USA). Eighteen complete experiments were performed in this study (six experiments in each treatment group). No animal died before the completion of the protocol and there were no missing data. We used a repeated measurement analysis of variance to take into account the correlated observations within the groups, with the within-factor time (baseline, epidural, acute PHT), and the grouping factor treatment (control, TEA, and LEA). Appropriate post hoc testing was performed using the Bonferroni – Holm adjustment for multiple comparisons.17 18 A P-value of 0.05 was considered statistically significant. In the Results section, F- and P-values for the interaction effect between time and treatment are given.
Results Haemodynamic effects of thoracic and lumbar epidural anaesthesia Thoracic epidural administration of bupivacaine 0.5% (1 ml) at the level of T2 produced a significant increase in skin temperature (.0.58C above changes in the reference point) from level C7 to T6 (Fig. 1). There was a small decrease in MAP and left ventricular contractility [Mw decreased from 10.7 (0.9 SEM) to 7.8 (0.6) mW s ml21] (Table 1, Fig. 2). Right ventricular contractility remained essentially unchanged. Lumbar epidural injection of bupivacaine 0.5% (4 ml) at the level of L2 produced a significant increase in skin temperature from level T13 to L6 (Fig. 1). This caused a significant decrease in MAP and SVR and an increase in HR (Table 1). Neither left nor right ventricular contractility was affected.
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experiments, we had determined that these specific volumes and doses were needed to produce a sympathetic block of 10 segments in the thoracic (Cervical 7– Thoracic 6) and lumbar (Thoracic 13– Lumbar 6) region with no overlapping areas between the groups. After epidural injection, right ventricular volumes were continuously monitored on the oscilloscope throughout the experiment to keep right ventricular end-diastolic volume constant with a colloid infusion (Geloplasma, Fresenius Kabi, Schelle, Belgium). Rectal temperature and skin temperatures at dermatomes extending from the cervical to the lumbar region were recorded before and repeated every 10 min after epidural injection with a microprobe thermometer (MT-D temperature probes, World Precision Instruments, UK).10 11 Thirty minutes after the start of epidural anaesthesia, haemodynamic measurements [including the assessment of right ventricular afterload, right and left ventricular contractility, HR, cardiac output (CO), mean arterial pressure, systemic vascular resistance (SVR), and peak right ventricular pressure] were repeated. In a final stage, right ventricular afterload was increased by inflating the balloon in the main PA, to obtain a threefold increase in effective pulmonary arterial elastance (PA-Ea), calculated as the quotient of right ventricular end-systolic pressure to stroke volume. After 30 min of sustained right ventricular pressure overload, when haemodynamics had stabilized, the final set of measurements was performed. Animals were then killed with an overdose of propofol followed by an i.v. bolus of potassium chloride.
Missant et al.
Vertebrae
+1
0
+1 °C
+1
0
+1 °C
+1
0
+1 °C
Cervical
Thoracic
Lumbar
Control
TEA
LEA
Fig 1 Increase in skin temperature after epidural injections in control animals and in animals with a TEA and LEA, respectively. The increase in skin temperature measured 30 min after epidural injection is presented as a mirrored bar plot. The vertebral column is indicated on the left side to represent all dermatomes from C4 (top) to L6 (bottom). An increase in skin temperature at a particular vertebral level is displayed as a mirror bar according to the scale indicated on top of the figure for each group separately. A temperature increase of .0.58C was considered to indicate an effective block of the sympathetic nervous system at that particular level.
Parameter
Group
Baseline Mean (SEM)
EDA Mean (SEM)
PA occlusion Mean (SEM)
HR (beats min21)
C T L C T L C T L C T L C T L C T L C T L C T L C T L C T L
97 (8) 98 (7) 86 (5) 3.0 (0.38) 2.9 (0.22) 2.7 (0.18) 105 (2) 111 (5) 112 (3) 2774 (314) 2873 (114) 3205 (195) 0.72 (0.13) 0.77 (0.09) 0.68 (0.09) 23 (4) 20 (3) 21 (3) 0.41 (0.04) 0.49 (0.07) 0.55 (0.10) 1.75 (0.12) 1.95 (0.10) 1.84 (0.09) 1.93 (0.25) 2.10 (0.25) 1.92 (0.16) 11.00 (1.13) 10.68 (0.89) 10.06 (0.75)
97 (8) 93 (5) 101 (5)* 3.1 (0.4) 2.8 (0.4) 3.1 (0.3) 105 (3) 90 (5)* 78 (7)*,‡ 2658 (243) 2600 (295) 1812 (192)*,‡ 0.68 (0.11) 0.66 (0.09) 0.68 (0.13) 22 (5) 21 (4) 22 (5) 0.47 (0.05) 0.43 (0.06) 0.52 (0.07) 1.87 (0.15) 1.90 (0.14) 1.97 (0.11) 2.34 (0.41) 1.27 (0.22)*,‡ 1.97 (0.17) 11.78 (1.26) 7.79 (0.58)*,‡ 11.11 (0.80)
120 (7)*,† 97 (4)‡ 115 (4)*,† 2.9 (0.3) 1.9 (0.3)*,†,‡ 2.7 (0.3) 97 (4)*,† 75 (7)*,†,‡ 72 (8)*,‡ 2518 (159) 2895 (426) 1851 (165)*,‡ 1.63 (0.26)*,† 1.91 (0.20)*,† 2.13 (0.29)*,† 41 (8)*,† 44 (9)*,† 50 (6)*,† 0.92 (0.08)*,† 0.55 (0.06)‡ 1.05 (0.22)*,† 2.90 (0.23)*,† 1.86 (0.23)‡ 2.92 (0.20)*,† 2.32 (0.37) 1.30 (0.19)*,‡ 2.07 (0.39) 10.92 (1.09) 7.27 (0.72)*,‡ 11.33 (0.92)
CO (litre min
21
)
MAP (mm Hg) SVR (dyne s cm25) PA-Ea (mm Hg ml21)
Peak RVP (mm Hg) RV Ees (mm Hg ml21) RV Mw (mW s ml21) LV Ees (mm Hg ml21)
LV Mw (mW s ml
21
)
Effects of an acute increase in right ventricular afterload A three-fold increase in PA-Ea by gradual inflation of the pulmonary intra-arterial balloon was successfully obtained in all three groups (Table 1). In control animals, this manoeuvre resulted in an increase in HR and right ventricular contractility [Mw from 1.9 (0.1) to 2.9 (0.2) mW s ml21] whereas left
F-value
P-value
6.4014
0.0008
4.2194
0.0079
7.3340
0.0003
6.3666
0.0008
1.6857
0.1793
1.8802
0.1398
2.7645
0.0467
8.5831
0.0001
4.616
0.0050
8.2110
0.0001
ventricular contractility did not change (Fig. 2). There was a mild decrease in MAP (Table 1). Animals treated with LEA reacted with a lower SVR and MAP but a similar increase in HR and right ventricular contractility when compared with control animals (Table 1, Fig. 2). In contrast, animals pretreated with a TEA did not show an increase in HR and right ventricular contractility after
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Table 1 Ventricular function and general haemodynamics in control animals and animals with a TEA and LEA during baseline, after epidural injection, and after PA occlusion. Values are represented as mean (SEM). EDA, epidural anaesthesia; C, control animals; T, thoracic epidural anaesthesia; L, lumbar epidural anaesthesia; HR, heart rate; CO, cardiac output; MAP, mean arterial pressure; SVR, systemic vascular resistance; PA-Ea, effective pulmonary arterial elastance; RVP, right ventricular pressure; RV, right ventricle; LV, left ventricle; Ees, slope of the ESPVR; Mw, slope of the PRSW relationship; *P,0.05 vs baseline; † P,0.05 vs EDA; ‡P,0.05 vs C. F- and P-values refer to the interaction effect between time and treatment. Bold entries indicate statistically significant difference (defined as P,0.05)
Epidural anaesthesia and acute right ventricular pressure overload
A
3.5 RV Mw (mW s ml–1)
LV Mw (mW s ml–1)
14
12
10
8
F : 8.2110 P : 0.0001 C TEA LEA
6 0
Baseline
*‡
2.5
F : 8.5831 P : 0.0001
2.0
EDA
Baseline
RV Ees (mm Hg ml–1)
2.5 2.0 F : 4.6160 P : 0.0050 *‡
‡
PA occlusion 1.4
C TEA LEA
*†*†
1.2 1.0
EDA
D C TEA LEA
*†
*†
F : 2.7645 P : 0.0467
0.8 0.6 ‡
0.4
*‡
0.0
PA occlusion
0.0 Baseline
EDA
PA occlusion
Baseline
EDA
PA occlusion
Fig 2 Right and left ventricular contractility during baseline, epidural anaesthesia, and acute PA occlusion in control animals and animals with a thoracic or lumbar epidural anaesthesia. The effects of epidural anaesthesia on the slope of the preload-recruitable stroke work relationship (Mw) (A and B) and the slope of the end-systolic pressure– volume relationship (Ees) (C and D) during baseline, epidural anaesthesia (EDA), and during acute PA occlusion (PA occlusion) in the left (LV) and right ventricle (RV). Values are presented as mean (SEM). C, control animals; TEA, thoracic epidural anaesthesia; LEA, lumbar epidural anaesthesia; Ees, slope of the ESPVR; Mw, slope of the PRSW relationship; PA, pulmonary artery. *P,0.05 vs baseline; †P,0.05 vs EDA; ‡P,0.05 vs C.
PA balloon occlusion (Table 1, Fig. 2) and suffered a pronounced decrease in MAP and CO (Table 1). Left ventricular contractility remained unchanged as in the other groups (Fig. 2). There were no significant changes in right or left ventricular volumes throughout the study.
Discussion These data show that high TEA impairs the haemodynamic response to acute mechanical right ventricular pressure overload, whereas an LEA, restricted to the lower thoracic level does not. The findings support our hypothesis that cardiac sympathetic nerves are involved in the homeostatic control of right ventricular function during pressure overload. When subjected to a partial occlusion of the PA, both control animals and those treated with selective LEA responded with an increase in right ventricular contractility and maintained cardiac output in spite of a high afterload. This positive inotropic reflex of the right ventricle was completely abolished in the TEA-treated group and these animals suffered a pronounced decrease in cardiac output.
The phenomenon of increased right ventricular contractile state in response to high afterload has been documented earlier in a variety of experimental models of acute and chronic right ventricular pressure overload and has been termed homeometric autoregulation.19 – 21 The underlying mechanisms are not clear yet but may at least partially involve activation of the sympathetic nervous system. Also in humans, even small increases in right ventricular afterload are associated with a reversible increase in sympathetic output, and patients with chronic pulmonary hypertension have been shown to have elevated sympatho-adrenergic activity which could not be fully explained by hypoxiainduced chemoreceptor activation.22 23 In a previous study, we reported that TEA directly affects the right ventricular positive inotropic response to hypoxia-induced PHT.9 However, in that study, it was difficult to exclude the potentially confounding role of arterial hypoxia on sympatho-adrenergic output and right ventricular function. More importantly, the sympatholytic effects of epidural anaesthesia extended far beyond the targeted cardiac region and caused pronounced systemic vasodilation as well. Systemic vasodilatation can have an independent detrimental effect on the pressure-overloaded
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LV Ees (mm Hg ml–1)
3.0
1.5 0.0
C
1.0
C TEA LEA
*‡
3.0
1.5
B
Missant et al.
of epidural anaesthesia in this risk group. In addition, our findings may provide a clue in the differential diagnosis and treatment of postoperative haemodynamic instability when patients treated with TEA show signs of right ventricular dysfunction. The clinical impact of the results obtained with LEA should not be over-emphasized either and are no proof of its safety. In the controlled experimental setting of this study, preload changes were strictly corrected with fluids as guided by continuous monitoring of end-diastolic volumes. In addition, only a limited number of segments were blocked and the systemic hypotensive effect was rather mild. Under these conditions, LEA appeared to have minimal impact on the haemodynamic response to increased right ventricular afterload. This is in agreement with the case series that have reported successful outcomes with the use of LEA in parturients with pulmonary hypertension.26 We acknowledge that our study has several limitations which should be taken into account when translating the data to a clinical context. The use of an acute mechanical obstruction as a model for right ventricular pressure overload has limited direct clinical correlates except perhaps for the unique condition when a PA is partially clamped during extensive lung surgery. As explained earlier, our technique was chosen for methodological reasons, that is, to eliminate confounding factors such as arterial hypoxia or concomitant changes in pulmonary vascular tone. In the closed-chest animal model, this was best obtained with an intravascular balloon occluder. General anaesthesia was used in all animals and undoubtedly also affected the cardiovascular responses under investigation. However, TEA is mostly used as an adjunct to general anaesthesia and all groups received the same anaesthetic regimen simulating contemporary clinical anaesthesia practice. Although we used propofol instead of barbiturates, this is probably not the reason why baseline cardiac outputs were lower than in our previous study. Major differences in the invasiveness and surgical stress between closed- and open-chest preparations are more likely to explain this finding. We restricted the number of repetitive haemodynamic measurements to the absolute minimum. The reported time points were carefully selected to be best representative for each intervention at steady state. This strategy was preferred over more frequent data sampling primarily because the IVC occlusions which are required to assess PV loop-derived contractility indices tend to destabilize the cardiovascular system during critical right ventricular pressure overload. In conclusion, in a closed-chest animal model of acute right ventricular pressure overload, a selective TEA abolished the inotropic response to an acute increase in right ventricular afterload and aggravated the haemodynamic consequences, whereas a selective LEA only reduced SVR without detrimental effects on right ventricular contractility.
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right ventricle by reducing coronary perfusion and disrupting parallel ventricular interaction.24 In the present study, we intended to avoid such problems by (i) using a controlled mechanical obstruction of the PA to produce right ventricular overload and (ii) subjecting separate experimental groups to either a selective high thoracic or selective LEA to differentiate the cardiac from the vascular sympatholytic effects on right ventricular function. Pilot studies in our lab had indicated that only bupivacaine 0.5% (1 ml) was required to cause a sympathetic block extending from T1 to T6, that is, the area containing all cardiac sympathetic efferents in pigs.25 Interestingly, this dose is only one-seventh of the dose used in our previous paper, yet in the present study was sufficient to completely abolish the right ventricular inotropic response to mechanically induced pressure overload. Importantly, selective cardiac sympathetic denervation severely compromised right ventricular contractile function during pulmonary hypertension, but had no effect on SVR. In contrast, LEA for which bupivacaine 0.5% (4 ml) was needed to block a similar number of segments caused a significant decrease in SVR but did not affect the cardiac response to PA occlusion. This observation, in our opinion, leaves little doubt that cardiac sympathetic denervation was the primary cause of impaired tolerance to right ventricular pressure overload in the present study. In theory, a reduced baseline performance of the left ventricle caused by cardiac autonomic denervation could also interfere with the right ventricle’s capacity to overcome pressure overload. In fact, right ventricular function and pressure development partly rely on left ventricular pressure development in normal conditions.5 However, the following observations suggest that this was not a primary mechanism in our study: first, in the absence of pressure overload, left ventricular function decreased significantly after TEA but had no effect on right ventricular contractility. Secondly, in animals without TEA, there was no increase in left ventricular function when right ventricular afterload was raised, still, right ventricular contractility increased significantly. These observations suggest that the changes in right ventricular contractility were site-specific rather than secondary to ventricular interdependence. The exact mechanisms underlying the differential regulation of right and left ventricular contractility are not clear yet but, as discussed earlier, differences in sympathetic and parasympathetic innervation of both ventricles have been reported earlier.9 The clinical relevance of our observation remains to be demonstrated, however, and the data should not be considered as arguments against the use of an excellent analgesic technique like TEA. Instead, they suggest that a subgroup of patients at risk for acute right ventricular pressure overload may be at increased risk for cardiovascular collapse when neuroaxial anaesthesia extends to the cardiac sympathetic nerves. Awareness about this potential interaction could help clinicians optimize the application
Epidural anaesthesia and acute right ventricular pressure overload
Funding Supported by the Research Grant Programme of the European Society of Anaesthesiology and the Belgian Society of Anaesthesia and Resuscitation (P.F.W.). C.M. receives a PhD fellowship from the Fund of Scientific Research (FWO) Flanders, Belgium. S.R. was supported by the Medical Faculty of the RWTH Aachen, Germany.
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1 Ramakrishna G, Sprung J, Ravi BS, Chandrasekaran K, McGoon MD. Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality. J Am Coll Cardiol 2005; 45: 1691 – 9 2 Lai HC, Lai HC, Wang KY, Lee WL, Ting CT, Liu TJ. Severe pulmonary hypertension complicates postoperative outcome of noncardiac surgery. Br J Anaesth 2007; 99: 184 – 90 3 Bonnin M, Mercier FJ, Sitbon O, et al. Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology 2005; 102: 1133 – 7 4 Veering BT, Cousins MJ. Cardiovascular and pulmonary effects of epidural anaesthesia. Anaesth Intensive Care 2000; 28: 620 – 35 5 Santamore WP, Dell’Italia LJ. Ventricular interdependence: significant left ventricular contributions to right ventricular systolic function. Prog Cardiovasc Dis 1998; 40: 289 – 308 6 Afifi S, Shayan S, Al-Qamari A. Pulmonary hypertension and right ventricular function: interdependence in pathophysiology and management. Int Anesthesiol Clin 2009; 47: 97 – 120 7 Fischer LG, Van AH, Burkle H. Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists. Anesth Analg 2003; 96: 1603– 16 8 Blaise G, Langleben D, Hubert B. Pulmonary arterial hypertension: pathophysiology and anesthetic approach. Anesthesiology 2003; 99: 1415 – 32 9 Rex S, Missant C, Segers P, Wouters PF. Thoracic epidural anesthesia impairs the hemodynamic response to acute pulmonary hypertension by deteriorating right ventricular– pulmonary arterial coupling. Crit Care Med 2007; 35: 222 – 9 10 Di Filippo A, Natale V, Del PF, Ciapetti M, Bressan F, Falchi S. Skin temperature during sympathetic block: a clinical comparison of bupivacaine 0.5% and ropivacaine 0.5% or 0.75%. Anaesth Intensive Care 2006; 34: 334 – 7 11 Stevens MF, Werdehausen R, Hermanns H, Lipfert P. Skin temperature during regional anesthesia of the lower extremity. Anesth Analg 2006; 102: 1247 – 51
12 Rex S, Missant C, Segers P, Rossaint R, Wouters PF. Epoprostenol treatment of acute pulmonary hypertension is associated with a paradoxical decrease in right ventricular contractility. Intensive Care Med 2008; 34: 179– 89 13 Steendijk P, Staal E, Jukema JW, Baan J. Hypertonic saline method accurately determines parallel conductance for dual-field conductance catheter. Am J Physiol Heart Circ Physiol 2001; 281: H755– 63 14 Dickstein ML, Yano O, Spotnitz HM, Burkhoff D. Assessment of right ventricular contractile state with the conductance catheter technique in the pig. Cardiovasc Res 1995; 29: 820 – 6 15 Burkhoff D, Mirsky I, Suga H. Assessment of systolic and diastolic ventricular properties via pressure – volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol 2005; 289: H501– 12 16 Karunanithi MK, Michniewicz J, Copeland SE, Feneley MP. Right ventricular preload recruitable stroke work, end-systolic pressure – volume, and dP/dtmax-end-diastolic volume relations compared as indexes of right ventricular contractile performance in conscious dogs. Circ Res 1992; 70: 1169 – 79 17 Ludbrook J. Repeated measurements and multiple comparisons in cardiovascular research. Cardiovasc Res 1994; 28: 303 – 11 18 Ludbrook J. Multiple comparison procedures updated. Clin Exp Pharmacol Physiol 1998; 25: 1032 – 7 19 De Vroomen M, Cardozo RH, Steendijk P, Van Bel F, Baan J. Improved contractile performance of right ventricle in response to increased RV afterload in newborn lamb. Am J Physiol Heart Circ Physiol 2000; 278: H100– 5 20 De Vroomen M, Steendijk P, Lopes Cardozo RH, Brouwers HH, Van Bel F, Baan J. Enhanced systolic function of the right ventricle during respiratory distress syndrome in newborn lambs. Am J Physiol Heart Circ Physiol 2001; 280: H392– 400 21 Faber MJ, Dalinghaus M, Lankhuizen IM, et al. Right and left ventricular function after chronic pulmonary artery banding in rats assessed with biventricular pressure –volume loops. Am J Physiol Heart Circ Physiol 2006; 291: H1580– 6 22 Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de Borne P. Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 2004; 110: 1308 –12 23 Ciarka A, Vachiery JL, Houssiere A, et al. Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension. Chest 2007; 131: 1831 – 7 24 Mebazaa A, Karpati P, Renaud E, Algotsson L. Acute right ventricular failure—from pathophysiology to new treatments. Intensive Care Med 2004; 30: 185– 96 25 McKibben J, Getty R. Innervation of heart of domesticated animals: pig. Am J Vet Res 1969; 30: 779 – 89 26 Smedstad KG, Cramb R, Morison DH. Pulmonary hypertension and pregnancy: a series of eight cases. Can J Anaesth 1994; 41: 502–12
doi:10.1093/bja/aep354
Advance Access publication December 22, 2009
CARDIOVASCULAR Differential effects of lumbar and thoracic epidural anaesthesia on the haemodynamic response to acute right ventricular pressure overload C. Missant1†, P. Claus2†, S. Rex3 4 and P. F. Wouters5* 1
Centre for Experimental Anaesthesiology, Emergency and Intensive Care Medicine, Department of Acute Medical Sciences and 2Division of Imaging and Cardiovascular Dynamics, Department of Cardiovascular Diseases, Catholic University Leuven, Belgium. 3Department of Anaesthesiology and 4Department of Intensive Care, RWTH Aachen, Germany. 5Department of Anaesthesiology, University of Ghent, Belgium
Background. The safety of epidural anaesthesia in patients at risk for right ventricular pressure overload remains controversial. We compared the haemodynamic effects of vascular and cardiac autonomic nerve block, induced by selective lumbar (LEA) and high thoracic epidural anaesthesia (TEA), respectively, in an animal model subjected to controlled acute right ventricular pressure overload. Methods. Eighteen pigs were instrumented with epidural catheters at the thoracic (T) and lumbar (L) level and received separate injections at T2 (1 ml) and L3 (4 ml) with saline (s) or bupivacaine 0.5% (b). Three groups of six animals were studied: (i) a control group (LsþTs), (ii) LEA group (LbþTs), and (iii) TEA group (LsþTb). Haemodynamic measurements including biventricular pressure-volumetry were performed. Right ventricular afterload was then increased by inflating a pulmonary artery (PA) balloon. Measurements were repeated after 30 min of sustained right ventricular afterload increase. Results. LEA decreased systemic vascular resistance (SVR) and did not affect ventricular function. TEA had minor effects on SVR but decreased left ventricular contractility while baseline right ventricular function was not affected. Control and LEA-treated animals responded similarly to a PA balloon occlusion with an increase in right ventricular contractility and heart rate. Animals pretreated with a TEA did not show this positive inotropic response and developed low cardiac output in the presence of right ventricular pressure overload. Conclusions. In contrast to LEA, TEA reduced the haemodynamic tolerance to PA balloon occlusion by inhibiting the right ventricular positive inotropic response to acute pressure overload. Br J Anaesth 2010; 104: 143–9 Keywords: anaesthetic techniques, epidural; complications, pulmonary hypertension; heart, myocardial function; heart, ventricles; lung, intravascular pressure Accepted for publication: October 7, 2009
Pulmonary hypertension remains an important risk factor in anaesthesia, yet surprisingly little experimental data exist to guide clinicians in selecting a proper anaesthetic technique for such patients.1 2 In particular, the use of epidural anaesthesia continues to evoke controversy.3 Epidural injection of local anaesthetics invariably produces segmental autonomic denervation, causing
vasodilation in systemic arteries and veins.4 Systemic vasodilation is particularly dangerous in the presence of a pressure-overloaded right ventricle because it compromises ventricular interdependence, decreases myocardial perfusion, and reduces venous return, all of which can †
These two authors contributed equally to this study.
# The Author [2009]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
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*Corresponding author: Department of Anaesthesia, University Hospitals Ghent, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: [email protected]
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measured at regular intervals (ABL 520, Radiometer A/S, Bro¨nsho¨j, Denmark) and the ventilation was adjusted to maintain normocapnia and normoxia. A balanced electrolyte solution was administered at a rate of 8 ml kg21 h21. Normothermia was maintained using an infrared heating lamp. Two 18 G epidural catheters (B. Braun Melsungen AG, Melsungen, Germany) were inserted at the height of the lumbar vertebrae L3/4 and L4/5 using the loss-of-resistance technique. Guided by radioscopic control, one catheter was advanced until its tip was situated at the level of L2, whereas the other catheter was advanced to thoracic vertebra T2. Correct position of the catheters was verified by the injection of contrast agent (Iomeron 300, Byk Belga N.V./S.A., Brussels, Belgium), and it was ensured that the contrast agent spread symmetrically in rostral and caudal directions. Haemostatic sheaths (Terumo Europe, Haasrode, Belgium) were inserted in the right and left femoral veins. Under radioscopic guidance, a 6 Fr valvuloplasty balloon was advanced into the main pulmonary artery (PA). In addition, a 10 Fr sizing balloon catheter was positioned in the inferior vena cava (IVC) for controlled alterations of ventricular preload. And finally, a 16 G silicone catheter was advanced through the right femoral artery with its tip in the descending aorta. A lateral cutdown was performed in the cervical region and 8 Fr introducer sheaths were inserted in the left and right carotid arteries and the right external jugular vein. Combined micro-tipped multi-segment pressure –volume catheters (SPC 560, SPC 570, Millar Instruments, Houston, TX, USA) were inserted, under radioscopic guidance, into the left and the right ventricles via the left carotid artery and the right external jugular vein, respectively.
Methods
Experimental protocol
The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and was approved by the institution’s ethics committee for animal research.
After completion of instrumentation and achieving a haemodynamic steady state, baseline measurements were performed with the ventilation suspended at end-expiration. Data were acquired during steady-state conditions and during a brief period of IVC occlusion, for the assessment of the preload-recruitable stroke work (PRSW) and the end-systolic pressure – volume relationship (ESPVR). After baseline measurements, animals were randomly assigned to receive placebo, TEA, or LEA treatment. The investigators were unaware of the treatment modality and received two unlabelled syringes for injection at the lumbar (4 ml) and thoracic (1 ml) level, respectively. The control group (n¼6) received NaCl 0.9% in both syringes, the TEA group (n¼6) received bupivacaine 0.5% for the thoracic and NaCl 0.9% for the lumbar catheter, and the LEA group (n¼6) received NaCl 0.9% for the thoracic and bupivacaine 0.5% for the lumbar catheter. In pilot
Instrumentation Eighteen pigs [mean weight 36 (SD 2) kg] were included in this study. After i.m. premedication with ketamine (20 mg kg21), piritramide (1 mg kg21), and atropine (0.5 mg), anaesthesia was induced with i.v. propofol (2 mg kg21) and tracheal intubation was performed. Anaesthesia was maintained with a continuous i.v. infusion of propofol (5 mg kg21 h21), sufentanil (3 mg kg21 h21), and pancuronium (0.2 mg kg21 h21). The lungs were mechanically ventilated with a mixture of oxygen and room air [mean tidal volume 10 (1) ml kg21]. Arterial blood gases were
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precipitate acute right ventricular failure and haemodynamic collapse.5 – 9 On the basis of experimental data, we recently proposed yet another mechanism through which neuroaxial anaesthesia may interfere with the delicate circulatory balance in a pressure-overloaded right ventricle and pulmonary circulation. We observed that thoracic epidural anaesthesia (TEA) limited the contractile response of the right ventricle to acute pressure overload in an experimental model for hypoxia-induced pulmonary hypertension.9 We hypothesized that this was due to a selective inhibition of the cardiac sympathetic afferent and efferent nerves. However, TEA also had profound systemic vasodilatory effects in this experimental model, probably because the autonomic denervation extended far beyond the targeted area of the cardiac sympathetic nerves. The present study was designed specifically to differentiate between the effects of cardiac autonomic denervation and those produced by vasodilation caused by vascular sympatholysis, in the pressure-overloaded right ventricle. From a clinical perspective, such a differentiation is crucial as well because the extent of vascular and cardiac autonomic block varies with the particular epidural technique used. Local anaesthetic drugs were therefore targeted to primarily block either the cardiac (with high TEA) or the vascular sympathetic nerves (with lumbar epidural anaesthesia; LEA) in distinct groups of animals subjected to a standardized acute right ventricular pressure overload. The extent of autonomic block was verified with thermography. Haemodynamic changes were quantified using load and heart rate (HR) independent indices of contractility based on ventricular pressure – volume loop analysis in an anaesthetized, mechanically ventilated closed chest animal model.
Epidural anaesthesia and acute right ventricular pressure overload
Data acquisition and analysis The conductance catheters were connected to a signalprocessing unit (Sigma 5 DF, CDLeycom, Zoetermeer, The Netherlands). The theory of conductance volumetry has been described extensively previously.12 Parallel conductance was measured by injecting 10 ml hypertonic saline into the right atrium13 and blood resistivity was determined. The correction factor a was re-calculated for each measurement. All variables were digitized at 250 Hz and stored for off-line analysis with custom-made algorithms written in Matlab (The Mathworks Inc., Natick, MA, USA). Ventricular contractility was quantified by the slope (Mw) of the PRSW relationship and the slope (Ees) of the ESPVR.14 15 These load-independent indices of contractility have been validated specifically for the right ventricle16 and were determined according to the standard laboratory practice.12 Ees was calculated by linear fitting through coordinates of successive end-systolic pressure – volume points, obtained during a rapid IVC occlusion. Mw was calculated as the slope of the linear relationship between stroke work (the integrated area of each pressure
volume loop) and the corresponding end-diastolic volume. For both indices, only data showing R 2 values equal to or above 0.95 with linear regression analysis over the full range of volumes were accepted. Right ventricular afterload was determined as PA-Ea, calculated as the ratio of right ventricular end-systolic pressure to stroke volume. CO was measured using the transpulmonary thermodilution technique. Each measurement consisted of three successive injections of a 15 ml ice-cold saline bolus and the mean CO value was recorded for statistical analysis. SVR was calculated as the pressure gradient over mean flow: (MAP – RVEDP)/CO, where MAP is mean arterial pressure and RVEDP the right ventricular end-diastolic pressure.
Statistical analysis Data are presented as mean (SEM). Results were statistically analysed using a commercially available software package (Statistica for Windows version 6.0, Statsoft, Tulsa, OK, USA). Eighteen complete experiments were performed in this study (six experiments in each treatment group). No animal died before the completion of the protocol and there were no missing data. We used a repeated measurement analysis of variance to take into account the correlated observations within the groups, with the within-factor time (baseline, epidural, acute PHT), and the grouping factor treatment (control, TEA, and LEA). Appropriate post hoc testing was performed using the Bonferroni – Holm adjustment for multiple comparisons.17 18 A P-value of 0.05 was considered statistically significant. In the Results section, F- and P-values for the interaction effect between time and treatment are given.
Results Haemodynamic effects of thoracic and lumbar epidural anaesthesia Thoracic epidural administration of bupivacaine 0.5% (1 ml) at the level of T2 produced a significant increase in skin temperature (.0.58C above changes in the reference point) from level C7 to T6 (Fig. 1). There was a small decrease in MAP and left ventricular contractility [Mw decreased from 10.7 (0.9 SEM) to 7.8 (0.6) mW s ml21] (Table 1, Fig. 2). Right ventricular contractility remained essentially unchanged. Lumbar epidural injection of bupivacaine 0.5% (4 ml) at the level of L2 produced a significant increase in skin temperature from level T13 to L6 (Fig. 1). This caused a significant decrease in MAP and SVR and an increase in HR (Table 1). Neither left nor right ventricular contractility was affected.
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experiments, we had determined that these specific volumes and doses were needed to produce a sympathetic block of 10 segments in the thoracic (Cervical 7– Thoracic 6) and lumbar (Thoracic 13– Lumbar 6) region with no overlapping areas between the groups. After epidural injection, right ventricular volumes were continuously monitored on the oscilloscope throughout the experiment to keep right ventricular end-diastolic volume constant with a colloid infusion (Geloplasma, Fresenius Kabi, Schelle, Belgium). Rectal temperature and skin temperatures at dermatomes extending from the cervical to the lumbar region were recorded before and repeated every 10 min after epidural injection with a microprobe thermometer (MT-D temperature probes, World Precision Instruments, UK).10 11 Thirty minutes after the start of epidural anaesthesia, haemodynamic measurements [including the assessment of right ventricular afterload, right and left ventricular contractility, HR, cardiac output (CO), mean arterial pressure, systemic vascular resistance (SVR), and peak right ventricular pressure] were repeated. In a final stage, right ventricular afterload was increased by inflating the balloon in the main PA, to obtain a threefold increase in effective pulmonary arterial elastance (PA-Ea), calculated as the quotient of right ventricular end-systolic pressure to stroke volume. After 30 min of sustained right ventricular pressure overload, when haemodynamics had stabilized, the final set of measurements was performed. Animals were then killed with an overdose of propofol followed by an i.v. bolus of potassium chloride.
Missant et al.
Vertebrae
+1
0
+1 °C
+1
0
+1 °C
+1
0
+1 °C
Cervical
Thoracic
Lumbar
Control
TEA
LEA
Fig 1 Increase in skin temperature after epidural injections in control animals and in animals with a TEA and LEA, respectively. The increase in skin temperature measured 30 min after epidural injection is presented as a mirrored bar plot. The vertebral column is indicated on the left side to represent all dermatomes from C4 (top) to L6 (bottom). An increase in skin temperature at a particular vertebral level is displayed as a mirror bar according to the scale indicated on top of the figure for each group separately. A temperature increase of .0.58C was considered to indicate an effective block of the sympathetic nervous system at that particular level.
Parameter
Group
Baseline Mean (SEM)
EDA Mean (SEM)
PA occlusion Mean (SEM)
HR (beats min21)
C T L C T L C T L C T L C T L C T L C T L C T L C T L C T L
97 (8) 98 (7) 86 (5) 3.0 (0.38) 2.9 (0.22) 2.7 (0.18) 105 (2) 111 (5) 112 (3) 2774 (314) 2873 (114) 3205 (195) 0.72 (0.13) 0.77 (0.09) 0.68 (0.09) 23 (4) 20 (3) 21 (3) 0.41 (0.04) 0.49 (0.07) 0.55 (0.10) 1.75 (0.12) 1.95 (0.10) 1.84 (0.09) 1.93 (0.25) 2.10 (0.25) 1.92 (0.16) 11.00 (1.13) 10.68 (0.89) 10.06 (0.75)
97 (8) 93 (5) 101 (5)* 3.1 (0.4) 2.8 (0.4) 3.1 (0.3) 105 (3) 90 (5)* 78 (7)*,‡ 2658 (243) 2600 (295) 1812 (192)*,‡ 0.68 (0.11) 0.66 (0.09) 0.68 (0.13) 22 (5) 21 (4) 22 (5) 0.47 (0.05) 0.43 (0.06) 0.52 (0.07) 1.87 (0.15) 1.90 (0.14) 1.97 (0.11) 2.34 (0.41) 1.27 (0.22)*,‡ 1.97 (0.17) 11.78 (1.26) 7.79 (0.58)*,‡ 11.11 (0.80)
120 (7)*,† 97 (4)‡ 115 (4)*,† 2.9 (0.3) 1.9 (0.3)*,†,‡ 2.7 (0.3) 97 (4)*,† 75 (7)*,†,‡ 72 (8)*,‡ 2518 (159) 2895 (426) 1851 (165)*,‡ 1.63 (0.26)*,† 1.91 (0.20)*,† 2.13 (0.29)*,† 41 (8)*,† 44 (9)*,† 50 (6)*,† 0.92 (0.08)*,† 0.55 (0.06)‡ 1.05 (0.22)*,† 2.90 (0.23)*,† 1.86 (0.23)‡ 2.92 (0.20)*,† 2.32 (0.37) 1.30 (0.19)*,‡ 2.07 (0.39) 10.92 (1.09) 7.27 (0.72)*,‡ 11.33 (0.92)
CO (litre min
21
)
MAP (mm Hg) SVR (dyne s cm25) PA-Ea (mm Hg ml21)
Peak RVP (mm Hg) RV Ees (mm Hg ml21) RV Mw (mW s ml21) LV Ees (mm Hg ml21)
LV Mw (mW s ml
21
)
Effects of an acute increase in right ventricular afterload A three-fold increase in PA-Ea by gradual inflation of the pulmonary intra-arterial balloon was successfully obtained in all three groups (Table 1). In control animals, this manoeuvre resulted in an increase in HR and right ventricular contractility [Mw from 1.9 (0.1) to 2.9 (0.2) mW s ml21] whereas left
F-value
P-value
6.4014
0.0008
4.2194
0.0079
7.3340
0.0003
6.3666
0.0008
1.6857
0.1793
1.8802
0.1398
2.7645
0.0467
8.5831
0.0001
4.616
0.0050
8.2110
0.0001
ventricular contractility did not change (Fig. 2). There was a mild decrease in MAP (Table 1). Animals treated with LEA reacted with a lower SVR and MAP but a similar increase in HR and right ventricular contractility when compared with control animals (Table 1, Fig. 2). In contrast, animals pretreated with a TEA did not show an increase in HR and right ventricular contractility after
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Table 1 Ventricular function and general haemodynamics in control animals and animals with a TEA and LEA during baseline, after epidural injection, and after PA occlusion. Values are represented as mean (SEM). EDA, epidural anaesthesia; C, control animals; T, thoracic epidural anaesthesia; L, lumbar epidural anaesthesia; HR, heart rate; CO, cardiac output; MAP, mean arterial pressure; SVR, systemic vascular resistance; PA-Ea, effective pulmonary arterial elastance; RVP, right ventricular pressure; RV, right ventricle; LV, left ventricle; Ees, slope of the ESPVR; Mw, slope of the PRSW relationship; *P,0.05 vs baseline; † P,0.05 vs EDA; ‡P,0.05 vs C. F- and P-values refer to the interaction effect between time and treatment. Bold entries indicate statistically significant difference (defined as P,0.05)
Epidural anaesthesia and acute right ventricular pressure overload
A
3.5 RV Mw (mW s ml–1)
LV Mw (mW s ml–1)
14
12
10
8
F : 8.2110 P : 0.0001 C TEA LEA
6 0
Baseline
*‡
2.5
F : 8.5831 P : 0.0001
2.0
EDA
Baseline
RV Ees (mm Hg ml–1)
2.5 2.0 F : 4.6160 P : 0.0050 *‡
‡
PA occlusion 1.4
C TEA LEA
*†*†
1.2 1.0
EDA
D C TEA LEA
*†
*†
F : 2.7645 P : 0.0467
0.8 0.6 ‡
0.4
*‡
0.0
PA occlusion
0.0 Baseline
EDA
PA occlusion
Baseline
EDA
PA occlusion
Fig 2 Right and left ventricular contractility during baseline, epidural anaesthesia, and acute PA occlusion in control animals and animals with a thoracic or lumbar epidural anaesthesia. The effects of epidural anaesthesia on the slope of the preload-recruitable stroke work relationship (Mw) (A and B) and the slope of the end-systolic pressure– volume relationship (Ees) (C and D) during baseline, epidural anaesthesia (EDA), and during acute PA occlusion (PA occlusion) in the left (LV) and right ventricle (RV). Values are presented as mean (SEM). C, control animals; TEA, thoracic epidural anaesthesia; LEA, lumbar epidural anaesthesia; Ees, slope of the ESPVR; Mw, slope of the PRSW relationship; PA, pulmonary artery. *P,0.05 vs baseline; †P,0.05 vs EDA; ‡P,0.05 vs C.
PA balloon occlusion (Table 1, Fig. 2) and suffered a pronounced decrease in MAP and CO (Table 1). Left ventricular contractility remained unchanged as in the other groups (Fig. 2). There were no significant changes in right or left ventricular volumes throughout the study.
Discussion These data show that high TEA impairs the haemodynamic response to acute mechanical right ventricular pressure overload, whereas an LEA, restricted to the lower thoracic level does not. The findings support our hypothesis that cardiac sympathetic nerves are involved in the homeostatic control of right ventricular function during pressure overload. When subjected to a partial occlusion of the PA, both control animals and those treated with selective LEA responded with an increase in right ventricular contractility and maintained cardiac output in spite of a high afterload. This positive inotropic reflex of the right ventricle was completely abolished in the TEA-treated group and these animals suffered a pronounced decrease in cardiac output.
The phenomenon of increased right ventricular contractile state in response to high afterload has been documented earlier in a variety of experimental models of acute and chronic right ventricular pressure overload and has been termed homeometric autoregulation.19 – 21 The underlying mechanisms are not clear yet but may at least partially involve activation of the sympathetic nervous system. Also in humans, even small increases in right ventricular afterload are associated with a reversible increase in sympathetic output, and patients with chronic pulmonary hypertension have been shown to have elevated sympatho-adrenergic activity which could not be fully explained by hypoxiainduced chemoreceptor activation.22 23 In a previous study, we reported that TEA directly affects the right ventricular positive inotropic response to hypoxia-induced PHT.9 However, in that study, it was difficult to exclude the potentially confounding role of arterial hypoxia on sympatho-adrenergic output and right ventricular function. More importantly, the sympatholytic effects of epidural anaesthesia extended far beyond the targeted cardiac region and caused pronounced systemic vasodilation as well. Systemic vasodilatation can have an independent detrimental effect on the pressure-overloaded
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LV Ees (mm Hg ml–1)
3.0
1.5 0.0
C
1.0
C TEA LEA
*‡
3.0
1.5
B
Missant et al.
of epidural anaesthesia in this risk group. In addition, our findings may provide a clue in the differential diagnosis and treatment of postoperative haemodynamic instability when patients treated with TEA show signs of right ventricular dysfunction. The clinical impact of the results obtained with LEA should not be over-emphasized either and are no proof of its safety. In the controlled experimental setting of this study, preload changes were strictly corrected with fluids as guided by continuous monitoring of end-diastolic volumes. In addition, only a limited number of segments were blocked and the systemic hypotensive effect was rather mild. Under these conditions, LEA appeared to have minimal impact on the haemodynamic response to increased right ventricular afterload. This is in agreement with the case series that have reported successful outcomes with the use of LEA in parturients with pulmonary hypertension.26 We acknowledge that our study has several limitations which should be taken into account when translating the data to a clinical context. The use of an acute mechanical obstruction as a model for right ventricular pressure overload has limited direct clinical correlates except perhaps for the unique condition when a PA is partially clamped during extensive lung surgery. As explained earlier, our technique was chosen for methodological reasons, that is, to eliminate confounding factors such as arterial hypoxia or concomitant changes in pulmonary vascular tone. In the closed-chest animal model, this was best obtained with an intravascular balloon occluder. General anaesthesia was used in all animals and undoubtedly also affected the cardiovascular responses under investigation. However, TEA is mostly used as an adjunct to general anaesthesia and all groups received the same anaesthetic regimen simulating contemporary clinical anaesthesia practice. Although we used propofol instead of barbiturates, this is probably not the reason why baseline cardiac outputs were lower than in our previous study. Major differences in the invasiveness and surgical stress between closed- and open-chest preparations are more likely to explain this finding. We restricted the number of repetitive haemodynamic measurements to the absolute minimum. The reported time points were carefully selected to be best representative for each intervention at steady state. This strategy was preferred over more frequent data sampling primarily because the IVC occlusions which are required to assess PV loop-derived contractility indices tend to destabilize the cardiovascular system during critical right ventricular pressure overload. In conclusion, in a closed-chest animal model of acute right ventricular pressure overload, a selective TEA abolished the inotropic response to an acute increase in right ventricular afterload and aggravated the haemodynamic consequences, whereas a selective LEA only reduced SVR without detrimental effects on right ventricular contractility.
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right ventricle by reducing coronary perfusion and disrupting parallel ventricular interaction.24 In the present study, we intended to avoid such problems by (i) using a controlled mechanical obstruction of the PA to produce right ventricular overload and (ii) subjecting separate experimental groups to either a selective high thoracic or selective LEA to differentiate the cardiac from the vascular sympatholytic effects on right ventricular function. Pilot studies in our lab had indicated that only bupivacaine 0.5% (1 ml) was required to cause a sympathetic block extending from T1 to T6, that is, the area containing all cardiac sympathetic efferents in pigs.25 Interestingly, this dose is only one-seventh of the dose used in our previous paper, yet in the present study was sufficient to completely abolish the right ventricular inotropic response to mechanically induced pressure overload. Importantly, selective cardiac sympathetic denervation severely compromised right ventricular contractile function during pulmonary hypertension, but had no effect on SVR. In contrast, LEA for which bupivacaine 0.5% (4 ml) was needed to block a similar number of segments caused a significant decrease in SVR but did not affect the cardiac response to PA occlusion. This observation, in our opinion, leaves little doubt that cardiac sympathetic denervation was the primary cause of impaired tolerance to right ventricular pressure overload in the present study. In theory, a reduced baseline performance of the left ventricle caused by cardiac autonomic denervation could also interfere with the right ventricle’s capacity to overcome pressure overload. In fact, right ventricular function and pressure development partly rely on left ventricular pressure development in normal conditions.5 However, the following observations suggest that this was not a primary mechanism in our study: first, in the absence of pressure overload, left ventricular function decreased significantly after TEA but had no effect on right ventricular contractility. Secondly, in animals without TEA, there was no increase in left ventricular function when right ventricular afterload was raised, still, right ventricular contractility increased significantly. These observations suggest that the changes in right ventricular contractility were site-specific rather than secondary to ventricular interdependence. The exact mechanisms underlying the differential regulation of right and left ventricular contractility are not clear yet but, as discussed earlier, differences in sympathetic and parasympathetic innervation of both ventricles have been reported earlier.9 The clinical relevance of our observation remains to be demonstrated, however, and the data should not be considered as arguments against the use of an excellent analgesic technique like TEA. Instead, they suggest that a subgroup of patients at risk for acute right ventricular pressure overload may be at increased risk for cardiovascular collapse when neuroaxial anaesthesia extends to the cardiac sympathetic nerves. Awareness about this potential interaction could help clinicians optimize the application
Epidural anaesthesia and acute right ventricular pressure overload
Funding Supported by the Research Grant Programme of the European Society of Anaesthesiology and the Belgian Society of Anaesthesia and Resuscitation (P.F.W.). C.M. receives a PhD fellowship from the Fund of Scientific Research (FWO) Flanders, Belgium. S.R. was supported by the Medical Faculty of the RWTH Aachen, Germany.
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