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EFFECTS OF LIGNOCAINE AND BUPIVACAINE ON REGIONAL MYOCARDIAL FUNCTION AND CORONARY BLOOD FLOW IN ANAESTHETIZED DOGS
Br. J. Anaesth. (1988), 60, 671-679
EFFECTS OF LIGNOCAINE AND BUPIVACAINE ON REGIONAL MYOCARDIAL FUNCTION AND CORONARY BLOOD FLOW IN ANAESTHETIZED DOGS B. J. LEONE, J. J. LEHOT, W. B. RUNCIMAN, R. N. WELDING, J. G. RAMSAY, C. C. ARVIEUX, W. A. RYDER AND P. FOEX
B.J.LEONE, M.D.; J. J. LEHOT,* M.D.; W. B. RUNCIMAN,+ B.SC.(MED.), M.B. B.CH., PH.D., F.F.A.R.A.C.S. J R. N . WELDING; J. G. RAMSAY,^ B.SC, M.D., F.R.C.P.(C); C. C. ARVIEUX,§ M.D.; W.A.RYDER; P. FOEX, M.D., D.PHIL., F.F.A.R.C.S. Nuffield
Department of Anaesthetics, The Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE. Accepted for Publication: November 12, 1987. Present addresses: * Departement d'Anesthesie-Reanimation, Hopital Cardiovasculaire et Pneumologique L. Pradel, B.P. LyonMontchat, 69394 Lyon Cedex 3, France. t Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia. X Royal Victoria Hospital, Department of Anaesthesia, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. § Departement d'Anesthesie-Reanimation, Centre Hospitalier Universitaire de Grenoble, 38700 La Tronche, France.
SUMMARY Empirical i. v. doses of lignocaine or bupivacaine of equal local anaesthetic potency were administered to halothane-anaesthetized dogs. Both local anaesthetics caused the expected depression of global haemodynamic function. Regional myocardial systolic shortening was depressed similarly by both agents. Regional myocardial dysfunction, seen as post-systolic shortening, occurred to a similar extent with both lignocaine and bupivacaine. Coronary blood flow and coronary perfusion pressure were significantly correlated during the administration of lignocaine; bupivacaine had erratic effects on coronary blood flow and no correlation between coronary blood flow and coronary perfusion pressure was seen. These results suggest that regional myocardial dysfunction occurs with both local anaesthetics and does not account for the apparent increased cardiotoxicity of bupivacaine. Bupivacaine did. however, cause wider individual variations compared with lignocaine with respect to coronary blood flow.
the occurrence of asynchronous left ventricular wall motion could be related to the cardiotoxicity of the local anaesthetics. MATERIAL AND METHODS
Twelve mongrel dogs (wt 17-33 kg) were premedicated with morphine sulphate 0.1 mg kg"1 and anaesthesia was induced with thiopentone 7 mg kg"1. After intubation of the trachea, positive pressure ventilation was instituted at a rate of 12 b.p.m. and the tidal volume adjusted to maintain normocarbia, as measured by end-tidal infra-red analysis. Halothane (1.2 % inspired) was
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Lignocaine and bupivacaine are used widely in association with techniques of extradural regional anaesthesia and i.v. regional anaesthesia [1,2]. However, after reports of severe cardiotoxicity associated with the apparent i.v. injection of bupivacaine [3,4], several investigators have reported that bupivacaine is more cardiotoxic than lignocaine [5-7], whereas others have not [8]. Regional myocardial function is a sensitive indicator of myocardial ischaemia [9]. For example, we have reported that the combination of volatile anaesthetics and the calcium channel blocker, verapamil, caused regional myocardial dysfunction (seen as post-systolic shortening (PSS)) in myocardium with normal coronary arteries [10,11]. As local anaesthetics alter sodium conductance and may disrupt calcium fluxes [1], we wondered whether the administration of lignocaine or bupivacaine i.v. would cause regional myocardial dysfunction, similar to that seen with verapamil, in the presence of a normal coronary circulation. We also examined whether
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The techniques of ultrasonic sonomicrometry have been described previously [12-14]. Briefly, as ultrasound travels at a constant speed of 1.56 mm us"1 through cardiac tissue, continuous measurement of myocardial segment length can be obtained. After completion of the surgery the preparation was allowed to stabilize for 1 h. During this time, arterial blood-gas tensions were determined and any required changes in ventilation or corrections to acid-base balance undertaken. Instruments were calibrated and left ventricular end-diastolic pressure (LVEDP) measured. Dextran 70 (average mol. wt 70000 daltons) was given as necessary to maintain an LVEDP of 5 mm Hg. A 30-min period following any intervention elapsed before the beginning of the definitive investigation. Experimental programme
To examine the effects of lignocaine or bupivacaine, the dogs were randomly allocated to one of two groups. Group 1 received i.v. injections of lignocaine and group 2 i.v. bupivacaine. The doses of both local anaesthetic agents used encompass the body weight normalized range for human anaesthesia. Doses were not scaled to individual body weights within this range as body weight has been shown to be a poor predictor of local anaesthetic blood concentration [15]. The initial dose of lignocaine was 50 mg, and each subsequent dose was twice the preceding dose, yielding doses of 50 mg, 100 mg and 200 mg for the three injections given. Likewise, each dose of bupivacaine was twice the previous dose, after an initial injection of 12.5 mg to compensate for the fourfold greater anaesthetic potency of bupivacaine compared with lignocaine. This schedule yielded bupivacaine doses of 12.5 mg, 25 mg and 50 mg for the three injections. Before the first dose, a baseline set of measurements was recorded. To allow equilibration of drugs between heart and brain, samples for measurements of blood concentrations of drugs were taken 10 min after each injection. After the recording of data was complete, the next dose of local anaesthetic was administered. Computation At the conclusion of the study the LAD was cannulated and calibration of the LAD flow probe performed by injecting 5-ml aliquots of blood
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used to maintain anaesthesia throughout the study. A heating element incorporated into the operating table maintained body temperature between 36 and 38 °C, as measured by an oesophageal temperature probe. The animal was placed in the right lateral decubitus position and a catheter inserted, via the femoral vein, into the inferior vena cava. An infusion of Hartmann's solution was started at a rate of 4 ml kg"1 h"1. The left common carotid artery was exposed, and a stiff 8-French gauge (2.76 mm o.d.) cannula was inserted and advanced to within 1 cm of the aortic valve. This cannula was connected to a calibrated pressure transducer (Druck Ltd, Groby, Leicester, U.K.) for the measurement of systemic pressures and was also used for blood sampling. Lead II of the electrocardiogram was monitored throughout the experimental procedure. A left thoracotomy was performed and the 4th and 5th ribs excised. The pericardium was opened and the aortic root dissected free of its fat pad. An appropriately-sized electromagnetic flow probe (Transflow 601, Skalar Medical, Delft, Holland) was placed around the aortic root for flow measurement. A stiff 8-French gauge (2.76 mm o.d.) cannula was inserted via the apical dimple into the left ventricle and attached to a calibrated pressure transducer (Druck Ltd, Groby, Leicester, U.K.) to obtain measurements of left ventricular pressure. A cannula was placed in the pulmonary artery via the pulmonary outflow tract to permit measurement of cardiac output (indocyanine green). The left anterior descending coronary artery (LAD) was dissected free of the epicardium. Measurements of coronary blood flow were obtained using a 2-mm electromagnetic flow probe (Transflow 601, Skalar Medical, Delft, Holland) placed around the artery. An occluding snare was placed just distal to the flow probe to allow determinations of zero flow. Measurements of myocardial segment length were obtained using three pairs of piezo-electric crystals inserted to the subendocardium of the apex, mid-wall and base of the heart. The apical tissue was supplied by the LAD and the basal region by the left circumflex coronary artery (LC). Data on myocardial segment length were, therefore, recorded from left ventricular tissue in territory supplied by the LAD (LAD segment), in the mid-wall area (INT segment), and in territory supplied by the LC (LC segment).
BRITISH JOURNAL OF ANAESTHESIA
LIGNOCAINE, BUPIVACAINE AND REGIONAL MYOCARDIAL FUNCTION
DAP and LVEDP. Cardiac output (CO) was determined from heart rate (HR) and stroke volume obtained from the aortic flowmeter. Dye dilution curves using indocyanine green were performed to calibrate the aortic flowmeter. PR interval was determined from lead II of the electrocardiogram. Percentage changes from baseline values were determined for CPP, CBF, SAP, LV dP/drmax and CO, with baseline values normalized to 100%. Regional function was examined by calculating systolic shortening and post-systolic shortening. Systolic shortening (SS) was defined as EDL minus ESL, and expressed as a percentage of EDL to compensate for preload-induced changes in performance. Post-systolic shortening (PSS) was defined as the difference between ESL and the minimum segment length measured during diastole. This was expressed as a percentage of total segmental shortening to compensate for changes in inotropy. EDL was normalized to a baseline value of 10.0 mm to adjust for differences in absolute intercrystal distances between animals resulting from initial placement [14]. Results were analysed for statistical significance using two-way analysis of variance and Duncan's test. However, some variables, notably PSS, exhibited skewed distributions and were analysed by the non-parametric Friedman two-way analysis of variance and sign test, as appropriate. Unpaired Student's t tests were used for comparisons of normalized values between lignocaine and bupivacaine. Linear regression was performed on normalized CPP, CBF and regional function data. In all cases, P < 0.05 was considered significant.
TABLE I. Global haemodynamic data (mean± SEM) during baseline conditions and after administration of lignocaine 50 mg, 100 mg and 200 mg. *P<0.05 v. baseline by two-way analysis of variance and Duncan's multiple range lest, + P < 0.05 v. baseline by Friedman two-way analysis of variance and sign test
HR (beat mirr1) SAP (mm Hg) LVEDP (mm Hg) CPP (mm Hg) LV dP/d, max (mm Hg s"1) CO (litre min"1) SVR (dyn s cm"5) CBF (n = 5) (ml 100 g"1 mirr1) PR interval (ms)
Baseline
50 mg
100 mg
200 mg
99±5 106 ±6 6.5 + 0.7 73±5 1260±110
108 ±4 90 + 5* 7.8 ±0.8 63 ±3* 890 ±90*
106 ±6 77 + 4* 10.0±0.9* 48 ±4* 660 ±70*
104 ±6 54 ±5* 10.0 + 0.4* 29 ±4* 410±40*
1.97±0.14 3725 ±440 30.4 + 6.7
1.66±0.10* 3815±350 26.5 ±5.6
1.25±0.13* 4270 + 310 22.9±6.2f
0.77±0.11* 4680 ±275* 11.6±7.5+
105 ±3
101±3
101+4
116 + 8*
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through the LAD cannula. After calibration, 5 ml of Evans blue was injected through the LAD cannula. The resulting area of stained myocardium, representing the territory supplied by the LAD, was separated from non-stained myocardium. The atria were removed and the stained ventricular myocardial fragments weighed, thus enabling LAD flow measurements to be normalized as mlmin"V100g of myocardium. The data were recorded as hard copy analogue signals on a Mingograf 81 (Elema Schoenander, Stockholm, Sweden). The first derivative of left ventricular pressure (LV dP/dt) was recorded, and its peak value measured (LV dP/dt max ). Aortic flow was both differentiated, to obtain aortic blood acceleration, and integrated, to obtain stroke volume. For purposes of measuring regional function, the ends of systole and diastole were defined as the first positive deflection of LV dP/dt and the first point after systole when aortic flow returned to zero, respectively. End-diastolic and end-systolic lengths (EDL, ESL, respectively) were measured using a paper speed of 250 mm s"1 to ensure accurate determinations of end-systole and end-diastole. Data from the hard copy recordings were digitized manually. These were then analysed on a VAX computer using SAS, a commercially available statistical analysis programme (SAS, Inc, Cary, N.C., U.S.A.). Mean arterial pressure (MAP) was calculated from the systolic and diastolic systemic arterial pressures (SAP, DAP, respectively). Coronary perfusion pressure (CPP) was calculated in the conventional manner as the difference between
673
BRITISH JOURNAL OF ANAESTHESIA
674
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120
100
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dose 1
Lignocaine
A
dose 2
The global haemodynamic data are presented in table I. Heart rate did not change as the dose of lignocaine increased. However, after each dose, SAP, CPP, CO and LV dP/drmax decreased significantly. CBF decreased significantly at the two higher doses of lignocaine. PR interval increased significantly after the third dose of lignocaine. The average plasma drug concentrations were: 1.13 + 0.09 ug ml"1 (w = 6) after dose 1, 2.89±0.17 \ig ml"1 {n = 5) after dose 2, and 6.92+1.08 ug ml"1 (w = 6) after dose 3. The normalized CPP and CBF values were compared using linear regression and a significant correlation was shown between the two variables (r = 0.95, d f = 4 , P < 0.01). The slope of the resultant regression line was 1.06 + 0.07 (fig. 1). Data on regional function are shown in table II. Lignocaine caused a significant increase in EDL after the initial dose in the LC segment and significant increases in EDL with the second and third doses in all three myocardial segments. SS was significantly decreased with each dose of lignocaine in all three segments. Significant increases in PSS were apparent in the LAD territory after the second and third doses of lignocaine. Increases in PSS in the intermediate and LC segments achieved statistical significance only after the second dose. Global haemodynamic and regional function data were normalized and expressed as a percentage of baseline values. Normalized CBF
A O dose
0 D
-
1 If
-
60
-
Z 40 >•
-
tr
ironar
TJ O
20
3
/
[
w 6 0.95 P<0.01
.3 0
I
t
t
20 40 60 80 100 120 Coronary perfusion pressure (% of baseline)
FIG. 1. Comparison between coronary blood flow (CBF) and coronary perfusion pressure (CPP) during baseline conditions and after three doses of lignocaine in five dogs. Data for CBF and CPP were normalized to baseline values of 100%. Each symbol represents results from an individual dog; the degree of shading indicates the lignocaine dose.
RESULTS
CBF measurements were performed in five dogs in both the lignocaine and bupivacaine groups. All other data for each local anaesthetic are from six dogs.
TABLE II. Regional myocardial function data (mean+ S EM) during baseline conditions and after administration of lignocaine 50 mg, 100 mg and 200 mg. * P < 0.05 v. baseline by two-way analysis of variance and Duncan's test. + P < 0.05 v. baseline by Friedman two-way analysis of variance and sign test
Baseline
50 mg
100 mg
200 mg
10.0 ±0.0
10.3±0.0
10.5 ±0.2*
10.5±0.2*
20.2 ±2.2 4.6±2.3
13.4±2.5* 23.5 ±10.6
10.6 ±2.0* 29.0±10.5f
9.4 ±1.0* 25.2 ±6.4+
10.0 ±0.0
10.2 + 0.1
10.5±0.2*
10.7 ±0.2*
14.4±2.0 8.7 ±4.7
10.8± 1.8* 13.1 ±5.9
8.6± 1.5* 24.9 ±8.9
7.8+1.2* 28.3± 11.7
10.0 ±0.0
10.2±0.1*
10.6 ±0.6*
10.8±0.2*
13.2 + 1.9 14.9 ±5.4
9.6+1.7* 24.1 ±4.6
7.2±1.3* 33.6 ±7.4+
6.3±0.8* 20.2 ±6.0
LAD
EDL (mm) (normalized) SS (%) PSS (%) INT
EDL (mm) (normalized) SS (° o ) PSS (° o ) LC EDL (mm) (normalized) SS («„) PSS (»„)
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• •
LIGNOCAINE, BUPIVACAINE AND REGIONAL MYOCARDIAL FUNCTION 120 100-
120
675
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basel ine)
80-
-if) 60
o
200 0
20
40
60
80
100
120
Coronary blood flow C/.of baseline)
FIG. 2. Comparison between normalized coronary blood flow and absolute PSS values during baseline conditions and after three doses of lignocaine ( • ) or three doses of bupivacaine (O)- Data were obtained from five dogs. No significant correlation was found (lignocaine: r = 0.5, df = 16, ns; bupivacaine: r = 0.36, df = 16, ns).
and normalized SS were tested for correlation and no significant relationship was found. Similarly, PSS was not significantly correlated with normalized CBF (fig. 2). Bupivacaine Table III shows the global haemodynamic data. The administration of bupivacaine did not alter heart rate significantly. The initial dose of bupivacaine did not result in any changes in SAP, CPP and CO, but the subsequent doses caused significant decreases in these variables. LV dP/dt m a x , however, decreased significantly with each dose. CBF was decreased significantly at the two higher doses of bupivacaine. Owing to
80
60
40
20
j
20
40
60
80
100
Coronary perfusion pressure (% of baseline) FIG. 3. Comparison between coronary blood flow (CBF) and coronary perfusion pressure (CPP) during baseline conditions and after three doses of bupivacaine in five dogs. Data for CBF and CPP were normalized to baseline values of 100%. Each symbol represents results from an individual dog; the degree of shading indicates the bupivacaine dose.
difficulties with storage and analysis of blood samples, several plasma bupivacaine concentrations were not determined. The average plasma drug concentrations were: 0.49 + 0.07 ugml" 1 (w = 4) after dose 1, 0.68 + 0.09 ug ml" 1 (« = 6) after dose 2, and 1.22 + 0.23 ug ml" 1 (n = 3) after dose 3. PR interval was significantly increased after the second and third doses of bupivacaine. The normalized CPP and CBF values were
TABLE III. Global haemodynamic data (mean±SEAT) during baseline conditions and after administration of bupivacaine 12.5 mg, 25 mg and 50 mg. * P < 0.05 v. baseline by two-way analysis of variance and Duncan's multiple range test. + P < 0.05 v. baseline by Friedman two-way analysis of variance and sign test
HR (beat min"1) SAP (mm Hg) LVEDP (mm Hg) CPP (mm Hg) LV dP/dtmax (mm Hg s"1) CO (litre min"1) SVR (dyn s cm"6) CBF (n = 5) (ml 100 g~' min"1) PR interval (ms)
120
Baseline
12.5 mg
25 mg
50 mg
123+11 105 ±5 6.3 + 0.6 73±6 1500+150
123±13 98 + 4 7.0 ±0.8 68 + 4 1240 ±140*
122±11 90 + 6* 8.3+1.1*
120±9 75 + 8* 9.7 ±1.0* 46 + 7* 680 ±90*
2.67 + 0.37 2700 + 555 29.9 + 8.8
2.37 ±0.35 3175 + 530 28.3±11.0
103 + 8
111 ±9
62 ±5*
1020 + 100* 1.96 + 0.35* 3620 + 635
20.5±8.3t
1.44 ±0.36* 4190±865 13.3±6.8f
116±8*
127+10*
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40-]
onary blood f low (
2
100
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TABLE IV. Regional myocardial function data (mean + SEAT) during baseline conditions and after administration of bupivacaine 12.5 mg, 25 mg and 50 mg. * P < 0.05 v. baseline by two-way analysis of variance and Duncan's test. •)• P < 0.05 v. baseline by Friedman two-way analysis of variance and sign test
25 mg
Baseline
12.5 mg
10.0±0.0
10.1 ±0.1
10.3±0.1*
10.4±0.1*
17.2 + 1.3 10.0 + 5.0
13.8+1.1* 24.4 ±5.3
10.1 + 1.3*
29.0±6.6f
8.4 + 1.8* 33.8±10.3f
10.0 ±0.0
10.1+0.1
10.3±0.1*
10.4±0.1*
12.5 + 2.2 5.1 ±3.8
9.5 ±2.2 23.5 + 7Af
8.2 ±1.5* 25.6±6.6f
6.5 + 1.9* 23.5 ±10.7
10.0 ±0.0
10.6±0.1*
10.3±0.1*
10.4±0.1*
10.6 + 0.8 10.3±4.1
10.2± 1.2 14.7±3.7
7.8± 1.1* 16.4±5.7
6.6 + 1.2* 23.8 ±9.9
50 mg
LAD
EDL (mm) (normalized) SS (%) PSS (%) INT
LC
EDL (mm) (normalized) SS (%) PSS (%)
100 80
100
100
11 I1 I 80
80
1/1
V
60 40 20 0
o 60
60
140
% 20
20
1
FIG. 4. The effects of lignocaine (open columns) and bupivacaine (cross-hatched columns) on three indices of global myocardial performance (SAP, LV d/'/di mox) and CO). All data were normalized to baseline values of 100%, and values obtained after local anaesthetic administration expressed as a percentage of baseline. 1 = Lignocaine 50 mg, bupivacaine 12.5 mg; 2 = lignocaine 100 mg, bupivacaine 25 mg; 3 = lignocaine 200 mg, bupivacaine 50 mg. Bars show the mean values, and error bars represent the SEM. * P < 0.05 v. baseline by two-way analysis of variance and Duncan's test; + P < 0.05 between lignocaine and bupivacaine values by unpaired Student's t test.
compared and no significant correlation was found (r = 0.34, df = 4, P > 0.1) (fig. 3). Data on regional function are presented in table IV. Bupivacaine caused an increase in EDL in the LC segment with the initial dose, and caused increases in EDL in all segments with the second and third doses. SS was decreased in the LAD territory with the first dose and further injections caused a decrease in SS in all segments. PSS increased significantly in the LAD region after the second and third doses of bupivacaine and was increased in the intermediate territory after the first and second, but not the third, dose.
No significant increase in PSS occurred in the LC segment. Normalized CBF and normalized SS values were compared and no significant correlation found. The absolute PSS values had no significant correlation with normalized CBF (fig. 2). Comparisons were made of normalized SAP, LV dP/dj max , and CO data between lignocaine and bupivacaine (fig. 4). Each dose caused a significant decrease from baseline values of each variable, except for SAP with the first bupivacaine dose. Significant differences between the local anaesthetics occurred solely in LV dP/dfmax, and
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EDL (mm) (normalized SS (%) PSS (%)
#
LIGNOCAINE, BUPIVACAINE AND REGIONAL MYOCARDIAL FUNCTION 100 ^ 60 c
I 60 X>
d 40 to
9 20
100
* T *
T
TOO
80
• T jeo S20-
1
FIG. 5. The effects of lignocaine (open columns) and bupivacaine (cross-hatched columns) on systolic shortening (SS) in the apical (LAD), mid-wall (INT), and basal (LC) regions of the left ventricle. Values are expressed as a percentage of baseline values. 1 = Lignocaine 50 mg, bupivacaine 12.5 mg; 2 = lignocaine 100 mg, bupivacaine 25 mg; 3 = lignocaine 200 mg, bupivacaine 50 mg. *P < 0.05 v. baseline by two-way analysis of variance and Duncan's test.
these differences were seen with all three doses. Normalized SS data were compared between the local anaesthetics in the myocardial territories measured. Similar depression of SS occurred in the LAD, INT, and LC segments with both local anaesthetics (fig. 5). DISCUSSION
Myocardial depression is a feature of the i.v. administration of lignocaine [16]. Laboratory investigations in awake animals, however, have shown stimulation of the cardiovascular system [17], which has been attributed to the central nervous system effects of lignocaine [8]. Bupivacaine, as well as other amide and ester local anaesthetics, is also a myocardial depressant [1,5,8,16,18]. Some investigators have reported that the degree of cardiovascular depression is related to anaesthetic potency [8], while others have suggested that bupivacaine is more cardiotoxic, especially in pregnancy and in situations of hypoxia and acidosis [6,19-21]. Many of the comparisons between lignocaine and bupivacaine have centred on the electrophysiological properties of the drugs. It now seems established that bupivacaine has a much greater, although somewhat unpredictable, potential to cause serious cardiac arrhythmias [5—7]. In the light of these apparent differences between lignocaine and bupivacaine on myocardial function, we have investigated their properties on global haemodynamics and regional wall motion in halothane-anaesthetized dogs.
This general anaesthetic eliminated the potential influence of sympathetic nervous system activation caused by local anaesthetics [17]. We chose to give a bolus of a fixed dose of local anaesthetic, rather than on a dose per kilogram basis, to mimic accidental i.v. injection into the systemic circulation during the performance of regional anaesthesia, which is commonly administered as an empirical maximum dose rather than on a milligram per kilogram basis [22]. The first two doses of both lignocaine and bupivacaine would be comparable to those used for extradural and i.v. regional anaesthesia [1]. The ranges of blood concentrations at the time they were measured encompass those that would be expected after normal regional anaesthetic procedures. Thus, although undoubtedly within the toxic range after the bolus injections, the concentrations had returned to acceptable values well before the next injection was made [15]. The significant depression of LV dP/dfmax and of regional function in all myocardial segments seen with the initial and subsequent doses of the local anaesthetics agrees with previous reports of myocardial depression with these agents [1,5,8,16]. The depression of global haemodynamics (fig. 4) and regional myocardial function (fig. 5) was similar with lignocaine and bupivacaine. It has been reported that PSS occurs in myocardium with compromised blood flow as the halothane concentration is increased [23]. PSS has also recently been observed in normal myocardium with normal coronary blood supply
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channel blocking properties of these local anaesthetics, as an enhancement of the cardiodepressant effects of bupivacaine has been shown with nifedipine [26] and verapamil [27]. PSS may be a measure of altered contractile performance, possibly as a result of changes in myocardial membrane ion conductance, myocardial metabolism, or local subendocardial blood flow, induced by lignocaine and bupivacaine. In summary, the i.v. administration of lignocaine or bupivacaine caused similar depression of global haemodynamics and regional myocardial function and the appearance of regional left ventricular asynchronous wall function (PSS). There was no relationship between PSS and CBF for either drug, and both drugs caused similar degrees of regional dysfunction, suggesting that regional contractile abnormalities are not the cause of the apparently increased cardiotoxicity of bupivacaine compared with lignocaine. The erratic effect of bupivacaine on CBF may result from changes in coronary vascular resistance; lignocaine, by comparison, exhibited more predictable CBF responses to i.v. injections. ACKNOWLEDGEMENTS This work was supported in part by Medical Research Council grants G8002204SA and G8306850SA. J. J. Lehot was the recipient of an MRC/INSERM fellowship and J. G. Ramsay a McLaughlin Travelling fellowship (Canada). W. B. Runciman was the recipient of a Wellcome-Ramaciotti Research Travel Grant; some equipment was provided by the Flinders Medical Centre Research Foundation. We thank Dr G. T. Tucker of Sheffield University, who arranged the assays of lignocaine and bupivacaine. We are also grateful for Dr L. E. Mather's thoughtful review of this manuscript. REFERENCES 1. Covino BG, Vassallo HG. Local Anesthetics: Mechanisms of Action and Clinical Use. New York: Grune and Stratum, 1979. 2. Gooding JM, Tavakoli MM, Fitzpatrick WD, Bagley JN. Bupivacaine: preferred agent for intravenous regional anesthesia? Southern Medical Journal 1981; 74: 1282-1283. 3. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 1979; 51: 285-287. 4. Ryan DW. Accidental intravenous injection of bupivacaine: a complication of obstetrical epidural anaesthesia. British Journal of Anaesthesia 1973; 45: 907-908. 5. de Jong RH, Ronfeld RA, DeRosa RA. Cardiovascular effects of convulsant and supraconvulsant doses of amide local anesthetics. Anesthesia and Analgesia 1982; 61: 3-9.
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when verapamil was administered i.v. in combination with halothane [10,11]. As lignocaine and bupivacaine are sodium channel blockers, and may disturb calcium conductance, we performed the present study to determine if there was an interaction between these local anaesthetics and halothane producing regional dysfunction. PSS in the LAD region increased after the initial dose of bupivacaine and lignocaine, and this increase became significant after the second and third doses. Bupivacaine caused a significant increase in PSS after the initial dose in the INT region, but did not affect the LC region. Lignocaine caused an insignificant increase in PSS after each dose in the INT region, and significant regional dysfunction was present only after the second dose in the LC region. Thus regional dysfunction does occur with both lignocaine and bupivacaine, yet bupivacaine causes changes in the apex and mid-wall regions of the left ventricle, while lignocaine seems to cause predominantly apical dysfunction. Bupivacaine differed from lignocaine in respect of effects on PR interval. There was a significant increase in PR interval after the second dose of bupivacaine, whereas lignocaine significantly slowed atrioventricular conduction only at the highest dose. This agrees with previous work suggesting that bupivacaine has a greater effect on myocardial conduction than lignocaine [5]. Lignocaine caused a reduction in CBF which was closely related to the reduction in CPP (fig. 1). Bupivacaine, however, had erratic effects on CBF when compared with those on CPP (fig. 3). This suggests differing effects on coronary conductance by these two agents. Both lignocaine and bupivacaine have been shown to be arteriolar constrictors in moderate doses [24,25], but the results of this study imply different properties with respect to the intact coronary vasculature. The effects of bupivacaine on CBF showed a wide scatter and suggest that, even widi high CPP values, CBF is changed unpredictably and may be decreased precipitously. The absolute values for PSS did not correlate with changes in CBF with either local anaesthetic (fig. 2). This suggests that the changes seen in PSS may result from an interaction between the local anaesthetics and myocardial cellular function rather than from alterations in regional blood supply, although redistribution of local blood flow and myocardial metabolic function were not examined. This may be related to the calcium
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17. 18. 19. 20.
21. 22. 23.
24. 25. 26.
27.
Woods EF. Effect of local anesthetics on the cardiovascular system of the dog. Anesthesiology 1963; 24: 620-624. Kao F, Jalar U. The central action of lignocaine and its effect on cardiac output. British Journal of Pharmacology 1959; 14: 522-526. Feldman HS, Covino BM, Sage DJ. Direct chronotropic and inotropic effects of local anesthetic agents in isolated guinea pig atria. Regional Anesthesia 1982; 7: 149-156. Marx GF. Cardiotoxicity of local anesthetics—the plot thickens. Anesthesiology 1984; 60: 3-5. Morishima HO, Pederson H, Finster M, Tsuji A, Hiroaka H, Feldman HS, Arthur GR, Covino BG. Is bupivacaine more cardiotoxic than lidocaine? (abstract). Anesthesiology 1983; 59: A409. Moore DC, Crawford RD, Scurlock JE. Severe hypoxia and acidosis following local anesthetic-induced convulsions. Anesthesiology 1980; 53: 259-260. Mather LE, Cousins MJ. Local anaesthetics and their current clinical use. Drugs 1979; 18: 185-205. Lowenstein E, Foex P, Francis CM, Davies WL, Yusuf S, Ryder WA. Regional ischemic ventricular dysfunction in myocardium supplied by a narrowed coronary artery with increasing halothane concentration in the dog. Anesthesiology 1981; 55: 349-359. Johns RA, DiFazio CA, Longnecker DE. Lidocaine constricts or dilates rat arterioles in a dose-dependent manner. Anesthesiology 1985; 62: 141-144. Johns RA, Seyede WC, DiFazio CA, Longnecker DE. Bupivacaine causes dose-dependent arteriolar constriction. Anesthesiology 1985; 63: A226. Howie MB, Candler E, Mortimer W, Silver M, Frolicher D, McSweeney T. Does nifedipine enhance the cardiovascular toxicity of bupivacaine? Anesthesiology 1985; 63: A225. Edouard A, Froidevaux R, Berdeaux A, Ahmad R, Samii K, Noviant Y. Bupivacaine accentuates the cardiovascular depressant effects of verapamil in conscious dogs. European Journal
249-259.
of Anaesthesiology
1987; 4:
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6. Tanz RD, Heskett T, Loehning RW, Fairfax CA. Comparative cardiotoxicity of bupivacaine and lidocaine in the isolated perfused mammalian heart. Anesthesia and Analgesia 1984; 64: 549-556. 7. Kotelko DM, Shnider SM, Dailey PA, Brizgus RV, Levinson G, Shapiro WA, Koilke M, Rosen MA. Bupivacaine-induced cardiac arrhythmias in sheep. Anesthesiology 1984; 60: 10-18. 8. Liu P, Feldman HS, Covino BM, Giasi R, Covino BJ. Acute cardiovascular toxicity of intravenous amide local anesthetics in anesthetized dogs. Anesthesia and Analgesia 1982; 61: 317-322. 9. Doyle RL, Foex P, Ryder WA, Jones LA. Differences in ischaemic dysfunction following gradual vs. abrupt coronary occlusion: effects on isovolumic relaxation. Cardiovascular Research 1987; 21: 507-514. 10. Ramsay JG, Cutfield GR, Francis CM, Devlin WH, Foex P. Halothane-verapamil causes regional myocardial dysfunction in the dog. British Journal of Anaesthesia 1986; 58: 321-326. 11. Lehot JJ, Leone BJ, Foex P. Calcium reverses global and regional myocardial dysfunction caused by the combination of verapamil and halo thane. Acta Anaesthesiologica Scandinavica 1987; 31: 441^48. 12. Bugge-Asperheim B, Leraand S, Kiil F. Local dimension changes of the myocardium measured by ultrasonic technique. Scandinavian Journal of Clinical and Laboratory Investigation 1969; 24: 361-371. 13. Hagl S, Hemisch W, Meisner H, Erben R, Baum M, Mendler N. The effect of hemodilution on regional myocardial function in the presence of coronary stenosis. Basic Research in Cardiology 1977; 72: 344-364. 14. Theroux P, Franklin D, Ross J jr, Kemper WS. Regional myocardial function during acute coronary artery occlusion and its modification by pharmacologic agents in the dog. Circulation Research 1974; 35: 896-908. 15. Tucker GT, Mather LE. Clinical pharmacokinetics of local anaesthetics. Clinical Pharmcokinetics 1979; 4: 241-278. 16. Stewart DM, Rogers WP, Mahaffey JE, Witherspoon S,
679
EFFECTS OF LIGNOCAINE AND BUPIVACAINE ON REGIONAL MYOCARDIAL FUNCTION AND CORONARY BLOOD FLOW IN ANAESTHETIZED DOGS B. J. LEONE, J. J. LEHOT, W. B. RUNCIMAN, R. N. WELDING, J. G. RAMSAY, C. C. ARVIEUX, W. A. RYDER AND P. FOEX
B.J.LEONE, M.D.; J. J. LEHOT,* M.D.; W. B. RUNCIMAN,+ B.SC.(MED.), M.B. B.CH., PH.D., F.F.A.R.A.C.S. J R. N . WELDING; J. G. RAMSAY,^ B.SC, M.D., F.R.C.P.(C); C. C. ARVIEUX,§ M.D.; W.A.RYDER; P. FOEX, M.D., D.PHIL., F.F.A.R.C.S. Nuffield
Department of Anaesthetics, The Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE. Accepted for Publication: November 12, 1987. Present addresses: * Departement d'Anesthesie-Reanimation, Hopital Cardiovasculaire et Pneumologique L. Pradel, B.P. LyonMontchat, 69394 Lyon Cedex 3, France. t Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia. X Royal Victoria Hospital, Department of Anaesthesia, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. § Departement d'Anesthesie-Reanimation, Centre Hospitalier Universitaire de Grenoble, 38700 La Tronche, France.
SUMMARY Empirical i. v. doses of lignocaine or bupivacaine of equal local anaesthetic potency were administered to halothane-anaesthetized dogs. Both local anaesthetics caused the expected depression of global haemodynamic function. Regional myocardial systolic shortening was depressed similarly by both agents. Regional myocardial dysfunction, seen as post-systolic shortening, occurred to a similar extent with both lignocaine and bupivacaine. Coronary blood flow and coronary perfusion pressure were significantly correlated during the administration of lignocaine; bupivacaine had erratic effects on coronary blood flow and no correlation between coronary blood flow and coronary perfusion pressure was seen. These results suggest that regional myocardial dysfunction occurs with both local anaesthetics and does not account for the apparent increased cardiotoxicity of bupivacaine. Bupivacaine did. however, cause wider individual variations compared with lignocaine with respect to coronary blood flow.
the occurrence of asynchronous left ventricular wall motion could be related to the cardiotoxicity of the local anaesthetics. MATERIAL AND METHODS
Twelve mongrel dogs (wt 17-33 kg) were premedicated with morphine sulphate 0.1 mg kg"1 and anaesthesia was induced with thiopentone 7 mg kg"1. After intubation of the trachea, positive pressure ventilation was instituted at a rate of 12 b.p.m. and the tidal volume adjusted to maintain normocarbia, as measured by end-tidal infra-red analysis. Halothane (1.2 % inspired) was
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Lignocaine and bupivacaine are used widely in association with techniques of extradural regional anaesthesia and i.v. regional anaesthesia [1,2]. However, after reports of severe cardiotoxicity associated with the apparent i.v. injection of bupivacaine [3,4], several investigators have reported that bupivacaine is more cardiotoxic than lignocaine [5-7], whereas others have not [8]. Regional myocardial function is a sensitive indicator of myocardial ischaemia [9]. For example, we have reported that the combination of volatile anaesthetics and the calcium channel blocker, verapamil, caused regional myocardial dysfunction (seen as post-systolic shortening (PSS)) in myocardium with normal coronary arteries [10,11]. As local anaesthetics alter sodium conductance and may disrupt calcium fluxes [1], we wondered whether the administration of lignocaine or bupivacaine i.v. would cause regional myocardial dysfunction, similar to that seen with verapamil, in the presence of a normal coronary circulation. We also examined whether
672
The techniques of ultrasonic sonomicrometry have been described previously [12-14]. Briefly, as ultrasound travels at a constant speed of 1.56 mm us"1 through cardiac tissue, continuous measurement of myocardial segment length can be obtained. After completion of the surgery the preparation was allowed to stabilize for 1 h. During this time, arterial blood-gas tensions were determined and any required changes in ventilation or corrections to acid-base balance undertaken. Instruments were calibrated and left ventricular end-diastolic pressure (LVEDP) measured. Dextran 70 (average mol. wt 70000 daltons) was given as necessary to maintain an LVEDP of 5 mm Hg. A 30-min period following any intervention elapsed before the beginning of the definitive investigation. Experimental programme
To examine the effects of lignocaine or bupivacaine, the dogs were randomly allocated to one of two groups. Group 1 received i.v. injections of lignocaine and group 2 i.v. bupivacaine. The doses of both local anaesthetic agents used encompass the body weight normalized range for human anaesthesia. Doses were not scaled to individual body weights within this range as body weight has been shown to be a poor predictor of local anaesthetic blood concentration [15]. The initial dose of lignocaine was 50 mg, and each subsequent dose was twice the preceding dose, yielding doses of 50 mg, 100 mg and 200 mg for the three injections given. Likewise, each dose of bupivacaine was twice the previous dose, after an initial injection of 12.5 mg to compensate for the fourfold greater anaesthetic potency of bupivacaine compared with lignocaine. This schedule yielded bupivacaine doses of 12.5 mg, 25 mg and 50 mg for the three injections. Before the first dose, a baseline set of measurements was recorded. To allow equilibration of drugs between heart and brain, samples for measurements of blood concentrations of drugs were taken 10 min after each injection. After the recording of data was complete, the next dose of local anaesthetic was administered. Computation At the conclusion of the study the LAD was cannulated and calibration of the LAD flow probe performed by injecting 5-ml aliquots of blood
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used to maintain anaesthesia throughout the study. A heating element incorporated into the operating table maintained body temperature between 36 and 38 °C, as measured by an oesophageal temperature probe. The animal was placed in the right lateral decubitus position and a catheter inserted, via the femoral vein, into the inferior vena cava. An infusion of Hartmann's solution was started at a rate of 4 ml kg"1 h"1. The left common carotid artery was exposed, and a stiff 8-French gauge (2.76 mm o.d.) cannula was inserted and advanced to within 1 cm of the aortic valve. This cannula was connected to a calibrated pressure transducer (Druck Ltd, Groby, Leicester, U.K.) for the measurement of systemic pressures and was also used for blood sampling. Lead II of the electrocardiogram was monitored throughout the experimental procedure. A left thoracotomy was performed and the 4th and 5th ribs excised. The pericardium was opened and the aortic root dissected free of its fat pad. An appropriately-sized electromagnetic flow probe (Transflow 601, Skalar Medical, Delft, Holland) was placed around the aortic root for flow measurement. A stiff 8-French gauge (2.76 mm o.d.) cannula was inserted via the apical dimple into the left ventricle and attached to a calibrated pressure transducer (Druck Ltd, Groby, Leicester, U.K.) to obtain measurements of left ventricular pressure. A cannula was placed in the pulmonary artery via the pulmonary outflow tract to permit measurement of cardiac output (indocyanine green). The left anterior descending coronary artery (LAD) was dissected free of the epicardium. Measurements of coronary blood flow were obtained using a 2-mm electromagnetic flow probe (Transflow 601, Skalar Medical, Delft, Holland) placed around the artery. An occluding snare was placed just distal to the flow probe to allow determinations of zero flow. Measurements of myocardial segment length were obtained using three pairs of piezo-electric crystals inserted to the subendocardium of the apex, mid-wall and base of the heart. The apical tissue was supplied by the LAD and the basal region by the left circumflex coronary artery (LC). Data on myocardial segment length were, therefore, recorded from left ventricular tissue in territory supplied by the LAD (LAD segment), in the mid-wall area (INT segment), and in territory supplied by the LC (LC segment).
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DAP and LVEDP. Cardiac output (CO) was determined from heart rate (HR) and stroke volume obtained from the aortic flowmeter. Dye dilution curves using indocyanine green were performed to calibrate the aortic flowmeter. PR interval was determined from lead II of the electrocardiogram. Percentage changes from baseline values were determined for CPP, CBF, SAP, LV dP/drmax and CO, with baseline values normalized to 100%. Regional function was examined by calculating systolic shortening and post-systolic shortening. Systolic shortening (SS) was defined as EDL minus ESL, and expressed as a percentage of EDL to compensate for preload-induced changes in performance. Post-systolic shortening (PSS) was defined as the difference between ESL and the minimum segment length measured during diastole. This was expressed as a percentage of total segmental shortening to compensate for changes in inotropy. EDL was normalized to a baseline value of 10.0 mm to adjust for differences in absolute intercrystal distances between animals resulting from initial placement [14]. Results were analysed for statistical significance using two-way analysis of variance and Duncan's test. However, some variables, notably PSS, exhibited skewed distributions and were analysed by the non-parametric Friedman two-way analysis of variance and sign test, as appropriate. Unpaired Student's t tests were used for comparisons of normalized values between lignocaine and bupivacaine. Linear regression was performed on normalized CPP, CBF and regional function data. In all cases, P < 0.05 was considered significant.
TABLE I. Global haemodynamic data (mean± SEM) during baseline conditions and after administration of lignocaine 50 mg, 100 mg and 200 mg. *P<0.05 v. baseline by two-way analysis of variance and Duncan's multiple range lest, + P < 0.05 v. baseline by Friedman two-way analysis of variance and sign test
HR (beat mirr1) SAP (mm Hg) LVEDP (mm Hg) CPP (mm Hg) LV dP/d, max (mm Hg s"1) CO (litre min"1) SVR (dyn s cm"5) CBF (n = 5) (ml 100 g"1 mirr1) PR interval (ms)
Baseline
50 mg
100 mg
200 mg
99±5 106 ±6 6.5 + 0.7 73±5 1260±110
108 ±4 90 + 5* 7.8 ±0.8 63 ±3* 890 ±90*
106 ±6 77 + 4* 10.0±0.9* 48 ±4* 660 ±70*
104 ±6 54 ±5* 10.0 + 0.4* 29 ±4* 410±40*
1.97±0.14 3725 ±440 30.4 + 6.7
1.66±0.10* 3815±350 26.5 ±5.6
1.25±0.13* 4270 + 310 22.9±6.2f
0.77±0.11* 4680 ±275* 11.6±7.5+
105 ±3
101±3
101+4
116 + 8*
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through the LAD cannula. After calibration, 5 ml of Evans blue was injected through the LAD cannula. The resulting area of stained myocardium, representing the territory supplied by the LAD, was separated from non-stained myocardium. The atria were removed and the stained ventricular myocardial fragments weighed, thus enabling LAD flow measurements to be normalized as mlmin"V100g of myocardium. The data were recorded as hard copy analogue signals on a Mingograf 81 (Elema Schoenander, Stockholm, Sweden). The first derivative of left ventricular pressure (LV dP/dt) was recorded, and its peak value measured (LV dP/dt max ). Aortic flow was both differentiated, to obtain aortic blood acceleration, and integrated, to obtain stroke volume. For purposes of measuring regional function, the ends of systole and diastole were defined as the first positive deflection of LV dP/dt and the first point after systole when aortic flow returned to zero, respectively. End-diastolic and end-systolic lengths (EDL, ESL, respectively) were measured using a paper speed of 250 mm s"1 to ensure accurate determinations of end-systole and end-diastole. Data from the hard copy recordings were digitized manually. These were then analysed on a VAX computer using SAS, a commercially available statistical analysis programme (SAS, Inc, Cary, N.C., U.S.A.). Mean arterial pressure (MAP) was calculated from the systolic and diastolic systemic arterial pressures (SAP, DAP, respectively). Coronary perfusion pressure (CPP) was calculated in the conventional manner as the difference between
673
BRITISH JOURNAL OF ANAESTHESIA
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120
100
8 Mow I
n 80 'o
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* <> a
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dose 1
Lignocaine
A
dose 2
The global haemodynamic data are presented in table I. Heart rate did not change as the dose of lignocaine increased. However, after each dose, SAP, CPP, CO and LV dP/drmax decreased significantly. CBF decreased significantly at the two higher doses of lignocaine. PR interval increased significantly after the third dose of lignocaine. The average plasma drug concentrations were: 1.13 + 0.09 ug ml"1 (w = 6) after dose 1, 2.89±0.17 \ig ml"1 {n = 5) after dose 2, and 6.92+1.08 ug ml"1 (w = 6) after dose 3. The normalized CPP and CBF values were compared using linear regression and a significant correlation was shown between the two variables (r = 0.95, d f = 4 , P < 0.01). The slope of the resultant regression line was 1.06 + 0.07 (fig. 1). Data on regional function are shown in table II. Lignocaine caused a significant increase in EDL after the initial dose in the LC segment and significant increases in EDL with the second and third doses in all three myocardial segments. SS was significantly decreased with each dose of lignocaine in all three segments. Significant increases in PSS were apparent in the LAD territory after the second and third doses of lignocaine. Increases in PSS in the intermediate and LC segments achieved statistical significance only after the second dose. Global haemodynamic and regional function data were normalized and expressed as a percentage of baseline values. Normalized CBF
A O dose
0 D
-
1 If
-
60
-
Z 40 >•
-
tr
ironar
TJ O
20
3
/
[
w 6 0.95 P<0.01
.3 0
I
t
t
20 40 60 80 100 120 Coronary perfusion pressure (% of baseline)
FIG. 1. Comparison between coronary blood flow (CBF) and coronary perfusion pressure (CPP) during baseline conditions and after three doses of lignocaine in five dogs. Data for CBF and CPP were normalized to baseline values of 100%. Each symbol represents results from an individual dog; the degree of shading indicates the lignocaine dose.
RESULTS
CBF measurements were performed in five dogs in both the lignocaine and bupivacaine groups. All other data for each local anaesthetic are from six dogs.
TABLE II. Regional myocardial function data (mean+ S EM) during baseline conditions and after administration of lignocaine 50 mg, 100 mg and 200 mg. * P < 0.05 v. baseline by two-way analysis of variance and Duncan's test. + P < 0.05 v. baseline by Friedman two-way analysis of variance and sign test
Baseline
50 mg
100 mg
200 mg
10.0 ±0.0
10.3±0.0
10.5 ±0.2*
10.5±0.2*
20.2 ±2.2 4.6±2.3
13.4±2.5* 23.5 ±10.6
10.6 ±2.0* 29.0±10.5f
9.4 ±1.0* 25.2 ±6.4+
10.0 ±0.0
10.2 + 0.1
10.5±0.2*
10.7 ±0.2*
14.4±2.0 8.7 ±4.7
10.8± 1.8* 13.1 ±5.9
8.6± 1.5* 24.9 ±8.9
7.8+1.2* 28.3± 11.7
10.0 ±0.0
10.2±0.1*
10.6 ±0.6*
10.8±0.2*
13.2 + 1.9 14.9 ±5.4
9.6+1.7* 24.1 ±4.6
7.2±1.3* 33.6 ±7.4+
6.3±0.8* 20.2 ±6.0
LAD
EDL (mm) (normalized) SS (%) PSS (%) INT
EDL (mm) (normalized) SS (° o ) PSS (° o ) LC EDL (mm) (normalized) SS («„) PSS (»„)
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• •
LIGNOCAINE, BUPIVACAINE AND REGIONAL MYOCARDIAL FUNCTION 120 100-
120
675
# • • A • dosei » <> d A 3 dose 2 O 0 D A O dose 3
basel ine)
80-
-if) 60
o
200 0
20
40
60
80
100
120
Coronary blood flow C/.of baseline)
FIG. 2. Comparison between normalized coronary blood flow and absolute PSS values during baseline conditions and after three doses of lignocaine ( • ) or three doses of bupivacaine (O)- Data were obtained from five dogs. No significant correlation was found (lignocaine: r = 0.5, df = 16, ns; bupivacaine: r = 0.36, df = 16, ns).
and normalized SS were tested for correlation and no significant relationship was found. Similarly, PSS was not significantly correlated with normalized CBF (fig. 2). Bupivacaine Table III shows the global haemodynamic data. The administration of bupivacaine did not alter heart rate significantly. The initial dose of bupivacaine did not result in any changes in SAP, CPP and CO, but the subsequent doses caused significant decreases in these variables. LV dP/dt m a x , however, decreased significantly with each dose. CBF was decreased significantly at the two higher doses of bupivacaine. Owing to
80
60
40
20
j
20
40
60
80
100
Coronary perfusion pressure (% of baseline) FIG. 3. Comparison between coronary blood flow (CBF) and coronary perfusion pressure (CPP) during baseline conditions and after three doses of bupivacaine in five dogs. Data for CBF and CPP were normalized to baseline values of 100%. Each symbol represents results from an individual dog; the degree of shading indicates the bupivacaine dose.
difficulties with storage and analysis of blood samples, several plasma bupivacaine concentrations were not determined. The average plasma drug concentrations were: 0.49 + 0.07 ugml" 1 (w = 4) after dose 1, 0.68 + 0.09 ug ml" 1 (« = 6) after dose 2, and 1.22 + 0.23 ug ml" 1 (n = 3) after dose 3. PR interval was significantly increased after the second and third doses of bupivacaine. The normalized CPP and CBF values were
TABLE III. Global haemodynamic data (mean±SEAT) during baseline conditions and after administration of bupivacaine 12.5 mg, 25 mg and 50 mg. * P < 0.05 v. baseline by two-way analysis of variance and Duncan's multiple range test. + P < 0.05 v. baseline by Friedman two-way analysis of variance and sign test
HR (beat min"1) SAP (mm Hg) LVEDP (mm Hg) CPP (mm Hg) LV dP/dtmax (mm Hg s"1) CO (litre min"1) SVR (dyn s cm"6) CBF (n = 5) (ml 100 g~' min"1) PR interval (ms)
120
Baseline
12.5 mg
25 mg
50 mg
123+11 105 ±5 6.3 + 0.6 73±6 1500+150
123±13 98 + 4 7.0 ±0.8 68 + 4 1240 ±140*
122±11 90 + 6* 8.3+1.1*
120±9 75 + 8* 9.7 ±1.0* 46 + 7* 680 ±90*
2.67 + 0.37 2700 + 555 29.9 + 8.8
2.37 ±0.35 3175 + 530 28.3±11.0
103 + 8
111 ±9
62 ±5*
1020 + 100* 1.96 + 0.35* 3620 + 635
20.5±8.3t
1.44 ±0.36* 4190±865 13.3±6.8f
116±8*
127+10*
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40-]
onary blood f low (
2
100
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TABLE IV. Regional myocardial function data (mean + SEAT) during baseline conditions and after administration of bupivacaine 12.5 mg, 25 mg and 50 mg. * P < 0.05 v. baseline by two-way analysis of variance and Duncan's test. •)• P < 0.05 v. baseline by Friedman two-way analysis of variance and sign test
25 mg
Baseline
12.5 mg
10.0±0.0
10.1 ±0.1
10.3±0.1*
10.4±0.1*
17.2 + 1.3 10.0 + 5.0
13.8+1.1* 24.4 ±5.3
10.1 + 1.3*
29.0±6.6f
8.4 + 1.8* 33.8±10.3f
10.0 ±0.0
10.1+0.1
10.3±0.1*
10.4±0.1*
12.5 + 2.2 5.1 ±3.8
9.5 ±2.2 23.5 + 7Af
8.2 ±1.5* 25.6±6.6f
6.5 + 1.9* 23.5 ±10.7
10.0 ±0.0
10.6±0.1*
10.3±0.1*
10.4±0.1*
10.6 + 0.8 10.3±4.1
10.2± 1.2 14.7±3.7
7.8± 1.1* 16.4±5.7
6.6 + 1.2* 23.8 ±9.9
50 mg
LAD
EDL (mm) (normalized) SS (%) PSS (%) INT
LC
EDL (mm) (normalized) SS (%) PSS (%)
100 80
100
100
11 I1 I 80
80
1/1
V
60 40 20 0
o 60
60
140
% 20
20
1
FIG. 4. The effects of lignocaine (open columns) and bupivacaine (cross-hatched columns) on three indices of global myocardial performance (SAP, LV d/'/di mox) and CO). All data were normalized to baseline values of 100%, and values obtained after local anaesthetic administration expressed as a percentage of baseline. 1 = Lignocaine 50 mg, bupivacaine 12.5 mg; 2 = lignocaine 100 mg, bupivacaine 25 mg; 3 = lignocaine 200 mg, bupivacaine 50 mg. Bars show the mean values, and error bars represent the SEM. * P < 0.05 v. baseline by two-way analysis of variance and Duncan's test; + P < 0.05 between lignocaine and bupivacaine values by unpaired Student's t test.
compared and no significant correlation was found (r = 0.34, df = 4, P > 0.1) (fig. 3). Data on regional function are presented in table IV. Bupivacaine caused an increase in EDL in the LC segment with the initial dose, and caused increases in EDL in all segments with the second and third doses. SS was decreased in the LAD territory with the first dose and further injections caused a decrease in SS in all segments. PSS increased significantly in the LAD region after the second and third doses of bupivacaine and was increased in the intermediate territory after the first and second, but not the third, dose.
No significant increase in PSS occurred in the LC segment. Normalized CBF and normalized SS values were compared and no significant correlation found. The absolute PSS values had no significant correlation with normalized CBF (fig. 2). Comparisons were made of normalized SAP, LV dP/dj max , and CO data between lignocaine and bupivacaine (fig. 4). Each dose caused a significant decrease from baseline values of each variable, except for SAP with the first bupivacaine dose. Significant differences between the local anaesthetics occurred solely in LV dP/dfmax, and
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FIG. 5. The effects of lignocaine (open columns) and bupivacaine (cross-hatched columns) on systolic shortening (SS) in the apical (LAD), mid-wall (INT), and basal (LC) regions of the left ventricle. Values are expressed as a percentage of baseline values. 1 = Lignocaine 50 mg, bupivacaine 12.5 mg; 2 = lignocaine 100 mg, bupivacaine 25 mg; 3 = lignocaine 200 mg, bupivacaine 50 mg. *P < 0.05 v. baseline by two-way analysis of variance and Duncan's test.
these differences were seen with all three doses. Normalized SS data were compared between the local anaesthetics in the myocardial territories measured. Similar depression of SS occurred in the LAD, INT, and LC segments with both local anaesthetics (fig. 5). DISCUSSION
Myocardial depression is a feature of the i.v. administration of lignocaine [16]. Laboratory investigations in awake animals, however, have shown stimulation of the cardiovascular system [17], which has been attributed to the central nervous system effects of lignocaine [8]. Bupivacaine, as well as other amide and ester local anaesthetics, is also a myocardial depressant [1,5,8,16,18]. Some investigators have reported that the degree of cardiovascular depression is related to anaesthetic potency [8], while others have suggested that bupivacaine is more cardiotoxic, especially in pregnancy and in situations of hypoxia and acidosis [6,19-21]. Many of the comparisons between lignocaine and bupivacaine have centred on the electrophysiological properties of the drugs. It now seems established that bupivacaine has a much greater, although somewhat unpredictable, potential to cause serious cardiac arrhythmias [5—7]. In the light of these apparent differences between lignocaine and bupivacaine on myocardial function, we have investigated their properties on global haemodynamics and regional wall motion in halothane-anaesthetized dogs.
This general anaesthetic eliminated the potential influence of sympathetic nervous system activation caused by local anaesthetics [17]. We chose to give a bolus of a fixed dose of local anaesthetic, rather than on a dose per kilogram basis, to mimic accidental i.v. injection into the systemic circulation during the performance of regional anaesthesia, which is commonly administered as an empirical maximum dose rather than on a milligram per kilogram basis [22]. The first two doses of both lignocaine and bupivacaine would be comparable to those used for extradural and i.v. regional anaesthesia [1]. The ranges of blood concentrations at the time they were measured encompass those that would be expected after normal regional anaesthetic procedures. Thus, although undoubtedly within the toxic range after the bolus injections, the concentrations had returned to acceptable values well before the next injection was made [15]. The significant depression of LV dP/dfmax and of regional function in all myocardial segments seen with the initial and subsequent doses of the local anaesthetics agrees with previous reports of myocardial depression with these agents [1,5,8,16]. The depression of global haemodynamics (fig. 4) and regional myocardial function (fig. 5) was similar with lignocaine and bupivacaine. It has been reported that PSS occurs in myocardium with compromised blood flow as the halothane concentration is increased [23]. PSS has also recently been observed in normal myocardium with normal coronary blood supply
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channel blocking properties of these local anaesthetics, as an enhancement of the cardiodepressant effects of bupivacaine has been shown with nifedipine [26] and verapamil [27]. PSS may be a measure of altered contractile performance, possibly as a result of changes in myocardial membrane ion conductance, myocardial metabolism, or local subendocardial blood flow, induced by lignocaine and bupivacaine. In summary, the i.v. administration of lignocaine or bupivacaine caused similar depression of global haemodynamics and regional myocardial function and the appearance of regional left ventricular asynchronous wall function (PSS). There was no relationship between PSS and CBF for either drug, and both drugs caused similar degrees of regional dysfunction, suggesting that regional contractile abnormalities are not the cause of the apparently increased cardiotoxicity of bupivacaine compared with lignocaine. The erratic effect of bupivacaine on CBF may result from changes in coronary vascular resistance; lignocaine, by comparison, exhibited more predictable CBF responses to i.v. injections. ACKNOWLEDGEMENTS This work was supported in part by Medical Research Council grants G8002204SA and G8306850SA. J. J. Lehot was the recipient of an MRC/INSERM fellowship and J. G. Ramsay a McLaughlin Travelling fellowship (Canada). W. B. Runciman was the recipient of a Wellcome-Ramaciotti Research Travel Grant; some equipment was provided by the Flinders Medical Centre Research Foundation. We thank Dr G. T. Tucker of Sheffield University, who arranged the assays of lignocaine and bupivacaine. We are also grateful for Dr L. E. Mather's thoughtful review of this manuscript. REFERENCES 1. Covino BG, Vassallo HG. Local Anesthetics: Mechanisms of Action and Clinical Use. New York: Grune and Stratum, 1979. 2. Gooding JM, Tavakoli MM, Fitzpatrick WD, Bagley JN. Bupivacaine: preferred agent for intravenous regional anesthesia? Southern Medical Journal 1981; 74: 1282-1283. 3. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 1979; 51: 285-287. 4. Ryan DW. Accidental intravenous injection of bupivacaine: a complication of obstetrical epidural anaesthesia. British Journal of Anaesthesia 1973; 45: 907-908. 5. de Jong RH, Ronfeld RA, DeRosa RA. Cardiovascular effects of convulsant and supraconvulsant doses of amide local anesthetics. Anesthesia and Analgesia 1982; 61: 3-9.
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when verapamil was administered i.v. in combination with halothane [10,11]. As lignocaine and bupivacaine are sodium channel blockers, and may disturb calcium conductance, we performed the present study to determine if there was an interaction between these local anaesthetics and halothane producing regional dysfunction. PSS in the LAD region increased after the initial dose of bupivacaine and lignocaine, and this increase became significant after the second and third doses. Bupivacaine caused a significant increase in PSS after the initial dose in the INT region, but did not affect the LC region. Lignocaine caused an insignificant increase in PSS after each dose in the INT region, and significant regional dysfunction was present only after the second dose in the LC region. Thus regional dysfunction does occur with both lignocaine and bupivacaine, yet bupivacaine causes changes in the apex and mid-wall regions of the left ventricle, while lignocaine seems to cause predominantly apical dysfunction. Bupivacaine differed from lignocaine in respect of effects on PR interval. There was a significant increase in PR interval after the second dose of bupivacaine, whereas lignocaine significantly slowed atrioventricular conduction only at the highest dose. This agrees with previous work suggesting that bupivacaine has a greater effect on myocardial conduction than lignocaine [5]. Lignocaine caused a reduction in CBF which was closely related to the reduction in CPP (fig. 1). Bupivacaine, however, had erratic effects on CBF when compared with those on CPP (fig. 3). This suggests differing effects on coronary conductance by these two agents. Both lignocaine and bupivacaine have been shown to be arteriolar constrictors in moderate doses [24,25], but the results of this study imply different properties with respect to the intact coronary vasculature. The effects of bupivacaine on CBF showed a wide scatter and suggest that, even widi high CPP values, CBF is changed unpredictably and may be decreased precipitously. The absolute values for PSS did not correlate with changes in CBF with either local anaesthetic (fig. 2). This suggests that the changes seen in PSS may result from an interaction between the local anaesthetics and myocardial cellular function rather than from alterations in regional blood supply, although redistribution of local blood flow and myocardial metabolic function were not examined. This may be related to the calcium
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