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* From the Department of Anesthesiology and Intensive Care Medicine and the
Department Of Emergency and Critical Care Medicine, Kanazawa University School of Medicine, Kanazawa, Japan.
Address correspondence to: Dr. Yuzo Mizukoshi, Department of Anesthesiology and Intensive Care Medicine, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Phone: +81-76-265-2434; Fax: +81-76-234-4267; E-mail: ymizkosi{at}med.kanazawa-u.ac.jp
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Abstract |
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Methods: We randomly assigned 22 Japanese white rabbits anesthetized with isoflurane (1.0%) to two groups according to the absence (control group, n=11) or presence (EA group, n=11) of thoracolumbar EA. After epidural injection (0.5 mL•kg–1 of 0.9% saline in the control group or 1% mepivacaine in the EA group) and during subsequent hypercapnia (mean arterial CO2 tension 85 mmHg), we measured left ventricular pressure, left ventricular volume by using conductance catheter and plasma catecholamine concentrations. Left ventricular contractility was assessed by the slope of the linear approximation of the left ventricular end-systolic pressure-volume relationship, [i.e., end-systolic elastance (Ees)].
Results: The combination of hypercapnic acidosis and thoracolumbar EA caused a 65% decrease in Ees (P <0.05). Hypercapnic acidosis alone caused a 16% decrease (P <0.05) and thoracolumbar EA alone caused a 49% decrease in Ees (P <0.05). In the EA group, epidural injection caused an 85% decrease in the epinephrine concentration (P <0.05) and a 39% decrease in the norepinephrine concentration (P <0.05), even during hypercapnic acidosis. However, in the control group, hypercapnic acidosis caused no change in the circulating epinephrine concentration but a 74% increase in the circulating norepinephrine concentration (P <0.05).
Conclusion: Combined hypercapnic acidosis and EA markedly reduce left ventricular contractility in an additive fashion in rabbits receiving general anesthesia.
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Introduction |
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Methods |
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Preparations
Twenty-two Japanese white rabbits 3.3 to 4.0 kg were anesthetized by inhalation of isoflurane. An epidural catheter (0.6 mm outer diameter, Hakko, Tokyo, Japan) was then inserted percutaneously, employing the loss-of-resistance technique.9 A space between the fifth and seventh lumbar vertebra was chosen as the site of puncture. The catheter was advanced 8 to 10 cm cephalad into the epidural space. Correct placement of the catheter and spread of contrast medium were verified radiographically using 0.5 mL•kg–1 of iopamidol. An ear vein was cannulated to infuse Ringer's acetate solution at a rate of 10 mL•kg–1•hr–1. Anesthesia was maintained with 2.0% isoflurane during the surgical procedures. The trachea was intubated and the animal mechanically ventilated to maintain an arterial CO2 tension (PaCO2) between 35 and 45 mmHg. The carotid artery was cannulated to monitor the MAP and to sample blood. Lead II of the electrocardiogram was recorded continuously.
Pressure-volume relationship
The chest was opened along the sternum, and a 6-electrode conductance catheter (2Fr, Unique Medical, Tokyo, Japan) was inserted into the left ventricle from the apex toward the aortic valve to measure ventricular volume. A catheter-tipped micromanometer (4Fr, Keller, Winterthur, Switzerland) was inserted into the left ventricle from the apex to determine left ventricular pressure. Specific blood conductance was measured on samples placed in a cuvette. The conditioning amplifier (Integral 3 model-VPR-1002, Unique Medical), which converts the voltages from the conductance catheter to volume, was then calibrated and all of the signals, including left ventricular pressure and volume and the electrocardiogram, were digitized (AD12-8, Contec, Osaka, Japan) at a sampling rate of 480 Hz. They were sent to a dedicated laboratory computer system (ThinkPad 600, IBM Japan, Tokyo, Japan) for instantaneous left ventricular pressure-volume loop monitoring and subsequent analysis (VPS-101, Unique Medical). Correct positioning of the catheters was verified by monitoring the pressure-volume loops. The conductance method used to determine left ventricular volume is based on measuring the conductivity of the blood inside the left ventricular cavity.10 Ees was determined from multiple pressure-volume loops obtained during partial occlusion of the pulmonary artery and was calculated using an iterative linear regression method.11 The effective arterial elastance (Ea) was defined as the ratio of end-systolic pressure to stroke volume (SV). The end-diastolic volume (EDV) and Ea represent indices of preload and afterload,12 respectively.
Experimental protocol
After placement of the catheters, the concentration of inspired isoflurane was decreased to 1.0%, and at least 20 min was allowed for blood gases and hemodynamic parameters to stabilize. The animals were randomly assigned to two groups according to the absence (control group, n=11) or presence (EA group, n=11) of thoracolumbar EA. Arterial blood was sampled for blood gas analysis and for determining plasma catecholamine concentrations. Hemodynamic variables, including MAP, heart rate (HR), left ventricular volume and pressure were measured. CO, SV, Ees, and Ea were calculated. After baseline measurements were obtained, either 0.5 mL•kg–1 of 0.9% saline (control group) or 1% mepivacaine (EA group) was injected via the epidural catheter. Biochemical analysis and hemodynamic measurements were performed 15 min after the epidural injection and 15 min after the start of hypercapnic challenge. Switching the inspired gas from 50% O2/50% N2 to a hypercapnic gas mixture (50% O2 / 10% CO2 / 40% N2) induced hypercapnic acidosis. Arterial blood gases were measured using an automated blood gas analyzer (ABL-3, Radiometer, Copenhagen, Denmark). Blood used for the determination of catecholamines was placed in 5 mL sodium ethylenediaminetetraacetic acid vacuum tubes on ice prior to centrifugation for 15 min at 2,000 x g and 4°C. Plasma was decanted and stored at –20°C until analysis.
Statistical analysis
Data are presented as the mean ± SD. Between-group differences and within-group changes over time were analyzed by two-way analysis of variance with repeated measures using Super ANOVA (Abacus Concepts, Berkeley, USA). A value for P <0.05 was considered statistically significant. When the analysis of variance detected a significant between-group or within-group difference, unpaired t test and the least-squares means contrast was performed, respectively.
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Results |
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Blood gas analysis
The mean PaCO2 increased to 84–85 mmHg in the control and EA groups 15 min after the start of hypercapnic challenge (Table I
). There were no significant between-group differences at any point during the experimental period.
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). After epidural injection, the control group had no change in any of the hemodynamic variables. In contrast, the EA group had a 49% decrease in Ees and a 17% decrease in CO, compared with the baseline values. After the subsequent hypercapnic challenge, the control group had a 16% decrease in Ees and a 26% decrease in CO. In contrast, the EA group had a 65% decrease in Ees and a 20% decrease in CO, compared with baseline values. Thus, the impact of hypercapnic acidosis and thoracolumbar EA on the CO was not additive, but that on the Ees was additive.
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). Before the hypercapnic challenge, the plasma concentrations of both catecholamines were significantly lower in the EA group. Hypercapnic acidosis caused no significant change in the epinephrine concentration but resulted in a 74% increase in the norepinephrine concentration in the control group. In contrast, hypercapnia caused an 85% decrease in the epinephrine concentration and a 39% decrease in the norepinephrine concentration in the EA group compared with the baseline values.
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Discussion |
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We have previously demonstrated that hypercapnic acidosis alone increases CO and MAP in dogs.5 Hypercapnia induces both direct and indirect cardiovascular effects. It directly depresses myocardial contractility, dilates the peripheral arterioles, and stimulates the sympathetic nervous system at several levels. Therefore, the cardiovascular responses to hypercapnia result from a direct effect of CO2 as well as indirect effect on the sympathetic nervous system. However, no direct indices of left ventricular contractility were measured in our previous study. Therefore we could not differentiate the direct and indirect effects of CO2 during hypercapnic acidosis.
There are many conventional measures of left ventricular performance, including ejection fraction, maximum rate of change of left ventricular pressure,13 circumferential fibre shortening,14 fractional area change,15 and pressure- dimension indices.6,16,17 All of these measures are influenced not only by the contractile state but also by loading conditions.8,18,19 However, Ees reflects the contractile state and is relatively insensitive to loading conditions.6–8,18 We therefore compared left ventricular contractility by measuring Ees.
Studies in isolated myocardial muscle and excised hearts have demonstrated that hypercapnic acidosis directly depresses contractility.20–24 Walley et al. reported that hypercapnic acidosis (PaCO2 92 mmHg) decreases Ees by 19% in dogs anesthetized with fentanyl.25 In contrast to previous studies in humans or dogs, hypercapnic acidosis caused bradycardia and reduced CO in our study of rabbits. We hypothesize that this finding is due to activation of compensatory reflexes.26 We also found no increase in the epinephrine concentration during hypercapnia, and this may contribute to the bradycardia observed during hypercapnic acidosis in rabbits. Although the changes in HR and CO can vary based on the animal studied, we confirmed that hypercapnic acidosis during general anesthesia reduces left ventricular contractility in vivo.
In spite of several previous clinical and experimental studies, questions remain about the effect of EA on left ventricular contractility, which has variously been reported to be unchanged,27,28 decreased,29,30 or even increased.31,32 This variability is attributable to differences in study design, the subjects studied, and the measures used to assess left ventricular contractility. Our results demonstrate that thoracolumbar EA reduced Ees by 49% compared with the baseline value. The contrast medium spread extensively and circulating catecholamines decreased in the EA group. Therefore, the decreased contractility appears to be the result of both sympathetic denervation of the heart and blockade of the humoral sympathetic system. Goertz et al. reported that high thoracic EA decreases Ees in humans by 50%.30 The decrease in Ees in humans is similar to that observed during thoracolumbar EA in the present study. Thoracolumbar EA causes the blockade of afferences and efferences between the heart and the central nervous system (cardiac denervation). This results in a decreased norepinephrine level in the circulation. If, in addition, lumbar denervation is obtained, the adrenal grand will not release epinephrine (humoral aspect of the sympathetic system).
We previously found that the combination of hypercapnic acidosis and thoracolumbar EA decreased CO and MAP in dogs.5 We assumed that sympathetic blockade and cardiac denervation caused by thoracolumbar EA unmasked the direct effects of CO2 on left ventricular contractility and vascular tone. However, there was no direct evidence of reduced left ventricular contractility in our previous study. The present study evaluated directly the effect of combined hypercapnic acidosis and thoracolumbar EA on left ventricular contractility, and demonstrated that this combination reduced contractility in an additive fashion. Miyabe et al. previously reported that thoracic EA reduces the time to cardiac arrest in apneic rabbits.33 Because apnea causes not only hypercapnia but also hypoxia, we cannot directly compare their results with ours. However, the markedly reduced left ventricular contractility demonstrated in our study may have contributed to this reduced time to cardiac arrest.
With regard to CO, the impact of hypercapnic acidosis and thoracolumbar EA are not additive. Therefore, from the standpoint of "non-cardiac organs", the combination of hypercapnic acidosis and thoracolumbar EA has potentially no major impact in patients without heart failure.
There are several limitations to the current study. First, there are species differences with respect to the cardiovascular responses to hypercapnic acidosis. Acute hypercapnic acidosis causes increased HR and CO in dogs5,25 and humans,4 but decreases HR and CO in rabbits. Therefore, it may not be appropriate to simply extrapolate our results to humans. Second, our findings may not have direct clinical applicability because hypercapnic acidosis was induced acutely by inhalation of high concentration of CO2, a situation unlikely to occur during clinical anesthesia. Third, the general anesthesia technique used in our study may have influenced results.8 However, the minimum alveolar concentration for isoflurane in rabbits is 2.05%,34 and the effect of light anesthesia, such as that used in the current study, is most likely minor.
In summary, the current study shows that, in anesthetized rabbits, the combination of marked hypercapnic acidosis and EA reduces left ventricular contractility in an additive fashion. Inasmuch as extrapolation to the clinical setting is feasible, our findings suggest that, during the combined administration of epidural and general anesthesia, it is specially important to avoid hypercapnia.
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Footnotes |
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Revision received March 11, 2001. Accepted for publication February 6, 2001.
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References |
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