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© 2001 International Anesthesia Research Society
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Abstract |
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We hypothesized that sympathetic stimulation is the main mechanism contributing to hemodynamic failure in pulmonary embolism. We investigated the effects of epidural anesthesia-induced sympathetic blockade, restricted to thoracic and lumbar levels, during pulmonary embolism. Two experiments were performed in chronically instrumented ewes. In the first experiment, six sheep received 6 mL bupivacaine 0.175% (Thoracic Epidural Anesthesia [TEA] group), and six sheep received 6 mL saline 0.9% (TEA-Control group), respectively, via an epidural catheter (T3 level). In the second experiment, six sheep received 2.8 mL bupivacaine 0.375% (Lumbar Epidural Anesthesia [LEA] group), and six sheep received 2.8 mL saline 0.9% (LEA-Control group) epidurally (L4 level). Embolization was performed by IV injection of au- tologous blood clots (Experiment 1, 0.75 mL/kg; Experiment 2, 0.625 mL/kg). TEA was associated with significantly slower heart rates, decreased mean pulmonary artery pressures and central venous pressures, and significantly higher stroke volume index and oxygenation in comparison with the TEA-Control group. By contrast, LEA was associated with significantly faster heart rates and increased central venous pressures and with a significantly lower stroke volume index in comparison with the LEA-Control group. TEA significantly reduced, and LEA significantly increased, hemodynamic deterioration, suggesting beneficial effects of TEA on cardiopulmonary function during pulmonary thromboembolism.
IMPLICATIONS: Thoracic (but not lumbar) epidural anesthesia was associated with beneficial cardiopulmonary effects during experimental pulmonary thromboembolism in sheep.
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Introduction |
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Pulmonary embolism is a common hemodynamic disorder. The incidence—with a frequent mortality, especially in the immediate incidental period in hospitalized patients—varies considerably depending on the severity of embolism, patient groups, and underlying diseases (1). Pulmonary embolism causes pulmonary hypertension and an increase in right ventricular afterload, because of an obstruction in the pulmonary vasculature, and may therefore subsequently result in right ventricular failure, global heart failure, and death (2). During pulmonary embolism, a remarkable increase in sympathetic activity has been observed both in experimental models and in humans. This activity possibly aggravates the disease because of pulmonary vasoconstriction-induced enhancement of metabolic demand, oxygen consumption, and disturbance in myocardial energy release (3,4).
We hypothesized that activation of the sympathoadrenal system significantly contributes to hemodynamic deterioration during pulmonary embolism. It was further hypothesized that sympathetic blockade achieved by epidural anesthesia can have different effects, depending on whether the level of segmental blockade is thoracic or lumbar. If sympathetic blockade influences hemodynamics during pulmonary embolism, epidural anesthesia restricted to thoracic levels should have beneficial effects by reducing sympathetic activation at the heart and lung levels. Conversely, epidural anesthesia restricted to the lumbar levels should have no influence or may even aggravate hemodynamic deterioration through a compensatory increase in sympathetic activation in the unblocked thoracic segments (5). The purpose of this study was to investigate the cardiopulmonary effects of sympathetic blockade at the thoracic and lumbar levels induced by thoracic epidural anesthesia (TEA) and lumbar epidural anesthesia (LEA) during experimental pulmonary thromboembolism.
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Methods |
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We investigated cardiopulmonary function during pulmonary embolism in awake, spontaneously breathing sheep in two separate experiments: first, without or with sympathetic blockade at the thoracic levels (TEA), and second, without or with sympathetic blockade restricted to the lumbar levels (LEA).
The study was conducted with the relevant approval from our institution’s animal care committee. Twenty-four blackhead ewes (weight, 32–41 kg) were randomly assigned to four groups in two experiments, which were performed in a cross-over manner: Experiment 1, TEA group (n = 6) and Control group (TEA-Control, n = 6); Experiment 2, LEA group (n = 6) and Control group (LEA-Control, n = 6).
All of the ewes were chronically instrumented under general anesthesia (premedication, ketamine [Ketanest®; Parke-Davis, Berlin, Germany] 15 mg/kg IM; anesthesia, propofol [Disoprivan®; Abbott, Wiesbaden, Germany] 10 mg · kg-1 · h-1 IV]. Instrumentation included a pulmonary artery catheter via an introducer system (right jugular vein), a femoral artery catheter, and an additional introducer system in the left jugular vein for application of blood clots. The animals assigned to Experiment 1 received an epidural catheter, which was placed at the T3 level under radiographic control, and a forelimb temperature sensor to verify sympathetic blockade at thoracic levels.
The animals assigned to Experiment 2 received an epidural catheter, which was placed under radiographic control at lumbar level L4, and temperature sensors on one of the forelimbs and hindlimbs to verify sympathetic blockade at lumbar levels and to exclude sympathetic blockade at thoracic levels.
The epidural catheter was inserted at the level of L5/S1 in both experiments after the epidural space had been identified by using the loss-of-resistance technique. All ewes were kept in individual cages after instrumentation on a 12-h light/dark cycle, with food and water provided ad libitum. Each experiment was performed after a recovery period of at least 2 days.
On the day of the experiment, autologous blood (3 mL/kg), substituted with the same quantity of lactated Ringer’s solution, was drawn and poured into a stainless steel bowl. After coagulation, the clot was cut into small particles (0.5 x 0.5 x 0.5 cm) by using a standardized procedure and filled into 50-mL syringes. All procedures were performed under sterile conditions.
Experiment 1
After baseline measurements, animals in the TEA group received 6 mL bupivacaine 0.175% (a concentration that produced sympathetic blockade in pilot experiments), and animals in the TEA-Control group received 6 mL saline 0.9% epidurally. Thirty minutes after epidural application of bupivacaine or saline, embolization was performed by injecting 0.75 mL/kg blood clots via the jugular vein introducer system. The quantity of clots was selected according to preliminary dose-response studies to produce fulminant but nonlethal pulmonary embolism.
Experiment 2
After baseline measurements, animals in the LEA group received 2.8 mL bupivacaine 0.375%, and animals in the LEA-Control group received 2.8 mL saline 0.9% epidurally. Thirty minutes after epidural application of bupivacaine or saline, embolization was performed by injecting 0.625 mL/kg blood clots via the jugular vein introducer system. The reduced blood clot quantity compared with Experiment 1 was chosen to ensure survival in both groups, because animals died in pilot experiments when they received the same blood clot quantity as in Experiment 1 under LEA. However, according to previous dose-response experiments, the reduced blood clot quantity was still sufficient to produce fulminant pulmonary embolism. The concentration and amount of bupivacaine were chosen to allow the administration of the same quantity of bupivacaine as in Experiment 1 and to ensure that the sympathetic blockade was restricted to the lumbar levels.
Hemodynamic and oxygenation measurements were performed 1, 2, 4, and 6 h after embolization. The animals were killed with a saturated potassium chloride solution under ketamine anesthesia after the experiment. Depending on the experiment (1 or 2), a thoracic or lumbar bilateral laminectomy of several vertebrae was performed in an autopsy procedure, and methylene blue dye was applied via the epidural catheter to confirm the correct spatial (epidural) and level (T3 or L4) placement of the catheter.
The measured variables were heart rate, cardiac index, mean arterial pressure, mean pulmonary artery pressure, central venous pressure, core and limb temperature, and blood gas analyses. The observed variables were food and water consumption, stool production, and the animals’ behavior; these variables were assessed on a dichotomous basis.
The data are presented as mean ± SE. The measured variables were subjected to two-way analysis of variance for repeated measurements. A value of P < 0.05 was considered to indicate statistical significance. The observed variables were analyzed with Fisher’s exact test for nonparametric analysis for dichotomous criteria. A value of P < 0.05 was considered to indicate statistical significance.
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Results |
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Experiment 1
After thoracic epidural application of bupivacaine (TEA) or saline (TEA-Control), embolization with 0.75 mL/kg clots resulted in fulminant pulmonary embolism in both groups. During embolization, the mean pulmonary artery pressure significantly increased from 15 ± 1 to 48 ± 3 mm Hg (TEA) and from 14 ± 1 to 57 ± 1 mm Hg (TEA-Control), respectively. Compared with the TEA-Control group, the increase in heart rate and mean pulmonary artery pressure was significantly less in the TEA group. The embolism-induced increase in central venous pressure was also less in the TEA group. Despite the same degree of pulmonary artery embolism and the slower heart rate in the TEA group, there were no differences in the cardiac index, indicating a significantly smaller decrease in stroke volume index in the TEA group. Heart rate, stroke volume index, mean pulmonary artery pressure, and central venous pressure of the TEA and TEA-Control group are displayed in Figure 1.
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= TEA group; 
= TEA-Control group. *P < 0.05 versus Control group.The mean arterial pressure in the TEA group was less decreased compared with the TEA-Control group after embolization. However, these differences were not significant. Values of mean arterial pressure and systemic and pulmonary vascular resistance index are displayed in Table 1. Arterial oxygenation was significantly less decreased in the TEA group after pulmonary embolism (Fig. 2). Forelimb temperature significantly increased in the TEA group after epidural bupivacaine application, indicating sympathetic blockade. After embolization, the skin temperature in the front extremity remained at significantly increased levels compared with the Control group, which in contrast showed a decrease in skin temperature of the limbs after embolization.
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In the TEA group, there was a full motor blockade of the forelimbs. Partial motor blockade was observed in the hindlimbs.
The animals in the TEA-Control group were obviously restless and tachypneic, did not eat or drink, and had no stool production during the experiment. By contrast, all of the animals in the TEA group were calm and ate, drank, and had bowel movements at a normal frequency. They were not tachypneic. However, these findings did not result in significant differences in the arterial carbon dioxide levels between the groups in Experiment 1. The dichotomous assessment of observed variables is shown in Table 2.
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Experiment 2
Embolization with 0.625 mL/kg clots produced fulminant pulmonary embolism after lumbar epidural application of bupivacaine or saline. Mean pulmonary artery pressure increased to 56 ± 3 mm Hg in the LEA group and 53 ± 3 mm Hg in the LEA-Control group, respectively (not statistically different). LEA led to significantly increased heart rates compared with the LEA-Control group. Central venous pressure was increased, and arterial oxygenation and stroke volume index were significantly more reduced in the LEA group compared with the LEA-Control group (Figs. 2 and 3). As in Experiment 1, there were no significant differences in cardiac output and mean arterial pressure between the LEA and LEA-Control groups. Hindlimb skin temperature in the LEA group increased after epidural application of bupivacaine, indicating sympathetic blockade at the lumbar levels. However, after embolization, there was no significant difference between the two groups. Front extremity skin temperature did not show any significant differences from the Control group throughout the experiment.
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In the LEA group, motor blockade was restricted to the hindlimbs. There was no front extremity motor block.
All of the animals in the LEA and LEA-Control group were restless and tachypneic, did not eat or drink, and had no stool production during the experiment. The observed variables for Experiment 2 are summarized in Table 2.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The main findings of the present study are that TEA, but not LEA, improved hemodynamic function during pulmonary embolism. Moreover, LEA increased hemodynamic deterioration in this animal model.
Embolization with 0.75 and 0.625 mL/kg blood clots, respectively, resulted in significant increases in mean pulmonary artery pressures, heart rates, and central venous pressures and significant decreases in stroke volume indices and oxygenation versus the respective baseline measurements in awake, spontaneously breathing sheep. The measured values of these variables confirm the production of fulminant but nonlethal pulmonary embolism in this animal model.
Several models of experimental pulmonary embolism in different species have been described, with embolization being performed with autologous blood clots, glass beads, latex or charcoal particles, and Sephadex particles (Pharmacia Biotech, Uppsala, Sweden). Most studies of experimental pulmonary embolism have been conducted with the subjects under general anesthesia. Only a few investigations have been conducted in unanesthetized animals, and most of these have used air embolism models. However, a reproducible model of fulminant nonlethal pulmonary embolism with coagulated autologous blood clots in awake animals, with monitoring of gas exchange as well as pulmonary and systemic circulation, has never been described. In this study, we decided to use sheep, because studies reporting experiments with sepsis and pulmonary embolism have described the species as having similar hemodynamic and pulmonary behavior to that of humans (6,7). To imitate the clinical situation in humans, we used coagulated autologous blood clots instead of foreign bodies for embolization. The sheep remained awake throughout the experiment, to avoid the hemodynamic effects caused by anesthetics.
Different experimental pharmacologic approaches have been used to influence cardiopulmonary function during pulmonary embolism, including inhibition of thromboxane and serotonin synthesis, pharmacologic sympathectomy, and vagotomy (7,8). Some investigations were also conducted in the early 1960s that dealt with bilateral sympathectomy, bilateral vagotomy, and sedation during pulmonary embolism, but the results remained inconsistent (9). However, the effects of epidural anesthesia on cardiopulmonary performance during pulmonary embolism have not been previously reported.
Several studies in humans have dealt with the beneficial effects of achieving stress reduction by reducing sympathetic activation in the thoracic spinal segments (i.e., reducing stress on the heart and lungs), particularly in the perioperative period (10). Experimental and clinical data providing evidence of improved left ventricular function caused by TEA in coronary artery disease, unstable angina pectoris, and myocardial infarction have been published (11–16). Although the use of TEA in patients experiencing pulmonary hypertension has been discussed in some case reports, the data are still insufficient (17,18).
In this experiment, sympathetic blockade of thoracic spinal segments induced by TEA had beneficial effects on cardiopulmonary function. Heart rate remained almost unchanged after embolization. Although the same degree of embolization was achieved in both groups and there were reduced heart rates in the TEA group, there were no differences in the cardiac index between the TEA and Control groups, with a significantly smaller decrease in the stroke volume index in the animals receiving a thoracic sympathetic blockade.
LEA has been associated with several side effects on cardiac function. Reduction of myocardial blood flow distal from coronary artery stenosis, a missing decrease in oxygen demand (as observed during TEA), possibly even an increased oxygen demand by sympathetic activation in nonblocked thoracic segments, and impairment of myocardial wall motion have been reported (5,19–21). In this experiment, LEA resulted in a significant increase in heart rate after embolization compared with the Control group. Reduced arterial pressure values were not observed in the LEA group, and this can be explained by the sitting position resulting from the motor blockade, compensating for the vasodilation induced by sympatholytic drugs in the blocked lumbar segments.
One criticism of the study might be that the extent of the sympathetic blockade was assessed only in a dichotomous manner and was not precisely attributed to different spinal segments. In addition, in the awake animals it was not possible to use transesophageal echocardiography to provide more direct data on ventricular function.
However, these data demonstrate that during pulmonary thromboembolism, LEA has opposite effects on cardiopulmonary function in comparison with TEA. The increased central venous pressure and heart rate and the reduced stroke volume index suggest that there is significant impairment of cardiopulmonary function caused by LEA during pulmonary embolism. These findings support our hypothesis that LEA has disadvantageous effects by increasing sympathetic activation in the unblocked thoracic segments.
Also, the dichotomous assessment of behavioral variables in the animals throughout the experiments provides evidence of an unequivocal minor stress response to pulmonary embolism in animals receiving TEA. All of the animals in the TEA group consumed food and had normal stool production. Similar findings, suggesting beneficial effects of TEA on splanchnic perfusion, have been reported (22).
In this study, we observed beneficial effects produced by TEA, but not LEA, resulting in significantly less deterioration in cardiopulmonary function during a hemodynamic disorder frequently occurring in clinical practice.
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Acknowledgments |
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Supported by an educational grant of Astra-Zeneca GmbH.
The authors gratefully acknowledge the kind support of Dr. Heineke of the Institute for Medical Informatics and Biostatistics of the University for the statistical analysis of the results of this study.
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References |
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