Cardiac arrhythmias accompanying acute compression of the spinal cord

Transcription

1 J Neurosurg 52:52-59, 1980 Cardiac arrhythmias accompanying acute compression of the spinal cord DELBERT E. EVANS, PH.D., ARTHUR I. KOBRINE, M.D., AND HUGO V. RIZZOLI, M.D. Neurobiology Department, Armed Forces Radiobiology Research Institute, Bethesda, Maryland, and Department of Neurological Surgery, George Washington University Medical Center, Washington, D.C. This study was undertaken to determine the cardiovascular response to compression of the spinal cord and to determine the autonomic mechanisms involved. The electrocardiogram and arterial blood pressure were recorded in anesthetized monkeys during inflation of a balloon catheter in the epidural space of the mid-thoracic region. Acute spinal cord compression resulted in a wide variety of severe cardiac arrhythmias and acute hypertension. The arrhythmias were found to result from hyperactivity of both the sympathetic and parasympathetic divisions of the autonomic nervous system. KEY WORDS 9 spinal cord compression 9 cardiac arrhythmias 9 autonomic nervous system 9 acute hypertension 9 sympathetic nervous system 9 parasympathetic nervous system p REVIOtJS research has established that hyperactivity of the autonomic nervous system can cause alterations in blood pressure and disturbances in cardiac rhythm. In 1930, Beattie and colleagues 2 demonstrated that cardiac arrhythmias could be induced by stimulation of the hypothalamus. Since that time, considerable evidence has accumulated to show that either sympathetic or parasympathetic stimulation can induce cardiac arrhythmias?,15 It has also been shown that simultaneous activation of both divisions of the autonomic nervous system is more effective in causing arrhythmias than stimulation of either division alone. TM Furthermore, there is evidence that almost every type of clinically occurring cardiac arrhythmia can be experimentally induced by stimulation of the autonomic nervous system? 9 In recent years, studies have shown a significant involvement of the autonomic nervous system in various types of cardiac arrhythmias, including those accompanying digitalis intoxication, 11,~2 myocardial infarction, 3,4 and intracranial hemorrhage and stroke. ~~ Thus, it is not surprising that trauma to the nervous system may also result in cardiac arrhythmias and other cardiovascular changes. For example, we recently reported 7 that experimental head injury in the rhesus monkey consistently caused a variety of severe cardiac arrhythmias that were mediated by both sympathetic and parasympathetic mechanisms. The present study assessed the cardiovascular changes resulting from acute injury to the thoracic spinal cord. Our goals were to determine the severity and frequency of cardiac arrhythmias and blood pressure changes resulting from acute spinal cord compression, and to determine the autonomic mechanisms responsible for the cardiovascular changes observed. To produce a consistent degree of injury, we developed an animal model in which neuronal dysfunction of the spinal cord was assessed by recording evoked responses; spinal cord blood flow (SCBF) was measured by the hydrogen clearance technique. Materials and Methods Surgical and Monitoring Procedures Thirteen macaque monkeys, each weighing 3 to 4.5 kg, were initially anesthetized with phencyclidine hydrochloride (10 mg intramuscularly). Catheters were inserted into the femoral artery for recording blood pressure, and into the femoral vein for administering drugs; anesthesia was maintained for the duration of the experiment by intravenous administration of alpha-chloralose (100 mg/kg). A small-animal respirator controlled ventilation after the monkeys were intubated. At frequent intervals throughout the experiment, arterial blood gases and ph were deter- 52 J. Neurosurg. / Volume 52 / January, 1980

2 Cardiac arrhythmias in acute cord compression mined and kept within normal physiological limits by adjusting the rate and tidal volume of the respirator. Esophageal temperature was monitored and maintained at 37 ~ to 38~ by intermittent use of a heating pad. The electrocardiogram (Lead II) and arterial blood pressure were recorded continuously. The monkeys were placed in a stereotaxic apparatus and surgical exposures of the left sciatic nerve and the dura mater at C1-2 were made. Spinal evoked responses were obtained by application of electrical stimuli (10 V for 1 msec at 1 Hz) to the sciatic nerve and application of a bipolar recording electrode to the intact dura at C-1. Evoked responses were amplified by a differential amplifier, displayed on an oscilloscope,* and averaged by a computer of average transients. While the animal was at a surgical level of anesthesia, pancuronium bromide (0.1 mg/kg) was administered intravenously to prevent muscle movement during stimulation of the sciatic nerve. To record SCBF and to compress the spinal cord, we performed small laminotomies at T-6 and T-9. Using hydrogen clearance techniques described previously) 7 we inserted a platinum electrode into the left dorsal column at T-6 to measure blood flow. A mixture of hydrogen and oxygen was added to the inspired air during blood flow determinations, and the inspired oxygen concentration was measured to insure a minimum concentration of 21%. Blood flows were calculated from the tissue washout curve obtained after hydrogen breathing was terminated. Spinal Cord Compression In preparation for spinal cord compression, a No. 3 Fogarty catheter was inserted into the epidural space lateral to the spinal cord on the right side and advanced cephalad so that the uninflated balloon was positioned at approximately T-5. After obtaining control measurements of SCBF and spinal evoked responses, the spinal cord was acutely compressed by inflation of the balloon catheter with 0.2 to 0.25 ml of water. In separate animals, the balloon was inflated for periods of 1, 3, and 7 minutes. These periods of compression were used for determining whether the duration of compression altered the cardiovascular response. To determine the autonomic mechanisms involved in the cardiovascular response to spinal cord compression, the experimental design included repeated compression of the spinal cord after administering autonomic blocking drugs. The repeated compressions were made only after heart rate and blood pressure had returned to normal values. In untreated animals, repeated compression consistently produced arrhythmias and blood pressure responses similar to those *Tektronix Model 3A61 amplifier and Tektronix Model 565 oscilloscope manufactured by Tektronix, Inc., Beaverton, Oregon. FIG. 1. The effects of spinal cord compression on spinal evoked response and spinal cord blood flow (SCBF). Upper Tracing." Control SCBF = 13 ml/min/100 gm Lower Tracing." During balloon compression, SCBF =0.' that occurred after the initial compression. The effects of atropine (0.4 mg/kg) and propranolol (1.0 mg/kg) were studied in six animals, and the effects of phenoxybenzamine (5.0 mg/kg) and atropine (0.4 mg/kg) were studied in three animals. Each of the 13 animals in this study was used for a single, acute experiment. At the termination of experiments, animals were sacrificed by intravenous administration of potassium chloride. Results Effects of Spinal Cord Compression In all animals, inflation of the balloon eliminated the spinal cord evoked response and reduced the SCBF to zero within 1 minute (Fig. 1). Thus, the degree of compression was sufficient to disrupt both neuronal conduction and perfusion in the affected area. Acute compression of the midthoracie spinal cord resulted in a wide variety of severe cardiac arrhythmias, which were accompanied by acute hypertension. Figure 2 is an example of the blood pressure and electrocardiographic changes induced by spinal cord compression. The initial response was usually sinus or atrioventricular (AV) nodal bradycardia, beginning within one heart beat of spinal cord compression. These initial arrhythmias often preceded any change in arterial blood pressure, although blood pressure rose quickly thereafter, often doubling systolic and diastolic levels within 30 seconds after compression. The initial bradycardias were followed J. Neurosurg. / Volume 52 / January,

3 D. E. Evans, A. I. Kobrine and H. V. Rizzoli TABLE 1 Effects of spinal compression on cardiovaseular fimction* Duration of ComPression (rain) Max Reduction in Heart Rate total Max Increase Max Increase Onset of Duration of No. in Systolic in Diastolic Arrhythmias Arrhythmias of BP (ram Hg) BP (ram Hg) (sec) (rain) Animals *Values are means standard error. by premature AV nodal or ventricular beats, AV dissociation, or ventricular tachycardias. Bigeminal and trigeminal rhythms also occurred. The blood pressure and heart rate changes and the onset and duration of arrhythmias for all animals are summarized in Table 1. The changes in heart rate and mean blood pressure caused by compressions lasting 1, 3, and 7 minutes are plotted in Fig. 3. The data from Table 1 and Fig. 3 indicate that the duration of compression was not a determining factor in the cardiovascular changes resulting from spinal cord compression. FIG. 2. The effects of spinal cord compression on blood pressure (B.P.) and electrocardiogram (ECG). A utonomic Mechanisms To determine the mechanisms responsible for the arrhythmias and acute hypertensive response, the spinal cord was repeatedly compressed after the administration of autonomic blocking drugs. The effects of cholinergic and beta-adrenergic blocking agents were studied in six animals, and an example of the results in one animal is illustrated in Figs. 4, 5, and 6. Figure 4 illustrates the control response before the drugs were administered. In this animal, spinal compression caused an immediate sinus arrest and emergence of an AV nodal bradycardia. At 90 seconds there was a fast multifocal arrhythmia that became a continuous tachycardia within 3 minutes. Figure 5 illustrates the response in the same animal after administration of atropine. In contrast to the control response, spinal cord compression initially produced no bradycardia; however, at 90 seconds arrhythmias began to occur. Figure 6 illustrates the response in the same animal after subsequent administration of propranolol. After cholinergic and beta-adrenergic blockade, both the initial bradycardias and the later tachycardias were prevented. These results were consistently found after administration of both drugs. In each of six animals studied, atropine was found to eliminate the initial bradycardia, and subsequent administration of propranolol was found to prevent any arrhythmias from occurring after spinal cord compression. 54 J. Neurosurg. / Volume 52 / January, 1980

4 Cardiac arrhythmias in acute cord compression FIG. 3. The effects of compression of 1, 3, and 7 minutes' duration on heart rate and mean blood pressure (mm Hg). FIG. 4. The effects of spinal cord compression on blood pressure (B.P.), heart rate, and electrocardiogram (ECG). FIG. 5. The effects of atropine on the cardiovascular response to spinal cord compression. B.P. = blood pressure; ECG = electrocardiogram. J. Neurosurg. / Volume 52 / January,

5 D. E. Evans, A. I. Kobrine and H. V. Rizzoli TABLE 2 Effeets of autonomic bloeking drugs on eardiae arrhythmias induced by spinal cord compression Autonomic No. of Compres- Change in Blood Arrhythmias Blockers* sions Pressure none 13 increase initial nodal bradycardia; multifocal tachycardias atrophine 6 increase no bradycardia; multifocal tachycardias atropine and propranolol 6 increase no arrhythmias phenoxybenzamine 3 no change bradycardia phenoxybenzamine and atropine 3 no change no bradycardia *Dosage of blocking agents: atropine (0.4 mg/kg); propranolol (1.0 mg/kg); phenoxybenzamine (5.0 mg/kg). Fla. 6. The effects of atropine and propranolol on the cardiovascular response to spinal cord compression. B.P. = blood pressure; ECG = electrocardiogram. Results of the preceding experiments indicated that the arrhythmias resulting from spinal cord compression were mediated by both cholinergic (vagal) and beta-adrenergic mechanisms. To determine whether the vagally mediated bradycardias were reflexly evoked by the elevation of blood pressure, we conducted three experiments in which the acute hypertensive response was eliminated by the administration of the alpha-adrenergic blocking agent, phenoxybenzamine. Figure 7 illustrates the results of one of these experiments. Before the drug was given, spinal compression resulted in the usual bradycardias and an increase in blood pressure. After administration of phenoxybenzamine, the rise in blood pressure was prevented but the initial bradycardia still occurred. The subsequent administration of atropine eliminated the bradycardia. This result was found in each of the three animals studied. The effects of autonomic blocking agents on cardiac arrhythmias induced by spinal cord compression are summarized in Table 2. Discussion These experiments have demonstrated that severe cardiac arrhythmias and hypertensive episodes consistently occur in primates after acute compression of the mid-thoracic spinal cord. The initial sinus or AV bradycardias appeared to be mediated by the parasympathetic nervous system because they were eliminated by cholinergic blockade. The diverse and severe arrhythmias that followed appeared to be the result of both sympathetic and parasympathetic hyperactivity. Evidence of this was the finding that both beta-adrenergic and cholinergic blocking agents were necessary to eliminate these arrhythmias. The acute hypertensive response resulted from sympathetically mediated vasoconstriction because the response was eliminated by alpha-adrenergic blockade. There are several mechanisms by which spinal cord compression induces hyperactivity of the autonomic nervous system. The sympathetic hyperactivity has been shown to result from direct mechanical stimulation of the descending sympathetic nerves; 1 the mechanisms responsible for activation of the parasympathetic nervous system are more complex. Although the initial bradycardias were mediated by the vagus nerves, they were not reflexly initiated by the elevation of blood pressure. This conclusion is based on the observation that these arrhythmias often occurred before blood pressure was eliminated by alpha-adrenergic blockade. Thus, it is likely that stimulation of spinal afferent pathways to medullary cardiovascular centers initiated the vagal hyperactivity that caused the initial arrhythmias. It is probable, however, that baroreceptor-induced vagal hyperactivity may have contributed to the arrhythmias that later occurred after the blood pressure was elevated. Based on the preceding evidence, we believe that the arrhythmias resulting from spinal cord compression are caused by the following mechanisms. Compression produces mechanical deformation with resulting injury to both afferent and efferent tracts of the autonomic nervous system. Injury of afferent nerves 56 J. Neurosurg. / Volume 52 / January, 1980

6 Cardiac arrhythmias in acute cord compression FIG. 7. The effects of phenoxybenzamine and atropine on the cardiovascular response to spinal cord compression. B.P. = blood pressure; ECG = electrocardiogram. causes, by way of medullary reflex pathways, an immediate burst of vagal hyperactivity resulting in sinus or AV nodal bradycardia. Efferent sympathetic nerves are concurrently injured, causing diffuse stimulation of the heart and vasculature. This widespread sympathetic stimulation causes increases in heart rate, contractile force of the heart, and blood pressure. The elevated blood pressure, in turn, causes increased baroreceptor discharge, which causes, by reflex, augmentation of vagal hyperactivity to the heart. The autonomic imbalance caused by the simultaneous hyperactivity of sympathetic and parasympathetic nerves to the heart causes the severe multifocal arrhythmias. There is experimental evidence that such interactions of the autonomic nervous system can cause cardiac arrhythmias. 9,13 For example, we recently reported that electrical stimulation of the ventro- J. Neurosurg. / Volume 52 / January,

7 D. E. Evans, A. I. Kobrine and H. V. Rizzoli medial hypothalamus induced a sharp rise in heart rate and blood pressure, which was followed by severe multifocal arrhythmias after the stimulus was terminated. 9 Recordings from cardiac vagal nerves revealed bursts of neural activity concurrent with the arrhythmias. In that series of experiments, it was determined that these arrhythmias resulted from baroreceptor-induced vagal hyperactivity, which occurred during a period of increased sympathetic stimulation of the heart and vasculature. The arrhythmias resulting from hypothalamic stimulation were similar to those seen in the present study after spinal cord compression. In the present study, we did not identify the specific tracts that, when compressed, led to the cardiovascular responses. There is evidence, however, that the descending sympathetic tracts in the peripheral areas of the lateral funiculus primarily mediate vasopressor responses, 16 whereas those in the intermediolateral cell column exert direct cardiac effects? ~ Afferent fibers mediating both pressor and depressor functions have also been identified in the spinal cord? 6 It is likely that all of these tracts were involved in mediating the cardiovascular response to spinal cord compression. Other investigators have observed cardiovascular changes after various types of experimental spinal cord injury. Alexander and Kerr 1 observed in cats and monkeys that compression of the spinal cord at various levels produced rapid and pronounced increases in blood pressure. The pressor responses were greatest when the upper thoracic regions of the spinal cord were compressed. Bradycardia accompanied the rise in blood pressure, but no other arrhythmias were noted. Greenhoot and Mauck TM observed marked pressor responses, bradycardia, and a variety of multifocal arrhythmias in dogs after dropping a weight on the exposed cervical spinal cord. The cardiac arrhythmias could be eliminated by atropine or bilateral vagotomy, and thus, the authors concluded that the arrhythmias resulted from the combination of sympathetic and parasympathetic influences on the heart, the latter being reflexes evoked by the elevated arterial blood pressure. Eidelberg ~ also described pressor responses, bradycardia, and other arrhythmias that were associated with the application of a weighted foot to various levels of the spinal cord in cats. However, he found that atropine did not eliminate the bradycardia, and that neither hexamethonium (a ganglionic blocker) nor propranolol eliminated the other arrhythmias. In contrast, phenoxybenzamine eliminated the arrhythmias as well as the pressor responses. Eidelberg concluded that the arrhythmias were due to a "sudden overload imposed on the left ventricle." Results from the present study are in basic agreement with the conclusions of Greenhoot and Mauck, TM with the exception that they did not observe an initial bradycardia occurring before a rise in blood pressure. Our results are in conflict with those of Eidelberg 5 because we found evidence that cholinergic and betaadrenergic mechanisms mediated the arrhythmias after spinal compression. An explanation for Eidelberg's observation that neither the acute hypertension nor the arrhythmias could be blocked by hexamethonium may be that this drug is reported to block only nicotinic transmission through autonomic ganglia. 1~ To completely block transmission through cardiac autonomic ganglia, one must use both nicotinic (hexamethonium) and muscarinic (atropine) blocking agents. VanderArk, et al., ~3 observed similar pressor responses and cardiac arrhythmias following inflation of a balloon in the fourth ventricle. The arrhythmias could not be prevented by either beta-adrenergic blockade or atropine alone, but could be eliminated by combined sympathetic and parasympathetic blockade. Thus, these investigators concluded that the arrhythmias following experimental brain compression were the result of excessive sympathetic and parasympathetic stimulation to the heart. We have concluded from the present study that similar mechanisms are responsible for the cardiac arrhythmias induced by spinal cord compression. With regard to the clinical implications of the present study, several points should be considered. The frequency with which spinal cord compression in the monkey causes acute hypertensive episodes and severe cardiac arrhythmias suggests that similar cardiovascular events are a common occurrence in clinical cases of spinal cord injury. This could result in a number of problems of clinical significance. First, the acute hypertension could cause an increase in the amount of hemorrhage and edema surrounding the spinal cord lesion. Acute hypertension has been shown to increase edema and neuronal damage following experimental spinal cord injury. 21 Second, the occurrence of severe cardiac arrhythmias immediately after spinal cord injury may in itself be life threatening. Other precipitating factors, such as pre-existing heart disease or emotional stress and respiratory depression that may occur concurrently with traumatic spinal cord compression, would be expected to facilitate the development of fatal cardiac arrhythmias. 6,~ In addition to arrhythmias, myocardial necrosis might also occur if sympathetic hyperactivity persists for a period of hours or days after spinal injury. This type of myocardial damage has been observed after intracranial hemorrhage, and has been attributed to high levels of circulating catecholamines. 24 In the present study, autonomic hyperactivity was found to occur during the acute phase of spinal cord injury, but whether elevated levels of circulating catecholamines persist for an extended period of time is not known. With regard to the treatment of cardiovascular problems associated with spinal cord injury, there is little experimental evidence. Although we used a corn- 58 J. Neurosurg. / Volume 52 / January, 1980

8 Cardiac arrhythmias in acute cord compression bination of autonomic blocking drugs to prevent the pressor responses and cardiac arrhythmias following experimental spinal cord injury, it has not been determined whether these agents could be used with safety in the clinical situation. Further investigation is necessary to develop a rational therapeutic approach to the treatment of cardiovascular dysfunction associated with spinal cord injury. Acknowledgments The authors would like to express their appreciation to Mr. Victor Kieffer for technical assistance, Mr. John Polen for data reduction, Mr. Guy Bateman for the illustrations, and E. S. Grunewald and Mary M. Matzen for editorial assistance. References 1. Alexander S, Kerr FWL: Blood pressure responses in acute compression of the spinal cord. J Neurosurg 21: , Beattie J, Brow GR, Long CNH: The hypothalamus and the sympathetic nervous system. Res Pub Assoc Nerv Ment Dis 9: , Corr PB, Gillis RA: Autonomic neural influences on the dysrhythmias resulting from myocardial infarction. Circ Res 43:1-9, Corr PB, Gillis RA: Effect of autonomic neural influences on the cardiovascular changes induced by coronary occlusion. Am Heart J 89: , Eidelberg EE: Cardiovascular response to experimental spinal cord compression. J Neurosurg 38: , Engel GL: Psychologic stress, vasodepressor (vasovagal) syncope, and sudden death. Ann Intern Med 89: , Evans DE, Alter WA III, Shatsky SA, et al: Cardiac arrhythmias resulting from experimental head injury. J Neurosurg 45: , Evans DE, Gillis RA: Effect of diphenylhydantoin and lidocaine on cardiac arrhythmias induced by hypothalamic stimulation. J Pharmacol Exp Ther 191: , Evans DE, Gillis RA: Reflex mechanisms involved in cardiac arrhythmias induced by hypothalamic stimulation. Am J Physiol 234:HI99-H209, Flacke W, Gillis RA: Impulse transmission via nicotinic and muscarinic pathways in the stellate ganglion of the dog. J Pharmacol Exp Ther 163: , 1968 I 1. Gillis RA, Helke C J, Kellar K J, et al: Autonomic nervous system actions of cardiac glycosides. Biochem Pharmacol 27: , Gillis RA, Quest JA: Neural actions of digitalis. Annu Rev Med 29:73-79, Gillis RA, Raines A, Sohn Y J, et al: Neuroexcitatory effects of digitalis and their role in the development of cardiac arrhythmias. J Pharmacol Exp Ther 183: , Greenhoot JH, Mauck HP Jr: The effect of cervical cord injury on cardiac rhythm and conduction. Am Heart J 83: , Gunn CG, Sevelius G, Puiggari M J, et al: Vagal cardiomotor mechanisms in the hindbrain of the dog and cat. Am J Physiol 214: , Kerr FWL, Alexander S: Descending autonomic pathways in the spinal cord. Arch Neurol 10: , Kobrine AI, Doyle TF, Martins AN: Spinal cord blood flow in the rhesus monkey by the hydrogen clearance method. Surg Neurol 2: , Manning JW, Cotten MdeV: Mechanism of cardiac arrhythmias induced by diencephalic stimulation. Am J Physioi 203: , Mauck HP Jr, Hockman CH: Central nervous system mechanisms mediating cardiac rate and rhythm. Am Heart J 74:96-109, Norris JW, Froggatt GM, Hachinski VC: Cardiac arrhythmias in acute stroke. Stroke 9: , I. Rawe SE, Lee WA, Perot PL Jr: The histopathology of experimental spinal cord trauma. The effect of systemic blood pressure. J Neurosurg 48: , VanderArk GD: Cardiovascular changes with acute subdural hematoma. Surg Neurol 3: , VanderArk GD, Norton LW, Pomerantz M: The effects of brain stem compression on the heart. Surg Neurol 2: , Weidler D J: Myocardial damage and cardiac arrhythmias after intracranial hemorrhage. A critical review. Stroke 5: , Wolf S: Central autonomic influences on cardiac rate and rhythm. Mod Concepts Cardiovasc Dis 38:29-34, Wurster RD: Spinal sympathetic control of the heart, in Randall WC (ed): Neural Regulation of the Heart. New York: Oxford University Press, 1977, pp Address reprint requests to." Delbert E. Evans, Ph.D., Hyperbaric Medicine Program Center, Naval Medical Research Institute, Bethesda, Maryland J. Neurosurg. / Volume 52 / January