Anesth Analg 2002;94:948-953
© 2002 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
Intrathecal Lidocaine Prevents Cardiovascular Collapse and Neurogenic Pulmonary Edema in a Rat Model of Acute Intracranial Hypertension
Sean R.R. Hall, MSc*,
Louie Wang, MD, FRCPC
,
Brian Milne, MD, FRCPC,
Sally Ford, MD
, and
Murray Hong, PhD*
Departments of *Pharmacology & Toxicology, Anesthesiology, and Pathology, Queen’s University, Kingston, Ontario, Canada
Address correspondence and reprint requests to Murray Hong, PhD, Department of Anesthesiology, Kingston General Hospital, 76 Stuart St., Kingston, Ontario, Canada K7L 2V7. Address e-mail to mglh{at}post.queensu.ca
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Abstract
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Sympathetic hyperactivity during sudden intracranial hypertension leads to cardiovascular instability, myocardial dysfunction, and neurogenic pulmonary edema. Because spinal anesthesia is associated with sympatholysis, we investigated the protective effects of intrathecal lidocaine in a rodent model. Halothane-anesthetized rats were given a 10-µL intrathecal injection of saline (n = 10) or lidocaine 1% (n = 6). A subdural balloon catheter was inflated for 60 s to produce intracranial hypertension. Hemodynamics were monitored, and hearts and lungs were harvested for histological examination. In Saline versus Lidocaine-Treated rats, peak mean arterial blood pressure during balloon inflation was 115 ± 4 mm Hg versus 78 ± 8 mm Hg (P < 0.05), mean arterial blood pressure 30 min after balloon deflation was 47 ± 2 mm Hg versus 67 ± 3 mm Hg (P < 0.05), and lung weight was 1.54 ± 0.03 g versus 1.41 ± 0.04 g (P < 0.05), respectively. Cardiac dysrhythmias and electrocardiographic changes were more frequent in the Saline-Treated group (P < 0.05). Saline-Treated rats had extensive, hemorrhagic pulmonary edema, whereas the Lidocaine-Treated rats had only patchy areas of lung abnormality. Histological changes in the myocardium were rare, and no difference was found between the two groups. We conclude that intrathecal lidocaine prevents cardiovascular collapse and neurogenic pulmonary edema in a rat model of acute intracranial hypertension.
IMPLICATIONS:In a rat model of intracranial balloon inflation, intrathecal lidocaine prevented cardiovascular collapse and neurogenic pulmonary edema. Descending neural pathways are involved in the development of cardiopulmonary complications associated with acute intracranial hypertension.
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Introduction
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A cute head trauma with intracranial hypertension is associated with cardiovascular instability, myocardial dysfunction, and neurogenic pulmonary edema. Most clinically brain-dead patients require inotropic support1, and up to 20% of patients have myocardial injury severe enough to preclude cardiac transplantation (1). Furthermore, 50% of comatose patients with severe acute intracranial injuries develop pulmonary edema (2). Aggressive management of hypotension and hypoxemia is important to prevent aggravation of injury to the brain and other vital organs.
Sympathetic nervous system hyperactivity is the most likely mechanism responsible for the cardiorespiratory complications associated with acute intracranial hypertension. The origin of this response is postulated to be the group of adrenergic neurons that make up the C1 area in the medulla. Transection of the spinal cord caudal, but not cephalad, to this region prevents arterial hypertension during cerebral ischemia (3). Treatment of animals subjected to experimental intracranial hypertension with the ß-adrenergic receptor blocker propanolol prevents inflammatory infiltration of the myocardium (4) and reduces intrapulmonary shunt (5). In primates, myocyte injury associated with intracranial balloon inflation is prevented by surgical sympathectomy (6). In a clinical trial aimed at prevention of intracran-ial hypertension-associated cardiorespiratory complications, the ß-adrenergic blocker atenolol significantly reduced the occurrence of dysrhythmias and myocardial injury in patients with acute head injury (7). However, other modalities of sympatholysis have not been investigated.
The instillation of local anesthetics into the intrathecal space has been used primarily for surgical anesthesia and pain control. A major side effect is hypotension, which is secondary to the blockade of sympathetic activity. However, in the setting of acute brain injury, sympathetic blockade may provide protection against myocardial injury and neurogenic pulmonary edema. The purpose of this study was to determine if intrathecal lidocaine prevents cardiorespiratory complications in a rodent model of increased intracranial pressure (ICP).
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Methods
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All surgical procedures and experiments were conducted in accordance with the guidelines of the Canadian Council on Animal Care and approved by the Queen’s University Animal Care Committee. Adult male Sprague-Dawley rats (300–400 g; Charles River, St. Constant, PQ) were anesthetized using halothane (1%–1.2%) in oxygen and vecuronium (400 µg/kg) and were ventilated with the Harvard rodent respirator (frequency 50 strokes/min, tidal volume 12 mL/kg; Harvard Apparatus, Holliston, MA) via a tracheostomy. Rectal temperature was maintained at 37°C by placing rats on a thermostatically controlled heating pad connected to a temperature controller (Yellow Springs Instruments, Yellow Springs, OH). Mean arterial blood pressure (MAP) was monitored via a left femoral arterial catheter. IV saline infusion (5 mL/kg) and medications were given via a left femoral vein catheter. The rats were positioned prone in a stereotaxic frame (tooth bar–10 mm).
The atlanto-occipital membrane was slit, and a catheter (PE-10) was inserted 3.0 cm into the intrathecal space so that the tip rested at the T1 through T2 vertebrae segment (8). Through burr holes in the skull, a 3F Fogarty catheter was inserted into the left frontoparietal subdural space, and another catheter (PE-50) was placed in the right frontoparietal subdural space to monitor ICP. Holes were sealed with dental cement. ICP and MAP were continuously monitored (Spacelabs Model 90603, Spacelabs Inc, Redmond, WA), and cerebral perfusion pressure (CPP) was calculated (CPP = MAP - ICP). Heart rate (HR) and the electrocardiogram (ECG) were monitored using standard lead II subcutaneous needle electrodes (Grass Model 7 Polygraph, Grass Instruments Co, Quincy, MA).
The rats (n = 6) were treated with intrathecal lidocaine hydrochloride 1% (10 µL), and after 2 min, the subdural balloon catheter was inflated with 0.3 mL of saline for 60 s. ICP, MAP, CPP, HR, cardiac rhythm, and ECG changes were recorded during balloon inflation and at 1 min intervals for the first 5 min and at 5 min intervals for the next 25 min. Dysrhythmias were defined as a cardiac rhythm where there were at least 3 consecutive beats not originating from the sinus node, or a bigeminy or a trigeminy pattern. Control rats (n = 10) were given intrathecal saline (10 µL) before subdural balloon inflation, as described above.
Rats were killed with a halothane overdose. Hearts were perfused in situ with 0.9% saline (4°C) followed by 4% paraformaldehyde (4°C), excised, and stored in 4% paraformaldehyde (4°C) for a minimum of 24 h. Specimens were transferred to a 30% sucrose-phosphate buffered solution (pH 7.4). A 3-mm slice was taken parallel to the atrioventricular groove at the insertion of the papillary muscles. The slices were cut into 4-µm sections and stained with hematoxylin, phloxine, and eosin. A cardiac pathologist, blinded to experimental groups, examined each stained slide under a low power objective using a grid technique to assess the presence of contraction bands and hypereosinophilia. The observations were scored as (a) - = none, (b) ± = rare, seen in occasional fields, (c) + = rare, seen in multiple fields, (d) ++ = seen in approximately half of all fields, (e) +++ = at least one in every field, and (f) ++++ = multiple in every field. Lungs were excised from each rat, rinsed in cold saline (4°C), and weighed using an electronic laboratory bench top balance (Denver Instrument Company, Denver, CO) to determine wet weight in grams before fixation. Brains were excised to determine the extent of injury. Rats were excluded from the study when it was determined that either the subdural balloon catheter punctured the brain or inflation was not maintained over the left frontoparietal cortex.
ICP, MAP, CPP, and HR values are expressed as mean ± SEM. Unpaired Student’s t-tests were used to analyze lung weights and measured variables at baseline, peak, and 30 min postinflation in Lidocaine versus Saline-Treated groups. Fisher’s exact test was used to analyze the frequency of ECG changes and cardiac dysrhythmias. The Mann-Whitney U-test was used to analyze myocardial injury scores. One-way repeated measures analysis of variance and post hoc Student-Newman-Keuls test were used to analyze measured variables across time within treatment groups. Significance was determined at P < 0.05 for all comparisons.
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Results
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Sudden intracranial hypertension induced by subdural balloon inflation resulted in both intracerebral and subdural bleeding in both Control and Lidocaine-Treated rats (Fig. 1). Baseline ICP (13 ± 2 mm Hg), MAP (75 ± 2 mm Hg), and HR (351 ± 13 bpm) in Control rats increased during subdural balloon inflation (peaks were ICP 204 ± 15 mm Hg, MAP 115 ± 4 mm Hg, and HR 390 ± 15 bpm), and CPP was abolished because ICP was more than MAP (Fig. 2A–D). ICP rapidly declined after balloon deflation but remained above baseline levels for the duration of the experiments. There was an initial rapid decline followed by a slower decline in MAP; MAP was 47 ± 2 mm Hg at 30 min postinflation. HR returned to baseline by 1 min postinflation and continued to decline to 272 ± 7 bpm at 30 min. CPP was 12 ± 3 mm Hg at 30 min postinflation, indicating markedly impaired cerebral perfusion.
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Figure 1. Photomicrograph of rat brain sections, illustrating the typical extent of trauma taken from an experimental animal 30 min after a 60 s inflation of a subdural catheter over the left frontoparietal lobe. Starting at the optic chiasm (C), 2-mm coronal slices were taken in both the rostral and caudal direction (A-F). Note the increasing size of the intracerebral hemorrhage from rostral to caudal coronal sections (arrow head).
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Figure 2. Effect of a 60 s subdural balloon inflation over the left frontoparietal lobe on (A) intracranial pressure (ICP, mm Hg), (B) mean arterial blood pressure (MAP, mm Hg), (C) cerebral perfusion pressure (CPP, mm Hg), and (D) heart rate (HR, bpm) in rats pretreated with intrathecal saline (•, n = 10) or intrathecal lidocaine 1% (10 µL) ( , n = 6). Each point represents the mean ± SEM, * P < 0.05, within Saline and Lidocaine-Treatment groups compared with preinflation levels. # P < 0.05, intrathecal saline versus intrathecal lidocaine at peak and 30 min postinflation.
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Intrathecal lidocaine did not change baseline MAP (from 86 ± 4 mm Hg to 67 ± 7 mm Hg, P = 0.07, Fig. 2B), HR (from 354 ± 20 bpm to 314 ± 17 bpm, P = 0.269, Fig. 2D), or ICP (from 18 ± 4 mm Hg to 17 ± 3 mm Hg, P = 0.982, Fig. 2A). ICP increased during subdural balloon inflation, but unlike the Control rats, MAP and HR did not change (peaks were ICP 147 ± 15 mm Hg, MAP 78 ± 8 mm Hg, and HR 318 ± 14 bpm). Peak ICP in the Lidocaine group was less than that in the Control group; nonetheless, CPP was zero throughout the period of balloon inflation. The temporal profile of ICP after balloon deflation was similar to that in the Control rats, but this was not so for MAP and HR. MAP rapidly declined after balloon deflation but was sustained at baseline levels thereafter; MAP at 30 min postinflation (67 ± 3 mm Hg) was more than that in the Control group. HR initially decreased after balloon deflation, reaching a nadir at 2 min postinflation. HR increased thereafter, and at 30 min, HR (344 ± 30 bpm) was more than that in the Control rats. CPP after balloon deflation was greater in the Lidocaine versus Saline groups (31 ± 7 mm Hg versus 12 ± 3 mm Hg at 30 min, respectively), mirroring the difference in MAP.
Cardiac dysrhythmias and ECG abnormalities, such as premature ventricular contractions, Q waves, and ST-segment or T wave changes, were more frequent in Saline versus Lidocaine-Treated rats (Table 1). Most abnormalities appeared during balloon inflation or within the first 5 min after deflation. A typical ECG trace is shown in Figure 3.
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Figure 3. Electrocardiographic (ECG) tracings (lead II) obtained from rat pretreated with (A) intrathecal saline and (B) intrathecal lidocaine 1% at baseline, peak, and postsubdural balloon inflation. ECG abnormalities were present in the Saline-Treated rats during peak and postsubdural balloon inflation but absent in the Lidocaine-Treated rats.
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Extensive bilateral, hemorrhagic pulmonary edema was evident upon gross examination in Control rats and was confirmed histologically (Fig. 4A). In contrast, Lidocaine-Treated rats had only patchy areas of gross and microscopic abnormality (Fig. 4B). Lung weight in the Control group (1.54 ± 0.03 g) was more than that in the Lidocaine group (1.41 ± 0.04 g), confirming the development of more extensive pulmonary edema in the Control group.
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Figure 4. (A) Photomicrograph of the lung taken from a Saline-Treated rat after increased intracranial pressure (ICP). Pulmonary edema is evidenced by widening of the perivascular space (arrow). (B) Normal lung taken from a rat pretreated with intrathecal lidocaine 1%. Note that there is no expansion of the perivascular space.
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Microscopic examination of the hearts demonstrated contraction band necrosis and hypereosinophilia; however, these pathophysiologic changes were observed only rarely in the majority of the specimens. No difference was found between Lidocaine and Control groups (Table 2).
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Discussion
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The results demonstrate that intrathecal lidocaine prevents hemodynamic changes in a rat model of acute intracranial hypertension. Because lidocaine blocks neural transmission, our results are in agreement with those of Dampney et al. (3) who demonstrated the prevention of hypertension by cord transection in a rabbit model of cerebral ischemia. The development of cardiovascular collapse and neurogenic pulmonary edema in Control but not Lidocaine-Treated rats suggest that the hypertensive response during cerebral ischemia plays an important role in the development of subsequent cardiorespiratory complications.
The hypertensive response to acute intracranial hypertension is associated with massive increases in plasma catecholamines (9,10). The prevention of cardiorespiratory complications in our study was most likely a result of a lidocaine-mediated blockade of sympathetic neural transmission; however, this was not confirmed because sympathetic activity was not directly measured. The decreased frequency of cardiac dysrhythmias and ECG changes in Lidocaine-Treated rats is similar to the observations by Novitzky et al. (6) who showed the prevention of dysrhythmias and ischemic ECG changes by total cardiac sympathectomy in a baboon model of intracranial balloon inflation. Colgan et al. (5) demonstrated that blockade of ß-adrenergic activity with propanolol reduces pulmonary vascular pressures and intrapulmonary shunt in a dog model of intracranial hypertension. These results support the contention in our study that intrathecal lidocaine prevented the development of neurogenic pulmonary edema by blockade of sympathetic activity.
Peak ICP in Control rats was more than that in the Lidocaine-Treated rats despite similar intracranial manipulations. It is unlikely that this accounts for the observed differences in hemodynamic variables and cardiorespiratory complications because both groups of animals had no cerebral perfusion during balloon inflation. Acute hypertension in the Control group could increase cerebral blood volume and contribute to an increase of ICP; this hypertensive response was absent in the Lidocaine-Treated rats and would account for the decreased ICP during balloon inflation.
Pathophysiologic changes in myocardial histology were observed rarely in both the Control and Lidocaine-Treated rats, and no difference was observed between the two groups. These results are in contrast to those of Hunt and Gore (4) who showed a reduction in inflammatory myocardial infiltrates in propanolol-treated rats with intracranial hemorrhage. However, these authors did not find any evidence of muscle damage. Heart specimens were harvested five days after cranial injury, whereas in our study, the hearts were harvested after thirty minutes. The longer duration may be required before histological changes become evident.
In conclusion, our study demonstrated that acute intracranial hypertension produces dramatic hemodynamic changes in a rat model of intracranial balloon inflation. Intrathecal lidocaine prevents these changes and protects against the subsequent development of cardiovascular collapse and neurogenic pulmonary edema.
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Acknowledgments
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Supported, in part, by a grant from the Canadian Anesthesiologists’ Society and the Garfield Kelly Cardiovascular Research Foundation at Queen’s University.
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Footnotes
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1 Ali MJ, Wood G, Gelb AW. Organ donor problems and their management: a four year review of a Canadian transplant centre [abstract]. Can J Anaesth 1992;39:A125. 
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Accepted for publication November 14, 2001.
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Abstract
Introduction
