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Central dexmedetomidine attenuates cardiac dysfunction in a rodent model of intracranial hypertension

[La dexmédétomidine centrale atténue la dysfonction cardiaque chez un modèle rongeur d’hypertension intracrânienne]

Sean R. R. Hall, MSc^*, Louie Wang, MD, Brian Milne, MD and Murray Hong, PhD

^* From the Departments of Anesthesiology,
Pharmacology and Toxicology, Queen’s University, Kingston, Ontario, Canada.

Address correspondence to: Dr. Louie Wang, Department of Anesthesiology, Queen’s University, Kingston General Hospital, 76 Stuart Street, Kingston, Ontario K7L 3N6, Canada. E-mail: wangl{at}kgh.kari.net

	Abstract

TOP Abstract Introduction Methods Results Discussion References

 
Purpose: To determine if central sympathetic blockade by dexmedetomidine, a selective alpha₂ adrenergic receptor agonist, prevents cardiac dysfunction associated with intracranial hypertension (ICH) in a rat model.

Methods: Following intracisternal administration of dexmedetomidine (1 µg•µL^–1, 10 µL volume) or the stereoisomer levomedetomidine (1 µg•µL^–l, 10 µL volume) in halothane-anesthetized rats, a subdural balloon catheter was inflated for 60 sec to produce ICH. Intracranial pressure, hemodynamic, left ventricular (LV) pressures and electrocardiographic (ECG) changes were recorded. Plasma and myocardial catecholamines and malondialdehyde (MDA) levels were measured.

Results: After levomedetomidine administration, subdural balloon inflation precipitated an increase in mean arterial pressure (149 ± 33% of baseline), heart rate (122 ± 19% of baseline), LV systolic pressure (LVP), LV end-diastolic pressure (LVEDP), LV developed pressure (LVDP), LV dP/dtmax and rate pressure product (RPP) (132 ± 19%, 260 ± 142%, 119 ± 15%, 126 ± 24% and 146 ± 33% of baseline value, respectively). ICH decelerated LVP fall (), as increased from 7.75 ± 1.1 to 14.37 ± 4.5 msec. Moreover, plasma norepinephrine levels were elevated (169 ± 50% of baseline) and there was the appearance of cardiac dysrhythmias and other ECG abnormalities. This response was transient and cardiac function deteriorated in a temporal manner. Intracisternal dexmedetomidine prevented the rise in plasma norepinephrine, blocked the ECG abnormalities, and preserved cardiac function. Moreover, dexmedetomidine attenuated the rise in MDA levels.

Conclusions: The results demonstrate that dexmedetomidine attenuates cardiac dysfunction associated with ICH. Our results provide evidence for the role of central sympathetic hyperactivity in the development of cardiac dysfunction associated with ICH.

	Introduction

TOP Abstract Introduction Methods Results Discussion References

 
IT is well established that traumatic brain injury with intracranial hypertension (ICH) initiates a cascade of deleterious events that result in cardiac dysfunction^1,2 and the development of pulmonary edema.³ Most clinically brain-dead patients require inotropic therapy to support a failing circulatory system to facilitate organ procurement for transplantation. In some instances, the resulting cardiovascular functional changes may be severe enough to preclude cardiac transplantation⁴ or significantly influence the perioperative course.^5–7

In experimental animals, a sudden increase in intracranial pressure (ICP) results in hemodynamic perturbations, as well as significant electrocardiographic (ECG) abnormalities^8,9 that correspond well with elevated levels of plasma norepinephrine and epinephrine.^9,10 However, this hyperdynamic phase following the catecholamine surge is transient and leads to cardiovascular collapse. Clinical^1,11 and experimental^9,12–14 studies have shown that in dysfunctional hearts there is histological evidence of cardiomyocyte injury characteristic of catecholamine-mediated cardiac necrosis.¹⁵ However, the contribution this makes to the impairment in cardiac function is unclear.

The origin of the sympathoexcitatory response is postulated to be dependent upon the C1 medullary nuclei located within the rostral ventrolateral medulla (RVLM).^16,17 The RVLM provides an important input to sympathetic preganglionic neurons and serves as a major site mediating the sympatholytic effects of alpha₂ adrenergic receptor agonists.^18,19 Although blocking sympathetic activity with peripheral beta-receptor blockade,^20,21 cardiac sympathectomy¹² or spinal anesthesia²² protect the cardiovascular system from the deleterious effects of acute ICH, it is not known whether central sympatholysis affords the same protection.

Dexmedetomidine is a highly selective alpha₂ adrenergic receptor agonist that acts preferentially on the C1 medullary area to reduce central sympathetic tone¹⁸ and modulate central cardiovascular responses.²³ The goal of this study was to test the hypothesis that inhibition of sympathetic activity by intracisternal dexmedetomidine prevents cardiac dysfunction following ICH in rats.

	Methods

TOP Abstract Introduction Methods Results Discussion References

 
Anesthesia and monitoring
All surgical procedures and experiments were conducted in accordance with the guidelines of the Canadian Council on Animal Care and the Queen’s University Animal Care Committee. Adult male Sprague-Dawley rats (300–350 g, n = 19, Charles River, St-Constant, QC, Canada) were intubated for mechanical ventilation (Harvard Rodent respirator: frequency = 50/min) and anesthetized with halothane (4% induction, 1–1.2% maintenance, Capnomac Ultima, Datex, Helsinki, Finland) in oxygen. Body temperature was maintained at 37°C with a thermostatically controlled heating pad (Yellow Springs Instruments, OH, USA). Mean arterial pressure (MAP) was monitored via a right femoral arterial catheter (PE-50). Intravenous saline infusion (1.5 mL•hr^–1) and vecuronium bromide (1 mg•mL^–1, Abbott Laboratories, Saint-Laurent, QC, Canada) for muscle paralysis were administered via a right femoral vein catheter (PE-50).

Measurements of in vivo cardiac function
A catheter (PE-50) was inserted via the right common carotid artery, into the left ventricle (LV). LV contractile function was assessed by measuring LV systolic pressure (LVP), LV developed pressure (LVDP = LVP-LVEDP), the maximum rate of LV pressure rise (LV dP/dt_max) and t_d, the time from the onset of contraction to dP/dt_max.²⁴ Rate-pressure product [RPP = heart rate (HR) x LVDP] was used as a measure of cardiac performance. LV relaxation was assessed by measuring LV end-diastolic pressure (LVEDP), the maximum rate of LV pressure fall (LV dP/dt_min) and the time constant of isovolumic relaxation (tau, ), calculated as the negative inverse slope of the natural log of the pressure vs time relationship from peak LV dP/dt_min to 5 mmHg above LVEDP of the following beat based on the monoexponential pressure decay model of Weiss et al.²⁵ Following the placement of the LV catheter, animals were positioned prone in a stereotaxic frame (tooth bar – 10 mm).

Procedure for the induction of acute ICH
The experimental model has been described previously.²² Briefly, the atlanto-occipital membrane was exposed for the intracisternal administration of drugs. Through burr holes in the skull, a 3F Fogarty catheter (Baxter, Irvine, CA, USA) was inserted into the left frontoparietal subdural space and another fluid-filled catheter (PE-50) was placed in the right frontoparietal subdural space to record ICP. ICP, MAP and LVP were recorded (Model 7400 Grass Physiological Recorder; Grass Instruments Inc., Montreal, QC, Canada). HR was calculated from the ECG, which was monitored using standard lead II sc needle electrodes.

Dexmedetomidine (1 µg•µL^–l, 10 µL volume, n = 9, Farmos Group, Turku, Finland) was injected in the cisterna magna through a 30-gauge needle. After two minutes, the subdural balloon catheter was inflated with 0.3 mL saline for 60 sec to induce acute ICH. ICP, MAP, HR, LVP, and the ECG were recorded during the 60-sec inflation period and at one-minute intervals for the first five minutes and again at five-minute intervals for the next 25 min. Control rats (n = 10) were given an intracisternal injection of the inactive enantiomer levomedetomidine (1 µg•µL^–l, 10 µL volume, Farmos Group) before subdural balloon inflation, as described above.

Plasma and myocardial catecholamine content
Arterial blood samples were drawn before the intracisternal administration of the drug, and again at one and 30 min after balloon deflation and placed on ice. At the end of the experiment, hearts were excised and perfused with 0.9% saline (4°C) and frozen in liquid N₂ and stored at –80°C. The catecholamine content of the plasma and heart samples was determined using high-performance liquid chromatography with electrochemical detection (CoulArray, ESA Inc., Cambridge, MA, USA). Catecholamine concentrations were corrected for recovery during isolation by using the recovery of dihydroxybenzylamine. Catecholamine content was expressed as pg•mL^–1 of plasma.

Myocardial tissue lipid peroxidation
The extent of lipid peroxidation was determined by using the thiobarbituric acid reactive species (TBARS) method.²⁶ The amount of TBARS was quantified as malonaldehyde (MDA) per gram of myocardial wet weight. The absorbance of the supernatant was determined at 535 nm on a spectrophotometer (Beckman 7000, Beckman Coulter Canada Inc., Mississauga, ON, Canada) against a blank that contained all the reagents minus the sample. Commercially available 1,1,3,3-tetraethoxypropane was used as a standard.

Statistical analysis
Hemodynamic and LV functional variables are expressed as mean values ± SD. Data were digitized on-line at a sample rate of 500 Hz and filtered by a 50 Hz low-pass filter, collected and stored on a microprocessor. Raw data were analyzed with the BioBench (version 1.0) software program (National Instruments; Austin, TX, USA). To obtain data for analysis, we used the average of ten to 12 consecutive cardiac cycles that were not separated by abnormal rhythm at the beginning of each recording period. Unpaired Student’s t tests were used to analyze MDA levels and measured variables at baseline, peak and 30 min after balloon deflation in levomedetomidine vs dexmedetomidine treatment groups. Fisher’s exact test was used to analyze the frequency of cardiac dysrhythmias and other ECG changes. Dysrhythmias were defined as a cardiac rhythm in which there were at least three consecutive beats not originating from the sinus node, a bigeminy or a trigeminy pattern. One-way repeated measures analysis of variance (ANOVA) and post hoc Student Newman-Keuls test were used to analyze measured variables across time within treatment groups. Significance was determined as P < 0.05 for all comparisons.

	Results

TOP Abstract Introduction Methods Results Discussion References

 
Hemodynamic changes after acute ICH in levomedetomidine and dexmedetomidine treated rats
The extent of trauma to the brain following intracranial balloon inflation is shown in Figure 1. Following the injection of levomedetomidine, a sudden increase in ICP (from 6 ± 4 to 232 ± 45 mmHg, P < 0.001) following subdural balloon inflation resulted in a transient increase in MAP and HR, abolishing cerebral perfusion pressure (CPP); (Figure 2). Following this hyperdynamic response, both MAP and HR rapidly declined within minutes and remained depressed at the end of the experiment (Table I). Hemodynamic collapse resulted in a markedly impaired perfusion of the brain (CPP = 10 ± 10 mmHg, at 30 min post inflation).

View larger version (47K): [in this window] [in a new window]   FIGURE 1 Photomicrograph of brain sections taken from a lev-omedetomidine-pretreated rat illustrating the extent of trauma after subdural balloon inflation. Starting at the optic chiasm, 2 mm coronal slices were made in both the rostral and caudal direction. (A-F). Note the increase in size of the intracerebral hemorrhage from rostral to caudal coronal sections (arrow head).

View larger version (17K): [in this window] [in a new window]   FIGURE 2 Effect of a 60-sec subdural balloon inflation (–) on (A) mean arterial pressure (MAP) and (B) heart rate (HR) in rats pretreated with intracisternal dexmedetomidine (Dex) (full circle, 1 µg•µL–1, 10 µL volume, n = 9) or intracisternal levomedetomidine (Levo) (empty circle, 1 µg•µL–l, 10 µL volume, n = 10). Each point represents the mean ± SD, *P < 0.05, within the levomedetomidine pretreated group compared with preinflation levels. P < 0.05, within the dexmedetomidine-pretreated group compared with preinflation levels. #P < 0.05, dexmedetomidine vs levomedetomidine.

LV functional changes
In levomedetomidine treated rats, an increase in LVP, LV dP/dt_max (Figures 3 and 4), and a decrease in t_d (from 25.1 ± 3.3 to 21 ± 2.4 µsec, P < 0.001) was seen during acute ICH. After balloon deflation, there was a progressive decline in LVP, LVDP and LV dP/dt_max. In addition, time to dP/dt_max was increased (28.9 ± 3.1 µsec, P < 0.001). Cardiac performance assessed by the RPP was elevated during intracranial balloon inflation (Figure 4), rapidly declined after deflation and LV systolic function was severely impaired at the end of the experiment (Table I). During the period of raised ICP, there was an increase in LVEDP and (from 7.75 ± 1.1 to 14.37 ± 4.5 msec, P < 0.05), but no significant change in LV dP/dt_min (Figure 5). Following this, LV dP/dt_min rapidly declined and was below baseline levels at the end of the experiment (Table I).

View larger version (18K): [in this window] [in a new window]   FIGURE 3 Effect of a 60-sec subdural balloon inflation (–) on (A) left ventricular pressure (LVP) and (B) left ventricular developed pressure (LVDP) in rats pretreated with intracisternal dexmedetomidine (Dex) (full circle, 1 µg•µL–1, 10 µL volume, n = 9) or intracisternal levomedetomidine (Levo) (empty circle, 1 µg•µL–1, 10 µL volume, n = 10). Each point represents the mean ± SD, *P < 0.05, within the levomedetomidine pretreated group compared with preinflation levels. P < 0.05, within the dexmedetomidine-pretreated group compared with preinflation levels. #P < 0.05, dexmedetomidine vs levomedetomidine.

View larger version (18K): [in this window] [in a new window]   FIGURE 4 Effect of a 60-sec subdural balloon inflation (–) on (A) left ventricular pressure rise (LV dP/dtmax) and (B) rate-pressure product (RPP) in rats pretreated with intracisternal dexmedetomidine (Dex) (full circle, 1 µg•µL–1, 10 µL volume, n = 9) or intracisternal levomedetomidine (Levo) (empty circle, 1 µg•µL–1, 10 µL volume, n = 10). Each point represents the mean ± SD, *P < 0.05, within the levomedetomidine pretreated group compared with preinflation levels. P < 0.05, within the dexmedetomidine-pretreated group compared with preinflation levels. #P < 0.05, dexmedetomidine vs levomedetomidine.

View larger version (18K): [in this window] [in a new window]   FIGURE 5 Effect of a 60-sec subdural balloon inflation (–) on (A) left ventricular end diastolic pressure (LVEDP) and (B) LV dP/dtmin in rats pretreated with intracisternal dexmedetomidine (Dex) (full circle, 1 µg•µL–1, 10 µL volume, n = 9) or intracisternal levomedetomidine (Levo) (empty circle, 1 µg•µL–1, 10 µL volume, n = 10). Each point represents the mean ± SD, *P < 0.05, within the levomedetomidine pretreated group compared with preinflation levels. P < 0.05, within the dexmedetomidine-pretreated group compared with preinflation levels. #P < 0.05, dexmedetomidine vs levomedetomidine.

Rhythm and morphologic ECG abnormalities and plasma catecholamines
Cardiac dysrhythmias and ECG abnormalities were observed more frequently in levomedetomidine vs dexmedetomidine treated rats during the first five minutes following subdural balloon inflation (Table II). This response was associated with a rise in circulating norepinephrine (169 ± 50% of baseline, P < 0.05), and epinephrine (270 ± 319% of baseline, P > 0.05). Plasma catecholamine levels returned to baseline levels at the end of the experiment (norepinephrine 84 ± 41 and epinephrine 77 ± 39% of baseline levels, P > 0.05). Dexmedetomidine treatment prevented the rise in circulating catecholamines (norepinephrine 112 ± 109 and epinephrine 87 ± 76% of baseline, P > 0.05) and 30 min after balloon deflation they were below baseline levels (58 ± 25 and 54 ± 36% of baseline, respectively). At the end of the experiment, cardiac norepinephrine levels were not different between the two groups (levomedetomidine 14.1 ± 8.3 vs dexmedetomidine 23.3 ± 10.8 ng•g^–1 of tissue).

	Discussion

TOP Abstract Introduction Methods Results Discussion References

 
Traumatic brain injury with ICH results in physiological derangements that lead to significant impairment of cardiac function.^1,2 Disturbance in central sympathetic control has been suggested to be the most likely mechanism responsible for cardiovascular dysfunction associated with ICH. In this study, we found that intracisternal dexmedetomidine prevented the impairment in cardiac function following ICH in rats. Because dexmedetomidine reduces neural sympathetic activity by inhibiting presympathetic C1 adrenergic neurons,¹⁸ the present study is, to our knowledge, the first to demonstrate that central sympatholysis attenuates cardiac dysfunction following ICH. The results of the present study suggest that the initial hyperadrenergic state precipitated by sudden ICH plays an important role in the development of subsequent cardiovascular complications.

In our experiments, cardiac function was augmented immediately upon the sudden increase in ICP. Consistent with the notion that the hyperdynamic phase results from an increase in sympathetic activity,^9,27–29 plasma norepinephrine was elevated immediately following subdural balloon deflation in rats receiving the inactive isomer levomedetomidine. Dexmedetomidine blunted the catecholamine surge and the accompanying hyperdynamic response associated with ICH. Furthermore, despite lower plasma catecholamine levels at the end of the experiment, cardiac function was better in dexmedetomidine compared to levomedetomidine treated rats.

The presence of ECG abnormalities in patients suffering from acute intracranial disease has been well documented.^30,31 However, there is debate as to the causal relationship, whether the changes have a cerebral origin or represent a primary myocardial event. The latter mechanism is likely as dysrhythmias and ECG abnormalities were associated with cardiac dysfunction in levomedetomidine treated rats. Conversely, few ECG changes and preserved cardiac function were seen in dexmedetomidine treated rats. These results are similar to our earlier observations following pretreatment with intrathecal lidocaine.²² The prevention of the cardiac dysfunction in our study was most likely a result of dexmedetomidine-mediated blockade of central sympathetic hyperactivity.

The hyperadrenergic state resulting from the excessive release of both systemic and neuronal catecholamines following ICH represents an adaptive stress response mediated by brain-stem vasomotor centres to meet increased circulatory needs because of decreased cerebral perfusion.^16,17 However, the ICH-induced catecholamine stress, although transient in nature, may be detrimental to the normal functioning of the heart, as the present study showed that the initial hyperdynamic response of the heart gave way to cardiovascular collapse. In our experiments, sudden ICH precipitates a marked elevation in LVEDP (> 30 mmHg) and impairment in LV relaxation manifested by a prolonged isovolumic relaxation in control rats treated with levomedetomidine. This was followed by rapid deterioration in LV dP/dt, RPP and prolonged LVP fall. Dexmedetomidine attenuated the marked elevation in LVEDP (< 20 mmHg), prevented the impairment in LV relaxation and improved LV systolic and diastolic function. Dexmedetomidine not only attenuated the rise in plasma catecholamines but also attenuated the rise in myocardial MDA levels, a terminal product and sensitive marker of lipid peroxidation and tissue injury³² and this may explain, in part, the improvement in LV function.³³ Although the cellular mechanisms responsible for the impairment in cardiac function following acute ICH-induced catecholamine excess are unknown, there is a growing body of evidence demonstrating that catecholamines can have detrimental effects on the heart through increased production of free radicals and/or Ca²⁺ overload.^34,35 A consequence of catecholamine excess is the increased production of free radicals, highly reactive species that target both lipids and proteins within the heart. It has been shown that free radicals can promote sarcolemmal damage via membrane lipid peroxidation, altering permeability and causing cellular Ca²⁺ overload.^36–39

A limitation in the present study may have been the method of dexmedetomidine administration into the cisterna magna for its central action, as we are unable to exclude the possibility of the drug having a peripheral effect. However, due to the small dosage and volume of drug administered (1 µg•µL^–l, 10 µL volume, respectively), we feel that dexmedetomidine would not have a significant effect at the peripheral level. Secondly, we did not include a placebo control. However, the hemodynamic response and ECG changes following raised ICP in rats pretreated with levomedetomidine are similar to our previous report in rats following pretreatment with intrathecal saline.²² This suggests that levomedetomidine was an appropriate choice as a control group in this study.

The results of the present study provide evidence for the pathogenic role of central sympathetic hyper-activity in the development of cardiovascular complications during ICH. The excess production of catecholamines may damage the heart directly or indirectly via the production of hydroxyl radicals. A future direction of research may examine the relative roles of these mechanisms.

	Footnotes

 
Preliminary results of this study were previously presented at the 49th Annual Canadian Anesthesiologists’ Society (CAS) Meeting, June 1, 2002, Victoria, British Columbia, Canada.

Accepted for publication April 26, 2004. Revision accepted August 30, 2004.

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