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NEUROSURGICAL ANESTHESIA

The Effect of Electroencephalogram-Targeted High- and Low-Dose Propofol Infusion on Histopathological Damage After Traumatic Brain Injury in the Rat

Eva Eberspächer, DVM^*, Kerstin Heimann, DVM, Regina Hollweck, DS, Christian Werner, MD, Gerhard Schneider, MD, and Kristin Engelhard, MD

From the *Department of Surgical and Radiological Sciences, Veterinary Medical Teaching Hospital, University of California at Davis, Davis, California; Klinik für Anaesthesiologie; and Department for Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Klinik für Anästhesiologie, Klinikum der Johannes Gutenberg-Universität, Mainz, Germany.

Address correspondence and reprint requests to Eva Eberspächer, DVM, University of California, Veterinary Medical Teaching Hospital, Anesthesia/Critical Patient Care, One Shields Ave., Davis, CA. Address e-mail to eberspaecher{at}ucdavis.edu.

	Abstract

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BACKGROUND: Propofol is commonly used to sedate patients after traumatic brain injury. However, the dose-dependent neuroprotective effects of propofol after head trauma are unknown. We compared histopathological damage after 6 h of electroencephalogram-targeted high- and low-dose propofol infusion in rats subjected to controlled cortical impact (CCI).

METHODS: Animals were randomly assigned to CCI/propofol with electroencephalogram burst-suppression-ratio 1%–5% (CCI/lowprop), CCI/propofol with burst-suppression-ratio 30%–40% (CCI/highprop), control group CCI/1.0 vol % halothane (CCI/halo), or sham group with halothane anesthesia (SHAM/halo). Brain slices were stained with kresyl violet (KV) and hematoxylin/eosin (HE) to evaluate lesion volume, number of eosinophilic cells, and activation of caspase-3 in the hippocampus.

RESULTS: Lesion volume (mm³) and number of eosinophilic cells in the hippocampus did not differ significantly [lesion volumes: CCI/lowprop 31.55 ± 14.66 (KV) and 53.77 ± 8.62 (HE); CCI/highprop 33.81 ± 10.57 (KV) and 52.30 ± 11.55 (HE); CCI/halo 36.42 ± 17.06 (KV) and 57.95 ± 8.49 (HE)]. Activation of caspase-3 occurred in the ipsilateral hippocampus in all CCI-groups.

CONCLUSION: Despite different levels of cortical neuronal function, there were no relevant differences in the short-term histopathological damage. These results challenge the view that the neuroprotective effect of propofol relates to the suppression of cerebral metabolic demand.

	Introduction

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Propofol is extensively used for sedation of patients in intensive care units because of its favorable pharmacodynamic and pharmacokinetic profile (1). This includes characteristics such as the reduction in cerebral metabolism and intracranial pressure, as well as enhancement of -aminobutyric acid-mediated inhibition (2–4), which suggests potential cerebral-protective effects, particularly in patients with brain trauma. Propofol also allows for monitoring of sedative/hypnotic "depth" using spontaneous or processed parameters of the electroencephalogram (EEG). Several models of traumatic brain injury (TBI) have been designed to simulate human TBI for studies of pathophysiological processes and treatment options (5). Controlled cortical impact (CCI) is a reproducible model that facilitates close control of deformation parameters (6).

In the present study, we investigated the effect of EEG-targeted low- and high-dose propofol infusion on acute histopathological damage in rats subjected to a moderate CCI. Target parameters in this study were burst suppression (BS)-ratios of 1%–5% and 30%–40%, representing two different levels of suppression of the cortical neuronal function.

	METHODS

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These experiments were approved by the institutional animal care committee and performed in accordance to the German animal protection law "Deutsches Tierschutzgesetz." Thirty-nine male Sprague Dawley rats (400 ± 50 g) were delivered from Charles River Laboratories (Kisslegg, Germany) at least 7 days before operation day and kept in the animal facilities under standard laboratory conditions (12 h light/12 h dark, lights on at 6:00 am, 22°C, 60% humidity and free access to water and standard rat chow).

Preparation
On the day of trauma induction, nonfasted rats were anesthetized in a bell jar saturated with halothane, tracheally intubated, and mechanically ventilated (Harvard Rodent Ventilator, Model 683, Harvard Apparatus, South Natick, MA) with 1.2–1.7 vol % halothane in N₂O/O₂ (Fio₂ = 0.33, ETco₂ = 38–42 mm Hg; Capnomac, Datex, Helsinki, Finland). A catheter was inserted in the tail artery for continuous arterial blood pressure measurement and blood sampling; three additional catheters were placed in the left jugular vein for later infusion of propofol, fentanyl, and norepinephrine. Temperature probes were placed in the right temporal muscle and the rectum. Pericranial temperature was kept constant during the experiment at 37.5°C, using a servo-controlled overhead heating lamp. Needle electrodes were inserted subcutaneously for electrocardiogram monitoring (Cardiocap II, Datex). Rats were then placed in a stereotactic "U"-frame (model 962, Kopf Instruments, Tujunga, CA), using atraumatic ear bars. After a midline incision, the scalp was retracted, exposing the right parietal bone. A 6-mm craniotomy was performed between bregma and lambda, and the coronal ridge, using a high-speed dental drill with a 0.9-mm tip cooled with lactated Ringer’s solution. After drilling three sides without injuring the dura mater, the bone flap was opened over the saggital suture. Stainless-steel EEG-needle electrodes were bilaterally placed over the temporal muscle and occipitally (common reference) as well as on the base of the tail (ground electrode).

EEG Processing
EEG was continuously recorded using an Aspect A-1000 monitor (Aspect Medical Systems, Natick, MA). BS is a pattern of high-amplitude EEG activity interrupted by relatively low-amplitude activity. The periods of high activity (bursts) and those of low activity (suppressions) usually last a few seconds and occur in an unpredictable, irregular fashion. A BS-pattern can be produced by deep anesthesia with a number of anesthetics, including propofol. In the present study, the EEG BS-ratio was calculated to distinguish between two different levels of suppression of cortical activity. EEG suppression was defined as an amplitude less than ±5 µV. BS-ratio was calculated as the percentage of EEG suppression in a 63-s interval.

Controlled Cortical Impact
The CCI injury device (SHT-3 CCI Controller, custom-made, Johannes Gutenberg-Universität, Mainz, Germany) (6,7) consisted of a pneumatic cylinder rigidly mounted on a crossbar. On the lower end of the rod the impact tip (5 mm diameter) was attached. To induce CCI, this tip was vertically driven at a predetermined velocity (4 m/s), depth (1.75 mm), and duration (200 ms) of brain deformation.

Ten minutes before adjustment of the impact tip shaft, the halothane concentration was decreased to 1.0 vol % and baseline measurements were taken (BL; 0:00). Animals were now randomly assigned to the following protocols for 6 h: CCI/propofol with BS-ratio of 1%–5% (CCI/lowprop, n = 10), CCI/propofol with BS-ratio of 30%–40% (CCI/highprop, n = 10), control group CCI/1.0 vol % halothane (CCI/halo, n = 10), and sham operated animals with halothane anesthesia (SHAM/ halo, n = 9). After CCI induction, animals were quickly removed from the injury device, the bone flap was closed and sealed with histoacrylic glue (Histoacryl, B. Braun, Tuttlingen, Germany). The scalp incision was closed with interrupted sutures, and 0.2 mL of bupivacaine 0.5% (Curasan AG, Kleinostheim, Germany) was infiltrated. Ten milliliters of warm lactated Ringer’s solution was injected subcutaneously as a fluid depot. Nitrous oxide was replaced by air (Fio₂ = 0.33). The anesthesia protocol was now changed according to the randomization. Animals in CCI/lowprop and CCI/ highprop groups received a titrated bolus of 20–30 mg propofol IV (Disoprivan 2%, AstraZeneca, Wedel, Germany) over about 1 min to reach a BS-ratio of 1%–5% and 30%–40%, respectively, which was then maintained with a continuously adjusted propofol infusion administered by a pump (Model 11, Harvard Apparatus, Holliston, MA). Rats in CCI/halo and SHAM/halo groups were maintained with 1 vol % halothane in air/O₂ (Fio₂ = 0.33). All animals received a continuous infusion at the rate of 8–16 µg/h fentanyl (Fentanyl, Janssen-Cilag, Neuss, Germany) for analgesia and norepinephrine (Arterenol, Aventis Pharma, Frankfurt, Germany, 0–30 µg/h) to maintain mean arterial blood pressure (MAP). During the 6 h after the trauma period, physiological variables (MAP, heart rate, hemoglobin, Pao₂, Paco₂, pH, respiratory rate, glucose, rectal and pericranial temperature) were continuously monitored and documented at different time points: right after accomplishment of steady-state BS-pattern (0:20), and after 1, 2, 3, 4, 5, and 6 h. After completion of the last recording, anesthetic depth was increased, the animals were killed, and the brains were removed and frozen at –70°C.

Histological Evaluation
From each animal, sets of 11 consecutive coronal 10 µm cryostat brain sections with 1-mm intervals from a defined zero-point [macroscopically visible morphologic formation at –1600 µm ante bregma, Plate 11 (8)] were cut and mounted. One set of sections was stained with kresyl violet (KV) and another set with hematoxylin eosin (HE) and were examined by an investigator blinded to the treatment conditions.

The KV- and HE-stained sections were digitized using a camera (Evolution MP Camera, Media Cybernetics, Silver Spring, MD). The lesion area was measured by determining the cross-sectional injury in each image and multiplied by the exact thickness of the tissue between the slices. This slab volume technique was implemented on the image processing program Image-Pro-Express 4.5 and created the lesion volume (Media Cybernetics). Additionally, in the consecutive HE-stained slices, the number of eosinophilic cells in the hippocampal regions CA1, CA3, CA4 as well as the dorsal and ventral branch of the dentate gyrus was counted. Immunohistochemistry double staining for activated caspase-3 and NeuN (activated caspase-3 antibody, monoclonal, rabbit, BD PharMingen, San Jose; Antineuronal nuclei antibody, monoclonal, mouse, Chemicon International, Temecula; Biotinylated anti-rabbit and anti-mouse antibodies, VectorLabs, Burlingame) was performed in three consecutive sections from the cranial, middle, and caudal area of the lesion area to detect apoptotic cell death. A thymus section served as positive control and a naïve brain section as negative control.

Sample Size Calculation
Assuming that the common standard deviation is 15 mm³, an one-way analysis of variance (ANOVA) will have 80% power to detect a relevant effect size of 0.6 at the 0.05 level, when the sample size in each of the three groups is 7.

Statistical Analyses
Continuous data were expressed as mean ± sd. Comparability of treatment groups with respect to physiologic variables was analyzed among groups by using Kruskall–Wallis test, and in case of significance, the Mann–Whitney U-test was applied. A Friedman test and post hoc Wilcoxon’s test was used to detect differences in physiological variables for each group. Titration of propofol among treatment groups was analyzed using the repeated measurement model. In case of significance, post hoc tests were performed. The number of eosinophilic cells in the hippocampus was considered the total number over all slices. Inferential statistics among treatment groups with respect to cell stain were assessed by Kruskall–Wallis test and post hoc Mann–Whitney tests. For categorical variables, the ² Test and Fisher’s Exact Test were applied. Bonferroni method was used throughout the study to account for multiple testing. All tests were performed two tailed on a 5% level of significance. Statistical analyses were performed using SPSS 11.5 (SPSS, Chicago, IL).

Spearman correlation coefficient was used to determine the relationship between total damage (total number of eosinophilic cells over all regions) and extension of trauma.

	RESULTS

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Physiological Variables
Physiological variables before, during, and after CCI are shown in Table 1. Immediately after the impact as well as during the posttraumatic time period of 6 h, there were no differences in MAP, heart rate, hemoglobin concentration, Pao₂, Paco₂, pH, respiratory rate, and pericranial temperature among groups as well as when compared with baseline values.

In all animals, the plasma glucose concentration decreased over time with values always within physiologic range of rats.

Propofol Dosing
During the six posttraumatic hours, the propofol infusion rate was continuously adjusted to maintain BS-ratios of 1%–5% (CCI/lowprop) and 30%–40% (CCI/highprop). This approach resulted in significantly different doses among groups and a progressive dose-reduction over time (P < 0.001, Table 2).

Lesion Volume
Because of severe cortical and subcortical hemorrhage, two animals in the CCI/lowprop, three animals in CCI/highprop, and two animals in CCI/halo groups were excluded from evaluation of the lesion volume in KV- and the HE-staining. Lesion volume (MW ± sd; mm³) was not different between CCI/lowprop (KV: 31.55 ± 14.66; HE: 53.77 ± 8.62; n = 8) and CCI/ highprop groups (KV: 33.81 ± 10.57; HE: 52.30 ± 11.55; n = 7) or when compared with control (CCI/halo, KV: 36.42 ± 17.06; HE: 57.95 ± 8.49; n = 8) (Figs. 1a and b and 2a and b). Lesion volumes evaluated with KV-staining were significantly smaller than those evaluated with HE-staining (P < 0.001). The SHAM/halo group did not show any lesion.

View larger version (15K): [in this window] [in a new window]   Figure 1. Lesion areas in square millimeter (mean ± sem) evaluated in the brains of the groups CCI/lowprop (n = 8), CCI/highprop (n = 7), and CCI/halo (n = 9) in distance from a defined zero-point (mm) after staining with hematoxylin/eosin (Fig. 1a) and kresyl violet (Fig. 1b). CCI = controlled cortical impact.

View larger version (71K): [in this window] [in a new window]   Figure 2. Exemplary coronal brain section stained with hematoxylin/ eosin (Fig. 2a) and kresyl violet (Fig. 2b) of an animal from group CCI/ lowprop. Fig. 2c shows an exemplary coronal brain section (left) and detail of the right dentate gyrus (right) stained with immunohistochemistry for activated caspase-3 and neuronal nuclei of an animal from group CCI/ lowprop. Arrows point to positively stained neurons. CCI = controlled cortical impact.

No eosinophilic cells were detected in the contralateral hemisphere of CCI/lowprop, CCI/highprop, CCI/halo, and in both hemispheres of SHAM/halo groups.

Activated Caspase-3
Activated caspase-3 was randomly found in hippocampal, but not in cortical neurons (activated caspase-3 and NeuN positive) in all CCI groups at 6 h after trauma. However, because of the small number of positive cells, it was not possible to compare the presence of this apoptotic marker among groups (Fig. 2c).

	DISCUSSION

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The results indicate that 6 h of EEG-targeted low- and high-dose propofol infusion after CCI did not affect lesion volume or the number of eosinophilic hippocampal cells, despite differences in cortical functional activity. Indicators of commencing apoptotic processes were present. This suggests that the neuroprotective potential of propofol, as seen in models of cerebral ischemia, is not reproducible in this model of focal TBI when compared with halothane.

Propofol is a short-acting hypnotic that has proven to be a neuroprotective drug in several models of cerebral ischemia. It significantly improves motor function, decreases lesion volume (9), and neuronal death (10) and favorably modulates apoptosis-regulating proteins towards cell survival (11). Compared with the knowledge of effects of propofol in the ischemic brain, data about acute traumatic injury, like the CCI model, are rather limited. In a patch-clamp model of granule cells of the dentate gyrus propofol enhances synaptic inhibition pre- and postsynaptically and protects neurons from acute mechanical-induced cell death via enhancement of -aminobutyric acid A receptor functions (12). In an accelerated-impact weight-drop model in rats, propofol was protective when combined with hypothermia, as it reduces intracranial pressure and increases cerebral perfusion pressure under these conditions (13). In the present study, two infusion doses of propofol that produce BS-EEG with a different BS-ratio, indicating different levels of suppression of neuronal function, were chosen. To maintain this BS-ratio, the dose of propofol had to be titrated according to the EEG and decreased steadily over time (Table 2). The induction of BS-EEG is standard for evaluating the maximum effect of a drug. It is proposed that one mechanism of neuroprotection by anesthetics is their ability to decrease metabolic demand (14,15). Accordingly, we expected less protection and therefore an increase in lesion volume and number of eosinophilic cells in animals with lower BS-ratios (1%–5%). However, there was no difference in lesion volume and number of eosinophilic cells in the hippocampus between animals anesthetized with low- and high-dose propofol infusion or when compared with halothane anesthesia. This may be related to different courses of pathophysiological events after induction of ischemia versus acute trauma. Depending on the extent and duration of cerebral ischemia, residual low-flow perfusion, release of excitatory neurotransmitters, and edema formation occur over time, leading to apoptotic and necrotic cell death (16). After CCI, however, the primary injury caused by direct mechanical damage is immediate and marked, including axonal injury, disruption of the blood–brain barrier and hemorrhage (17,18). After the primary injury, a cascade of events mediated by endogenous signals is initiated. This leads then to secondary neurological injury, which includes inflammatory and excitotoxic damage, necrosis, and apoptotic-like changes. Among the many known effector proteins of apoptosis, a family of cytoplasmic enzymes, called caspases, may play an important role in the execution phases of programmed cell death. The presence and distribution of one member of this family, activated caspase-3, has been shown in the early phase after CCI (19). The present data confirm the expression of this marker 6 h after CCI; however, maximum expression is expected after 48 h (20).

It is possible that propofol did not decrease lesion volume 6 h after CCI because of the delayed onset of posttraumatic ischemic events that are potentially the target of propofol-mediated neuroprotection. Early detection of differences among groups may have been possible with more sensitive methods like immunohistochemical quantification of apoptosis-related proteins (11). However, reliable quantification of theses proteins in a brain damaged by a CCI is difficult. The area of interest would be too diffuse and widespread. In addition, the primary damage would have probably caused artifacts further impairing quantitative measurements.

Additional time points to assess histopathological damage, for example, when the secondary damage is most prominent (24 h to 3 days) and after scar formation is completed (i.e., 28 days), would have been helpful to determine a time course of events and potentially detect a neuroprotective effect of propofol. Also, in the low-dose propofol group, the target was already BS-EEG, indicating deep anesthesia. Therefore, the doses of propofol (and their suppressing effect on neuronal function) might not have been different enough to account for different results.

During the present study, halothane served as a control anesthetic, and there were no differences between control and CCI/propofol groups. An ideal control group would be represented by awake animals (i.e., no active "neuroprotective" background anesthetic effect). However, for ethical reasons, this is not possible to obtain; a common dilemma in brain outcome research. In the present setup, halothane was chosen in the lowest possible concentration as control anesthesia due to the lack of more suitable options, despite the potential protective effects of this anesthetic in higher doses or long-term exposure in the ischemia model (21,22).

The TBI model used in this study is well characterized, and the created lesion, compared to the more widely used fluid-percussion technique, is not as diffuse and therefore easier to analyze biomechanically (6). Compared to the weight-drop technique with closed or open scull, the CCI model creates a brain trauma in a highly reproducible and controlled fashion because it uses a pneumatic piston to deform a defined volume of exposed cortex over a range of impact velocities and dwell times. Relevant stages of the pathophysiology of human TBI, including contusion and axonal injury, are reproduced in this model. In a pilot study, we evaluated the impact depth that would cause a sufficient trauma, but leave the dura mater intact in an attempt to standardize the model even further. Additionally, the chosen impact parameters (Ø 5 mm, 1.75 mm, 4–5 m/s, 200 ms dwell time) create an injury severity that allows for future long-term studies that evaluate histopathology as well as cognitive and behavioral deficits (23). A compromising factor, however, is the potential of rupturing vessels during the impact that may lead to cortical and subcortical hemorrhage and therefore deteriorating the primary injury. Moderate to severe hemorrhage occurred in seven animals in the three CCI-groups (two each in CCI/lowprop and CCI/halo, three in CCI/highprop). These animals had to be excluded from evaluation of lesion volume, which was increased as a function of location and extent of bleeding. This made it impossible to compare these lesions with the lesions of nonbleeding animals.

Animals in this study were not fasted, because pilot studies indicated that glucose levels were within a reasonable range and more constant without fasting. The detrimental effect of hyperglycemia (glucose-loaded rats with plasma glucose 500 mg/100 mL) during ischemia is well known (24). However, hyperglycemic rats subjected to mild cortical impact injury had adverse effects only when a secondary ischemic insult was added after the impact injury (25). This suggests that fasting versus nonfasting is not an important factor in CCI models, as long as animals are handled stress-free and glucose levels range within normal values.

In conclusion, EEG-targeted low- and high-dose propofol infusion for 6 h after CCI did not affect lesion volume or the number of eosinophilic cells in the hippocampus. Although neuronal function was differently suppressed, the results in both propofol groups were comparable to those in the control group anesthetized with halothane. Long-term studies with the CCI model in combination with different anesthetic protocols are needed to further evaluate potential neuroprotective mechanisms and properties of anesthetics after brain trauma.

	Footnotes

 
Accepted for publication September 18, 2006.

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