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ANESTHETIC PHARMACOLOGY

The Neuropathologic Effects in Rats and Neurometabolic Effects in Humans of Large-Dose Remifentanil

W. Andrew Kofke, MD FCCM^*, Ahmed F. Attaallah, MD, Hiroto Kuwabara, MD PhD, Robert H. Garman, DVM, Elizabeth H. Sinz, MD, John Barbaccia, MD, Naresh Gupta, MD^||, and Jeffery P. Hogg, MD^||

*Department of Anesthesia, University of Pennsylvania, Philadelphia; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh; and Consultants in Veterinary Pathology, Inc, Murrysville, Pennsylvania; and Departments of Anesthesiology and || Radiology, West Virginia University, Morgantown, West Virginia

Address correspondence and reprint requests to W. Andrew Kofke, MD, FCCM, Department of Anesthesia, University of Pennsylvania, 7 Dulles Bldg., Philadelphia, PA 19104-4283. Address e-mail to kofkea{at}uphs.upenn.edu

	Abstract

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Given in clinically relevant large doses to rats, µ-opioids produce limbic system hypermetabolism and histopathology. This investigation extends these observations, in both rats and humans, for the short-acting drug remifentanil, which allows more precise control and assessment of the effects of duration of opioid exposure. We performed two series of experiments: one in rats for neuropathologic effects and the second in humans for neurometabolic effects. Fifty mechanically ventilated rats received saline solution or remifentanil 20–160 µg · kg^-1 · min^-1 for 3 h, followed by neuropathologic evaluation 7 days later. Four volunteers underwent induction of anesthesia and endotracheal intubation with propofol and rocuronium administration followed by remifentanil infusion at 1–3 µg · kg^-1 · min^-1 with positron emission tomography evaluation of cerebral metabolic rate for glucose. In rats, dose-related electroencephalogram activation was evident and 19 of 40 remifentanil-treated rats showed brain damage, primarily in the limbic system (P < 0.01). In humans, cerebral metabolic rate for glucose in the temporal lobe increased from 6.29 ± 0.32 to 7.68 ± 1.05 mg · 100 g^-1 · min^-1 (P < 0.05). These data indicate that prolonged large-dose remifentanil infusion is neurotoxic in rats with congruent metabolic effects with brief infusion in humans and suggest that some adverse effects reported in rats may be clinically relevant.

IMPLICATIONS: This study demonstrates dose-related remifentanil neurotoxicity in physiologically controlled rats with congruent brain metabolic effects in four humans undergoing positron emission tomography evaluation during brief large-dose remifentanil anesthesia. These data suggest that some adverse effects reported in rats may be clinically relevant.

	Introduction

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Several reports indicate that the clinically available µ-opioids fentanyl, sufentanil, and alfentanil can be neurotoxic in rats (1–3). These studies have shown that these µ-opioids produce limbic system increased metabolic rate, seizures, and brain damage. µ-Opioids also produce epileptiform activity in humans (4). Seizures, including those produced by opioids, produce brain damage in association with hyperemia and regional hypermetabolism (5). Although electrographic epileptiform activity may not be an attribute essential to the production of brain damage (6), it is likely that regional hypermetabolism is an important contributor to opioid neurotoxicity. Thus, a first step in determining whether the potential exists for human neurotoxicity would be to ascertain in humans whether µ-opioids induce limbic system activation that is anatomically homologous to that observed in rodents.

Remifentanil is a novel µ-agonist that is short-acting and has a predictable duration of effect. Overall, it represents a unique alternative to currently available opioids. In previous studies that demonstrated µ-opioid neurotoxicity (and hypermetabolism), the duration of opioid exposure was necessarily variable, as the drugs were metabolized in the hours after cessation of administration, thus obfuscating the role of duration of exposure to opioid.

The objectives of this research were twofold: 1) to determine whether remifentanil, with effects that can be maintained for a discrete period of time, causes dose-related limbic system injury in rats, and 2) to determine whether its use in humans produces anatomically congruent limbic system activation, which might be assumed to be a prerequisite needed to assign some clinical perspective to the rodent observations.

	Methods

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Two sets of experiments were done. Studies were done in part 1 in rodents and in part 2 in human volunteers. All rodent experiments were approved by the West Virginia University Institutional Animal Care and Use Committee. All human studies were approved by the West Virginia University IRB.

Rodent Studies
Young (2 mo old) male Sprague-Dawley rats (300-400 g) were used.

Dosage Groups.
Rats were randomly assigned to either normal saline infusion (plus halothane-controls), or to 1 of 4 remifentanil doses (20, 40, 80, and 160 µg · kg^-1 · min^-1) with an infusion duration of 3 h; n = 10 in each group.

Experimental Procedure.
Rats were anesthetized with 4% halothane in O₂, endotracheally intubated with 14-guage catheters, and mechanically ventilated (Analytical Specialties Ventilator, St. Louis, MO). Femoral artery and vein cannulae, biparietal stainless steel electroencephalogram (EEG) screws, and a subtemporalis temperature probe were inserted. Anesthesia during surgery consisted of 1%–2% halothane and N₂O/O₂ 70%:30%, after which halothane was stopped and 70% N₂O was continued for 1 h. After 60 min off halothane, N₂O was replaced with O₂; simultaneously, the saline or opioid solution was administered at 4 mL · kg^-1 · h^-1. Controls continued to receive 1%–2% halothane in O₂ during normal saline infusion. Opioid or normal saline infusion was continued for 3 h. Crystalline remifentanil was diluted in normal saline to the appropriate concentration and volume for each experimental group. Arterial blood gases were measured preinfusion and 15, 60, and 150 min after onset of infusion on 50–100 µL samples. Temperature was kept at 38°C with a servo-controlled homeothermic blanket. During drug infusion, PaO₂ was maintained >100 mm Hg, PaCO₂ 35–40 mm Hg, and mean arterial blood pressure (MAP) 80–140 mm Hg (by withdrawal and reinfusion of rat donor blood from a heparinized syringe maintained at 38°C via the femoral vein if needed). After 3 h of normal saline or remifentanil administration, each rat underwent up to 1 h of additional mechanical ventilation, with the trachea extubated upon return of spontaneous respirations. Vascular cannulae were removed and wounds were closed during the last 10 min of infusion. Subsequently, rats were placed in a chamber insufflated with 100% O₂ for 1 h after extubation. Seven days postinfusion, rats were anesthetized with halothane, tracheally intubated, and fixed via perfusion with 10% neutral buffered formalin (using thoracotomy with left ventricular cannulation). The calvaria were then removed and the exposed brains further immersion-fixed in neutral buffered formalin for at least 24 h before their removal. Any animal that did not survive the postinfusion period and in which the cause of death was not clear also underwent cerebral perfusion fixation. These rats were also included in this final analysis.

EEG Analysis.
The frequencies of spikes (amplitude >100 µV) occurring over a 30-s EEG epoch upon withdrawal of the last blood gas in the last 30 min of each experiment were determined in all rats.

Neuropathologic Analysis.
The brains were sliced in a standardized manner at approximately 3-mm intervals and the slices embedded in paraffin by routine techniques. Six-micrometer sections of each brain block were prepared and adjacent sections stained with either hematoxylin and eosin or Fluoro-Jade B with a DAPI counterstain. [Note: Fluoro-Jade is an anionic fluorochrome, which is a marker for degenerating neurons and their processes (7). When Fluoro-Jade-stained sections are viewed with epifluorescence, degenerating neurons fluoresce a yellow-green color; viable neurons may be counterstained with a variety of techniques. In this case, a DAPI stain (4,6-diamidino-2-phenylindole, a counterstain for Nissl substance) was used.] Thirty brain regions were selected for subjective quantitation. Degrees of neuropathologic alterations within a given anatomic region were scored based on subjective assessment of number and distribution of dead neurons. Scores were assigned by the same pathologist (RHG) who was unaware of the experimental treatment, as follows: 0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = marked, and 5 = severe. These grades are semiquantitative in that they reflect the approximate number of degenerating neurons present in the affected neuroanatomic areas. An overall neuropathologic score was calculated for each rat by summating the pathologic scores for all brain areas examined. Photomicrographs were captured digitally as raw data images with a photomicroscope-mounted camera (Nikon^® D1^®; Nikon USA, Melville, NY). The Fluoro-Jade B-stained sections were examined with an Olympus^® microscope (Olympus Corporation, Lake Success, NY) with an epifluorescent light source. A blue excitation filter was used to visualize the Fluoro-Jade B staining, and an ultraviolet excitation filter for viewing the DAPI stain.

Physiologic and EEG data were compared by using a one-way analysis of variance for each variable with post hoc Student’s t-tests. Summed neuropathologic scores underwent Kruskal-Wallis analysis of variance to detect an overall effect across the different groups followed by Mann-Whitney U-test of remifentanil-treated groups versus control.

Human Studies
After consent was obtained, four healthy (ASA status I or II) volunteers were enrolled. Each subject underwent placement of a radial arterial cannula followed by a baseline unanesthetized positron emission tomography (PET) scan. A 10-min transmission scan was collected before fluorodeoxyglucose (FDG) injection to allow correction for attenuation. Then FDG was injected IV. Twelve 5-min PET frames were collected across 60 min (8,9). A total of 15 0.3-mL arterial blood samples were withdrawn during the dynamic PET.

After the first PET scan, each subject relaxed in a waiting room with the arterial cannula maintained patent. Six hours later, each subject had monitoring initiated, including intraarterial blood pressure, electrocardiogram, pulse oximetry, inspired and expired oxygen and carbon dioxide analysis, train-of-four electromyography, and two-channel bispectral index (BIS) processed EEG (Aspect Medical, Inc., Natick, MA). For each subject, anesthesia was induced with remifentanil 1 µg · kg^-1 · min^-1 plus propofol 1 mg/kg followed by rocuronium 1 mg/kg; the trachea was intubated and ventilation was controlled artificially. Remifentanil was thereafter infused IV in a dose sufficient to keep the BIS <80 (1–3 µg · kg^-1 · min^-1). Thirty-five minutes after the induction of anesthesia, FDG was injected IV and a second PET scan was obtained. Before FDG injection, a 20-min background emission scan was obtained to confirm negligible residual radioactivity from the first study. A transmission scan was repeated after the emission scans. To decrease the potential for awareness, 15 min after the FDG injection, a propofol infusion was initiated at 25–50 µg · kg^-1 · min^-1. At the end of the PET scan, emergence from anesthesia occurred, and the tracheal tube was removed.

On a separate day, magnetic resonance imaging (MRI) for coregistration of PET data was performed in each subject on a 1.5 Tesla Signa scanner (GE Medical Systems, Milwaukee, WI).

All PET images were reconstructed by using software supplied by the manufacturer. Cerebral metabolic rate for glucose (CMRG) was calculated as described previously (8,9). PET-MRI coregistration was performed by using the external fiducial marker method (10).

Regions of interest (ROIs) were placed over the cerebellum, frontal, parietal, temporal, and occipital cortices, caudate nucleus, amygdala, and hippocampus bilaterally by tracing the outlines of the above structures on the MRI images, coregistered to the CMRG volume. The ROIs were applied to the PET images to obtain regional CMRG.

The CMRG volumes were further processed to identify brain regions with statistically significant pre- and postremifentanil change (11) normalized to the cerebellum (not affected by remifentanil).

ROI analyses were performed on the averaged values of left and right structures. Statistical hypothesis tests were done on baseline versus remifentanil CMRGs. Based on previous observations,¹ the temporal lobe was the primary area related to the hypothesis. Thus, a two-tailed paired Student’s t-test with P 0.05 accepted as significant was used for this ROI. The rest of the brain underwent t-tests with Bonferroni correction with P 0.05/6 = 0.008 accepted as statistically significant. The six other areas tested were frontal, parietal, occipital, hippocampal, amygdala, and caudate areas. Data were reported as mean ± SD.

The statistical analysis for the brain functional mapping portion of this study involved the identification of local maxima differences between CMRG in two conditions, and testing whether or not they were statistically different. We adopted the method of three-dimensional statistical analysis t-statistic volumes (12) on spatially normalized CMRG volumes for this purpose.

	Results

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Rodent Studies
Physiologic Data.
During the baseline period, there were no differences with respect to any of the physiologic variables among all groups. With the infusion of remifentanil, there were no statistically significant between-group differences in PaO₂, pHa, PaCO₂, and temperature. However, statistically significant differences from the Control group occurred in MAP, with Remifentanil-Treated groups approximately 10 mm Hg higher than the controls. Compared with controls, opioid infusions were associated with moderate increases in blood pressure (Table 1).

View larger version (41K): [in this window] [in a new window]   Figure 1. Biparietal electroencephalogram recordings of rats during infusion of different remifentanil doses. Analysis of spike frequency reveals a significant remifentanil effect (P < 0.0001).

No histologic lesions were observed in any of the 10 control brains examined. Varying degrees of acute neuronal degeneration were seen in 19 of the 40 Remifentanil-Treated rats. Evaluation of the summed overall pathologic scores indicated that the distribution and severity of brain damage was significantly worse in the Remifentanil-Treated rats (P = 0.01) (Table 2, Fig. 2). Lesions occurred in 2 of the rats from the 20 µg · kg^-1 · min^-1 group, 5 rats from the 40 µg · kg^-1 · min^-1 group, 5 rats from the 80 µg · kg^-1 · min^-1 group (1 of which died before the scheduled date for brain perfusion fixation), and 7 rats from the 160 µg · kg^-1 · min^-1 group. (One of the 160 µg · kg^-1 · min^-1 group rats had also died before the scheduled date for brain perfusion fixation). Both dead rats showed evidence of persisting postremifentanil neuroexcitation. Lesions were primarily confined to the limbic system and its associated areas and were most consistently present within the piriform and entorhinal cortices and within the hippocampus (Figs. 3 and 4).

View larger version (81K): [in this window] [in a new window]   Figure 2. Effects of increasing remifentanil doses on the number of animals with normal histology in the noted brain structures.

View larger version (115K): [in this window] [in a new window]   Figure 3. A, Low-power photomicrograph of the dorsal hippocampus of a remifentanil-exposed rat. The arrows point to the CA4 region and the arrowheads to the CA1 region. Within the hematoxylin and eosin-stained section at this magnification (top panel), moderate cell loss is suggested in the CA1 region, and the CA4 region also contains a few shrunken cells. However, the Fluoro-Jade B-stained section (lower panel) taken at the same magnification shows large numbers of degenerative cells in both of these regions. Degenerative cells are also apparent in the dorsal thalamus at the bottom left-hand side of the micrograph. Approximately 60x magnification. B, Medium-power photomicrograph of the pyramidal neuron layer of the CA1 region of the dorsal hippocampus of a remifentanil-exposed rat. In the top panel (hematoxylin and eosin-stained section), the arrows point to typical "red dead" neurons (i.e., characterized by acute eosinophilic neuron degeneration). Within the bottom panel (Fluoro-Jade B-stained section) taken from the same area, many more dead neurons (i.e., those stained brightly) can be visualized, and the Fluoro-Jade stain also highlights the degenerative processes of these neurons (e.g., at the two arrowheads). The single arrow points to red blood cells within a capillary (note that red blood cells are characterized by autofluorescence). Approximately 310x magnification.

View larger version (97K): [in this window] [in a new window]   Figure 4. Functional brain mapping in humans. Baseline awake scans were subtracted from scans acquired during remifentanil infusion. Areas with significant increases in cerebral metabolic rate for glucose (t > 4.05, P < 0.05) are displayed in lighter shades overlaid on a normalized magnetic resonance image. Scale for t-values is also shown. Magnetic resonance images are parallel to the anterior-posterior commissure plane: 21 mm below (left panel), 2 mm below (middle panel), and 5 mm above (right panel) the plane. Color version available by e-mail request to corresponding author.

Evaluation of the temporal lobe ROI revealed a significant CMRG effect (P = 0.05) with remifentanil increasing CMRG from 6.29 ± 0.32 to 7.68 ± 1.05 mg · 100 g^-1 · min^-1. Minimal effects were observed in the cerebellum. All other areas showed no statistically significant increases in CMRG.

A review of brain functional mapping data indicated increased CMRG in the temporal lobe and frontal area (Fig. 4). The temporal lobe effect was more pronounced on the left side.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study in rats, remifentanil produced epileptiform activity, and histologic evidence of brain injury that is clearly dose related with a uniform three-hour infusion. In addition, we describe the potential for remifentanil to increase temporal lobe metabolic rate in humans. This might be of clinical significance.

Dose Issues
Kofke et al. (3) have performed a dose-response study with fentanyl infused for two hours to rats. In these fentanyl studies, rats underwent two-hour infusions at a range of doses, followed by mechanical ventilation until awake enough to tolerate tracheal extubation. One concern with that study was that the rats that received the larger doses of fentanyl, may have actually had a longer exposure to the drug, given the larger plasma levels noted at the end of the larger-dose infusions. The present study, in which negligible postinfusion residual remifentanil effect would have been expected, confirms that the degree of opioid neurotoxicity is dose related.

Plasma concentrations of remifentanil in rats studied by Cox et al. (13) and Lozito et al. (14) have pharmacologic effects similar to the fentanyl doses previously used by Kofke et al. (3). Based on the approximate similarities in the potencies of remifentanil and fentanyl, these previously used fentanyl doses were used as the basis for choosing the doses of remifentanil in the present report. Cox et al. (13), in a study on rats, found a maximal EEG effect with remifentanil at a dose of 50 µg · kg^-1 · min^-1 and a blood concentration of 100 ng/mL. A half-maximal remifentanil EEG effect occurred at a plasma concentration of 9.4 ng/mL with an infusion of 5 µg · kg^-1 · min^-1. Notably, Lozito et al. (14) found remifentanil-induced loss of righting reflex with a bolus dose of 200 µg/kg. Assuming that the remifentanil doses we used in our rat groups produced comparable plasma levels, it seems that remifentanil-mediated neurotoxic effects occurred across a range of doses that might be considered to mimic the larger dosage ranges used in humans.

Neurotoxicity of Opioids
Several reports, in a variety of experimental contexts, support our observations that µ-opioids can be neurotoxic.

Cellular Level.
Several in vitro studies indicate that opioids can induce apoptosis in a variety of tissues and cell lines. Apoptosis is thought to be a component of cell injury after seizure, morphologically presenting as selective cell loss (15). Opioid-associated apoptosis has been reported in neural tissues, embryonic and immortalized neuron cultures, and neuroblastoma cell lines (16,17). The selective cell loss we observed is consistent with an apoptotic mechanism, although we did not specifically assess for that mechanism of neurotoxicity.

Rodents.
A report by Snead and Bearden (18) indicated that intracerebroventricular injection of various opioid agonist subtypes produce characteristic focal seizure activity. Subsequently, Kofke et al. (1), Tommasino et al. (19), and Young et al. (20), showed increased hippocampal glucose use in rats with autoradiography. Carlsson et al. (21) also showed fentanyl-induced hyperemia in rats. Finally, Kofke et al. (1–3) have demonstrated in several protocols and in this study that µ-opioids produce dose-related EEG seizures and histologic damage in rats.

Humans.
In humans, sustained seizures produce brain damage (22). This is supported by data from animal models (5,15,22,23). Several reports document that exogenously administered opioids can produce epileptiform activity on EEG recordings in humans (4,24,25). Moreover, we observed temporal lobe activation by remifentanil in this study in humans, similar to that seen in opioid-treated rats and subhuman primates.¹ These preliminary studies in seven primates (three subhuman and four human) provide support for the thesis that opioid-induced excitatory phenomena observed in subprimate animal models are relevant to humans. It is important to note however that our human observations are somewhat preliminary because there was no group that underwent the identical procedures without remifentanil and there is a possibility that results were confounded by the need for an induction dose of propofol. We were not willing to perform endotracheal intubation with neuromuscular blockade in the absence of a hypnotic drug and, because of the theoretical potential for adverse effects, we wished to keep the duration of exposure to remifentanil without concomitant hypnotic to as brief a period as possible. In addition, the sample size was small, the studies did not replicate the intraoperative setting, the magnitude of the effect was moderate, and any dose-response relationships were not explored. Unfortunately, it is unlikely that more comprehensive data can be acquired with isolated use of large-dose remifentanil in humans. Nonetheless, the congruence of our results in humans with prior rodent and monkey studies is striking and suggests that the observations across species of µ-opioid-mediated temporal lobe activation are not coincidence. Taken altogether, the available data do seem to consistently support the speculation that, in some very specific situations, such as prolonged sole use of large-dose opioids or with epilepsy, brain injury, or aging, there may be a potential for µ-opioids to be neurotoxic in humans.

	Acknowledgments

 
This research was supported institutionally by the West Virginia University Foundation.

The authors thank Rosalyn Garman and Rita Gabel for the excellent histologic preparations.

	Footnotes

 
¹ Kofke WA, Mintun M, Nemoto E, et al.: Opioid neurotoxicity: preliminary studies in monkeys undergoing positron emission tomographic (PET) assessment of regional glucose utilization [abstract]. J Neurosurg Anesth 1994;6:323.

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