February 1988
Vol. 29/2
Investigative Ophthalmology
& Visual Science
Articles
Extraocular Myotoxicity of the Retrobulbar Anesthetic
Bupivocoine Hydrochloride
John D. Porter, Daniel P. Edney, Esther J. McMohon, and Leigh Ann Burns
Morphopathological changes induced in the extraocular muscles by the local anesthetic agent bupivacaine hydrochloride were studied in the monkey using light and electron microscopy. Retrobulbar
anesthetic blocks, using 0.75% bupivacaine hydrochloride, were performed in five adult cynomolgus
monkeys. Morphological alterations in extraocular muscle fiber types were examined following survival periods of 3-27 days. Bupivacaine injections produced a mild and very limited myopathic response, with changes largely restricted to the global layer singly-innervated muscle fiber type which is
characterized by low mitochondrial content. For survival times beyond 3 days, this fiber type exhibited
peripheral migration and swelling of mitochondria and an outside-in pattern of myofibril dissolution.
Some affected fibers also exhibited the Ringbinden or ring fiber pathology. Maximal myotoxic response was observed at 14 days after injections, and pathological changes were largely resolved by 27
days. A more limited analysis of the effects of retrobulbar injection of lidocaine revealed similar
morphopathological responses, thereby suggesting that these effects are a property common to the
entire class of aminoacyl anesthetics. In contrast to previous observations in other skeletal musculature, the extraocular muscles proved to be unexpectedly resistant to local anesthetic treatment as only
limited alterations were observed. The observed muscle fiber type specificity was interpreted to result
from differences in the relative ability of muscle fiber types to adapt to anesthetic-induced elevations.of
intracellular free calcium levels. Invest Ophthalmol Vis Sci 29:163-174,1988
Bupivacaine hydrochloride (Marcaine®, Winthrop-Breon Laboratories, New York, NY) is an aminoacyl type local anesthetic commonly used in ophthalmic procedures due to its prolonged anesthetic
and akinetic properties. It is used either alone, or in
conjunction with more rapidly acting agents of the
same class (eg, lidocaine). While local anesthetics
serve to block generation and conduction of action
potentials by decreasing the transient voltage-dependant opening of sodium channels, these agents also
competitively displace calcium from intracellular
binding sites.1'2 An undesired side effect of many
local anesthetics has been the induction of skeletal
muscle damage in the vicinity of the application
site.3"9 A bupivacaine-induced elevation of muscle
fiber free calcium concentration is most likely responsible for the agent's myotoxic activity.10"12 Elevated intracellular free calcium levels trigger calcium-activated neutral proteases (calpain, EC
3.4.22.17)13"15 and, to a lesser extent, lysosomal enzymes, thereby leading to myofibrillar degradation.
Bupivacaine myotoxicity, in many respects, mimics
those myopathic changes which occur in Duchenne
muscular dystrophy.1316
Recent reports have suggested that the myotoxic
properties of retrobulbar anesthetics may be responsible for occasional postoperative diplopia and
ptosis.1718 Presumably, patients experience transient
motor deficits until the anesthetic-induced extraocular muscle damage is repaired. The present study was
designed to examine this hypothesis in the cynomolgus monkey, a species in which extraocular muscle organization and fiber types are virtually identical
to that of man.19-20 Specifically, these studies examined light and electron microscopic alterations induced in primate extraocular muscle fiber types by
single retrobulbar injections of bupivacaine hydro-
From the Department of Anatomy, University of Mississippi
Medical Center, Jackson, Mississippi.
Presented in part at the Annual Meeting of the Association for
Research in Vision and Ophthalmology, Sarasota, Florida, May
4-8, 1987.
Supported by USPHS grant 5 R01 EY-05464 from the National
Eye Institute, National Institutes of Health, Bethesda, Maryland.
Submitted for publication: April 28, 1987; accepted: September
24, 1987.
Reprint requests: John D. Porter, PhD, Department of Anatomy, University of Mississippi Medical Center, 2500 North State
Street, Jackson, MS 39216.
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1988
chloride or lidocaine hydrochloride. These local anesthetics produced ah unexpectedly mild myotoxic response in the extraocular muscles, consisting of the
breakdown of myofilaments in a particular muscle
fiber type. Furthermore, morphopathological
changes were correlated with muscle fiber mitochondrial and internal membrane system content. Fiber
types having high mitochondrial content were resistant to anesthetic-induced damage, while those fiber
types with low mitochondrial and high sarcoplasmic
reticulum content were subject to disruption by
aminoacyl anesthetics. Myotoxicity also correlated
with the innervation pattern of extraocular muscle
fiber types, in that only singly-innervated fibers were
affected.
Materials and Methods
Retrobulbar anesthetic blocks were performed in
five adult cynomolgus monkeys {Macaco, fascicularis). Monkeys were immobilized with ketamine hydrochloride, and 0.75% bupivacaine hydrochloride
(Marcaine®, Winthrop-Breon Laboratories) containing 75 units/ml hyaluronidase (Wydase®, Wyeth Laboratories, Philadelphia, PA) was slowly infused behind the left eye until complete anesthesia of the orbit
was obtained. Typically, 1-2 ml of bupivacaine hydrochloride was required to produce pupillary dilatation and loss of the corneal reflex. Anesthetic dosage
chosen was consistent with that in clinical use at this
and other institutions,21 although a cocktail containing two aminoacyl anesthetics (eg, one part 0.75%
bupivacaine to one part 2% lidocaine) is often used to
obtain rapid, yet prolonged anesthesia. Sterile saline
containing 75 units/ml hyaluronidase was similarly
introduced into the right orbit. All procedures involving animals conformed to the ARVO Resolution
on the Use of Animals in Research.
Following survival times of 3-27 days, monkeys
were anesthetized with pentobarbital sodium, heparinized, intubated and artificially respired with 95%
oxygen-5% carbon dioxide prior to sacrifice. Monkeys were perfused transcardially through a cannula
inserted into the ascending aorta. Physiological saline
solution containing 1% sodium nitrite was introduced, followed by 3 1 offixativesolution containing
1% paraformaldehyde and 1.25% glutaraldehyde in
0.1 M phosphate buffer (pH 7.4). Following perfusions extraocular muscles were removed by dissection
and immersed for 2 hr in cold fixative containing 4%
glutaraldehyde in 0.1 M phosphate buffer. Transverse
or longitudinal 500 /im sections of extraocular muscle were cut using a Smith-Mcllwain (Surrey, UK)
tissue sectioner, and were processed for the histochemical demonstration of acetylcholinesterase
Vol. 29
(AChE) using a copper thiocholine method.22 Tetraisopropyl pyrophosphoramide (iso-OMPA, 10~4 M;
Sigma, St. Louis, MO) was used as an inhibitor of
non-specific cholinesterase. Muscle sections were
then postfixed with 1% osmium tetroxide in 0.1 M
phosphate buffer, stained en block with 0.05% uranyl
acetate, dehydrated in methanol and propylene
oxide, and embedded in TAAB 812 resin. Muscle was
examined in semithin (1 fim) sections cut on an ultramicrotome and stained with 1% para-phenylenediamine. Regions of interest were trimmed and ultrathin (80-90 nm) sections were cut with a diamond
knife, collected on formvar-coated single-slot grids,
and stained with uranyl acetate and lead nitrate. Sections were examined and photographed with a Zeiss
10C (Thornwood, NY) electron microscope.
In order to determine whether bupivacaine myotoxicity was specific, or if it represents a general property of aminoacyl anesthetics, two additional monkeys received retrobulbar injections of 1 ml of 2%
lidocaine hydrochloride (Elkins-Sinn, Cherry Hill,
NJ). Animals were sacrificed after 14 day survival
and tissues were processed as described above.
In some experimental cases, brainstem blocks containing the oculomotor nucleus were removed following perfusions, postfixed, sectioned with a Vibratome, and processed for light and electron microscopy as described above.
Results
Retrobulbar application of bupivacaine hydrochloride produced rapid onset of pupillary mydriasis,
ptosis and loss of the corneal blink reflex in all monkeys. Akinesia was present for the anesthetic treated
orbit. Complete recovery from these effects required
8-10 hr. Anesthesia and akinesia of more limited duration was obtained from lidocaine hydrochloride injections. Lasting gross misalignment of the eyes and/
or movement deficits were not observed. Control injections of sterile saline produced only a transient
exophthalmos due to increased retrobulbar pressure.
Light Microscopic Observations
The extraocular muscles of the macaque monkey,
like those of all mammalian species, exhibit two distinct regions: the orbital and global layers.19 Six muscle fiber types are differentially distributed in these
layers. Fiber types are identified in semithin sections
largely on the basis of the staining pattern of sarcoplasmic masses (Fig. 1). Extraocular muscles are
unique among mammalian skeletal muscle in possessing not only singly-innervated fiber types, but also
two types of multiply-innervated fiber. AChE reac-
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Fig. 1. Phase contrast light photomicrographs of orbital (A) and global (B) layers of the monkey medial rectus muscle. (A) Orbital
singly-innervated fiber type (1) exhibits dense sarcoplasmic masses both centrally and subadjacent to the sarcolemma. Orbital multiply-innervated fiber (2) is small, with a fine staining pattern. Orbital layer exhibits dense capillary (c) network. Ax, axons (X510). (B) Global
singly-innervated fiber types (3-5) exhibit variations in pattern of staining of sarcoplasmic masses. Global multiply-innervated fiber (6) has
fine staining pattern. Dark staining material in muscle fibers of both layers largely reflects mitochondria! content (X510).
tion product at neuromuscular junction sites facilitated evaluation of innervation pattern.
Morphopathological alterations induced by single
retrobulbar injections of bupivacaine hydrochloride
were largely restricted to the global layer of the extraocular muscles (Fig. 2). This patterned distribution of
affected fibers was apparent in all experimental cases.
Alterations presented as peripheral dissolution of
myofilaments (Fig. 3). In order to construct the representation of affected fibers depicted in Figure 2, a
qualitative assessment of the degree of myofilament
breakdown was used. "Heavily affected fibers" were
identified as those exhibiting severe loss of myofilaments, while "lightly affected fibers" were characterized by loss of only a thin rim of sarcoplasm (see Fig.
3). In many cases, affected fibers also exhibited the
Ringbinden (or ring fiber) pathology, in which peripherally placed myofilaments are oriented orthogonal to the longitudinal axis of the fiber (Fig. 3B).
Affected fibers were largely those singly-innervated
fibers of the global layer which exhibit a fine pattern
of staining of sarcoplasmic material. No alterations
were observed in singly-innervated fibers of the orbital layer or in multiply-innervated fiber types of
either muscle layer. Sparse myopathic changes were
noted for the levator palpebrae superioris, largely because the affected fiber type comprises only a small
percentage of this muscle. Pathological changes were
not observed in control material.
A qualitatively identical pattern of morphopathological changes was observed in those monkeys that
received retrobulbar injections of lidocaine. While
the characteristic pattern of myofilament breakdown
was evident, there appeared to be smaller numbers of
pathological fibers in these cases.
The time course of bupivacaine-induced alterations is depicted in Table 1. Three days subsequent
to injections relatively few fibers exhibited changes
obvious at the light microscopic level. Pathological
orbital
light effect
heavy effect
global
1 mm
Fig. 2. Charting depicting distribution of pathological fibers in
transverse section of monkey medial rectus muscle 14 days after
retrobulbar application of bupivacaine hydrochloride. Each filled
circle indicates position of one affected fiber. See text and Figure 3
for definition of lightly and heavily affected fibers.
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DUPIVACAINE MYOTOXICITY / Porrer er ol.
Fig. 3. Phase contrast light photomicrographs of global layer of monkey rectus extraocular muscles 14 (A, B, C) and 27 (D) days after
bupivacaine treatment. (A) Low power micrograph illustrating the frequency of pathological fibers (X182). (B) Transverse section of muscle
fibers exhibiting peripheral dissolution of myofilaments (arrows). "Lightly affected fiber" (filled arrow) displays minimal breakdown of
filaments, while severe pathology is evident in "heavily affected fibers" (open arrows). Heavily affected fibers also demonstrate ring fiber
pathology. Normal global singly-innervated (3-5) and multiply-innervated (6)fibertypes are present infield(X390). (C) Longitudinal section
illustrating peripheral dissolution of myofilaments (arrows) in singly-innervated muscle fiber type (X390). (D) Low power micrograph
illustrating relative paucity of pathological fibers in comparison to that illustrated for the 14 day survival case (A) (XI82).
changes in primate extraocular muscles were maximal at 14 days subsequent to retrobulbar injection, at
which time 4.3% offibersin the medial rectus muscle
were affected. Alterations were largely resolved by 27
days after bupivacaine injections (Fig. 3D).
Electron Microscopic Observations
At the ultrastructural level the differential staining
pattern of sarcoplasmic masses that was used to distinguish extraocular muscle fiber types with the light
microscope was found to largely correspond to fiber
mitochondrial content. Three global types and one
orbital type of singly-innervated fiber could be distinguished on the basis of the number, size and distribution of mitochondria. Orbital and global multiply-innervated fibers were identified by their small size,
poor delineation of myofibrils and occurrence of
motor nerve terminals separated by 1 mm or more
along the longitudinal extent of the fiber.
Retrobulbar injections of bupivacaine or lidocaine
produced dissolution of myofilaments located
around the periphery of the singly-innervated muscle
fiber type with low mitochondrial content and extensive development of the internal membrane systems
(ie, sarcoplasmic reticulum and t-tubules; Fig. 4).
Pathogenic events followed a time course which was
similar in all experimental animals. Mitochondria,
which normally are small and homogenously distributed in this fiber type, initially migrated to a subsarcolemmal location where they increased dramatically
in size (Figs. 4, 5B). The few mitochondria remaining
in the central region of affected fibers retained normal characteristics. Swelling of subsarcolemmal elements of the sarcoplasmic reticulum also was noted
in short-term survival cases (Fig. 5A). While some
fibers never progressed further in the sequence of
events following bupivacaine injections, many muscle fibers subsequently exhibited an outside-in pattern of myofilament breakdown. Muscle fibers at an
early stage of myofilament dissolution frequently
presented peripherally placed myofibrils which were
oriented at a right angle to the longitudinal axis of the
fiber (Ringbinden or ring fibers; Fig. 4A). Such aberrant myofibrils had prominent Z lines, but due to
contraction the A and I bands were not readily dis-
cerned. Fibers in later stages of myofibril dissolution
exhibited severe swelling of those portions of the t-tubule system that were subadjacent to the sarcolemma
(Fig. 4B). In addition, subsarcolemmal tubular aggregates frequently occurred in heavily affected fibers
(Fig. 5C). In rare instances a fiber exhibited total
breakdown of myofilaments, ultimately containing
only granular sarcoplasm and scattered mitochondria.
A clear relationship existed between the number
and distribution of mitochondria present in a particular singly-innervated muscle fiber type and the degree
to which that fiber type was affected by bupivacaine.
The most severely affected fibers were those that normally exhibited few, small mitochondria. While pathological changes occurred in some fibers with high
mitochondrial content (Fig. 6), alterations in these
fibers were typically milder and much less frequent.
In general, the most severe changes in such fibers
were limited to swelling of peripheral mitochondria
and vacuolization, probably the result of mitochondrial distension and the accumulation of lipid. Fibers
with intermediate to high mitochondrial content did
not undergo severe myofilament breakdown. Lysosomes, usually associated with peripheral mitochondrial aggregates, also were observed in this fiber type.
Rarely afiberwith high mitochondrial content exhibited severe vacuolization and presumably would not
have survived. However, even in these instances the
patterned outside-in breakdown of myofilaments was
Table 1. Morphopathological changes in the medial
rectus muscle induced by retrobulbar
bupivacaine injections
*
Pathologicalfibers(%)'
Survival
(days)
Light
Heavy
Monkey
effect
effect
Total
06-27
06-04
03-24
06-09
07-15
3
5
10
14
27
0.08
0.22
2.15
3.33
1.82
0.03
0.03
0.48
0.98
0.26
0.11
0.25
2.63
4.31
2.08
* Lightly affected fiber is defined as minimal breakdown of myofibrils
around periphery of fiber, while heavy effect denotes extensive myofilament
breakdown (see Fig. 3).
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Fig. 4. Electron photomicrographs illustrating morphopathological alterations in global singly-innervated fiber type of the medial rectus
muscle 14 days after bupivacaine treatment. (A) The affected fiber exhibits an outside-in pattern of myofilament breakdown and an increase
in the number and size of peripheral mitochondria (normal mitochondria remaining in center of fiber indicated by arrowheads). Peripheral
myofibrils are oriented orthogonal to axis of thefiber,with Z-lines (Z) evident. Normal singly-innervatedfibers(SIF) surround affected fiber
(X5358). (B) Singly-innervated fiber at a more advanced stage of myofilament dissolution indicating clear sarcoplasm in periphery and
swollen mitochondria. Scalloped appearance of sarcolemma probably due to enlarged t-tubules (arrows). An activated satellite cell (S) intrudes
into affected fiber. Normal global multiply-innervated fiber (MIF) located adjacent to pathological fiber (X5358).
not noted. Multiply-innervated fiber types generally
were not affected by bupivacaine treatment (Fig. 4B).
Activated satellite cells (Fig. 4B) and premyocytes
(see Chou and Nonaka23) often were associated with
pathological fibers consistent with observations that
many fibers apparently recover from bupivacaine
treatment. Small peripheral clusters of myofilaments,
oriented along the longitudinal axis of the regenerating fiber, and scattered aggregations of internal
membrane system constituents were noted in premyocytes of 14 and 27 day survival cases. Other
fibers, however, did not survive and were fragmented
and engulfed by macrophages which increased in
abundance within 10-14 days of bupivacaine injection.
Oculomotor motoneurons, intramuscular nerves,
and neuromuscular junctions (Fig. 7) appeared normal in experimental material. Motoneurons had the
characteristic complement of organelles and distribution of axosomatic synaptic contacts. Neuromuscular
junctions retained the close apposition of axon terminal with sarcolemma, AChE reaction product in intercellular cleft and postjunctional folds, and postjunctional mitochondrial accumulations that characterize those of normal extraocular muscle. There was
no specific association of bupivacaine-induced morphopathological changes with sites of neuromuscular
junctions. In addition, there was no evidence that
bupivacaine produced morphological changes in the
vascular network of the extraocular muscles, since
capillary distribution and morphology appeared normal in experimental material.
Discussion
These studies have demonstrated that retrobulbar
application of bupivacaine hydrochloride produces
limited structural alterations in primate extraocular
muscles. Morphopathological changes correlated
with fiber type mitochondrial content, internal
membrane system development and innervation pattern. Among singly-innervated fiber types, those exhibiting the lowest mitochondrial content and highest
sarcoplasmic reticulum development were the most
sensitive to bupivacaine. Multiply-innervated fiber
types were unaffected by these treatments. The primarily myopathic nature of bupivacaine toxicity is
evident since neither motor system components nor
muscle vasculature exhibited alterations in these or
other24 studies. Interruption of the motor innervation
of the extraocular muscles produces disuse-related
changes in those muscle fiber types that are heavily
dependent upon oxidative energy mechanisms (ie,
singly-innervated fibers with high mitochondrial
content),25"27 and does not lead to changes like those
observed in the present study. Taken together, many
of the alterations observed in this study may be explained as resulting from a direct perturbation of fiber
calcium metabolism by bupivacaine. Limited data
which demonstrate similar myotoxicity for lidocaine
suggest that this is a property of all aminoacyl local
anesthetics.
Skeletal muscle calcium stores include both that
which is segregated into membrane-bound compartments, represented by the sarcoplasmic reticulum
and mitochondria, and that fraction which is free in
the cytosol. Excitation/contraction coupling is dependent upon fine control of intracellular free calcium concentration largely via the sarcolemmal
Ca2+-ATPase, which actively extrudes calcium, and
the calcium pump of the sarcoplasmic reticulum,
which sequesters calcium during muscle relaxation.28"30 In normal muscle, the calcium flux which
regulates contraction, a transient increase in free
levels that facilitates interaction of actin and myosin
myofilaments, occurs across the sarcoplasmic reticulum. Several experimental interventions, as well as
some naturally occurring myopathies, are associated
with alterations in calcium homeostasis—specifically, chronic elevations in intracellular cytosolic calcium that may trigger a cascade of events culminating
in fiber degeneration.13-31'32
Bupivacaine hydrochloride functions as a long-acting local anesthetic as a result of both its lipophilic
properties, which confer good mobility through biological membranes, and its high protein binding capacity. In addition to serving as a sodium channel
blocker, bupivacaine displaces calcium from membrane binding sites and increases the fluidity of, and
thus the ionic flux across, the sarcolemma.2 The
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Fig. 5. Electron photomicrographs of fibers in bupivacaine treated medial rectus muscles. (A) Swelling of peripheral elements of the
sarcoplasmic reticulum (open arrows) 3 days after bupivacaine treatment. Note normal size of sarcoplasmic reticulum (filled arrows) in deeper
region of same fiber. Mitochondria (m) and lipid droplets (I) are indicated (XI 6,000). (B) Enlargement of peripheral mitochondria (open
arrow) in contrast to those located more centrally (filled arrow) 5 days following bupivacaine injection (X 10,000). (C) Formation of
subsarcolemmal tubular aggregates (ag) 14 days after bupivacaine injection. Note total loss of myofilaments in this region of affected fiber
while adjacent multiply-innervated fiber (MIF) is normal (X26,000).
myotoxic properties of the aminoacyl anesthetics
probably stem from their primary effect of increasing
intracellular free calcium levels by these mechanisms,10"12 Since retrobulbar injections of lidocaine
also produced similar morphopathological changes in
monkey extraocular muscle, such limited extraocular
myotoxicity most likely is characteristic of the entire
family of aminoacyl anesthetics used in orbital surgery.
The role played by the sarcoplasmic reticulum and
mitochondria in calcium homeostasis is central to the
understanding of aminoacyl anesthetic myotoxicity.
In normal muscle, the sarcoplasmic reticulum is the
principal site of calcium release and uptake.28"30 This
is reflected in the present finding that the initial morphological changes in extraocular muscle subsequent
to bupivacaine application include swelling of sub-
sarcolemmal elements of the sarcoplasmic reticulum.
These changes may represent an adaptive response to
an increased flux of calcium across the surface membrane. While the affinity of mitochondrial transport
mechanisms for calcium is low, both the maximum
rate and capacity of calcium accumulation by mitochondria far exceed that of the sarcoplasmic reticulum.31'33 Present observations of mitochondrial
movement to the periphery and their subsequent increase in size may then indicate that mitochondria
become important as a calcium sink primarily at high
intracellular free calcium levels. Corollaries of excess
calcium accumulation by mitochondria (which requires energy) are the shunting of ATP away from
other cellular processes and the uncoupling of oxidative phosphorylation, which together further reduce
the ability of the muscle fiber to handle elevated free
Fig. 6. Electron photomicrograph of global layer singly-innervated fiber type
with high mitochondrial
content. From medial
rectus muscle 14 days after
bupivacaine treatment. For
fiber on left, note only slight
swelling of peripheral mitochondria (arrow). Fiber on
right exhibits limited degree of vacuolization (v).
Normal singly-innervated
fiber with low mitochondrial content is located
below (X5092).
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1988
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Fig. 7. Electron photomicrograph of neuromuscular
junction of pathological
fiber 14 days after bupivacaine treatment. Note normal appearance of axon terminals and characteristic localization of AChE reaction
product in junctional cleft
and postjunctional folds (arrowheads). While sarcoplasm deficient in myofilaments is normal at the neuromuscular junction, this
fiber exhibits excessive clear
sarcopiasm. As this micrograph is from a transversely
sectioned fiber, the appearance of abnormally oriented
myofibrils (ring fiber) is
noted (X85OO).
calcium levels.32"36 Taken together, mitochondria!
abnormalities represent a central element in many
extraocular muscle pathologies.25"27 Furthermore,
the formation of subsarcolemmal tubular aggregates
also may represent an adaptive response to elevated
calcium levels since these structures frequently occur
in myopathic disorders.26-37"39
Bupivacaine elicits a myotoxic response in extraocular muscle that is considerably milder than that seen
for other skeletal muscles.6"9 These intermuscle differences in toxicity, as well as the fiber type specificity
this anesthetic exhibits for the extraocular muscles,
are directly related to fiber mitochondrial and internal membrane system content. Because of their capacity for calcium uptake, mitochondria may confer
relative degrees of protection upon individual singlyinnervated muscle fiber types. Consistent with the
hypothesis that mitochondria serve as a calcium sink,
the fiber type affected in the present study presents
low mitochondrial content. It is likely that the protection provided by the generally high mitochondrial
content of most extraocular muscle singly-innervated
fiber types has limits, and excessive application of
bupivacaine may produce a more generalized pathological response in these muscles. Likewise, the high
sarcoplasmic reticulum content of the affected fiber
type may contribute to its sensitivity to bupivacaine
by providing a significant intracellular source of calcium. The absence of pathological alterations in the
multiply-innervated fiber types, which does not correlate with mitochondrial content, must be mediated
by some other mechanism.
The musclefibertoxicity of bupivacaine has implications for eye movement control subsequent to its
use in orbital surgery in humans. Rainin and Carlson17 hypothesize that local anesthetic myotoxicity is
responsible for the occasional transient ptosis and diplopia following ophthalmic procedures conducted
with retrobulbar anesthesia. To support this hypothesis, the authors cite data indicating that several
aminoacyl local anesthetics (lidocaine, mepivacaine,
and bupivacaine) produce a severe pathological response, which lacksfibertype specificity, in rat extraocular muscles.18 The gross atrophy observed following retrobulbar injections in the rat is similar to those
findings obtained for other skeletal muscles.4"6 Interspecies variations in muscle fiber types, as well as
differences in histological techniques employed,
create difficulties in comparing present findings with
those of Carlson and Rainin.18 The more generalized
response seen by these authors may result from either: (1) potentially higher bupivacaine concentration
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DUPIVACAINE MYOTOXICITY / Porrer er ol.
No. 2
at the muscle surface in their study; or (2) actual
lower mitochondrial content of rat extraocular muscle fiber types.40 The present study, by contrast, reports a mild fiber type-specific effect. Morphopathological changes produced by the retrobulbar injection
of bupivacaine, at the dose used in the present study,
most likely would not produce eye and lid position
deficits (eg, diplopia and ptosis). However, given the
low incidence of such postoperative deficits, these
data do not exclude the possibility that severe idiosyncratic reactions to bupivacaine anesthesia may be
responsible for occasional eye movement disorders.
For most skeletal musculature, it is well established
that the structural characteristics of an individual
musclefibertype correlate with its functional properties.41 Speed of contraction is largely determined by
the degree of development of internal membrane systems, and fatigability is a correlate of mitochondrial
content. While the existence of a tight structure/
function correlation has yet to be established for the
extraocular muscles, the morphological properties of
the affected muscle fiber type (ie, high development
of internal membrane systems and low mitochondrial content) suggest that it is phasically active in
rapid eye movements and fatigues easily. Thus, one
would then expect that retrobulbar application of
local anesthetics would produce transient reductions
in saccadic velocity rather than fixation disorders.
The precise functional effects of compromising particular extraocular muscle motor unit types, however,
remain to be determined.
Key words: extraocular muscle, myotoxicity, bupivacaine
hydrochloride, lidocaine hydrochloride, muscle calcium,
monkey
Acknowledgments
The authors thank Drs. Robert F. Spencer (Medical College of Virginia) and John P. Naftel (University of Mississippi Medical Center) for many helpful discussions and for
their comments on an earlier version of the manuscript.
Comments on the clinical implications of anesthetic effects
by Dr. Alan Scott (Smith-Kettlewell Institute for Visual
Sciences) also are much appreciated.
References
1. Ritchie JM and Greengard P: On the mode of action of local
anesthetics. Ann Rev Pharmacol 6:405, 1966.
2. Madeira VMC and Carvalho AP: Interaction of cations and
local anesthetics with isolated sarcolemma. Biochim Biophys
Acta 266:670, 1972.
3. Benoit PW and Belt WD: Some effects of local anesthetic
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