+++
Basic Considerations: Introduction
++
Although there are relatively few published reports of
anesthesia-related nerve injury associated with peripheral nerve blocks
(PNBs), it is likely that the commonly cited incidence (0.4%) of neurologic
injury is underestimated owing to underreporting.1–3
Most complications of PNBs were reported with upper extremity blocks. The
less frequent clinical application of lower extremity nerve blocks may be
the main reason why there are even fewer reports of anesthesia-related nerve
injury associated with lower extremity PNBs compared with upper extremity
PNBs.4 Although neurologic complications after PNBs can be
related to factors associated with the block technique (eg, needle trauma,
intraneuronal injection, neuronal ischemia, and toxicity of local
anesthetics), a search for other common causes should include positional and
surgical factors (eg, positioning, stretching, retractor injury, ischemia,
and hematoma formation). In some instances, the neurologic injury may be a
result of a combination of these factors.
++
In all four sections of this chapter, mechanisms and consequences of
acute neurologic injury related to the nerve block procedure are discussed
and, where appropriate, methods and techniques to reduce the risk of
complications are suggested. Specific nerve injuries with upper and lower
nerve block techniques, neuraxial anesthesia, and local anesthetic toxicity
are discussed elsewhere in this volume.
+++
Functional Histology of the Peripheral Nerves
++
Knowledge of the functional histology of the peripheral nerve is
important to understand the mechanisms of peripheral nerve injury; the
reader is referred to Chapters 3 and 4 for more in-depth discussion on this
subject. Here we briefly review salient features of the organization of the
peripheral nerves. A peripheral nerve is a complex structure consisting of
fascicles held together by the epineurium, an
enveloping, external connective sheath (Figure 69–1). Each
fascicle contains many nerve fibers and capillary blood vessels embedded in
a loose connective tissue, the
endoneurium.5 The
perineurium is a multilayered epithelial sheath that
surrounds individual fascicles and consists of several layers of perineural
cells. Therefore, in essence, a fascicle is a group of nerve fibers or a
bundle of nerves surrounded by perineurium. Of note, fascicles can be
organized in one of three common arrangements: monofascicular (single, large
fascicle); oligofascicular (few fascicles of various sizes); and
polyfascicular (many fascicles of various sizes).6
++
++
Nerve fibers can be myelinated or unmyelinated; sensory and motor nerves
contain both in a ratio of 4:1, respectively. Unmyelinated fibers are
composed of several axons, wrapped by a single Schwann cell. The axons of
myelinated nerve fibers are enveloped individually by a single Schwann cell.
A thin layer of collagen fibers, the endoneurium, surrounds the individually
myelinated or groups of unmyelinated fibers.
++
Nerve fibers depend on a specific endoneurial environment for their
function. Peripheral nerves are richly supplied by an extensive vascular
network in which the endoneurial capillaries have endothelial “tight
junctions,” a peripheral analogy to the blood–brain barrier. The
neurovascular bed is regulated by the sympathetic nervous system, and its
blood flow can be as high as 30–40 mL/100 g per minute.7
In addition to conducting nerve impulses, nerve fibers also maintain axonal
transport of various functionally important substances such as proteins and
precursors for receptors and transmitters. This process is highly dependent
on oxidative metabolism. Any of these structures and functions can be
deranged during a traumatic nerve injury, with the possible result of
temporary or permanent impairment or loss of neural function.
++
The size and number of the fascicles in a peripheral nerve
substantially vary from one peripheral nerve to another. In general, the
larger the nerve, the greater the number and size of the fascicles. In
addition, the larger the fascicle, the greater is the risk of intraneural
injection because large fascicles can accommodate the tip of the
needle.8 Of note, the fascicular bundles are not
continuous throughout the peripheral nerve. They divide and anastomose with
one another as frequently as every few millimeters.8
However, the axons within a small set of adjacent bundles redistribute
themselves so that they remain in approximately the same quadrant of the
nerve for several centimeters. This arrangement is of practical concern to
the surgeons trying to repair a severed nerve. If the cut is clean, it may
be possible to suture individual fascicular bundles together. In such a
scenario, there is a good probability that the distal segment of nerves
will be sutured to the central stump of motor
axons and sensory axons. In such cases, good functional
recovery is possible. If a short segment of the nerve is missing, however,
the fascicles in the various quadrants of the stump may no longer correspond
with one another, good axial alignment may not be possible, and functional
recovery is greatly compromised or improbable.8 This
arrangement of the peripheral nerve helps explain why intraneural injections
result in more serious consequences as opposed to clean needle nerve cuts, which
tend to heal much more readily.
++
+++
Mechanisms of Peripheral Nerve Injury
++
The cause of peripheral nerve injury related to the use of PNBs falls
into one of four categories (Table 69–1).
Laceration results when the nerve is cut partially or
completely, such as by a scalpel or a large-gauge cutting needle.
Stretch injuries to the nerves may result when nerves
or plexuses are stretched in a nonphysiologic or exaggerated physiologic
position, such as during shoulder manipulation under an interscalene block.
Pressure, as a mechanism of nerve injury, is
relatively common. A typical example of this mechanism is chronic
compression of the nerves by neighboring structures, such as fibrous bands,
scar tissue, or abnormal muscles that pass through fibro-osseous spaces if
the space is too small, such as the carpal tunnel. Such chronic compression
syndromes are called entrapment neuropathies.
Examples of pressure injuries applicable to PNBs include external pressure
over a period of hours (eg, a Saturday night palsy, resulting from pressure
of a chair back on the radial nerve of the insensate arm). The pressure may
be repeated and have a cumulative effect (eg, an ulnar neuropathy resulting
from habitually leaning on the elbow). Such a scenario is conceivable, for
instance, in a patient who positions the anesthetized arm (eg, long-acting
or continuous brachial plexus block) in a nonphysiologic position for a few
hours. Another example of pressure-related nerve injury is prolonged use of
a high-pressure tourniquet. An intraneural injection may lead to
sustained high intraneural pressure, which exceeds capillary occlusion
pressure, and leads to nerve ischemia.10
Finally, a forceful injection into a low-compliant connective tissue plane
(space) containing a peripheral nerve may lead to nerve ischemia and
neurologic dysfunction. Vascular nerve damage after nerve blocks can occur
when there is acute occlusion of the arteries from which the vasa nervorum
are derived or from a hemorrhage within a nerve sheath. With injection
injuries, the nerve may be directly impaled and the drug injected directly
into the nerve, or the drug may be injected into adjacent tissues, causing
an acute inflammatory reaction or chronic fibrosis—both indirectly
involving the nerve. Chemical nerve injury is the
result of tissue toxicity of injected solutions (eg, local anesthetic
toxicity, neurolysis with alcohol or phenol).
++
+++
Clinical Classification of Acute Nerve Injuries
++
Classification of acute nerve injuries is useful when considering the
physical and functional state of damaged nerves. In his classification,
Seddon11 introduced the terms neurapraxia, axonotmesis,
and neurotmesis (Table 69–2); Sunderland12
subsequently proposed a five-grade classification system.
++
++
Neuropraxia refers to nerve dysfunction
lasting several hours to 6 months after a blunt injury to the nerve. In
neuropraxia, the nerve axons and connective tissue structures remain intact.
The nerve dysfunction probably results from several factors, of which
focal demyelination is the most important abnormality. Intraneural hemorrhage,
pressure ischemia changes in the
vasa nervorum, disruption of the blood–nerve barrier and axon membranes,
and electrolyte disturbances all may add to the impairment of nerve
function. Because the nerve dysfunction is rarely complete, clinical
deficits are partial and recovery usually occurs within a few weeks,
although some neurapraxic lesions (with minimal or no axonal degeneration)
may take several months to recover.
++
Axonotmesis consists of physical interruption of the axons but within intact
Schwann cell tubes and intact connective tissue structures of the nerve (ie,
the endoneurium, perineurium, and epineurium).
Sunderland12 subdivided this group, depending on which of
the three structures were involved (see Table 69–2). With axonotmesis, the
nerve sheath remains intact, enabling regenerating nerve fibers to find
their way into the distal segment. Consequently, efficient axonal
regeneration can eventually take place.
++
Neurotmesis refers to a complete interruption of the entire nerve including the axons and
all connective tissue structures (epineurium included). Clinically, there is
total nerve dysfunction. With both axonotmesis and neurotmesis, axonal
disruption leads to wallerian degeneration, from which recovery occurs
through the slow process of axonal regeneration. However, with neurotmesis,
the two nerve ends may be completely separated, and the regenerating axons
may not be able to find the distal stump. For these reasons, effective
recovery does not occur unless the severed ends are sutured or joined by a
nerve graft. With closed injuries, the only way to distinguish clearly
between axonotmesis and neurotmesis is by surgical exploration and
intraoperative inspection of the nerve.
++
Note that most acute nerve injuries are mixed lesions.11
Different fascicles and nerve fibers typically sustain different degrees of
injury, which may make it difficult to assess the type of injury and predict
outcome even by electrophysiologic means. Recovery from a mixed lesion is
characteristically biphasic; it is relatively rapid for fibers with
neurapraxic damage, but much slower for axons that have been physically
interrupted and have undergone wallerian degeneration.
+++
Mechanical Nerve Injury
+++
Intraneural Injection and Its Prevention
++
Rather than a relatively clear injury caused by sharp needle cuts,
intraneural injection has the potential to create structural damage to the
fascicle(s) that is more extensive and less likely to heal (Figure
69–2). Indeed, the devastating sequelae of sensory and motor loss after
injection of various agents into peripheral nerves has been well
documented.13 Nearly all experimental studies on this
subject have demonstrated that the site of injection is critical in
determining the degree and nature of injury. More specifically, to induce
neurologic injury, the injectate must be injected intrafascicularly;
extrafascicular injections of the same substance typically do not cause
nerve injury.14 Thus, the main factor leading to a
substantial peripheral nerve damage associated with injection techniques is
injection of local anesthetic into a fascicle. This causes mechanical
destruction of the fascicular architecture and sets into motion a cascade of
pathophysiologic changes, including inflammation, cellular infiltration,
axonal degeneration, and others—all possibly leading to nerve scarring and permanent neurologic impairement.
++
++
Histologic features of injury after intraneural injection are rather
nonspecific and range from simple mechanical disruption and delamination to
fragmentation of the myelin sheath and marked cellular infiltration
(Figure 69–3). Using a variety of animal models of nerve injury, a
vast array of cellular changes following peripheral nerve trauma have been
documented.14 The extent of actual neurologic damage after
an intrafascicular injection can range from neuropraxia with minimal
structural damage to neurotmesis with severe axonal and myelin degeneration,
depending on the needle–nerve relationship, the agent injected, and the
dose of the drug used.15–19 In general, subperineural
changes tend to be more prominent compared with the central area of the
fascicle.20 In addition, injury to primary sensory neurons
that is not detectable histologically causes a shift in membrane channel
expression, sensitivity to algogenic substances, neuropeptide production,
and intracellular signal transduction both at the injury site and in the
cell body in the dorsal root ganglion. This leads to increased
excitability and acute or chronic pain often experienced by patients with
neurologic injury. It should be noted that intraneural injection and its
resultant mechanical injury are merely the inciting mechanisms; a host of
additional changes occur involving inflammatory reactions, chemical
neuritis, and intraneural hemorrhage, all of which eventually
may combine and lead to nerve
scarring and chronic neuropathic pain.
++
++
Little is known about how to avoid an intraneural injection. Pain with
injection has long been thought of as the cardinal sign of intraneural
injection; consequently, it is commonly suggested that blocks be avoided in
heavily premedicated or anesthetized patients. However, numerous case
reports have suggested that pain may not be reliable as a sole warning sign
of impending nerve injury, and it may present in only a minority of
cases.21–25 Fanelli and colleagues3
have reported unintended paresthesia in 14% of patients in their study;
however, univariate analysis of potential risk factors for postoperative
neurologic dysfunction failed to demonstrate paresthesia as a risk factor.
In addition, the sensory nature of the pain-paresthesia can be difficult to
interpret in clinical practice.26 For instance, a certain
degree of discomfort on injection (“pressure paresthesia”) is considered
normal and affirmative of impending successful blockade because this symptom
is thought to indicate that injection of local anesthetic has been made in
the vicinity of the targeted nerve.26 In clinical
practice, however, it can be difficult to discern when pain-paresthesia on
injection is normal and when it is the ominous sign of an intraneural
injection.27 Moreover, it is unclear how pain or
paresthesia on injection, even when present, can be used clinically to
prevent development of neurologic injury. For instance, in a prospective
study on neurologic complications of regional anesthesia by Auroy and
colleagues,2 neurologic injuries after paresthesia ensued,
although the participating anesthesiologists stopped the injection when pain
on injection was reported by the patients.
+++
Intensity of the Stimulating Current
++
The optimal current intensity resulting in accurate localization of a
nerve has been a topic of controversy.28–31 For
instance, stimulation at currents higher than 0.5 mA may result in block
failure because the needle tip is
positioned outside the fascial sheath that envelopes a
nerve, whereas
stimulation at currents lower than 0.2 mA theoretically pose a risk of
intraneural injection.32 Other authors suggest that a
motor response with a current intensity between 1.0 and 0.5 mA is sufficient
for accurate placement of the block needle28; still others
advise using a current of much lower intensity (0.5–0.1 mA).29,31
Others simply suggest stimulating with currents less than 0.75
mA,33,34 or progressively reducing the current to as low a
level as possible while still maintaining a motor
response.30
++
++
Many recently published reports on nerve blocks have suggested obtaining
nerve stimulation with currents of 0.2–0.5 mA (100 msec) before injecting
local anesthetics, believing that motor response with current intensities
lower than 0.2 mA may be associated with intraneural needle placement.
However logical these beliefs may sound, no published clinical reports
substantiate these concerns.
++
In current clinical practice, development of nerve
localization and injection monitoring techniques to reliably prevent
intraneural injection remains elusive.22 Nerve stimulators
are very useful for nerve localization; however, the needle–nerve
relationship cannot be precisely and reliably ascertained adequately, as
early literature suggests.28 Response to nerve stimulation
with a commonly used current intensity (1 mA) may be absent even when the
needle makes physical contact with or is inserted into a nerve35–37 (Figure 69–4). Occurrence of nerve injuries despite
using nerve stimulation to localize nerves further suggests that nerve
stimulators can at best provide only a rough approximation of the
needle–nerve relationship.1 A fundamental problem with
the nerve stimulation is that the current flows in all directions, following
the path of least resistance and not necessarily only toward the nerve.
Miniscule changes at the needle tip–tissue interface can make a substantial
difference in the preferential flow of current away from the nerve. This may
result in cessation of the motor response even when the needle is in
intimate relation with the nerve or when it is placed intraneurally. The
current interest for ultrasound-assisted nerve localization holds promise
for facilitating nerve localization and administration of nerve blocks.
However, the image resolution of this technology is insufficient to
visualize nerve fascicles and prevent intrafascicular injection.
++
+++
Resistance to Injection
++
Assessing resistance to injection is a common practice, similar to loss
of resistance to injection of air or saline using a “syringe feel” during
administration of epidural, paravertebral, or lumbar plexus blocks.
Similarly, assessing tissue resistance and injection compliance constitute
another means of estimating the anatomic location of the needle tip during
the practice of PNBs. For this, clinicians use a syringe feel to estimate
what may be an abnormal resistance to nerve block injection and thus reduce
the risk of intraneural injection.10,31,38 However, this
practice has significant inherent limitations.39 For
instance, the resistance to injection is greater with smaller needles,
introducing additional confusion as to what constitutes normal or abnormal
resistance. Second, rather than loss of resistance in an epidural injection,
there is no baseline pressure information or change in tissue compliance
during nerve block injection. In other words, with nerve block injection
there is no change in pressure that can be relied on. For instance, in a
study by Claudio and colleagues,39 all anesthesiologists
detected a change in pressure of as little as 0.5 psi during a simulated
nerve block injection. However, when gauging the absolute pressure,
clinicians substantially varied (by as much as 40 psi) in their perception
of what constituted an abnormal resistance to injection. Finally, no
information has been available on what constitutes normal or abnormal
injection pressure during nerve block injection. For these reasons,
subjective estimation of resistance to injection is at least as inaccurate
as perhaps estimating blood pressure by palpating radial artery pulse;
objective means of assessing resistance to injection should be far superior
in standardizing injection force and pressure.
++
++
To explain the mechanisms responsible for development of neuraxial
anesthesia after an interscalene block,40,41 Selander and
Sjostrand42 injected solutions of local anesthetic into
rabbit sciatic nerves and traced the spread of the anesthetic along the
nerve sheet. They postulated that an intraneural injection results in
significant intraneural spread of local anesthetic. In their model, these
investigators incidentally noticed that intraneural injections often
resulted in higher pressures (up to 9 psi) than those required for
perineural injections (<4 psi). Injection into a nerve fascicle
resulted in rupture of the perineurium and histologic evidence of disruption
of the fascicular anatomy. This study, however, used a small animal model,
microinjections (10–200 μL), miniature needles, and clinically
irrelevant injection rates (100–300 μL/min) and did not study
neurologic consequences after intraneural injections. Perhaps for these
reasons their results foretelling the possible association of injection
pressure with intrafascicular injection did not change the clinical
practice.
++
More recent studies, however, have used clinically more applicable injection
speeds and volumes of local anesthetic in a canine model of nerve
injury.4 The results of these studies suggest that
intrafascicular injection is associated with high injection pressures
(>20 psi) and carry a risk of neurologic
injury20 (Figures 69–5 and 69–6). Only
intraneural injections resulting in pressures greater than 20 psi have been
associated with clinically detectable neurologic deficits (Figure
69–7) as well as histologic evidence of injury to nerve fascicles.
++
++
++
++
The current evidence suggests that neurologic injury does not always develop
after an intraneural injection.37 In fact, injection after
an intraneural needle placement is more likely to result in deposition of
the local anesthetic between and not into the fascicles.20
Intraneural, but extrafascicular (interfascicular) injection probably occurs more commonly
than is thought in clinical practice.37 Such an injection
results in a block of unusually fast onset and long duration rather than in
neurologic injury. This is because an intraneural but extrafascicular
injection leads to intimate exposure of nerve fascicles to high
concentration and doses of local anesthetics. However, permanent neurologic
injury does not develop because the local anesthetic is deposited
outside the fascicles and the blocks slowly resolve after the injection without
evidence of histologic derangement.
+++
Needle Design and Direct Needle Trauma
++
Needle tip design and risk of neurologic injury have been matters of
considerable debate for more than three decades. Nearly 30 years ago,
Selander and colleagues43 suggested that the risk of
perforating a nerve fascicle was significantly lower when a short-bevel (eg,
angle of 45 degrees) needle was used as opposed to a long-bevel (angle of
12–15 degrees) needle. The results of their work are largely responsible
for the currently prevalent trend of using short-bevel needles (ie, angles
30–45 degrees) for most major peripheral nerve conduction blocks. However,
the more recent work of Rice and McMahon44 suggested that
when placed intraneurally, short-bevel needles cause more mechanical damage
than the long-bevel needles.44 In their experiment in a
rat model, deliberate penetration of the largest fascicle of the sciatic
nerve with short-bevel needles
resulted in the greatest degree of neural trauma. Their work suggests that
sharp needles produce clean, more-likely-to-heal cuts, whereas blunt needles
produce irregular and more extensive damage on the microscopic
images. In addition, the cuts produced by the sharper needles were more
likely to recover faster and more completely than were the irregular, more
traumatic injuries caused by the blunter, short-bevel
needles.44
++
Although the data on needle design and nerve injury have not been
clinically substantiated, the theoretical advantage of short-bevel needles
in reducing the risk of nerve penetration has influenced both practitioners
and needle manufacturers. Consequently, whenever practical, most clinicians
today prefer to use short-bevel needles for major conduction blocks of the
peripheral nerves and plexuses. Sharp-beveled, small-gauge needles, however,
continue to be used routinely for many nerve block procedures, such as
axillary transarterial brachial plexus block, wrist and ankle blocks,
cutaneous nerve block, and others.
++
Regardless of the considerations related to the needle design and risk of
nerve injury, the actual clinical significance of isolated, direct needle
trauma remains unclear. For instance, it is possible that both paresthesia
and nerve stimulation techniques of nerve localization often result in
unrecognized intraneural needle placement; yet the risk of neurologic injury
remains relatively low. Similarly, during femoral arterial cannulation
(arterial line insertion), it is likely that the needle is often
inadvertently inserted into the femoral nerve; yet injuries to the femoral
nerve are rare, and when they occur, they are usually attributed to hematoma
formation rather than needle injury.45 It is possible that
a needle-related trauma without accompanying intraneural injection results
in injury of a relatively minor magnitude, which readily heals and may go
clinically undetected. In contrast, needle trauma combined with injection of
local anesthetic into the nerve fascicles carries a risk of much more severe
injury.20
+++
Chemical Causes of Peripheral Nerve Injury
+++
Toxicity of Injected Solution
++
Nerves can be injured by direct contact with a needle, injection of a
drug into or around the nerve, pressure from a hematoma, or scarring around
the nerve.9,46–48
The degree of nerve damage after an injection depends on the exact site of
the injection and the type and quantity of the drug
used.15 The most severe damage is produced by
intrafascicular injections, although extrafascicular (subepineurial)
injections of some particularly toxic drugs can also produce nerve
damage.16,17 Benzylpenicillin, diazepam, and paraldehyde
are the most damaging; however, a number of other medications, such as
antibiotics, analgesics, sedatives, and antiemetic medications, are also
capable of damaging peripheral nerves when injected experimentally or
accidentally.15
++
Local anesthetics produce a variety of cytotoxic effects in cell
cultures, including inhibition of cell growth, motility, and survival, as
well as morphologic changes. The extent of these effects is proportionate to
the length of time the cells are exposed to the local anesthetic solution
and occur using local anesthetic at normal clinical concentrations. Within
normal ranges, the cytotoxic changes are greater as concentrations increase.
++
In the clinical setting, the exact site of local anesthetic deposition plays
a critical role in determining the pathogenic potential.49
After applying local anesthetics outside a fascicle, the regulatory function
of the perineural and endothelial blood–nerve barrier is only
minimally compromised. High concentrations of extrafascicular anesthetics
may produce axonal injury independent of edema formation and elevated
endoneurial fluid pressure.50 As with the effects of local
anesthetics in cell cultures, the duration of exposure and the concentration
of local anesthetic determine the degree and incidence of local
anesthetic—induced residual paralysis. Neurotoxicity of local anesthetics
are dealt with in greater detail elsewhere in this chapter.
++
Neurologic complications after regional anesthesia may also be caused by the
direct effects of local anesthetics on the nervous tissue. Toxicity has been
reported primarily with the intrathecal use of local anesthetics. However,
with the increasing popularity of PNB anesthesia, reports are surfacing
about the direct toxic effects of local anesthetics on peripheral
nerves.2 Several theories regarding the mechanism of
injury have been suggested. Prolonged exposure, high doses, high
concentrations, body positioning, and the specific agent used may cause
transient or permanent neurologic injury by a number of intracellular
mechanisms. Once the neurologic injury has occurred, it has been suggested
that additives such as epinephrine or a preexisting neurologic condition may
predispose the patient to the neurotoxic effects of local anesthetics (the
“double-crush” concept).
++
Experimental models of neurotoxicity of local anesthetics have included
application of local anesthetic to the sciatic nerve in animals, desheathed
nerve preparations, and dorsal root ganglion cells in culture using
concentration of local anesthetic comparable to those used
clinically.51 These studies have revealed considerable
information about the mechanism of injury. Sakura and
colleagues52 discovered that the mechanism did not involve
voltage-dependent sodium channels. They substituted tetrodotoxin for
lidocaine and found that tetrodotoxin blocked these channels as effectively
as lidocaine without producing the toxicity associated with lidocaine.
Johnson and colleagues53 discovered that cell toxicity may
be related to mitochondrial degradation. Local anesthetics caused the
mitochondria to depolarize and stop producing adenosine triphosphate (ATP).
With the loss of ATP, energy-dependent mechanisms are compromised, leading
to the accumulation of calcium intracellularly and activation of enzymes
that cause cell degradation. This was unrelated to hypoxia, because
lidocaine actually reduced oxygen demand.51 Cell death or
apoptosis was related to the concentration and/or the length of exposure.
Exposure to 1% lidocaine for more than 90 minutes was required to kill
50% of the cells. Exposures of less than 1 hour were
reversible, but exposure to lidocaine at 5% concentration caused
rapid cell death or necrosis.51
++
In addition to electrolyte imbalance (leading to cell death), loss of ATP
has been found to cause failure of axonal transport, compromising the
ability of the neuron to transport materials synthesized in the perikaryon
to the axon terminal.54 Fast axonal transport moves
neurotransmitters from the cell body to the nerve terminal. Lidocaine has
been shown to produce a reversible blockade of rapid axonal transport.
Recovery is dependent on the concentration and the exposure time of the
local anesthetic on the nerve tissue. High concentrations and/or prolonged
exposure has been postulated to cause prolonged or permanent nerve
injury.55 Furthermore, the loss of ATP leads to the
failure of the sequestration of neurotransmitters within the cells, leading
to an increase in the extracellular concentration of glutamate. Excessive
glutamate in the extracellular space through NMDA
(N-methyl-d-aspartate) receptors can exacerbate the
elevation of calcium within the cells, ultimately leading to further cell
degradation.56 This effect is noted only in the central
neuraxis, where glutamate is found.
++
Local anesthetics have been shown to cause membrane solubilization at high
concentrations. At clinical concentrations, they can form micelles that may
act as detergents to disrupt the cell membrane.57–60 Oda and
colleagues61 demonstrated that 5% lidocaine and 0.5% dibucaine were minimum concentrations causing irreversible neurologic
damage. No neurologic damage was seen with 2% lidocaine or 0.2%
dibucaine.
++
Neurotoxicity varies with the local anesthetic solution. In histopathologic,
electrophysiologic, and neuronal cell models, lidocaine and tetracaine have
been shown to have a greater potential for neurotoxicity than
bupivacaine.62 Additives, that is, epinephrine, can
increase the toxicity of both lidocaine and bupivacaine.63
A preexisting neurologic condition, such as peripheral neuropathy, injury,
or surgery, may predispose the patient to nerve injury from toxicity at
clinical doses (ie, the double-crush concept).64
++
In summary, local anesthetics have potentially cytotoxic effects. The
mechanisms appear to involve disruption of mitochondrial function,
electrolyte imbalance leading to detrimental intracellular calcium
accumulation, loss of axonal transport, and release of glutamate. The
toxicity and ultimate damage to nerve tissue are related to concentration of
the agent, site of action, time of exposure, and the specific local
anesthetic agent used. Most studies have demonstrated a greater effect on
intrathecal use compared with epidural or peripheral nerve exposure. This
may reflect the typically higher baricity, more concentrated dose of local
anesthetic bathing the spinal cord for a prolonged period of time compared
with a large volume, less concentrated solution typically used in
epidural, and peripheral nerve blocks.
+++
Vascular Mechanisms Causing Nerve Injury
++
Lack of blood flow to the primary afferent neuron results in metabolic
stress. The earliest response of the peripheral sensory neuron to ischemia
is depolarization and generation of spontaneous activity, symptomatically
perceived as paresthesias. This is followed by blockade of slow-conducting
myelinated fibers and eventually all neurons, possibly through accumulation
of excess intracellular calcium, which accounts for the loss of sensation
with initiation of limb ischemia. Nerve function returns within 6 hours if
ischemic times are less than 2 hours. Ischemic periods of up to 6 hours may
not produce permanent structural changes in nerves. However, detailed
pathologic examination after ischemia initially shows minimal changes, but
with 3 hours or more of reperfusion, edema and fiber degeneration develop
and last 1–2 weeks, followed by a phase of regeneration that will last 6
weeks. In addition to neuronal damage, oxidative injury associated with
ischemia and reperfusion also affects the Schwann cells, initiating
apoptosis.
++
The perineurium is a tough and resistant tissue layer. An injection into
this compartment or a fascicle can cause a prolonged increase in endoneurial
pressure exceeding the capillary perfusion pressure. This pressure, in turn,
can result in endoneurial ischemia.10,42 The addition of
vasoconstricting agents theoretically can enhance ischemia because of the
resultant vasoconstriction and reduction in blood flow. The addition of
epinephrine has been shown in vitro to decrease the blood supply to intact
nerves in the rabbit.65 However, in patients undergoing
lower extremity surgery, addition of epinephrine to the local anesthetic
solution used in combined femoral and sciatic nerve blocks has not been
shown to be a risk factor for developing post-block nerve
dysfunction.3
+++
Pressure Mechanisms Causing Nerve Injury
+++
Tourniquet Neuropathy
++
Tourniquet-induced neuropathy is well documented in the orthopedic
literature and ranges from mild neuropraxia to permanent neurologic
injury.66–69 The incidence of tourniquet paralysis has
been reported as 1 in 8000 operations.70 A prospective
study of lower extremity nerve blockade suggests that higher tourniquet
inflation pressure (>400 mm Hg) was associated with an increased
risk of transient nerve injury.3 Current recommendations
for appropriate use of the tourniquet include the maintenance of a pressure
of no more than 150 mm Hg greater than the systolic blood pressure and
deflation of the tourniquet every 90–120 minutes.69 Even
with these recommendations, post-tourniquet-application neuropraxia may
occur, particularly in the setting of preexisting
neuropathy.71,72
++
Little data exist regarding the safety of PNB in patients treated with
anticoagulants. Compressive hematoma formation leading to neuropathy has
been associated with needle misadventures when performing lower extremity
PNB, particularly with concomitant treatment with
anticoagulants.73,74 However, in contrast to spinal or
epidural hematoma, peripheral neuropathy from compressive hematoma typically
resolves completely.75–78 Regardless, these reports
emphasize the important differences in the risk-benefit ratio of PNBs
compared with neuraxial blocks in patients receiving anticoagulant therapy.