• Alain Borgeat, MD
• Admir Hadzic, MD

A. 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.

Figure 69-1. Histology of the peripheral nerve. Shown is a large fascicle of the peripheral nerve with its axons, surrounded by perineurium, epineurium, and nourishing blood vessels.

        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.

Clinical Pearls

        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 in-terscalene 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.

    Based on data from Seddon H: Three types of nerve injury. Brain 1943;66: 236-288; Sunderland S: A classification of peripheral nerve injuries producing loss of function. Brain 1951;74:491-516; and Lundborg G: Nerve Injury and Repair. Churchill Livingstone, 1988.

        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, ofwhich 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 electrophysio-logic 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.

Figure 69-2. Mechanical injection injury to the peripheral nerve. Shown is a large fascicle with a needle track, syrinx created by hydrostatic pressure of the injectate, as well as the needle track into the fascicle. Perineurium is seen bulging off the surface of the fascicle.

        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.

Figure 69-3. Fascicular injury after an intraneural injection. Shown is loss axonal degeneration, extravasation of erythrocytes, and inflammatory cell infiltration.

Pain on Injection

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 (0.50.1 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

Clinical Pearls

        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 nerve^35–37 (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.

Figure 69-4. Intensity of the electrical current required to obtain a motor response in a sciatic nerve block model in pigs. As the distance of the needle to the nerve decreases from 0.1 mm to the intraneural location of the needle, stimulation can be obtained with a current of progressively lesser intensity (minimum 0.08 mA/0.1 msec with needle intraneurally). However, when the needle was inserted intraneurally, motor response could not be obtained in 25% of the attempts even with currents of 0.5-1.7 mA. (From Hadzic A, et al. 2006. Unpublished data).

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.

Clinical Pearls

        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.

Figure 69-5. Injection pressures recorded during perineural injection of 2% lidocaine in a sciatic nerve block model in pigs. Using an injection speed of 15 mL/min and 25?gauge insulated nerve block needle, pressures were at or below 20 psi in all but one injection.

Figure 69-6. Injection pressures recorded during intraneural injection of 2% lidocaine in a sciatic nerve block model in pigs. Using an injection speed of 15 mL/min and 25-gauge insulated nerve block needle, pressures were significantly above 20 psi in all but two injections.

Figure 69-7. Twenty-four hours after perineural or intraneural application of 2% lidocaine in a sciatic nerve block model in pigs, the intraneural group continues to exhibit signs of paresis in the sciatic nerve distribution.

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 transarte-rial 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

Neural Ischemia

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 vasoconstrict-ing 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

Compressive Hematoma

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.

B.Peripheral Nerve Blocks in Anesthetized Patients

        INTRODUCTION

Regional anesthesia-associated nerve injury is a significant source of concern for patients, surgeons, and anesthesiologists alike. In addition, nerve injury is a potential medicolegal liability for anesthesiologists.⁷⁹ PNBs, in particular, are of significant concern because the typical technique involves placing the needle tip in the immediate vicinity of the nerve or plexus. Consequently, any postoperative neurologic impairment is automatically, and often unjustly, attributed to the PNB procedure.

        Few issues in regional anesthesia have been the subject of such intense controversy as whether PNBs carry a higher risk of neurologic complications when performed in anesthetized patients compared with awake patients. Opinions vary from heavy premedication being essential to the success of regional anesthesia to its being equated with negligence. Unfortunately, no large-scale controlled studies of the safety of PNBs in awake versus anesthetized patients exists, nor are such studies likely to be available in the future. Without randomized, controlled studies, experts are left to draw conclusions and make logical recommendations solely on their interpretation of the few available case reports and anecdotal experiences. However, any such recommendations regarding the use of sedation or general anesthesia in patients receiving PNBs could have significant medicolegal repercussions. Therefore, the multifaceted purpose of this text is to review the available literature that supports or refutes the practice of administering nerve blocks in anesthetized patients, to discuss the current controversies, and to provide insight into the future of the subspecialty with regard to this issue. Specific concerns regarding performance of PNBs in anesthetized patients are presented and addressed. Although the scientific value of case reports is often discounted, such reports may actually be more informative than large epidemiologic studies because they include a detailed account of periblock events, which is often lacking in epidemiologic studies.

        SYMPTOMS OF INTRANEURAL INJECTION

The premise behind the common recommendation that a PNB should be performed only in awake patients is that an awake patient can provide information that can prevent intraneural injection and therefore avoid neurologic injury. This is because it is believed that intraneural injections are excruciatingly painful and an awake protesting patient is the best available monitor. However, there are three significant problems with this logic.

        First, the literature does not support the widespread notion that relying on a fully awake patient’s report of pain on injection is a reliable method to prevent nerve injury. In fact, most neurologic complications reported in the literature have not been associated with pain on injection. ^{1–3,23–25,27,79–85} p_or instance, of 49 cases of nerve injury found in the literature search (Table 69-3), 48 patients (98%) were awake. Of these, 42 cases included specific information about the patient’s response to the injection; only 4 (10%) patients reported pain on injection. Some reports specifically state that the patient did not have pain, whereas in most others the authors commented that the block performance was uneventful. Note that the pain on administration of local anesthetic into nerve tissue may be absent even in the central neuraxial area. For instance, Kao et al.⁸⁶ reported a case of neural injury that was clearly related to spinal cord trauma from a thoracic catheter that had been inserted while the patient was anesthetized; the patient did not have pain during administration of local anesthetic postoperatively. More recently, Tripathi et al.⁸⁷ reported a case report of paraplegia after an intracordal injection during attempted steroid injection, whereas Tsui and Armstrong⁸⁸ reported a case of direct spinal cord injury after epidural injection. Both complications occurred in awake patients, who did not report pain on needle placement and consequent injection. These reports clearly indicate that reliance on pain as a symptom of injection into neurologic tissue is unreliable.

Related posts:

Regional Anesthesia in the Patient with Preexisting Neurologic Disease. The History of Local Anesthesia. Stimulating Catheters. Ultrasound-Assisted Nerve Blocks in Adults. Cutaneous Blocks for the Upper Extremity. Cervical Plexus Block.

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