New york school of regional anesthesia

In the past few years progress has been made in understanding the mechanisms and pathways involved in the modulation of pain, as well as in developing new therapeutic tools to provide satisfactory pain relief after surgery. The relationship between the intensity of acute postoperative pain and the duration of the patient’s recovery and functional outcome has been well established. For these reasons, the prevention and treatment of acute pain had become the focus of great interest for perioperative specialists. Postoperative pain differs from chronic pain by its shorter duration and its requirement for immediate relief, which dictate the development of suitable management protocols. Preemptive and preventive analgesia also represent concepts that only apply to acute postoperative pain. Finally, it is important to recognize the role of acute pain in the development of chronic pain syndrome.

Irrespective of its nature, pain is not an objective but rather a subjective symptom. In the surgical as well as medical environment, intrinsic and extrinsic factors affect individual pain thresholds. Accordingly, the clinician must be always aware that pain treatment must be approached using a multimodal and multipharmacologic approach; no one single technique by itself, including the use of continuous peripheral nerve block, provides adequate pain relief in all patients and in all circumstances. The first description of continuous peripheral nerve block was reported in 1946 by Paul Ansbro,[1] who described the placement at the supraclavicular level of a blunt needle secured to the patient’s skin using a cork, through which the needle was inserted before block placement. This cumbersome apparatus allowed the incremental injection of local anesthetic in order to prolong the duration of anesthesia in patients undergoing upper extremity surgery. In their report the authors used a short-onset/intermediate duration local anesthetic, like 1% procaine. After an initial 40-mL bolus the authors injected incremental doses based on the duration of surgery, up to a final volume ranging between 120 mL for 1.5-h surgery and 220 mL for 4-h surgery. During the following 3 years continuous perineural infusion techniques continued to be developed, and their indications extended; initially they were mainly used for upper extremity blocks, afterward they were also employed for lower limb blocks.

In 1977 Selander[2] reported on the injection of 30 to 50 mL of mepivacaine to conduct a continuous axillary block in 137 patients undergoing hand surgery, and in 1979 Manriquez and Pallares[3] reported on the repeated injection of 20 mL of 0.25% bupivacaine every 6 h to prolong the sympathetic block and pain control for 4 days.

In 1982 Matsuda and colleagues[4] reported on the use of either 30 mL of 1% lidocaine with epinephrine followed by 15 mL intermittently (1.5–2.75 h) or 40 mL of a 0.5% bupivacaine and 1% lidocaine mixture followed by intermittent injection of 20 mL (1.25–4.3 h) in 50 patients undergoing upper extremity reimplantation. Subsequently most of the groups have focused their clinical protocols on the use of low concentrations (0.125–0.25%) of bupivacaine.5–7

More recently, with the introduction of newlong-acting aminoamide local anesthetics, such as ropivacaine or levobupivacaine, the attention of clinicians has shifted to the evaluation of these new agents, often with interesting findings. Borgeat and coworkers[8] compared 0.2% ropivacaine and 0.15% bupivacaine (to account for the difference in potency between the two agents) in terms of their effects on motor function and demonstrated that they provided similar postoperative pain control, but 0.2% ropivacaine allowed for better preservation of motor function than bupivacaine. On the other hand, levobupivacaine at 0.125% concentration seems to provide the same level of motor preservation as 0.2% ropivacaine.9

The advantages of continuous block techniques have been largely demonstrated for major orthopedic surgery, implementing the rehabilitation of these patients after total arthroplasty allowing early, pain-free mobilization of the operated limb. Finally, the indication of this technique of pain control has also been expanded to outpatient procedures. In fact it is known that over 40% of ambulatory patients experience moderate to severe pain within the first 48 h after ambulatory orthopedic surgery. Although different therapeutic approaches have been advocated, none provide reliable pain control, and pain remains a major concern. Most frequently patients are discharged with oral medication that has limited effects on pain relief. Intraarticular injections of narcotic analgesics or local anesthetics have also been used, but these techniques have been shown to provide only limited and short-lasting pain relief. In recent years several groups have evaluated the use of continuous nerve blocks in outpatients. Most of these investigators used solutions of 0.125% bupivacaine or 0.2% ropivacaine infused through either elastomeric or electronic patient-controlled (PCA) pumps, with relevant benefits not only in terms of quality of postoperative analgesia, but also in improved quality of life during the first postoperative days.10–12

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The nerve roots are divided into three types according to their anatomic and functional properties: A, B, and C fibers. The A fibers are responsible for motor efferent conduction and are divided in Aα, Aβ, and Aγ fibers. They are all myelinated, like the Aδ fibers, which are sensory fibers carrying pressure and distension information. The B fibers are constituted of the autonomic pregangliar fibers, and the C fibers include all the amyelinic fibers of the posterior spinal roots as well as the postgangliar autonomic fibers.

In the myelinated nerve roots, the action potential conduction proceeds from one Ranvier node to the next (jumping, or saltatory, conduction). Because the size of the fibers is proportional to the length between one Ranvier node and the next, the speed of conduction of the action potential increases with the size of the fibers. Generally, the bigger the size of the nerve fibers, the greater the amount of local anesthetic solution required to block the conduction. Thus, the fibers of small size are blocked sooner than those of larger diameter. The B fibers of the autonomic system constitute an exception of this rule: even though they are myelinated fibers, a minimum concentration of local anesthetic solution is required to produce an effective blockade. This property of B fibers explains why the sympathetic blockade is observed before the block of the other fibers (Table 1). The difference in sensitivity to neural blockade allows determination of the minimum concentration of local anesthetic that blocks only the small fibers, mainly responsible for nociception, with minimum or no block of the lager fibers. This in turn, allows neural blockade to accomplish analgesia with no or minimum motor block; the basis of the differential sensory–motor blockade.

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The choice for a local anesthetic solution for peripheral nerve blocks is based on:

1. Onset time
2. Duration of blockade
3. Ability to produce a differential sensory–motor block
4. Potential for toxicity

The onset time of local anesthetics is influenced by the molecule’s pKa (the higher the pKa the slower the onset time of the nerve block in a physiologic environment) and diffusibility.13 On the other hand, the ability to cross the cell membrane depends on the molecular weight and the liposolubility of the molecule. All local anesthetics have nearly the same molecular weight, but the diffusibility of the local anesthetic molecules from the injection site depends on its hydrophilicity. The nonionized form of the molecule is more lipid-soluble than the ionized one, so it and can cross the cell membrane easier but diffuses less easily. The commercial solutions of local anesthetics have an acid pH, and the pKa of the different local anesthetics range from 7.9 to 8.1. Accordingly, the ionized form, which is less lipophilic, is more represented than the nonionized one.

As onset time decreases, the dose, volume, or concentration of a given local anesthetic can be increased. Other strategies include the modification of the pKa of the anesthetic solution by warming it or adding sodium bicarbonate to increase the number of nonionized local anesthetic molecules, especially with lidocaine and mepivacaine. The alkalinization of ropivacaine, bupivacaine, or levobupivacaine is much more difficult, because of their very high pKa. Another important aspect deserving consideration is the pH of tissues; for example, the local tissue acidosis related to inflammation can increase the ionized form of local anesthetic, thereby reducing its efficacy. The potency of a local anesthetic is usually expressed as the minimum effective concentration (Cm): the minimum anesthetic concentration that reduces the action potential of a nerve fiber bathed in a solution with a 7.2–7.4 pH and stimulated with a 30-Hz current by 50% within 5 min. The potency of local anesthetics is strictly related to their lipid-solubility; the more lipid-soluble a local anesthetic is, the greater its potency and consequently the lower its Cm.

The Cm of a local anesthetic also changes according to the size of the nerve fiber. Although the total amount of local anesthetic affects the onset, degree, and duration of the nerve block, its concentration primarily influences the intensity of the blockade. The smallest fibers (A-δ, β, and C), with a slower conduction speed, are more sensitive to the blocking activity of the local anesthetic solution than are those with a larger diameter (A-β and A-α) and fast conduction. In otherwords, the smallest fibers need a lower Cm than those of larger size. This aspect is related to the number of anesthetic molecules available to block the conduction; when using low concentrations the small number of local anesthetic molecules available will block only the small fibers. A possible explanation is the need for blocking three consecutive Ranvier nodes in order to produce a complete nerve block. Since the distance between consecutive Ranvier nodes increases as the size of the nerve fiber increases, low concentrations of local anesthetics blocks three consecutive nodes only in the small nerve fibers and not in the large ones. This is the basis for the differential sensory– motor blockade, which is more evident with the lipophilic agents with high pKa, such as bupivacaine, ropivacaine, and levobupivacaine.

The duration of the action of local anesthetic solutions depends on the protein binding as well as the clearance from the injection site.13 Table 2 shows the main chemical/physical properties of the considered local anesthetics, as well as their reported equipotent concentrations.

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Different local anesthetic solutions, including lidocaine, bupivacaine, ropivacaine,andmore recently levobupivacaine, have been used for continuous peripheral nerve blocks. When choosing a local anesthetic solution for continuous peripheral nerve blocks two main aspects are considered:

1. The need for the surgical anesthesia and
2. Maintenance of the block through a perineural catheter

Ideally, the local anesthetic would provide a fast and reliable onset time for surgery; long duration, good differentiation in sensory–motor block during postoperative continuous infusion; and a safe toxicity profile without a risk of accumulation in the postoperative period.

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The choice of the best anesthetic solution to induce the nerve block should be tailored to patient characteristics as well as the safe dose according to the type of block and effect desired (anesthesia versus analgesia). Local anesthetics with a short onset have the disadvantage of short duration that usually reduces their usefulness for painful procedures where prolonged postoperative analgesia is desirable. However, placing a catheter close to the nerve(s) allows for prolongation of the block with the same or another agent. Therefore, a shortonset/intermediate-duration anesthetic solution (eg, mepivacaine or lidocaine at concentrations ranging between 1.5% and 2%) can be used to initiate the block and accomplish surgical anesthesia. The block can then be extended with another agent as desired. Some authors use combinations of anesthetic solutions with different kinetic properties; the most frequent mixture is a combination of a short-onset anesthetic, like mepivacaine, with a long-duration one, such as bupivacaine, ropivacaine, or levobupivacaine. Theoretically, the advantage of mixing different anesthetics is that the risk of toxicity decreases with long-acting, more a toxic local anesthetic mixture. However, injection of two anesthetic drugs results in competitive binding to the protein carriers and the free concentration of the more toxic local anesthetic is similar to that produced by using it alone in a volume similar to the total injected volume of the mixture. Consequently, it questionable whether these mixtures reduce the overall toxicity.

The volumes and doses of local anesthetics depend on the type of surgery (eg, single block or combination of different blocks, such as for lower limb procedures), as well as on the use of additional anesthetic agents (eg, light general anesthesia) for intraoperative maintenance. Accordingly, the maximum doses suggested for each anesthetic drug should always kept in mind (Table 3). It should be noted, however, that significantly larger doses of local anesthetics than those recommended for intravenous administration may be safely used for peripheral nerve blocks.

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In several fields of anesthesia the pharmaceutical research is focused on the development of very short acting agents to be used through continuous infusion in order to allow rapid titration of the effects and easy handling of the anesthesia plan, but peripheral nerve blocks are mainly conducted using longer acting agents.

Capdevilla and colleagues[14,15] reported on the use of 1%lidocaine solution for continuous peripheral nerve blocks after major orthopedic surgery and demonstrated similar benefits to those obtained with bupivacaine and ropivacaine perineural infusions. Moreover, lidocaine also has the advantage of a reduced toxicity compared with bupivacaine, levobupivacaine, and even ropivacaine.13 In addition, using short-acting agents to maintain continuous peripheral nerve block also has the theoretical advantage of allowing a faster recovery of normal neurologic function (when indicated) after the infusion is stopped. Unfortunately, shorter acting anesthetic agents have been demonstrated to be less effective in providing a good differentiation between sensory and motor blocks. For instance, patient-controlled interscalene analgesia with 0.2% ropivacaine or 1% lidocaine after open shoulder surgery both result in a similar quality of pain relief.16 However, a more efficient recovery of motor function occurs in patients receiving 0.2% ropivacaine than in those receiving 1% lidocaine. This finding is similar to a previous report with epidural analgesia and can be explained by the different physical-chemical properties of the two agents: lidocaine penetrates nerve roots easier than ropivacaine, because of the different pKa and lipophilicity of the two agents.15 This property can explain the less effective differentiation between sensory and motor blocks with lidocaine than occur with ropivacaine. Even though the mild sparing effect on motor block can be considered as a minor problem, it is of clinical interest because a differentiation in sensory and motor blocks is an important endpoint in improving postoperative patient rehabilitation.

It is for this reason that most authors prefer to use long acting agents for continuous peripheral block techniques (eg, bupivacaine, ropivacaine, or levobupivacaine).

For the last 20 years, bupivacaine (0.125–0.25%) has been generally used for upper limb continuous peripheral nerve block; however, 0.2% ropivacaine provides a similarly effective analgesia with better preservation of motor function than an equipotent concentration of 0.15% bupivacaine.8 Levobupivacaine at 0.125% concentration has been reported to be similarly effective in pain relief to 0.2% ropivacaine,with a comparable preservation of motor function, whereas the use of 0.2% levobupivacaine resulted in deeper motor block than both 0.2% ropivacaine and 0.125% levobupivacaine.9,17 It is for these reasons that clinicians prefer to use low concentrations of long-acting agents to provide a postoperative analgesia with minimal impairment of motor function. Concentrations as low as 0.125–0.25% bupivacaine, 0.125–0.2% levobupivacaine, or 0.2% ropivacaine are usually used.

The infusion rate is usually adjusted according to the block technique selected. Several infusion regimens have been suggested, ranging from an intermittent bolus technique to a patient-controlled continuous perineural infusion. In general, continuous infusion combined with patient-controlled bolus doses optimizes analgesia and decreases the need for oral analgesic use compared with basal- or bolus-only dosing regimens.18–20

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Addition of various additives to local anesthetics has been suggested to hasten the onset, decrease systemic absorption, and prolong neural blockade or analgesia. The most commonly used additives for peripheral nerve blocks are vasoactive agents, alkalinizing agents, clonidine, and opioids. Unfortunately, few properly conducted studies have focused on the specifically proposed advantages for continuous peripheral nerve blocks.

Vasoconstrictors

The duration of a local anesthetic agent depends on the duration of the contact between the anesthetic agent and the nerve fibers as well as on the number of local anesthetic molecules bound to the sodium channels. A more intense and longer lasting block can be achieved by increasing the concentration and dose of the local anesthetic solution or pharmacologically reducing the removal of local anesthetic from the nerve target. Epinephrine, in a dose range of 5 mcg/mL (1:200.000), reduces the absorption of local anesthetics, increasing their concentration at the intended target nerves or plexuses. In general, addition of epinephrine to solutions of lidocaine, mepivacaine, or bupivacaine used for peripheral nerve blocks increases the duration and intensity of the block. However, a vasoconstrictor reduces the perfusion of the vasa nervorum, which potentially increases the risk of an ischemic nerve injury. For these reasons the extensive use of epinephrine as an adjuvant to local anesthetic solutions for continuous peripheral nerve blocks is not recommended, especially if continuous infusion rather than an intermittent bolus technique is used to manage postoperative pain. In addition, it is probably prudent to limit the concentration of epinephrine to 1:300,000 in peripheral nerve blockade.

Alkalinization

The pH of commercially available solutions of local anesthetic ranges from 3 to 6, 5, whereas their pKa ranges from 7.6 to 8.9. The alkalinization of local anesthetic solutions, usually obtained by adding 1 mEq of sodium bicarbonate to 10 mL of lidocaine, mepivacaine, and chloroprocaine reduces the onset time of a nerve block induced with these agents. This, however, does not occur when sodium bicarbonate is added to bupivacaine or ropivacaine.21,22 However, even though changing the pH of the anesthetic solution may shorten the onset time of the block, there are not clinically relevant advantages when a continuous peripheral nerve block is used. Importantly, the stability of anesthetic solutions with added bicarbonate is not well studied. Therefore, because the local anesthetic mixtures in the infusion are used for 24 h or longer, the use of sodium bicarbonate for continuous peripheral nerve blocks is not recommended.

Clonidine

The analgesic effects of μ2-agonists have been well documented. For instance, the addition of clonidine to local anesthetic solutions is known to improve the duration and quality of analgesia with peripheral nerve blocks. Clonidine reduces the onset time, prolongs postoperative analgesia, and improves the efficacy of nerve block during surgery. Several authors have reported on the use of low doses of clonidine for continuous peripheral nerve blocks using a concentration as low as 1 mcg/mL. The rationale for adding clonidine is to minimize the doses of local anesthetic solution required to produce an effective postoperative analgesia and thus reduce the risks of local anesthetic-related side effects; nonetheless, only few controlled studies have investigated the efficacy of this practice to improve analgesia for continuous perineural local anesthetic.

Ilfeld and coworkers[23] evaluated the usefulness of adding 1 mcg/mL clonidine to 0.2% ropivacaine for a continuous infraclavicular brachial plexus block in 34 outpatients undergoing moderately painful upper extremity orthopedic surgery. The authors reported that adding clonidine resulted in a statistically significant decrease in the number of self-administered bolus doses on the first two postoperative days, but this decreased actual local anesthetic consumptionby only 2–7 mL/day. In addition, no differences in any other investigated variable were reported, including sleep quality or oral analgesic requirements. Therefore, the clinical significance of this finding is questionable.

When clonidine is added to the initial bolus of local anesthetic (1 mcg/kg), or to both the initial bolus (1 mcg/kg) and the continuous infusion solution (1 mcg/mL) for continuous femoral nerve block after total knee arthroplasty, no differences were found among the groups in the degree of pain, total consumption of local anesthetic solution, sedation, and hemodynamic parameters during the first 48 h of infusion.24 However, persistent motor function impairment after 48 h of infusion was observed in 27% of patients receiving clonidine in the infusion solution, but only 6% of cases in patients not receiving clonidine at all, or receiving it only with the initial bolus (p = 0.05). This finding may be of clinical significance because it could potentially delay the recovery of normal motor function, which is important in orthopedic patients undergoing early rehabilitation. Similar results have been also reported during continuous epidural infusion of clonidine containing solutions of local anesthetics.25

Peripheral Opioids

Opioid agents are known to exert their analgesic activity directly in the neuraxis; the addition of opioids to local anesthetic solution improves the quality of anesthesia and postoperative analgesia during epidural and spinal block. Various biochemical and electrophysiologic studies have suggested and supported the existence and functional significance of opioid receptors on primary afferent neurons.26 The existence of such peripheral receptors has been demonstrated both immunocytochemically[27] and functionally.28 Occupation of these receptors has been suggested to result in the inhibition of either the propagation of action potentials or release of excitatory transmitters in primary afferent fibers. Adding small doses of opioids to local anesthetic solutions for peripheral nerve blocks has been suggested to result in an improvement in the onset time, quality, and duration of nerve block.29 Small concentrations of either fentanyl (1–2 mcg/mL), sufentanil (0.1 mcg/mL), or morphine (0.03 mg/mL) have been suggested for continuous peripheral nerve blocks. However, there is no evidence that addition of opioids to local anesthetics in peripheral nerve blocks results in any clinically significant benefit.

Tramadol is a weak opioid receptor agonist and an interesting opioid agent for use as an additive to local anesthetic due to its inhibitory effects on the reuptake of serotonin and norepinephrine. Tramadol has a local anesthetic-like effect on peripheral nerves,[30,31] and this could potentially provide a synergistic effect during continuous peripheral infusion of local anesthetic solutions. However, its clinical use has not be reported.

Table 4 shows the concentration and regimens suggested for maintenance of continuous peripheral nerve blocks with the main anesthetic solutions used in the literature and in our clinical experience, as well as the concentrations of additives.

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Although rare, administration of local anesthetic drugs can results in allergic reaction. These are however, primarily related to the use of aminoester drugs, such as procaine and chloroprocaine. The allergic reaction is related to the paraaminobenzoic acid, a preservative commonly found in cosmetic preparations. However, even when using amide-type local anesthetic solutions, allergies can occur when solutions contain preservatives (multidose preparations) or antibacterial additives.

Local tissue toxicity reactions are rare when clinically relevant concentrations of the anesthetic solution are used. However, local anesthetics can result in neurotoxicity in cases of intraneural injection. To minimize the risk of incorrect needle placement, much work on imaging-assisted nerve block placement and injection monitoring is underway. For instance, ultrasound scanning has been suggested to locate the nerve structures and more precisely place the perineural catheter.32,33 Such technology may allow both a real-time monitoring of the catheter placement and reduction in the dose required to accomplish a successful nerve block.34 Another important issue in decreasing the risk of intraneural injection is avoidance of high injection pressures during local anesthetic administration. Unintentional intraneural injection of local anesthetics is associated with resistance to injection and high injection pressures (>20 psi) and may result in mechanical injury and pressure ischemia of the nerve fascicles.35 Perineural injections result in a “seamless” injection; consequently, the injection pressures are low (<5 psi). In contrast, most intraneural injections are associated with a resistance to injection and high injection pressures exceeding 20 psi at the beginning of the injection. Such injections are followed by persistent motor deficitswith destruction of neural architecture and degeneration of axons at the histologic examination.35 Accordingly, to minimize the risk of this type of local anesthetic-related toxicity we should avoid injection if high injection pressures are encountered.

Systemic toxicity of local anesthetics can occur in cases of overdose or in cases of inadvertent intravascular injection. The severity of these systemic reactions is related to the maximum concentration achieved in the blood and may vary from simple reports of agitation, drowsiness, and metallic taste, to seizures, coma, and cardiac arrest with increasing plasma levels.

Theoretically, continuing infusion of a local anesthetic solution after surgery may be associated with a risk for drug accumulation. This can be especially troublesome in patients discharged home after surgery with an infusion of local anesthetic solution still running. Fortunately, however, pharmacokinetic studies during continuous peripheral nerve blocks reported on the safety of this technique, with unbound plasma concentrations of local anesthetic remaining well below threshold levels for systemic central nervous toxicity,[36–38] provided the catheter is located in the right position.39

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