Local anesthetic agents are discussed in Chapter 45 in detail, but some clinical points relating to neuraxial anesthesia are addressed here. The choice of neuraxial agents is determined by the nature and estimated duration of the surgical procedure, as well as postoperative issues such as planned discharge. Tables 47-4 and 47-5 list representative durations for doses of spinal and epidural agents. For spinal anesthesia, increasing the dose of agent administered prolongs the block, and unless counteracted by positioning and baricity, it may also increase peak block height. Longer-acting local anesthetics, such as bupivacaine, levobupivacaine, tetracaine, and ropivacaine, are typically chosen for longer procedures (>120 minutes). Lidocaine, mepivacaine, and prilocaine are considered to be of intermediate duration (60-120 minutes). Short-acting local anesthetics include procaine and 2-chloroprocaine, which are used for appropriately brief procedures (<60 minutes), particularly in outpatients.
Table 47-4 Typical Dose–Response Effects of Spinal Local Anesthetics ||Download (.pdf)
Table 47-4 Typical Dose–Response Effects of Spinal Local Anesthetics
|Local Anesthetic||Dose (mg)||Peak Block||Duration of Sensory Block (min)a||Duration of Motor Block (min)||Time Until Discharge (min)||Anesthetic Success Rate (%)a|
Table 47-5 Duration of Sensory Block for Commonly Used Local Anesthetics for Epidural Anesthesia ||Download (.pdf)
Table 47-5 Duration of Sensory Block for Commonly Used Local Anesthetics for Epidural Anesthesia
|Local Anesthetic||Concentration (%)||Time Until 2 Dermatome Regression (min)||Time Until Complete Regression|
Bupivacaine and levobupivacaine have the benefit of a very low incidence of transient neurologic symptoms29 (TNS; see section on Neurologic Complications); however, the variability in time to complete block resolution and achievement of discharge criteria provides a challenge in the ambulatory setting. Bupivacaine and levobupivacaine are used in epidural anesthesia when a longer block is desired. The use of 0.5% solutions is typical, but 0.75% solutions or adding epinephrine may provide increased motor block. Levobupivacaine is approximately equipotent to bupivacaine, with the exception of less systemic toxicity in animal models.
Ropivacaine was released for clinical use in 1996. When used as a spinal agent, ropivacaine has a clinical profile similar to bupivacaine at equipotent doses (ropivacaine is 60% as potent as bupivacaine) with little risk of TNS.30 Ropivacaine is used in concentrations of 0.5% to 1% for epidural anesthesia, providing blockade of somewhat shorter duration than bupivacaine. There is some evidence that ropivacaine may have less motor block when compared with bupivacaine when used for labor analgesia31; however, this effect is not reliably demonstrated when comparing equipotent doses.
Although tetracaine is used less commonly at this time, it remains the agent that provides the most reliable isobaric spinal anesthetic when the crystalline powder is reconstituted with the patient's cerebrospinal fluid. It should be noted that the use of vasoconstrictors might increase the risk of TNS with tetracaine.32
Investigators have modified use of long-acting agents as spinal anesthetics for short duration procedures by reducing the administered dose and thus reducing the duration of spinal blockade. When these agents are used for low-dose spinal anesthesia, this typically requires adjuvants (usually fentanyl) to have reliable block success.
Lidocaine has enjoyed widespread popularity and perceived safety as a neuraxial agent, but it has undergone increasing scrutiny given the high incidence of TNS seen when used for ambulatory spinal anesthesia (see Neurologic Complications, later). In an attempt to avoid this problem, lower doses of lidocaine have been investigated, usually requiring adjuvant agents to provide suitable reliability of spinal blockade. Lidocaine is used in concentrations of 1.5% and 2% for epidural anesthesia to provide reliable blockade for procedures lasting less than 120 minutes. However, continuous catheter techniques commonly use lidocaine, with reinjection typically required every 60 to 90 minutes.
Mepivacaine has a clinical profile similar to that of lidocaine when used as a neuraxial agent, although it has higher potency (1.3:1 compared with spinal lidocaine).33 It also may have similar concerns regarding the high incidence of TNS when used for outpatient spinal anesthesia, depending on concentration of agent.34 It is used in concentrations of 1% to 2% for epidural anesthesia, again with a clinical profile similar to lidocaine.
Prilocaine is an amide local anesthetic with pharmacologic properties similar to those of lidocaine when used as a spinal anesthetic.35 However, it shows a much lower incidence of TNS compared with spinal lidocaine and thus may be a favorable agent for ambulatory spinal anesthesia. Because of the risk of methemoglobinemia at required doses, prilocaine is generally considered unsuitable for epidural anesthesia. Currently, prilocaine is not available in the United States, but it is used commonly in Europe.
As the first synthesized local anesthetic, procaine has been used for spinal anesthesia since the early 1900s. Procaine provides brief spinal anesthesia, but has limited clinical usefulness given the high incidence of block failure (see Table 47-4) and side effects. For reasons that are poorly understood, spinal procaine carries a higher risk of nausea than do other local anesthetics (odds ratio [OR] 3:1).36 Although it has a lower incidence of TNS than spinal lidocaine (Table 47-6), spinal procaine is clearly not enticing as an agent for outpatient spinal anesthesia.
Table 47-6 Typical Incidences of TNS with Outpatient Spinal Anesthesia ||Download (.pdf)
2-Chloroprocaine has received increased attention as a spinal anesthetic because of the challenges of ambulatory spinal anesthesia and concerns of relative neurotoxicities of other local anesthetics (eg, lidocaine). One year after its introduction into clinical use (1952), Foldes and McNall described successful use of a preservative-free preparation of 2-chloroprocaine for spinal anesthesia in 214 patients. Subsequently, 2-chloroprocaine enjoyed increasing popularity as an agent for epidural anesthesia, particularly in the obstetric population. Unfortunately, reports of accidental intrathecal injection of large volumes of Nesacaine-CE (chloroprocaine hydrochloride; AstraZeneca, Mississauga, Ontario, Canada) intended for the epidural space, resulting in several cases of neurotoxicity with lower-extremity paralysis and sacral nerve dysfunction, came to attention in the 1980s. Studies in dogs suggest that the combination of the antioxidant sodium bisulfite in the presence of low pH was responsible for the neurotoxicity,37,38 and the formulation of 2-chloroprocaine was changed. Interestingly, a more recent laboratory study observed direct neurotoxicity from high doses of preservative-free 2-chloroprocaine in a rat model that was equivalent to 2% lidocaine and suggested that bisulfite was neuroprotective when added to 2-chloroprocaine.39 Currently, 2 of the commercially available formulations of 2-chloroprocaine (Nesacaine-MPF, Astra Pharmaceuticals, Wilmington, DE, and generic chloroprocaine, Bedford Pharmaceuticals, Bedford, OH) are preservative-free and antioxidant-free. Given the availability of these new preparations and growing concerns about the TNS associated with lidocaine, 2-chloroprocaine has been reinvestigated for off-label use as a short-acting spinal anesthetic. Work by Kopacz et al shows 2-chloroprocaine to be a reliable spinal anesthetic, with consistent time to block resolution and achievement of discharge criteria without identifiable occurrence of TNS.40-45 It should be noted that 2% 2-chloroprocaine may behave in a hyperbaric fashion,43 and that the addition of epinephrine to spinal 2-chloroprocaine is not recommended because of reports of flu-like symptoms in volunteers receiving this combination.40 As with fentanyl and plain bupivacaine, 2-chloroprocaine as a spinal anesthetic is currently an off-label use. However, the very low incidence of TNS and the rapid, dependable spinal block resolution is a very attractive profile for spinal anesthesia in ambulatory surgery. Given that the complete risk-to-benefit ratio of spinal 2-chloroprocaine is not known, clinicians should be mindful of restricting doses to not more than 40 mg, which is the most widely studied dose and ensure that only preservative-free, antioxidant-free preparations are utilized.
The use of 2% and 3% 2-chloroprocaine is an appropriate and US Food and Drug Administration (FDA)–approved choice for epidural anesthesia of short duration. After the release of Nesacaine-MPF, which contains ethylenediaminetetraacetic acid (EDTA), back pain following block resolution was reported with the use of high volumes of injected agent (>40 mL).47 One proposed mechanism for this observation is tetanic spasm of the paraspinous muscles resulting from chelation of calcium by the EDTA. However, this was never proved and reports of back pain persist, despite the use of EDTA-free solutions. Given the potential for any solution intended for the epidural space to be accidentally injected into the subarachnoid space, it may be prudent to use only 2-chloroprocaine preparations that are preservative- and antioxidant-free for neuraxial blockade.
Initially, interest in adjuvant medications for neuraxial anesthesia centered around increasing the duration and intensity of blockade (eg, epinephrine, phenylephrine). As the percentage of operations performed in the ambulatory setting increases, interest is shifting to identifying adjuncts that will augment block depth and reliability without prolonging recovery, especially motor block recovery (eg, fentanyl) (Table 47-7).
Table 47-7 Analgesic Adjuvants for Neuraxial Anesthesia ||Download (.pdf)
Table 47-7 Analgesic Adjuvants for Neuraxial Anesthesia
|Agent||Dose||Typical Anesthetic Effect||Comments|
|Fentanyl||Spinal 10-25 μg|
25% increase in duration of surgical anesthesia
33% increase in anesthetic success with small doses of local anesthetic
60% incidence of easily treated pruritus
|No delay of anesthetic recovery|
|Epidural 1-2 μg/kg|
2-fold reduction in volatile anesthetic requirements
Decreased visceral pain with Cesarean section
|Bolus administration may act at spinal level, infusions act via systemic uptake and redistribution to brainstem|
|Clonidine||Spinal 15-45 μg|
29% increase in duration of motor block
37% increase in anesthetic success with small doses of local anesthetic
Mild perioperative sedation and decrease in heart rate and blood pressure
|No delay of anesthetic recovery|
|Epidural 150 μg|
2-3 fold increase in duration of sensory anesthesia
Increased time to first analgesic request
|Less oxygen desaturation, pruitis, and urinary retention compared to opioids|
|Epinephrine||Spinal 0.1-0.6 mg||Dose-related increase in surgical anesthesia and motor block||Dose-related increase in time until recovery of the same or greater magnitude|
|Epidural 5 μg/mL|
Increased duration, intensity of block with lidocaine and 2-chloroprocaine
Will intensify block, but less effect on duration with bupivacaine
Minimal effect with ropivacaine
|Decreased plasma levels with lidocaine and bupivacaine, but not ropivacaine|
|Neostigmine||Spinal 6.25-50 μg|
Dose related increase in surgical anesthesia and motor block
60% incidence of nausea and vomiting
|Dose-related increase in time until recovery of the same or greater magnitude|
|Epidural 1-4 μg/kg|
Dose-dependent analgesic effect
Increased time to first analgesic request
|Reports of sedation with higher doses, less nausea than with intrathecal administration|
The potent analgesic effects of neuraxial opioids have been exploited to improve perioperative analgesia and reduce the supraspinally mediated side effects of sedation and respiratory depression seen with systemic opioids. Neuraxial opioids that diffuse into the spinal cord exert spinal analgesia by modulating C-fibers to decrease afferent nociceptive input,48 inhibiting Ca2+ influx presynaptically, and increasing K+ conductance and hyperpolarizing ascending neurons postsynaptically.49
Owing to its relative hydrophilic nature, neuraxial morphine provides highly selective, prolonged spinal analgesia, but is not typically used to augment intraoperative anesthesia because of slow onset. The lipophilic opioids, such as fentanyl (note that intrathecal use is not FDA-approved), are more suited for intraoperative use in the intrathecal space because of rapid onset, modest duration, and lower risk of delayed respiratory depression (though greater risk of early respiratory depression). The rapid onset of fentanyl is due to multiple factors, including the relatively large dose typically used, noting that 25 μg of fentanyl is roughly equivalent to 2.5 mg of morphine. The addition of 10 to 25 μg fentanyl to low-dose lidocaine and bupivacaine spinal anesthetics dramatically improves anesthetic success without delaying achievement of discharge criteria for ambulatory patients.50,51 However, when used with the ultra–short-acting spinal anesthetic 2-chloroprocaine, fentanyl can slightly delay discharge (95 vs 104 minutes) and increase pruritus.42
The administration of epidural fentanyl can reduce volatile requirements more than intravenous fentanyl (>2-fold at 2 μg/kg).52 The method of delivery of epidural fentanyl may be important for optimal effect. Ginosar et al53 showed that when epidural fentanyl is given as a bolus, it imparts segmental analgesia consistent with spinal level of action, but if given as an epidural infusion, the analgesia is mediated through systemic uptake and supraspinal effect, as is seen with sufentanil and alfentanil.54
Interest in α2-agonists, such as clonidine, has been rising in the field of regional anesthesia given their ability to enhance neuraxial analgesia without the respiratory depression and pruritus common to opioids. As with analgesia, the sedation, hypotension, and bradycardia seen with neuraxial clonidine are dose dependent.55 Additionally, less urinary retention is seen with intrathecal clonidine than with intrathecal morphine.56 Clonidine exerts its analgesic effects by binding to α2-adrenoreceptors (on primary afferents, substantia gelatinosa, and several brainstem nuclei attributed to analgesic mechanisms), attenuating A-δ and C-fiber nociception, producing conduction blockade via increased potassium conductance,57,58 as well as by increasing acetylcholine and norepinephrine in the CSF, inhibiting the release of substance P.58 Although clonidine rapidly redistributes systemically to the periphery after epidural or spinal administration, the analgesic effect is spinally mediated, as evidenced by the lack of correlation between time of analgesia and peripheral blood levels. Through extensive testing for neurotoxicity and safety in several animal models, neuraxial clonidine shows no histopathologic or behavioral evidence of injury or toxicity and is FDA approved for epidural infusion for inadequately controlled cancer pain.
Although previously investigated as a sole anesthetic,59 the majority of the clinical use of intrathecal clonidine is in combination with local anesthetics to produce dose-dependent prolongation of both sensory and motor block.60-63 Showing a promising role in ambulatory anesthesia, De Kock et al64 demonstrated that the addition of as little as 15 μg of clonidine to 8 mg of ropivacaine for spinal anesthesia in outpatients undergoing knee arthroscopy produced a considerable increase in anesthetic success (from 70% to 90%) without significant effect on recovery time. However, increasing the dose to 45 μg increased time to resolution of motor and sensory block and time to void from 170 to 215 minutes. Adding clonidine to local anesthetics intensifies and prolongs epidural blockade and can reduce local anesthetic dose requirement.65,66 The typical dose of clonidine for addition to local anesthetics for epidural bolus administration is 150 μg, or 2 μg/kg.67-69 Klimscha et al68 demonstrated that the addition of 150 μg of clonidine to 10 mL of 0.5% bupivacaine for epidural anesthesia increased the mean duration of anesthesia from 1.8 to 5.3 hours, reduced pain scores, and increased time to first postoperative analgesic request. These benefits of clinical doses of neuraxial clonidine typically persist for approximately 3 hours and can be achieved without increasing hemodynamic instability more than local anesthetic alone or significantly altering responsiveness to resuscitation drugs.69-72
Vasoconstricting agents, namely epinephrine and phenylephrine, are commonly added to local anesthetic solutions and have a long history of clinical use to prolong the anesthetic effect, provide more reliable block, and intensify anesthesia and analgesia.73-76 Drugs with α-adrenergic activity appear to accentuate local anesthetic block by both pharmacokinetic and pharmacodynamic mechanisms. Pharmacokinetically, vasoconstriction of the arterioles in the dura mater,77 and thus decreased blood flow, can reduce uptake of local anesthetics into the circulation, thus maintaining concentrations at the site of injection and reducing peak plasma concentrations. Additionally, intrinsic analgesic effects of epinephrine are exerted via stimulation of presynaptic α2 adrenoreceptors found at the terminals of primary afferents. These receptors are also found centrally on neurons in the superficial laminae of the spinal cord and several brainstem nuclei that participate in analgesic mechanisms. α2-Agonists can also produce motor block via actions on primary motor afferents.78
For spinal anesthesia, epinephrine is commonly used in a dose of 0.2 mg (although doses of 0.1-0.6 mg have been described), which, when added to a bupivacaine spinal anesthetic, increases time of regression to L2 by 25%.79,80 The addition of epinephrine to spinal anesthetics prolongs motor block and delays the return of bladder function, which is problematic for ambulatory surgery patients trying to meet discharge criteria. Chiu et al,81 using volunteers, showed that adding 0.2 mg of epinephrine to 50 mg of hyperbaric lidocaine prolonged surgical anesthesia (as demonstrated by tolerance of transcutaneous electrical stimulation) by 30 minutes, whereas time to void and discharge time were increased by 80 minutes.
As for safety, intrathecal epinephrine by itself, in clinically relevant doses, shows no neurotoxicity in humans. Spinal cord blood flow is well maintained in the dog and cat model in doses up to 0.5 mg.77 However, animal studies suggest that epinephrine may worsen the degree of injury associated with local anesthetic neurotoxicity.82 Smith et al40 reported consistent flu-like symptoms (myalgias, malaise, arthralgias, back stiffness, loss of appetite) when epinephrine was added to spinal 2-chloroprocaine in a volunteer study. Phenylephrine may increase the risk of TNS, as suggested by Sakura et al32 in a study of tetracaine spinal anesthesia.
With epidural anesthesia, the typical use of epinephrine is in concentrations of 1:200 000, or 5 μg/mL. The clinical effect of epinephrine on duration of anesthesia depends on the local anesthetic used. Epinephrine is more effective at prolonging the anesthetic duration of shorter-acting agents, such as lidocaine and 2-chloroprocaine. Adding 1:200 000 epinephrine to 2% lidocaine will nearly double the time to resolution of blockade.83 Agents with longer duration of action show much less prolongation of anesthesia with the addition of epinephrine. Adding epinephrine to ropivacaine will intensify the block, but will not prolong the duration of epidural anesthesia or affect plasma concentrations.74 This is likely a result of the inherent vasoconstricting effects of ropivacaine, as well as the clearance of ropivacaine not being dependent on blood flow. Other agents do show reduction of plasma concentrations when epinephrine is added.73,75 Epinephrine 1:200 000 will decrease plasma lidocaine and chloroprocaine concentrations by 20% to 30%, but will decrease plasma bupivacaine concentrations only by 10% to 20%. The effect of epinephrine on plasma concentrations of local anesthetics has long been thought to be caused by constriction of the epidural venous plexus, reducing blood flow and slower uptake of local anesthetics. More recent evidence implies that reduced dural blood flow and increased hepatic clearance may be more important in this phenomenon.84 Furthermore, work by Bernards et al85 suggests that systemic effects on vasculature of epidurally administered epinephrine may alter volume of distribution and thus contribute to the altered plasma concentrations of local anesthetics. Its potential to prolong discharge times and delay bladder function limits the usefulness of adding epinephrine to epidural agents for ambulatory surgery. The premixed solutions of local anesthetics with epinephrine that are commercially available are prepared more acidic to prevent spontaneous epinephrine oxidation. Because this lower pH slows the onset of block and inhibits the vasoconstricting actions of epinephrine, adding "fresh" epinephrine to local anesthetic solutions at the time of use is preferred. When phenylephrine is added to epidural solutions, the systemic absorption results in increased vascular resistance (as opposed to the decrease in systemic vascular resistance [SVR] seen with epidural epinephrine at 1:200 000 concentration), without the benefit of increased contractility or chronotropy seen with epinephrine. Consequently, phenylephrine is typically only used in the subarachnoid space.
The acetylcholinesterase inhibitor neostigmine has been investigated as a neuraxial analgesic adjunct because of its ability to provide analgesia without hemodynamic depression. Unfortunately, its tendency to induce nausea and delay recovery from neuraxial blockade limits clinical use. Intrathecal neostigmine inhibits the breakdown of acetylcholine in the meninges and spinal cord via reversible inhibition of acetylcholinesterase. Animal models suggest that acetylcholine plays a role in spinal analgesia through stimulation of cholinergic receptors in the substantia gelatinosa and superficial laminae of the spinal cord dorsal horn86-88 and perhaps through stimulating nitric oxide production in the spinal cord.89 Whereas intrathecal injection of cholinergic agonists stimulates all receptors of a particular class, neostigmine increases endogenous acetylcholine in a manner dependent on the tonic release of this neurotransmitter within each particular region of the spinal cord. Hood et al90 evaluated safety, analgesic efficacy, and side effects of intrathecal neostigmine in volunteers. All doses produced analgesia without sedation, pruritus, respiratory depression, hypotension, or bradycardia; however, there was dose-related motor weakness, decreases in deep tendon reflexes, urinary incontinence, and nausea and vomiting. Further studies in patients revealed similar incidence of nausea and vomiting that proved to be both prolonged and difficult to treat.91-93 Liu et al93 showed that when added to low-dose (7.5 mg) bupivacaine spinal anesthetics, 50 μg of neostigmine enhanced motor and sensory block, but delayed achievement of discharge criteria. Doses of 6.25 and 12.5 μg did not prolong anesthesia but still elicited nausea and delayed discharge. Intrathecal neostigmine does counteract hypotension resulting from bupivacaine spinal anesthesia in rats,94 but these effects are not reproducible in human subjects.95 Low and moderate doses of neostigmine are considered to have little or no cardiovascular effects.
Lauretti et al96 studied the analgesic effect of epidural neostigmine, in doses from 1 to 4 μg/kg added to epidural lidocaine, and showed a dose-independent analgesic effect, increasing time to first analgesic request from 3.5 to 8 hours, with less nausea and vomiting than seen with intrathecal administration. Other studies report similar results with doses in the range of 1 to 10 μg/kg, without reporting increased nausea,97-102 but reporting some suggestion of sedation.101
Alkalinization and Carbonation
Alkalinizing local anesthetic solutions to raise the pH closer to the pKa of the local anesthetic, thereby increasing the proportion of the nonionized form available to cross cell membranes, is thought to speed the onset of epidural anesthesia. Although this is well demonstrated with peripheral nerves in vitro,103 studies attempting to demonstrate this clinically in epidural anesthesia are conflicting.
Most studies show that alkalinization speeds onset of epidural blockade with lidocaine,104-109 bupivacaine,104,110,111 mepivacaine,104,112,113 and chloroprocaine114,115 by up to 10 minutes. Ropivacaine seems not to show faster onset with alkalinization,116 but as with the other drugs, there is evidence that alkalinization can intensify epidural anesthesia and improve spread to sacral dermatomes.105,108,109,117 One trend that is noted is that the effects of alkalinization are greatest on solutions containing epinephrine, whether freshly added or prepackaged. This is perhaps a result of pH-dependent vasoconstrictive actions of epinephrine. Alternatively, this may be attributed to the fact that commercially available epinephrine-containing solutions are prepared at lower pH (usually with bisulfite), ranging from 3.2 to 4.2, in efforts to preserve the epinephrine.
Typically recommended volumes of 8.4% sodium bicarbonate to be added to local anesthetic solutions are 1 mL per each 10 mL of lidocaine or mepivacaine, 0.1 mL per 10 mL of bupivacaine, and 0.3 mL per 10 mL of 2-chloroprocaine. Because of the tendency to precipitate, adding sodium bicarbonate to ropivacaine solutions is not recommended. It should be noted that the degree of alkalinization is limited by precipitation, and all preparations should be inspected for precipitation before administration. Alternatively, the carbonate salts of local anesthetics have a more rapid onset of epidural blockade than standard hydrochloride preparations.118 However, carbonated drugs are of limited availability and may be more prone to induce hypotension with epidural administration.119