Structure and Metabolism
2-CP and tetracaine are the ester local anesthetics used routinely in clinical practice. The ester linkage of the local anesthetic's aromatic ring and the alkyl chain-tertiary amine sets them apart from the amide-linked agents like lidocaine. The ester linkage allows these agents to be hydrolyzed by plasma pseudocholinesterase. This process is more rapid than the hepatic microsomal metabolism of the amide local anesthetics and thus, contributes to greater safety. In pregnancy, the activity of plasma pseudocholinesterase is decreased by 40 to 50%, but this seems to have little clinical effect on the metabolism of 2-CP (2). The half-life of 2-CP in maternal plasma is still less than 60 seconds (3, 4). An unexpected intravenous injection would be rapidly metabolized and, in fact, it seems difficult to achieve toxic levels with routine clinical use of this drug (Chapter 36). This is a unique feature of 2-chloroprocaine which makes it extremely safe.
Toxicity
Systemic toxicity of local anesthetics ranges from numbness of the tongue and light headedness to convulsions and respiratory-cardiovascular arrest (Table 36.4). 2-CP is perhaps the least toxic when considering (systemic) central nervous system (CNS) toxicity (bupivacaine > lidocaine > 2-CP) (Table 36.6) (Table E.2) (5). While cardiac toxicity is all too easily achieved with bupivacaine, it is not a problem with 2-CP. However, the increased use of 2-CP in the mid 1970's and into the early 1980's led to the discovery of a potentially unique neurotoxicity. In the clinical setting, prolonged or permanent sensory and motor deficits resulted from unexpected, large subarachnoid injections (6, 7). The recent concerns regarding the neurotoxicity of lidocaine suggest that perhaps all local anesthetics can be toxic to some degree (8), although the ester-linked agents are not more likely to be neurotoxic (9).
The preparation of 2-CP which was reported to cause toxicity was Nesacaine-CE with a pH of approximately 2.7 to 4.0 which contained metabisulfite (2 mg/ml). Interestingly, the original formula contained methylparaben which was removed in the 1960's. The proposal by Gissen et al. (10) suggested that the metabisulfite in 2-CP generated sulfur dioxide (lipid soluble) which diffused into neural tissue and generated intracellular sulfurous acid, profound local acidosis and, thus, neurotoxicity. The metabisulfite has been removed from the formulation and the pH raised slightly. The current product in common use (Nesacaine-MPF, Astra), however, now contains ethylene diamine-tetra acetic acid (EDTA) to stabilize the local anesthetic. This, potentially, could lead to new forms of complication or toxicity.
Backaches - the 'New Toxicity' (Chapter 84)
There have been numerous clinical reports of back pain following the epidural administration of large volumes of 2-CP (12, 13) since the first report by Orkin and Bogetz (11). It appears that when volumes greater than 25 to 30mls of epidural 2-CP are used, intense back pain may result in some patients. This may require epidural fentanyl, lidocaine or intravenous narcotics or, possibly, calcium chloride to treat the pain. This does not seem to be a problem in the parturient. Thus, while there are significant limits placed on the use of 2-CP in some clinical settings, it is not a serious consideration in labor analgesia or anesthesia.
Obstetric Considerations
High doses of all local anesthetics will lead to a decreased uterine blood flow (UBF). This has been confirmed in human uterine arteries in vitro and in the sheep model in vivo (14, 15). In clinical doses there is no change in UBF with 2-CP (Figure 106.1a) (Figure 106.1b) (15, 16). Umbilical cord blood flow, while challenging to measure, is another indicator of the adequacy of the maternal-fetal placental unit. Noninvasive Doppler imaging has been used to evaluate cord blood flow and demonstrated no adverse effect of epidural local anesthetics. In parturients receiving epidural analgesia with 2% 2-CP, Doppler measurements indicated a beneficial effect upon umbilical artery vascular resistance (17). In addition, intervillous blood flow has been shown to increase with both epidural bupivacaine and 2-CP during normal labor (18). Finally, large doses of local anesthetics may increase uterine tone and contractility which would decrease uteroplacental perfusion (Chapter 76). This could easily be achieved with a paracervical block with 2-CP (Figure 46.2), for example, but in clinical concentrations with regional anesthesia this is not a concern. Thus, 2-CP should have no adverse effect on the maternal-fetal well-being in routine clinical practice and, in fact, may actually lead to increased umbilical blood flow in some patients.
Fetal and Newborn Effects
All local anesthetics cross the placenta and levels can be measured in the fetus and newborn (Chapter 77). However, as drugs reach the fetus they undergo metabolism and excretion. Historical concerns about the neurobehavioural response of newborn infants after epidural lidocaine administration for labor analgesia led to a series of extensive evaluations of the effects of local anesthetics on the newborn (19) (Chapter 25). While subtle changes can be detected with all commonly used local anesthetics, there is no indication that these changes are significant with regards to a long-term outcome (20, 21, 22, 23). It is clear that there are other perinatal factors that are far more important than the choice of a local anesthetic. There has also been concern about the effects of local anesthetics on fetal heart rate (FHR) changes. Alterations in FHR beat-to-beat variability and a greater incidence of periodic decelerations have been reported with all local anesthetics used for labor analgesia (Chapter 3) (Table 3.1). This does not appear to be the case when large doses of local anesthetics are given for cesarean section to patients not in labor (24). Any FHR changes found during labor are transient and seem to have no effect upon the condition of the newborn and are likely to be due to other factors than the direct effect of a local anesthetic.
With regards to possible teratogenicity of local anesthetics, this would appear to be a theoretical risk as opposed to real clinical concern. On the other hand, as agents for in vitro fertilization are evaluated, it has been suggested that all local anesthetics adversely affect mice in vitro fertilization and embryo development in the order chloroprocaine > lidocaine> bupivacaine (25). The relevance of this work to clinical practice is yet to be determined. In summary, while all local anesthetics have been extensively evaluated for fetal and newborn effects, it is my view that there is probably no real difference in 2-CP versus lidocaine versus bupivacaine and that all of these agents can be used safely for labor and delivery.
2-Chloroprocaine and Intraspinal Narcotics
It has been reported that the use of epidural 2-CP may interfere with the quality and duration of pain relief produced by epidural morphine or fentanyl (26, 27). 2-CP or its metabolite, chloroaminobenzoic acid, may act as a mu receptor antagonist. However, this is difficult to demonstrate. It has been claimed that kappa receptors are not antagonized by 2-chloroprocaine (28). However, the receptor specific antagonism hypothesis has been challenged (29). I suspect that the chief problem is simply the rapid fade of a block with 2-CP (a quality that is desirable in some situations) which leads to a "window effect" before the onset of analgesia from epidural narcotics. While this issue remains controversial and proof of narcotic receptor antagonism may yet be established, close attention to the pain relief achieved with epidural narcotics after the administration of epidural 2-CP will solve the issue from the clinical viewpoint. The administration of small doses of intravenous fentanyl or morphine or an additional epidural dose of fentanyl or sufentanil added to epidural morphine will bring about adequate pain relief.
Use of 2-CP in Labor and Delivery
2-CP is an ideal drug in many ways. It has a rapid onset, high efficacy, rapid metabolism, and short half-life in both mother and fetus. These features make it a very appealing drug for epidural use. Our clinical group demonstrated the rapid onset (2-3 min) of epidurally administered 3% 2-CP in patients for postpartum tubal ligation with T4 level being achieved in 10 +/- 4min (Figure 106.2) (30) (Chapter 67). On the other hand, the reality is that its use is limited because of the very short duration of action. If 8 to 10ml of 2% 2-CP are given for labor analgesia, it is highly effective but the duration of action is only 45 to 50 minutes and the offset is exceedingly rapid. Thus, the drug must be topped-up promptly approximately every 45 minutes or the patient will rapidly go from feeling very comfortable to exceedingly uncomfortable. 2-CP has been administered as a continuous infusion for labor (0.75%) (31), as well as a continuous infusion for cesarean delivery (3.0%) (32). While this approach has been satisfactory, others have suggested that a tachyphylaxis may well develop and, thus, the continuous infusion technique is not commonly used. While labor epidurals may be initiated with chloroprocaine to achieve pain relief rapidly, this is not commonly done, both because of the short duration of action and the potential interference with the later use of epidural narcotics or bupivacaine. 2-CP (3%) has been shown to be very effective for cesarean section (32) and is popular in some institutions because of its rapid onset and the rapid fade of the block. This latter property may cut down on the recovery room stay.
The greatest use of 2-CP today may be either to "save" an inadequate epidural block (Chapter 94) where it is felt that the catheter is in place but a high dose of an amide local anesthetic has already been given, or to achieve a rapid onset of epidural anesthesia when good conditions for surgery are urgently needed. In the "chloroprocaine save" the addition of 10 to 20mls of 3% 2-CP may be adequate to achieve analgesia in a block that was previously "patchy" and to avoid the toxicity that would result from giving larger doses of an amide local anesthetic.
If an effective labor epidural is in place and a surgical delivery or cesarean section must be urgently performed, the addition of 12 to 15mls (to as much as 25mls) of 3% 2-CP will provide rapid anesthesia within 10 minutes. The higher dose of 2-CP would be required for a cesarean delivery while the lower dose will achieve adequate analgesia for a forceps or a vacuum delivery. Thus, while 2-CP was initially very popular as a routine drug for a cesarean section, it is now used most often in specific situations which are, generally, urgent or clinically complicated.
While it is an excellent local anesthetic and clearly has a place in obstetric clinical practice, its role today in obstetric anesthesia is limited. When using 2-CP the drug's short comings must be considered, but it is a unique local anesthetic and, when used appropriately, it is an excellent choice.
References:
1. Kreis O: Uber Medullarnarkose bei Gebarenden. Zentralbl Gynakol 24:724, 1900.
2. Shnider SM: Serum cholinesterase activity during pregnancy, labor and the puerperium. Anesthesiology 26:335-339, 1965.
3. Kuhnert BR, Kuhnert PM, Prochaska AL, Gross TL: Plasma levels of 2-chloroprocaine in obstetric patients and their neonates after epidural anesthesia. Anesthesiology 53:21-25, 1980.
4. Kuhnert BR, Kuhnert PM, Philipson EH, et al: The half-life of 2-chloroprocaine. Anesth Analg 65:273-278, 1986.
5. Covino BG, Vassallo HG: Local anesthetics: Mechanisms of Action and Clinical Use. New York, Grune & Stratton, 1976, p 126.
6. Ravindran R, Bond VK, Tasch MD, et al: Prolonged neural blockade following regional analgesia with 2-chloroprocaine. Anesth Analg 59:447-451, 1980.
7. Reisner LK, Hochman BN, Plumer MH: Persistent neurologic deficit and adhesive arachnoiditis following intrathecal 2-chloroprocaine injection. Anesth Analg 59:452-454, 1980.
8. Fenerty J, Sonner J, Sakura S, Drasner K: Transient radicular pain following spinal anesthesia: Review of the literaure and a report of a case involving 2% lidocaine. International Journal of Obstetric Anesthesia (in press, 1996).
9. Kalichman MW, Moorhouse DF, Powell HC, Myers RR: Relative neural toxicity of local anesthetics. J Neuropathol Exp Neurol 52:234-240, 1993.
10. Gissen AJ, Datta S, Lambert D: The chloroprocalne controversy. I. A hypothesis to explain the neural complications of chloroprocalne epidural. Reg Anesth 9:124-134, 1984.
11. Orkin FK, Bogetz MS: Back pain following uncomplicated epidural anesthesia with chloroprocaine. Anesthesiology 71 :A716, 1989.
12. Hynson JM, Sessler Dl, Glosten B: Back pain in volunteers after epidural anesthesia with chloroprocaine. Anesth Analg 72:253-256, 1991.
13. Stevens RA, Bray JG, Chester WL, et al: Back pain after epidural anesthesia with chloroprocaine in volunteers: preliminary report. Reg Anesth 16: 199-203, 1991.
14. Fishburne JI, Greiss FC, Hopkinson R, Rhyne AL: Responses of the gravid uterine vasculature to arterial levels of local anesthetic agents. Am J Obstet Gynecol 33:753-761, 1979.
15. Wallis KL, Shnider SM, Hicks JS, Spivey HT: Epidural anesthesia in the normotensive pregnant ewe: Effects of uterine blood flow and fetal acid-base status. Anesthesiology 4:481-487, 1976.
16. Chestnut DH, Weiner CP, Herrig JE: The effect of intravenously administered 2-chloroprocaine upon uterine artery blood flow velocity in gravid guinea pigs. Anesthesiology 70:305-308, 1989.
17. Marx GF, Patel S, Betman JA, et al: Umbilical blood flow velocity waveforms in different maternal positions and with epidural analgesia. Obstet Gynecol 68:61-64, 1986.
18. Hollmen AI, Jouppila R, Jouppila P, et al: Effect of extradural analgesia using bupivacaine and 2-chloroprocaine on intervillous blood flow during labour. Br J Anaesth 54:837, 1982.
19. Scanlon JW, Brown WU, Weiss JB, Alper MH: Neurobehavioral response of newborn infants after maternal epidural anesthesia. Anesthesiology 40: 121-128, 1974.
20. Abboud TK, Khoo SS, Miller F, et al: Maternal, fetal and neonatal responses after epidural anesthesia with bupivacaine, 2-chloroprocaine or lidocaine. Anesth Analg 61:638-644, 1982.
21. Abboud TK, Afrassiabi A, Sarkis F, et al: Continuous infusion epidural analgesia in parturients receiving bupivacaine, chloroprocaine or lidocaine: maternal, fetal, and neonatal effects. Anesth Analg 63:421-428, 1984.
22.. Kileff ME, James FM, Dewan DM, Floyd HM: Neonatal neurobehavioral responses after epidural anesthesia for cesarean section using lidocaine and bupivacaine. Anesth Analg 63:413-417, 1984.
23. Kuhnert BR, Harrison MJ, Linn PL, Kuhnert PM: Effects of maternal epidural anesthesia on neonatal behavior. Anesth Analg 63:301-308, 1984.
24. Loftus JR, Holbrook RH, Cohen SE: Fetal heart rate after epidural lidocaine and bupivacaine for elective cesarean section. Anesthesiology 75:406-412, 1991.
25. Schnell VL, Sacco AG, Savoy-Moore RT, Ataya KM, Moghissi KS: Effects of oocyte exposure to local anesthetics on in vitro fertilization and embryo development in the mouse. Toxicology 6:323-327, 1992.
26. Kotelko DM, Thigpen JW, Shnider SM, et al: Postoperative epidural morphine analgesia after various local anesthetics. Anesthesiology 59:A413, 1983.
27. Malinow AM, Mokriski BLK, Wakefield ML, et al: Choice of local anesthetic affects post-cesarean epidural fentanyl analgesia. Reg Anesth 13: 141-145, 1988.
28. Camann WR, Hartigan PM, Gilbertson LI, et al: Chloroprocaine antagonism of epidural opioid analgesia: a receptor-specific phenomenon? Anesthesiology 73:860-863, 1990.
29. Camann WR, Hurley RH, Gilbertson LI, Long ML, Datta S: Epidural nalbuphine for analgesia following caesarean delivery: dose-response and effect of local anaesthetic choice. Can J Anaesth 38:728-732, 1991.
30. Glosten B, Dailey PA, Preston PG, Shnider SM, Ross BK, Rosen MA, Hughes SC: pH-adjusted 2-chloroprocaine for epidural anesthesia in patients undergoing postpartum tubal ligation. Anesthesiology 68:948-950, 1988.
31. Abboud T, Abrasiabi A, Sarkis F, et al: Continuous infusion epidural analgesia in parturients receiving bupivacaine, chloroprocaine or lidocaine: Maternal, fetal and neonatal effects. Anesth Analg 63:421-428, 1984.
32. De Leon-Casasola OA, Syed N, Lema M J, Emrich L: Continuous 2-chloroprocaine infusion versus intermittent bolus injections of bupivacaine or 2-chloroprocaine for epidural anesthesia in cesarean delivery. Reg Anesth 16: 154-160, 1991.
33. Crosby E, Read D: Salvaging inadequate epidural anaesthetics: "The chloroprocaine save." Can J Anaesth 38:136-137, 1991.