ADRENALINE (EPINEPHRINE).
Adrenaline was probably first used by Braun in 1903 to prolong the action of cocaine by reducing the local blood supply and delaying its uptake.
When adrenaline is absorbed slowly from the maternal epidural space, it usually causes a rise in cardiac output and heart rate with a concomitant fall in peripheral vascular resistance, leaving the mean arterial pressure unchanged or slightly reduced.
The use of adrenaline in obstetrics is somewhat controversial because it can cause a reduction in utero-placental blood flow (Chapter 76). This is particularly true in pregnancy induced hypertension where vasospasm may already be present (1, 2) (Chapter 39).
Advantages: Adrenaline increases the speed of onset of epidural block and, in most of the studies performed, enhances both the spread and quality of the block. It also prolongs the effects of lignocaine and reduces peak local anaesthetic blood levels and toxicity (3, 4, 5) (Table 36.3).
Disadvantages: Uterine contractile activity may be diminished for up to 60 minutes (6). Uterine blood flow may be reduced (7) and labour slowed (8) when adrenaline has been added to the epidural local anaesthetic solution.
It has been suggested that adrenaline may exert an independent analgesic effect at spinal cord level as a consequence of its anti-nociceptive effect at spinal alpha-adrenoreceptors (9).
The effective epidural dose of adrenaline for obstetrics is approximately 5mcg/ml. This can be added fresh by the operator. Solutions premixed by the manufacturers are available in concentrations ranging from 1:400,000 (2.5mcg/ml) to 1:200,000 (5mcg/ml).
Subarachnoid adrenaline (200mcg) does prolong the action of spinal anaesthetics, but is rarely used, partly out of concern for the potential to cause spinal cord ischaemia.
BICARBONATE.
This is not a new additive. Bignon, in 1892, reported that making cocaine alkaline greatly increased its anaesthetic potency. Commercial supplies of amide-type local anaesthetics have a pH between 3.2 and 6.5 (20), but with the pKa of these solutions being between 7.5 and 9.0, less than 3% of the local anaesthetic will be present as the nonionized free base (10). As it is the nonionized form of the local anaesthetic that crosses nerve sheaths and membranes, it follows that if the pH of the agents could be made less acidic (or closer to the pKa) then, in the body, more of the nonionized form will be present and the onset of nerve-block will be more rapid.
Studies of epidural block in obstetric patients using small doses of sodium bicarbonate have produced conflicting results. Tackley and Coe (11) demonstrated that 0.15ml of an 8.4% solution of sodium bicarbonate added to 10ml bupivacaine 0.5% for Caesarean section can produce a more rapid onset of both sensory and motor blockade as well as a prolongation of duration of action. This effect has been confirmed by some (12) but not by others (13, 14).
If too much bicarbonate is added, however, precipitation of the free base may occur because the nonionized form is only slightly soluble in water. An alternative to bicarbonate is to add carbon dioxide to the local anaesthetic ampoule to achieve a pCO2 of about 600mm Hg. These solutions, of which carbonated lignocaine is the most widely used, have been shown to produce a better quality and quicker onset of sensory blockade than similar 'non-gassed' solutions in obstetric patients (15).
NARCOTICS.
Opioids are now routinely added to many intraspinal solutions. In some cases, intraspinal narcotics have become the sole analgesic agent (Chapter 60).
DEXTROSE.
Dextrose, in a concentration ranging from 3% to 5%, is frequently added to subarachnoid local anaesthetic solutions to adjust the baricity of the solution in relation to cerebro-spinal fluid (Figure 30.1).
PRESERVATIVES AND ANTIMICROBIALS.
The widely used amide-type local anaesthetic agents are extremely stable chemical compounds and, if stored in glass or plastic containers, will not deteriorate over an almost indefinite period. Adrenaline, however, will break down in solution and the antioxidant sodium metabisulphite (0.1%) is added as a stabilizer, increasing the shelf-life to 2 years. If the adrenaline is to maintain its potency, these ampoules or vials may only be autoclaved once .
Although multidose vials are currently being phased out in many countries, some still remain in use and frequently contain an antimicrobial agent. Methylparaben has been used in epidural and spinal solutions over many years and is effective as both an antibacterial and an antifungal agent, although it may be responsible for some of the rare cases of "allergic" reactions to local anaesthetics (16) (Chapter 69). Chlorocresol is a more effective antimicrobial agent but is neurotoxic and unsuitable for use in solutions for major nerve-blocks. It is used solely in solutions for local infiltration. It is anticipated that, in the near future, most local anaesthetics will be supplied in single-use plastic (polypropylene) vials without preservatives.
Narcotics for intraspinal use and, even the normal saline diluent, should be specified as "preservative-free" by the manufacturers. Some morphine products still contain metabisulphite and fentanyl may include citric acid. Benzyl alcohol has, in the past, been occasionally added to saline.
OTHER (NEWER) AGENTS.
As the cellular mechanisms involved in the physiological responses to pain at the spinal cord level are being revealed, the search for alternative analgesics has intensified. Intraspinal alpha2-adrenergic agonists (clonidine and dexmedetomidine) induce analgesia by a pathway involving nitric oxide and acetylcholine release and are potentiated by intrathecal neostigmine (17). Their use as sole agents in labour is limited by the production of excessive sedation or hypotension. Synergistic reactions with other analgesics, which will allow a reduced dosage and diminished side-effects, are being investigated.
Other prospective intraspinal agents under review include:
adenosine A1 agonists,
ketorolac (18),
GABA (gamma aminobutyric acid) agonists,
midazolam,
ketamine,
somatostatin, and
MDA (n-methyl D-aspartate) antagonists (19).
CARRIER VEHICLES
The search for a suitable carrier vehicle to prolong the duration of intraspinal local anaesthetics has been under way for many years. The latest candidate is 50% glycerin which has been combined with 0.125% bupivacaine (18). This mixture might be suitable for post-Caesarean section analgesia. An alternative is the encapsulation of bupivacaine into liposomes.
References:
1.
Holdcroft A. Use of adrenaline in obstetric analgesia. Anaesthesia 1992 47:987-990.
4. Scott DB, Jebson PJ, Braid DP, Ortengren B, Frisch P. Factors affecting plasma levels of lignocaine and prilocaine. British Journal of Anaesthesia 1972 44:1040-1049.
6. Craft JB Jr, Epstein BS, Coakley CS. Effect of lidocaine with epinephrine versus lidocaine (plain) on induced labor. Anesthesia and Analgesia 1972 51:243-246.
8. Gunther RE, Bauman J. Obstetrical caudal anesthesia. I. A randomized study comparing 1% lidocaine with 1% lidocaine plus epinephrine. Anesthesiology 1969 31:5.
9. Collins JG, Matsumoto M, Kitahata LM. Suppression by spinally administered epinephrine of noxiously evoked dorsal horn neuron activity in cats; evidence for spinal epinephrine analgesia. Anesthesia and Analgesia 1983 62:253-254
20. Moore DC The pH of local anesthetic solutions. Anesth Analg 60:833-834, 1981
12. Capogna G, Constantino P, Muratori A et al. The addition of bicarbonate improves the quality of intraoperative analgesia of lidocaine-fentanyl epidural anesthesia for cesarean section. Regional Anesthesia 1992 ;17:S32.
15. Bromage PR. Unblocked segments in epidural analgesia for relief of pain in labour. British Journal of Anaesthesia 1972; 44:676-679.
16. Aldrete JA, Johnson DA. Evaluation of intracutaneous testing for investigation of allergy to local anesthetic agents. Anesthesia and Analgesia 1970 49:173
18. Arkoosh VA. What's new in obstetric anesthesia, 1993? International Journal of Obstetric Anesthesia 1994; 3:21 9-226.
19. Information partly supplied by Astra Pharmaceuticals Pty Ltd.