Local anesthetics are the primary pharmacologic drugs used in obstetric anesthesia; they are used to provide regional analgesia for labor and delivery, as well as anesthesia for cesarean delivery. The most common local anesthetics used in obstetrics are listed in Table 3.7 . At the author’s institution, lidocaine is primarily used to test epidural catheters for location and establish labor analgesia, bupivacaine to maintain labor analgesia, and chloroprocaine to provide anesthesia for instrumental and operative deliveries. The bulleted sections that follow represent an overview of local anesthetic properties and toxicity.
Table 3.6 Complications and Side Effects Associated with Epidural Analgesia ∗
Complication or Side Effect Incidence Backache at insertion site 75 % –90 % Inadequate labor analgesia 15 % –25 %
Hypotension Varies with dose
Motor block Varies with dose
Urinary retention Varies with dose
Require replacement 8 % –10 %
Fetal bradycardia 8 %
Intravenous cannulation 1 % –6 % Inadvertent dural puncture (Wet Tap) 1 % –2 % Post dural puncture headache 1 % Inadvertent spinal catheter <1 %
Subdural catheter Rare (1:1000)
High spinal block Rare (1:10,000)
Permanent neurologic injury Extremely rare (<1:10,000) Epidural hematoma Extremely rare (<1:100,000) Epidural abscess Extremely rare (<1:100,000)
Death Extremely rare (<1:100,000)
∗ The listed incidence for each complication or side effect is an average value obtained from multiple sources within the literature.
44 Pain Relief for Labor and Delivery
Table 3.7 Commonly Administered Local Anesthetics in Obstetrics
Drug Class Concentration Dose ∗ Onset Duration of Labor Analgesia ∗ ∗
pka Protein Bound Chloroprocaine Ester 2 % –3 % 10–30 ml Rapid 30 min 8.7 0 Lidocaine Amide 1 % –2 % 10–30 ml Intermediate 45 min 7.9 70 Bupivacaine Amide 0.04 % –0.5 % 10–30 ml Slow 60 min 8.1 95 Levobupivacaine Amide 0.04 % –0.5 % 10–30 ml Slow 60 min 8.1 97 Ropivacaine Amide 0.04 % –0.5 % 10–30 ml Slow 60 min 8.1 94
∗ Local anesthetics should be administered incrementally rather than as a bolus (5 ml aliquots)
∗ ∗ Duration of labor analgesia from a single 15 ml epidural dose administered incrementally.
Obstetric Anesthesia45 Local Anesthetics (see also Chapter 1)
Local anesthetics are classifi ed as either esters or amides, according to the alkyl chain linking the lipophilic carbon ring and the tertiary amine.
Esters:
Include cocaine, tetracaine, procaine, and chloroprocaine
•
Are degraded in the plasma by pseudocholinesterase and nonspe-
•
cifi c esterases
Are hydrolyzed to produce para-aminobenzoic acid (PABA), which
•
gives them greater allergic potential than the amides Amides:
Include lidocaine, etidocaine, mepivacaine, prilocaine, bupivacaine,
•
ropivacaine, and levobupivacaine Are metabolized in the liver
•
All local anesthetics are weak bases with pKa values approximating 8.0.
At physiologic pH, most of the local anesthetic molecules exist in the ionized form but only unionized molecules diffuse through tissues and cross cell membranes.
Physiochemical properties such as pKa, lipid solubility, and protein
•
binding determine the clinical properties of various local anesthet- ics, including variability in speed of onset, potency, and duration of action.
Speed of onset is generally inversely related to pKa, since local
•
anesthetics with lower pKa values have a higher fraction of union- ized molecules.
Blood levels of local anesthetics are infl uenced by the total dose of drug administered, its physiochemical properties, the addition of vasoconstrictors, metabolism, and the vascularity of the site where administered. Using lidocaine as an example:
Although 5 mg/kg administered within the epidural space is consid-
•
ered safe, 20 mg injected directly into the carotid artery will likely produce a seizure.
A similar dose administered into the following compartments
•
produces varying plasma levels that directly correlate with the vascularity of each site in the following order: intercostal > caudal >
epidural > brachial plexus = femoral.
The addition of epinephrine 1:200,000 lowers plasma concentra-
•
tions and prolongs the duration of the block.
46Pain Relief for Labor and Delivery
Local anesthetics have no adverse effects on uterine or umbilical artery blood fl ow at clinically relative doses.
They can produce in uterine artery vasoconstriction and uterine
•
hypertonus at higher concentrations.
Unionized local anesthetic molecules freely cross the placenta.
•
Since fetal pH is lower than the maternal pH, more local anesthetic
•
becomes ionized and accumulates in the fetal circulation, in a phenomenon known as “ion trapping.”
This “ion trapping” effect may become clinically signifi cant in a
•
distressed, acidotic fetus.
Local Anesthetic Toxicity
All local anesthetics are toxic if administered in high enough doses.
As blood levels increase, local anesthetics fi rst cause excitatory neu- rologic symptoms, such as tinnitus, perioral numbness and seizures, followed by CNS depression, respiratory arrest, and eventual cardiac arrest (Table 3.8 ).
Cardiotoxicity is relative to the specifi c drug, total dose adminis- tered and the local anesthetic concentration in the blood. A small dose of local anesthetic administered directly into the carotid artery will produce a seizure but poses no risk of a cardiac arrest, while a large bolus (intended for the epidural space) inadvertently injected intravenously can cause cardiac arrest.
Bupivacaine is the most cardiotoxic of clinically used local anesthet-
•
ics. If the dose of bupivacaine required to produce cardiac toxicity is 1 , the equivalent dose of ropivacaine is 2 ; for lidocaine it is 8–16 and for chloroprocaine > 16.
Table 3.8 Signs and Symptoms of Local Anesthetic Toxicity ∗
1. Tinnitus, perioral numbness
2. Inability to communicate appropriately (glassy-eyed look) 3. Loss of consciousness
4. Seizure 5. Respiratory arrest 6. Cardiac arrest
∗ All local anesthetics can produce these reactions. The signs and symptoms generally occur in the listed order as blood concentrations increase. A test dose containing local anesthetic should produce the fi rst two symptoms but not loss of consciousness, seizures, or cardiopulmonary arrest. To prevent severe toxic reactions, local anesthetics should always be administered in fractionated doses (5 ml aliquots).
Obstetric Anesthesia47 Chloroprocaine has the least potential for inducing cardiotoxicity,
•
due to rapid metabolism.
Testing epidural catheters after placement, fractionated dosing, and vigilance are the keys to preventing local anesthetic toxicity.
The
• spinal test dose will rule out an intrathecal catheter, and is intended to be large enough to produce pain relief and motor block but not high spinal block.
The
• intravenous test dose will detect an intravenous catheter, and is intended to be large enough to produce early signs of CNS toxicity, but not so large as to produce seizures or cardiopulmonary arrest.
Fractionated dosing entails administering 5 ml aliquots at least 30–60 seconds apart, while observing the patient for signs and symptoms of intravascular or intrathecal injection.
The relatively small doses and slow injection will lessen risk of a
•
catastrophic toxic event.
Large boluses of concentrated local anesthetic should never
•
be injected as a single rapid bolus, even with a functioning epidural catheter, since catheters can migrate into epidural veins or intrathecally.
Even in urgent situations, large volumes of local anesthetic (i.e.,
•
30 ml) can be administered over 3–4 minutes in 5 ml increments.
Lipid Treatment of Local Anesthetic Toxicity
The term “lipid rescue” was fi rst coined in 2003 and is a new treat- ment modality for local anesthetic toxicity that has shown promising results in animal models and in numerous case reports. Experimental models have shown that infusion of a lipid emulsion increases the dose of bupivacaine needed to cause asystole in rats. Infusion of a lipid emulsion has improved resuscitation success after bupivacaine-in- duced cardiac arrest in dogs, is superior to either vasopressin alone or vasopressin in combination with epinephrine for resuscitation of local anesthetic toxicity in rodents, and has been used successfully to treat many cases of local anesthetic toxicity in humans.
Recommendations for Use of Lipid Rescue:
At present, no standard protocol exists
•
Intralipid
• ® (lipid emulsion) solution should be stocked on labor and delivery units for easy access in emergencies.
If standard adult cardiac life support (ACLS) is not immediately suc-
•
cessful after LA overdose, consider administration of Intralipid ® (Table 3.9 ).
48Pain Relief for Labor and Delivery
Specifi c Drugs Used in Obstetric Anesthesia Bupivacaine
Bupivacaine is the most commonly used local anesthetic to maintain labor analgesia for a number of reasons:
Dilute concentrations produce proportionally greater sensory
•
block than motor block.
Bupivacaine has limited placental transfer since it is highly protein-
• bound.
Plain 0.25
• % bupivacaine or 0.125 % bupoivacaine with opioid 10–15 ml produces analgesia in 10–15 min that lasts approximately 60 min before the patient requests additional analgesia.
Continuous infusions of dilute bupivacaine 0.04
• % –0.125 % at rates
of 10–15 ml/h, with or without opioids, provide labor analgesia with minimal side effects.
Ropivacaine and Levobupivacaine
Bupivacaine is prepared as a 50/50 % racemic mixture of D- and L-isomers. The D-isomer binds cardiac sodium channels more tightly than the L-isomer, and is consequently more cardiotoxic.
Levobupivacaine and ropivacaine were developed as alternatives to bupivacaine, and are preparations of nearly pure L-isomers.
Bupivacaine, levobupivacaine, and ropivacaine belong to the same pipecoloxylidide family and are structural analogs. Ropivacaine has a three-carbon side chain, while bupivacaine and levobupivacaine have four-carbon side chains.
Ropivacaine produces less motor block than either bupivacaine or levobupivacaine, at the same concentration; however, the three drugs produce clinically indistinguishable labor analgesia. Similar concentra- tions and dosing regimens of ropivacaine or levobupivacaine should be administered when used as alternatives to bupivacaine. While these newer agents result in slightly less motor block than bupivacaine at equal concentrations, several factors have slowed their clinical acceptance.
Table 3.9 Recommended Lipid Rescue Protocol for Local Anesthetic Induced Cardiac Arrest
20
• % Intralipid solution: 1.5 ml/kg as an initial bolus, followed by 0.25–0.5 ml/kg/min for 30–120 minutes
•
Repeat bolus 1–2 times for persistent asystole
•
Increase infusion rate by 0.25 ml/kg/min if the blood pressure declines
•
Obstetric Anesthesia49 Ropivacaine and levobupivacaine cost more than bupivacaine.
•
The benefi t of the reduced motor block in laboring parturients
•
remains unproven.
The incidence of local anesthetic induced cardiac arrest in obstetric
•
anesthesia practice is exceedingly rare.
Lidocaine
Plain 1 % –2 % lidocaine 10–15 ml produces labor analgesia in 5–10 minutes that lasts approximately 45 minutes before the patient requests additional analgesia. Alkalinization with 8.4 % sodium bicar- bonate 1 meq/10 ml of local anesthetic decreases onset time to approximately 3–6 minutes. Lidocaine is commonly used to test epidural catheters, initiate labor analgesia, treat breakthrough pain, or produce anesthesia for instrumental or operative deliveries. It is not routinely used as a maintenance agent because it produces more motor block and has greater placental transfer than bupivacaine.
Chloroprocaine
Plain 2 % chloroprocaine 10–15 ml produces labor analgesia in 3–6 minutes that lasts approximately 30 minutes before the patient requests additional analgesia. Chloroprocaine is not routinely used as a maintenance agent because its short duration of action makes management diffi cult.
3 % chloroprocaine is well suited for producing surgical anesthesia for instrumental or operative deliveries.
It has a very rapid onset of action.
•
It produces dense sensory and motor block.
•
It has a short duration of action.
•
It has a very favorable safety profi le; it is metabolized by plasma
•
esterases, resulting in a plasma half-life of approximately 30 seconds, making it one of the least toxic local anesthetics.
Despite these benefi ts, chloroprocaine has several drawbacks. It has been associated with neurologic injury when administered intrathe- cally. In some patients, it may produce transient but uncomfortable back pain, and when administered together with epidural opioids, the opioid effect is inconsistent in both quality and duration. Although the exact mechanism is unknown, chloroprocaine reduces fentanyl and morphine analgesia, even after the block has receded. Although statis- tically signifi cant, this effect does not appear to be clinically signifi cant.
Chloroprocaine-induced neurotoxicity has been associated with both the pH of the solution and the use of the preservative
50Pain Relief for Labor and Delivery
sodium metabisulfi te. Because of these concerns, a preservative-free preparation of chloroprocaine has been marketed. In addition, since the preparation’s pH was increased from 3.0 to 7.0 several years ago, there have been no further reports of neurotoxicity. Nevertheless, in cases of unintentional dural puncture with the epidural needle avoiding chloroprocaine seems prudent.
Chloroprocaine induced back pain has been related to localized muscle hypocalcemia induced from the preservative EDTA (which binds calcium ions). Patients have developed severe muscle spasms of the upper back following large doses ( > 50 ml) of chloroprocaine;
usually after epidural analgesia has receded. Commercial preparations using EDTA are no longer available.
When considering a risk/benefi t ratio for this drug, it is the author’s opinion that the benefi ts of chloroprocaine clearly outweigh the risks of these rare complications.
Chloroprocaine should be avoided in patients with known abnor- mal psuedocholinesterase (1:3,000 patients).
Opioids (See also Chapter 5)
Opioids produce analgesia by binding to opioid receptors both in the spinal cord (spinal receptors) and within the brain (supraspinal recep- tors). Although opioids reliably produce analgesia in early labor, they are less effective during the later phases of labor and for delivery.
Visceral pain fi bers (early labor pain) are primarily located in
•
the periphery of the spinal cord and have a larger population of opioid receptors, making them more amenable to opioid-induced modulation.
Somatic pain fi bers (late labor and delivery pain) are located more
•
deeply within the spinal cord and have fewer associated opioid receptors.
Since opioids do not produce complete labor analgesia, they are most often co-administered with local anesthetics.
Lipid Soluble Opioids
Fentanyl (2–4 mcg/ml) and sufentanil (0.3–0.5 mcg/ml) are the most commonly used opioids in obstetrics (combined with local anesthetic to produce labor analgesia).
Side effects produced by fentanyl and sufentanil are similar at
•
equipotent doses.
Pruritus is the most frequently encountered side effect (60
• % –
100 % incidence), but rarely requires treatment. If necessary,
Obstetric Anesthesia51 pruritus is readily treated with an agonist-antagonist such as nalbu- phine 5 mg.
Less common side effects include nausea, urinary retention, dys-
•
phoria and respiratory depression.
Lipid soluble opioids are associated with “early respiratory depres-
•
sion,” which occurs within 30 min of administration. It is likely due to rapid systemic uptake or rapid cephalad distribution within the central nervous system and, may be more likely following repeat doses.
All side effects, including respiratory depression, can be reversed with
•
naloxone (40 mcg boluses titrated to effect are recommended).
Overview of Fentanyl Mechanism of Action in Obstetrics
The addition of fentanyl 2 mcg/ml to dilute concentrations of local anesthetic (typically bupivacaine 0.0625 % –0.125 % ) for labor analgesia reduces local anesthetic use by 25 % –30 % .
Epidural fentanyl at 20 mcg/h, a typical obstetric dose, and in
•
contrast to intravenous fentanyl, reduces epidural bupivacaine use in laboring women, which indirectly indicates a spinal analgesic effect.
In contrast, epidural fentanyl alone offers little advantage over intrave- nous administration to treat postoperative pain.
Fentanyl requirements, blood concentrations, analgesia and side
•
effects are similar.
Treatment of postoperative pain requires relatively large doses of
•
fentanyl ( > 100 mcg/h).
At these higher doses, epidural fentanyl is absorbed systemically
•
and activates both spinal and supraspinal opioid receptors.
Hydrophilic Opioids
Morphine and meperidine (pethidine) have been used in obstetrics, but much less commonly than lipid soluble opioids. The onset of anal- gesia from neuraxial administration of morphine is slow (up to 1 hour).
Epidural morphine is associated with biphasic “early and late respira- tory depression.”
Early respiratory depression is probably due to rapid systemic
•
uptake, and occurs within 1 hour of administration.
Late respiratory depression occurs 6–18 hours after administration
•
and is secondary to rostral spread within the CSF leading to brain- stem depression of respiration.
52Pain Relief for Labor and Delivery
Neuraxial meperidine has local anesthetic-like as well as opioid prop- erties, but clinical data are lacking, so recommendations about its use and safety for labor analgesia cannot be made at this time.
Adjuncts
The holy grail of analgesia in obstetrics is a medication or combination that produces long-lasting, complete pain relief without side effects.
Since all current medications produce side effects, a variety of epidural and spinal adjuncts have been studied in an attempt to improve or prolong labor analgesia while minimizing side effects (Table 3.10 ).
Unfortunately, each adjunct studied (e.g., epinephrine, neostigmine) produced undesirable side effects or, as is the case with clonidine, its routine use is precluded in the United States. The following is a sum- mary of three adjuncts studied to date.
Epinephrine , an α -adrenergic receptor agonist, enhances analgesia, reduces blood levels of local anesthetics, increases onset times, and prolongs block duration.
Epidural doses of 1:200,000–600,000 are often used for continuous
•
epidural analgesia.
Single-shot spinal doses of 200 mcg or less have been reported.
•
Epinephrine increases the degree and duration of motor block,
•
especially with continuous infusions.
Clonidine , an α 2 adrenergic receptor agonist, is the most promising epidural adjunct.
At an epidural dose of 4 mcg/ml, clonidine signifi cantly reduces
•
PCEA bupivacaine/fentanyl use in laboring women without increas- ing side effects.
Spinal doses of 15–50 mcg prolong labor analgesia from bupivacaine/
•
sufentanil but produce sedation and hypotension.
Clonidine is expensive in the United States, and has an FDA “Black
•
Box Warning” against its use in obstetrics.
In theory, parturients that deliver vaginally may be at increased risk of morphine-induced respiratory depression since they expe- rience less postpartum pain than parturients requiring an opera- tive delivery. Additionally, parturients are more sensitive to nearly all anesthetics, and are usually sent to unmonitored postpartum wards.
For these reasons, epidural or intrathecal morphine is not
•
recommended for vaginal delivery.
Obstetric Anesthesia53
Neostigmine is an anticholinesterase that enhances analgesia by indirectly increasing spinal levels of acetylcholine.
At a spinal dose of 10 mcg, neostigmine fails to enhance labor anal-
•
gesia but produces severe nausea.
At epidural doses up to 500 mcg, preliminary studies indicate that
•
it enhances labor analgesia without producing nausea, but is still under investigation and cannot be recommended for routine use at this time.