Cesarean delivery is one of the most common surgical procedures. In the United States, more than 1 million cesarean sections are performed each year, accounting for more than 30% of births. The majority of these procedures are performed using a regional technique; general anesthesia is reserved for patients who have a contraindication to a regional block or for emergencies, when there is not enough time for a regional block. Consequently, general anesthesia for cesarean delivery is relatively rare, and providers may be less comfortable administering it to parturients. Their discomfort is warranted. Although straightforward, general anesthetic for cesarean section is fraught with adverse events, including an increased risk of awareness, aspiration, difficult airway with hypoxia, drug-related uterine atony, and neonatal respiratory depression.

Numerous studies have characterized how physiologic changes of pregnancy alter the distribution, metabolism, and concentration-effect relationship of anesthetic drugs. Unfortunately, for most anesthetics, this body of knowledge has not transferred into dosing recommendations specific to the parturient. Anesthesiologists are left to rely on experience and careful titration to achieve unconsciousness and analgesia while avoiding adverse effects.

The purpose of this chapter is to review how physiologic changes associated with pregnancy influence kinetic and dynamic behavior of anesthetic drugs when used for general anesthesia under emergency conditions and explore through simulation how dosing technique may contribute to worrisome adverse effects.

Intravenous Agents

A summary of physiologic changes that influence intravenous anesthetic drug kinetics is presented in Table 37–1. Volume of distribution increases for most drugs due to a 40% to 45% increase in blood volume as well as an increase in body fat and total body water during pregnancy.¹ Protein binding is reduced secondary to a 25% decline in albumin levels toward the end of pregnancy. Although levels of α-1-acid glycoprotein can decline in pregnancy, as an acute phase protein, levels exhibit a variable pattern. In some studies, third-trimester levels did not differ significantly from those obtained from nonpregnant women of childbearing age.² Accelerated redistribution of intravenous anesthetics can be expected secondary to a 40% increase in cardiac output.¹

Elimination and metabolism are significantly altered during pregnancy. Hepatic blood flow does not appreciably change; however, some enzymatic activity is decreased (CYP1A2, CYP2C19) and some increased (CYP3A4, CYP2D6, CYP2C9, UGT).³ Therefore, hepatic clearance for a particular drug will be highly dependent on the exact metabolism and may increase (as can be expected for benzodiazepines and propofol that are metabolized by CYP, or morphine, which is metabolized by UGT), decrease (eg, caffeine, which is metabolized by CYP1A2) or remain unchanged.^2,3 Renal clearance during pregnancy is increased. The glomerular filtration rate increases 50% above prepregnancy levels.^2,3 Possible changes of tubular secretion and reabsorption of drugs are not well defined. Activity of pseudocholinesterase is diminished by 25%; however, succinylcholine recovery is not prolonged in pregnant patients.⁴

Inhalation Agents

Pharmacokinetics of inhaled anesthetics is also altered in pregnancy. When altering the concentration of inhaled anesthetics, alveolar concentration will rise more rapidly as a result of decreased functional residual capacity and increased minute ventilation; however, this is partially offset by increased cardiac output.

Intravenous Agents

The data on potency of intravenous anesthetic drugs in pregnancy are limited. Studies with propofol suggest that there is little or no change during the first trimester. Mongardon et al examined 57 patients at 11 weeks’ gestation. Although the researchers found a statistically significant difference in mean propofol dose required for loss of consciousness in comparison to a nonpregnant control group, the difference was clinically negligible (1.8 versus 1.9 mg/kg), with predicted propofol effect-site concentration of 4.6 versus 5.0 mcg/mL.⁵ Higuchi et al studied 36 patients at 6 to 12 weeks’ gestation and concluded that venous propofol concentration at the time of loss of consciousness did not differ from the nonpregnant group.⁶ Studies exploring propofol necessary for loss of consciousness later in pregnancy (ie, second or third trimester) when the influence of physiologic changes associated with pregnancy are perhaps more pronounced are not available.

Potency of other induction agents has not been directly evaluated. Common practice is to use induction doses that do not differ from nonpregnant patients: thiopental 4 mg/kg, etomidate 0.3 mg/kg, propofol 2 mg/kg, and ketamine 1 mg/kg.⁷

Inhalation Agents

Multiple studies by Chen et al provide solid evidence of 30% reduction of minimum alveolar concentration (MAC) of all volatile anesthetics as early as 8 weeks’ gestation.^8,9 It was observed that MAC remains reduced for 24 to 36 hours postpartum with normalization to prepregnancy levels by 72 hours after delivery.¹⁰ Although progesterone is likely responsible for decreased MAC in pregnancy, a simple linear correlation has not been demonstrated; the exact mechanism is unclear.¹⁰

Overall, predictions of intravenous drug behavior in pregnant patients are near impossible to make. For example, following an intravenous bolus of an anesthetic drug, plasma concentrations may be higher or lower because of several competing physiologic changes. Plasma concentrations may be less due to an increased volume of distribution. The amount of free drug available to exert an effect should increase due to a decrease in plasma protein that normally binds up most of the circulating drug. Peak concentrations decline faster due to rapid redistribution. Hepatic metabolism will vary by drug and its associated enzymatic pathway. Drugs that are removed unchanged by the kidney may have increased clearance.

There is a paucity of literature exploring anesthetic drugs in late pregnancy. From what information is available, Table 37–2 presents pharmacokinetic changes for selected anesthetics. One group has explored propofol pharmacokinetics in pregnancy and reported a similar volume of distribution yet more rapid clearance compared to nonpregnant females in several studies.^11,12

The majority of work describing the pharmacokinetics of thiopental in pregnancy was done 40 years ago. The data are conflicting. Some investigators reported an increase in the volume of distribution, whereas others reported an increased in clearance.^{13,14, and 15} Interestingly, 10% of the thiopental induction dose was still detected in maternal blood 12 hours after induction.¹⁶

Pharmacokinetic assessment of ketamine suggested reduced clearance in pregnancy.¹⁷ There are no studies evaluating pharmacokinetics of etomidate in pregnancy. Higher clearance, shorter half-life, and unchanged volume of distribution were observed for morphine.¹⁸

There are several competing goals and concerns (Table 37–3) when using general anesthetic for cesarean delivery that make up the “dilemma of obstetric anesthesia and analgesia.” It is necessary to provide adequate anesthetic depth to ensure maternal comfort, limit fetal drug transmission, provide hemodynamic stability in the face of impending blood loss, and avoid uterolytic effects of volatile anesthetics.¹⁹

Historically, induction of general anesthesia was performed with thiopental and succinylcholine followed by nitrous oxide and an inhalational anesthetic. Although this is still regarded as a standard, with more modern drugs available, induction techniques may vary. In fact, induction drugs vary on how they meet the induction goals described above.

Neonatal Depression

A main goal is to minimize neonate anesthetic effects. Anesthetic drugs are highly lipophilic and rapidly cross the placentofetal barrier. A measure of drug crossover to the neonate is the umbilical artery–to–umbilical vein ratio. This ratio is 0.87 for thiopental, 0.70 for propofol, and 0.5 for etomidate.

Propofol has been faulted for higher incidence of neonatal depression. This was based on a single publication from 1989 where parturients were induced with 2.8 mg/kg propofol or 5 mg/kg of thiopental. Twenty-five percent of the neonates born to mothers who had received propofol had lower Apgar scores than those who received thiopental (7.7 versus 8.2).²⁰ In contrast, several other studies showed comparable Apgar scores in propofol versus thiopental induction.^{12,21,22, and 23} Data on the effect of maintenance propofol infusion on neonatal depression are inconclusive. Gin et al noted decreased neurobehavioral scores in infants delivered after 2-mg/kg propofol bolus followed by a 150-mcg/kg/min, but not a 100-mcg/kg/min, propofol infusion.¹¹ Similarly, a 1.5- to 2.5-mg/kg induction bolus of propofol followed by a 200-mcg/kg/min propofol infusion,²⁴ a 2.5-mg/kg bolus followed by an 83-mcg/kg/min propofol infusion,²⁵ and a 2-mg/kg bolus followed by a 100-mcg/kg/min infusion²⁶ did not cause any appreciable difference in Apgar scores or neurobehavioral assessment. No correlation between neonatal propofol levels and Apgar or neurobehavioral scores was found.