Neuraxial anesthesia is undoubtedly the most appropriate technique for elective cesarean delivery. It is associated with a decreased risk of aspiration and failed intubation, and therefore maternal mortality, when compared with general anesthesia.1 Mothers are awake to experience the happy event and other family members may be present. Moreover, general anesthesia for cesarean delivery appears to be associated with a higher risk of awareness than many other surgical procedures.2 Finally, recent evidence that drugs used during general anesthesia are associated with apoptosis of fetal/neonatal brain neurons in animal models has left anesthesiologists questioning whether human fetal exposure is also harmful to the developing brain.3
Historically, epidural anesthesia was the primary neuraxial technique for cesarean delivery because spinal anesthesia was associated with a high risk of postdural puncture headache. The introduction of pencil-point spinal needles in the late 1980s and the associated dramatic decrease in the incidence of postdural puncture headache led to a renewed interest in spinal anesthesia in the early 1990s.4
A 1995 landmark study by Riley et al.5 established the advantages of spinal compared with epidural anesthesia for cesarean delivery. The study evaluated most of the criteria that define a successful anesthetic technique and demonstrated that single-shot spinal anesthesia was superior to epidural anesthesia for the vast majority of patients. Spinal anesthesia was faster to perform, surgical anesthesia was attained more rapidly, anesthesia was more effective (less breakthrough pain), and costs were lower (primarily because of less operating room time) than epidural anesthesia. These results have since been replicated by other investigators and by practitioners in their routine practice. Single-shot spinal anesthesia has thus become the technique of choice for elective cesarean delivery in most countries.6,7
Unfortunately, rapid and extensive spread of anesthesia, both considered major advantages of single-shot spinal anesthesia, lead to the almost universal occurrence of hypotension. Maternal consequences are usually limited to nausea and vomiting but occasionally lead to severe hypotension or even death in patients with a compromised cardiac reserve. The neonate may also be adversely affected by maternal hypotension and reduced uteroplacental perfusion. In most instances, however, maternal hypotension of short duration is associated with transient fetal carbon dioxide retention and is of limited clinical consequence.8
This creates a dilemma for the anesthesiologist (and the patient): dense (better) anesthesia is associated with a higher incidence and severity of hypotension. It is beyond the scope of this editorial to describe the various studies that have led anesthesiologists to agree that frequent measurement of arterial blood pressure and aggressive treatment of hypotension are necessary to prevent maternal nausea and vomiting and neonatal acidosis.9 The dilemma remains only partly solved by current techniques. Multiple studies have shown that rapid IV fluid administration before, or at the time of initiation of neuraxial anesthesia, mitigates but does not prevent hypotension. Vasopressors are usually required to prevent or treat hypotension. However, ephedrine, especially when used in large doses, is associated with fetal lactic acidosis, and large doses of phenylephrine are required to maintain arterial blood pressure during spinal anesthesia for cesarean delivery.10,11
The deep and extensive sympathetic block that underlies the etiology of spinal anesthesia-induced hypotension is a direct consequence of neuraxial local anesthetic administration. Thus, another method to decrease the incidence and severity of hypotension is to manipulate the local anesthetic dose, i.e., to use the smallest possible “adequate dose” to produce “optimal” anesthesia. Considering only the end point of anesthetic efficacy, studies have determined the dose-response (adequate anesthesia) relationship of the most commonly used local anesthetics. Bupivacaine, either racemic or its levorotatory enantiomer, provides anesthesia in almost all patients (ED95) at doses that range between 11 and 13 mg.12,13 The ED95 of ropivacaine (when used alone) is close to 26 mg.14 Unfortunately, these doses carry a high risk of hypotension. Several studies have convincingly demonstrated that lower local anesthetic doses are associated with a lower incidence of hypotension. For example, Van de Velde et al.15 compared hyperbaric bupivacaine 6.5 and 9.5 mg and Teoh et al.16 compared 3.75 and 9 mg, whereas Ben-David et al.17 compared plain bupivacaine 5 and 10 mg combined with 25 μg of fentanyl. Although these studies showed a lower incidence of hypotension with the lower dose, it is not clear that there is a linear relationship between the dose and the risk of hypotension. In the studies described above, the dose range was large and comparator doses were quite “high” or “low.” It is not surprising that low doses were associated with minimal hemodynamic derangements because lower dermatomal levels and less extended sympathetic (i.e., splanchnic) block were observed.
Because the technique of using low intrathecal doses has an increased risk of intraoperative pain and shorter duration of effective anesthesia with a slower onset, it would be useful to test whether “every milligram has an effect” and to identify a single dose that is associated with adequate anesthetic conditions and a minimal risk of hypotension.18 It is in this context that Leo et al.19 in the current issue of Anesthesia & Analgesia evaluate efficacy and side effects of spinal anesthesia within an “intermediate,” small dose range of bupivacaine (7, 8, and 9 mg). The authors chose to use combined spinal-epidural (CSE) anesthesia for at least two reasons. First, they suggest that the use of CSE may further reduce the required dose and thus provide efficient anesthesia while minimizing the incidence of hypotension. This approach, however, is controversial as studies have not consistently shown that CSE anesthesia is associated with lower dose requirements compared with single-shot spinal anesthesia using the same local anesthetic dose. Indeed, several studies from Singapore (same institution) have demonstrated such a difference in both obstetric and nonobstetric populations, but other studies from Singapore and elsewhere have not replicated these results.20–22
The second reason is that having the epidural catheter in place is necessary to rescue the block if anesthesia is inadequate or becomes inadequate during surgery, as might occur with a low dose. In the study by Leo et al.19, the time for sensory blockade to recede two dermatomes from the highest level was 90–100 min, an interval adequate for most cesarean procedures. However, two-dermatome regression, although often used as an outcome variable in studies of neuraxial anesthesia, is not a magic number. There is no evidence that this correlates with adequate surgical anesthesia, and in fact, anesthesia is not just regressing from cephalad to caudad, but the density of anesthesia is lessening over the entire field of the block concurrently with regression of the cephalad level of sensory blockade. Thus, although the study was not adequately powered to find a difference among groups, twice as many patients in the 7 mg (40%) compared with 8 and 9 mg groups required supplemental epidural anesthesia. Therefore, the use of lower doses of local anesthetics, and therefore, a lower incidence of hypotension, comes with a trade-off. It requires the use of CSE anesthesia. This trade-off negates some of the advantages of spinal compared with epidural anesthesia; namely, the neuraxial procedure time is shorter and less complicated, the risk of postdural puncture headache may be lower, and equipment costs are also lower. Moreover, the risk of failed neuraxial anesthesia may be increased with CSE compared with single-shot spinal anesthesia, because the epidural catheter is untested and may not be correctly sited in the epidural space.
Although cesarean delivery is a procedure performed on a daily basis throughout the world, the results of this study are difficult to reconcile with other studies and practices. This raises the question of external validity. For example, with a 15 mL/kg fluid co-load using a starch solution, the 9 mg group had a 70% incidence of hypotension (using a definition similar to that used by other investigators). This is a surprisingly high incidence given the efficacy of starches as intravascular volume expanders and the relatively low dose of bupivacaine (e.g., less than the ED95).23 Moreover, it is surprising that the sensory level to cold was at or higher than the T3 dermatome in all patients, even in patients allocated to receive 7 mg of hyperbaric bupivacaine. In the practice of the two editorialists, even when using larger bupivacaine doses combined with a lipid soluble opioid, these high levels are unusual.
Important differences in demographic characteristics in the population studied by Leo et al.19 might partly explain these differences. Data from Asia might not be easily translated to Western practice. Although it is often stated that there is no clear relation between height and spread of anesthesia in individual patients, this may not be true for populations of patients, and differences in body habitus between Asian and Western women may modify the normal dose-response relationship.24 In the current study, the mean height was 158–160 cm, whereas the mean height of United States patients studied by the Stanford University group was 161–167 cm, i.e., not overlapping values.13,19 Others have suggested that adjustment for height and weight is useful but comparison of results from Asian and Western studies on the basis of body mass index calculation does not provide a satisfactory answer because Western women were not only taller but also had a larger body weight.13,25
There are other technical reasons why the results of this (or any study) on the “optimal” dose might not be generalizable. These include:
- Genetic factors: we do not yet know much about genetic differences in susceptibility to local anesthetic blockade, but there is evidence that polymorphism in the mu-opioid receptor affects response to opioids, and the Asian population has a different genetic profile than the European American population.26 Therefore, mixing the local anesthetic with opioids could confound the results because the Asian population might respond differently to the opioid than non-Asians.
- Opioid use: most obstetric anesthesiologists add lipid soluble opioids (fentanyl or sufentanil) to bupivacaine but these investigators did not.
- The lumbar vertebral interspace: injection into a higher lumbar interspace results in more cephalad distribution of sensory blockade.27 Anesthesiologists are poor at accurately identifying the intended interspace and may frequently inject anesthetic into an interspace that differs by one or two levels from the intended interspace.28
Other technical aspects of the procedure: for example, we doubt that anesthesiologists can accurately and precisely draw up and administer 7, 8, and 9 mg of bupivacaine 0.5% (1.4–1.8 mL) into a 3-mL syringe.
Other aspects of care that are often not detailed or standardized among institutions, or even among individual anesthesiologists in a single institution, including block position (lateral versus sitting) or vasopressor use. In one study, for example, block height differed between patients randomized to treatment with phenylephrine versus ephedrine.29
Patient expectations may also be different from one country to another. The authors of this study did not initiate epidural anesthesia until two-segment regression or a pain score of 40 mm/100 mm was obtained. In some institutions, however, a pain score of 40 mm during a surgical procedure may be considered much too high and a T6 sensory level to cold much too low.
Another reason that the specific results of this, and other similar studies, are not generalizable relates to differences in surgical technique. This variable is not explicitly described in many studies. In the current study, cesarean delivery was performed using a traditional Pfannenstiel technique. Anesthetic needs may be reduced in institutions in which the Joel Cohen method is used (lower incision and no peritoneal closure).30 Applying fundal pressure to facilitate delivery enhances hemodynamic compromise.31 Exteriorizing the uterus during repair generally requires more dense anesthesia. Population characteristics may also indirectly influence surgical technique. For example, the surgical procedure may be technically more difficult and longer in the generally larger patients found in North America compared with the smaller patients in Asia. Finally, laboring patients may have different anesthetic requirements than nonlaboring patients. Yoo et al.32 recently demonstrated that during standard sevoflurane anesthesia for cesarean delivery, laboring patients had lower bispectral index values than nonlaboring patients.
Leo et al.19 performed a well-designed, meticulous study to ascertain the “optimal” local anesthetic dose for CSE anesthesia for elective cesarean delivery. Their goal was adequate anesthesia with the lowest incidence of hypotension. Unfortunately, their results are probably not generalizable to other institutions, countries, or patient populations. It is not clear whether studies of this type are even worth performing, given the myriad variables that affect outcome, and are often not controlled in study design. Future studies of this type must provide specific details on the anesthetic and surgical technique if we are to learn which factors influence outcome (dose) to optimize the anesthetic technique. Studies must be large enough to have enough power to evaluate less common but important side effects, including incidence of postdural puncture headache. Today, the most important criteria for choosing the optimal neuraxial anesthetic technique and drug dose(s) for cesarean delivery are anesthetic efficacy (onset, duration, and spread) and the occurrence (incidence and severity) of hypotension. By manipulating only the intrathecal dose, it remains difficult to reach our double-edged target, and the optimal dose may not be universal. Low-dose CSE anesthesia may not be the optimal technique for all patients and institutions. Although some patient-related factors (which may be difficult to control) may play a role, attention to every technique-related detail is important and a combination of strategies (e.g., specific techniques, equipment, drug(s), doses, fluid and vasopressor management, patient position/drug baricity) has the potential to significantly influence and improve our practice.
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