International Journal of Obstetric Anesthesia (2012) xxx, xxxxxx 0959-289X/$ - see front matter c 2012 Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.ijoa.2012.03.006

EDITORIAL

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Mini-dose single-shot spinal anesthesia for cesarean delivery: for whom the bell-shaped curve tolls
Perchance he for whom this bell tolls may ... know not it tolls for him; and perchance I may think myself so much better than I am, as that they who are about me, and see my state, may have caused it to toll for me, and I know not that ... No man is an island entire of itself ... therefore never send to know for whom the bells tolls; it tolls for thee. John Donne, Meditation 17, Devotions upon Emergent Occasions Single-shot spinal anesthesia is the most common anesthetic choice for cesarean delivery in contemporary practice. It is fast, cheap and provides relatively predictable and generally excellent surgical anesthesia. Moreover, it is safe; usually. However, a common side effect is dose-dependent sympatholysis with maternal hypotension, which may be profound, especially if exacerbated by aortocaval compression or hypovolemia. Multiple strategies have been developed to limit maternal hypotension during spinal anesthesia for cesarean delivery;1 most notably pre-hydration2 or co-hydration,3 increased use of vasopressors, particularly phenylephrine,4 and reduced local anesthetic dose. In particular, several studies517 have reported using doses below 8 mg intrathecal bupivacaine (and as low as 3.75 mg9 and 2.5 mg14), co-administered with an opioid. The use of mini-dose local anesthesia as a single-shot spinal for cesarean delivery has been advocated5,7,9 but concerns have been expressed regarding the safety of using small anesthetic doses without a catheter-based route for supplemental neuraxial analgesia.1821 Regarding the effective dose for surgical anesthesia, it may be argued both that the conventional dose of bupivacaine for cesarean delivery is too high, and that the mini-dose is too low. The doses used in mini-dose spinal anesthesia for cesarean delivery are typically around or below the reported ED50 for hyperbaric (7.64 0.45 mg)22 and isobaric bupivacaine (7.25 0.6 mg),23 although none of the studies of mini-dose spinal anesthesia for cesarean delivery report anything approaching a 50% anesthesia failure rate. Current editions of standard general anesthesia textbooks still recommend large hyperbaric bupivacaine doses of 12.513.5 mg,24 12 mg (915)25 and <15 mg26 combined with opioids. These doses are all in excess of the reported ED95 for hyperbaric bupivacaine (11.0 0.95 mg)22 when co-administered with representative doses of spinal opioids (fentanyl 10 lg, morphine 200 lg). Advocates of mini-dose spinals may argue that the dose-ranging studies for both hyperbaric22 and isobaric bupivacaine23 over-estimate the true ED95. The ED95 is calculated from the at portion of the dose-response (or in this case the logistic regression) curve and is considerably less precise than the more robust ED50. Additionally, those studies22,23 used quite rigorous criteria to dene anesthesia success (bilateral T6 sensory level to pinprick by 10 min and no visual analog pain score (VAPS) <20 mm at any point during surgery). Furthermore, those studies were performed using combined spinalepidural (CSE), and the presence of an epidural catheter may have encouraged anesthesia rescue at a lower degree of patient discomfort than might have been the case if the only available options were intravenous sedation or general anesthesia. Conversely, the proposition that an epidural catheter may have encouraged more liberal anesthesia rescue articulates precisely the dangers inherent in mini-dose single-shot spinals, where a patient experiencing intraoperative pain is exposed to three unpalatable alternatives to continue to suffer distressing pain, to receive potentially hazardous sedating systemic analgesia or to undergo an unplanned general anesthetic. Furthermore, some have argued that the reported ED95 with CSE may actually under-estimate the real dose requirement for a single-shot spinal. The epidural component of CSE (without epidural drug or saline administration) has been reported to raise the anesthetic sensory level from a spinal bolus and lower the ED50,27,28 although this nding has been disputed by others.29 The main reported advantage for mini-dose spinal anesthesia is to reduce maternal hypotension, vasopressor requirement, and nausea and vomiting. Other reported advantages include less prolonged motor block, faster discharge from the post-anesthesia care unit (PACU) and improved maternal satisfaction. Maternal hypotensive symptoms are typically limited to nausea, vomiting and occasionally pre-syncope. However, in susceptible high-risk patients with baseline hemodynamic compromise, superimposed sympatholysis may be far more serious and may precipitate circulatory col-

2 lapse and even death. According to data from the Condential Enquiries into Maternal Deaths in South Africa,30 spinal anesthesia has become the leading cause of maternal death directly attributable to anesthesia (30% of direct anesthetic deaths in 1998, 42% in 1999 2001, 41% in 20022004 and 72% in 20052007). Almost all of these cases involved high spinal, hypotension, circulatory collapse or a combination of these diagnoses.30 However, in most of these cases, the hemodynamic collapse was due more to the inappropriate selection of patients with hypovolemia than to the inappropriate selection of dose.30 The effects of maternal hypotension may also affect the fetus or neonate. Neonates born by elective cesarean delivery under spinal anesthesia are slightly more acidemic when compared to neonates delivered following either epidural or general anesthesia;31 this may be clinically signicant if the fetus is compromised at baseline. While fetal/neonatal acidemia may be, in part, a direct consequence of maternal hypotension and uteroplacental hypoperfusion, current evidence suggests that it is primarily a consequence of the choice of the vasopressor used to treat or prevent it.32 Although mini-dose spinals are usually associated with less maternal hypotension, the relationship is not always consistent. Intraoperative hypotension may be dened in multiple ways33,34 and there is no uniformity of denition in these studies. Hypotension remains a common side effect, even in very low doses. For example, in one study that compared spinal bupivacaine 10 mg with 4 mg, the incidence of maternal hypotension only reduced from 100% to 70%.10 Similarly, in a study that compared hyperbaric bupivacaine 12 mg and isobaric bupivacaine 4.5 mg, no difference was found in maternal hypotension.12 The lowest incidence of maternal hypotension (6%) following spinal anesthesia for cesarean delivery was reported by Vercauteren et al.6 who co-administered intrathecal hyperbaric bupivacaine 6.6 mg and sufentanil 3.3 lg; all patients also received prophylactic intravenous ephedrine 5 mg at the time of spinal drug administration. A similar dose was studied by Van de Velde et al.17 comparing hyperbaric bupivacaine 9.5 mg with 6.5 mg coadministered with sufentanil 2.5 lg. The incidence of hypotension was more common in the 9.5 mg group (68% versus 16%), was more pronounced and of longer duration, and required more ephedrine. However, an integral part of their technique17,18 was the placement of an epidural catheter for spinal rescue and dosing the catheter if the uterus was not closed by 45 min.18 A similar approach was taken by Fan et al.14 who studied four doses of intrathecal bupivacaine (2.5, 5, 7.5, and 10 mg) as part of a CSE technique. They reported that the 5 mg group was associated with less hypotension, nausea, and dyspnea than the 7.5 and 10 mg groups, but patients in the 5 mg group required a mean supplemental epidural dose of 2% lidocaine 10 mL in order to attain adequate

Editorial anesthesia, compared with no supplement requirement with higher doses. However, reducing the dose of spinal bupivacaine has been shown, not surprisingly, to also increase intraoperative pain.35 In one study, half the patients receiving intrathecal bupivacaine 5 mg for cesarean delivery complained of (non-quantied) discomfort during surgery.5 In another study comparing bupivacaine 7, 8 and 9 mg, an intraoperative VAPS pain score of 40 mm was used as the threshold for analgesic supplementation. This remarkably high pain level was observed in 15% after 9 mg, 20% after 8 mg and 40% after 7 mg.11 In a single-shot spinal study comparing isobaric bupivacaine 4.5 mg and hyperbaric bupivacaine 12 mg, both with fentanyl 50 lg and morphine 200 lg, 19% (5/27) of patients in the mini-dose group required sedating systemic analgesia (as compared with 1/25 in the conventional group).12 In another single-shot spinal study using hyperbaric bupivacaine 6.5 mg co-administered with fentanyl 20 lg, almost 10% (2/21) of patients required unplanned intraoperative conversion to general anesthesia.13 In addition to the effects of reducing the dose of spinal local anesthetic on intraoperative pain, there is also a corresponding increase in the time to anesthesia onset36 and a reduction in anesthesia duration,11,36 which may make mini-dose single-shot spinals particularly prone to failure in urgent cesarean delivery or if the intraoperative course is prolonged. A recent systematic review and meta-analysis assessed all randomized controlled trials that compared mini-dose and conventional dose spinals for cesarean delivery.37 They included 12 studies (693 patients) in the nal analysis and assessed analgesic supplementation as the primary endpoint. The authors pooled data into two groups: 68 mg bupivacaine and >8 mg bupivacaine. The weighted average doses in the mini-dose and conventional-dose groups were 7 and 11 mg, respectively. These doses almost exactly correspond to the ED50 and ED95 for hyperbaric bupivacaine.22 They found an almost four-fold increase in likelihood for anesthesia supplementation in the mini-dose group (RR 3.76, 95% CI 2.385.92; P < 0.00001); the number needed to treat to cause additional harm was 4 (95% CI 27). Results from different studies were consistent in magnitude and direction. By contrast, mini-dose spinals were associated with less hypotension (RR 0.78; 95% CI 0.650.93; P = 0.005) and less nausea and vomiting (RR 0.71; 95% CI 0.550.93; P = 0.001). However the reductions in nausea and hypotension following mini-dose spinals were less impressive than the increase in supplemental anesthesia requirement. The authors concluded that lower anesthetic doses cannot be recommended unless an epidural catheter is in place (CSE) to rescue the block if anesthesia is inadequate or becomes inadequate during surgery.

Editorial The anesthetic effect following a xed dose of spinal drug may be regarded as a spectrum with unwanted side effects at both extremes. Excessive anesthesia may be experienced by over-responders and is associated with more pronounced hypotension (associated with nausea and vomiting), prolonged motor blockade, delayed post anesthesia care unit (PACU) discharge and rarely high spinal with respiratory muscle weakness. At the other extreme, inadequate anesthesia in under-responders causes pain and discomfort, nausea and vomiting from unblocked peritoneal stimulation, and requirement for further anesthetic supplementation. The majority of patients in the center are generally comfortable, although it should be stressed from the data presented that hypotension and nausea are both common occurrences in minidose spinal anesthesia. Furthermore, nausea and vomiting may be associated with oxytocin and ergometrine administration, irrespective of the response to anesthesia. While the dose of spinal local anesthetic is the most important factor in determining the anesthetic effect, many other factors are involved in the heterogeneous response.38 Drug factors include baricity, drug volume, speed of injection and co-administered opioid or nonopioid analgesics (for each adjuvant drug: dose, potency and pharmacokinetic properties such as lipid solubility). Patient factors may include age, body habitus (weight, height, vertebral column length), patient position during and after the block, vertebral interspace used and the volume of cerebrospinal uid at that space. Psychosocial, ethnic, and pharmacogenomic factors are also important sources of patient heterogeneity. The depth and duration of the surgical stimulus is also not uniform and varies extensively between surgeons and institutions

3 (particularly if performing uterine exteriorization) and between patients (particularly if there are adhesions from previous surgery). The proportion of the population that responds with any given anesthetic effect along this spectrum is distributed in an approximately bell-shaped curve (Fig. 1). The danger of reporting a mean analgesic response to a xed drug dose is that it tends to place undue weight on the central tendency. This applies also to the mean dose requirement, ED50, in a dose-ranging study. These data are useful for comparative pharmacological studies (e.g. MLAC) but should not be used to directly guide therapy. Clinical complications occur most frequently among outliers and the safety of any technique must be judged by how it responds to those cases. As so many variables determine both the anesthetic effect and the surgical stimulus, a standard single dose aimed at the ED50 is unwise. A mini-dose spinal anesthetic using CSE may be the optimal technique, avoiding excessive anesthesia in over-responders yet providing a rescue approach for under-responders. However, depending on local clinical realities, CSE may not always be appropriate. It is more complicated and may potentially have more complications (inadvertent spinal or intravascular placement); it is more expensive, and there is no guarantee that the epidural top-up will provide the dense anesthetic effect provided by spinal anesthesia. If for these (or other) reasons a catheter-based technique is not suitable, then it is preferable to perform a single-shot spinal using a current conventional dose (1012 mg hyperbaric bupivacaine with opioid) and use a prophylactic or therapeutic phenylephrine infusion as appropriate. Treating or preventing hypotension with phenylephrine and co-

Fig. 1 Speculative population response to a xed dose of intrathecal anesthetic. Limits of A and B depend on drug dose and on heterogeneity in drug factors, patient factors and surgical stimulus (see text for details). Although the distribution is represented here as Gaussian, this is for illustration purposes only; this is not based on observed data and is more likely skewed to the right and may exhibit kurtosis, with a reduced proportion around the central tendency and a relatively high proportion of outliers.

4 hydration is certainly safer than either sedating an agitated parturient with intraoperative pain or converting to unplanned general anesthesia. The use of mini-dose single-shot spinal anesthesia for cesarean delivery, without a catheter-based option for rescue, exposes the patient to avoidable risk. In routine medical interventions it is not sufcient to cite how often we successfully get away with it. If we reect on our own limitations (perchance I may think myself so much better than I am) and if we consider that our next patient is a potential outlier (no man is an island entire of itself), then we will know for whom the bell-shaped curve tolls. Y. Ginosar Mother and Child Anesthesia Unit Department of Anesthesiology Hadassah Hebrew University Medical Center Jerusalem, Israel E-mail address: yginosar@netvision.net.il

Editorial
11. Leo S, Sng BL, Lin Y, Sia ATH. A randomized comparison of low doses of hyperbaric bupivacaine in combined spinal-epidural anesthesia for cesarean delivery. Anesth Analg 2009;109:16005. 12. Bryson GL, MacNeil R, Jeyaraj LM, Rosaeg OP. Small dose spinal bupivacaine for Cesarean delivery does not reduce hypotension but accelerates motor recovery. Can J Anesth 2007;54: 5317. rez A, Bermejo JM, Gilsanz F. Randomized 13. Guasch E, Sua controlled trial comparing a low dose to a conventional dose of hyperbaric bupivacaine for scheduled cesarean section. Rev Esp Anestesiol Reanim 2005;52:7580. 14. Fan SZ, Susetio L, Wang YP, Cheng YJ, Liu CC. Low dose of intrathecal hyperbaric bupivacaine combined with epidural lidocaine for cesarean section: a balance block technique. Anesth Analg 1994;78:4747. 15. Kiran S, Singal SK. A comparative study of three different doses of 0.5% hyperbaric bupivacaine for spinal anaesthesia in elective caesarean section. Int J Obstet Anaesth 2002;11:1859. 16. Choi DH, Ahn HJ, Kim JA. Combined low-dose spinalepidural anesthesia versus single-shot spinal anesthesia for elective cesarean delivery. Int J Obstet Anesth 2006;15:137. 17. Van de Velde M, Van Schoubroeck D, Jani J, Teunkens A, Missant C, Deprest J. Combined spinal epidural anesthesia for Cesarean section: dose dependent effects of hyperbaric bupivacaine on maternal hemodynamics. Anesth Analg 2006;103:18790. 18. Roofthooft E, Van de Velde M. Low-dose spinal anaesthesia for Caesarean section to prevent spinal-induced hypotension. Curr Opin Anaesth 2008;21:25962. 19. Dyer RA, Joubert IA. Low-dose spinal anaesthesia for Caesarean section. Curr Opin Anaesth 2004;17:3018. 20. Benhamou D, Wong C. Neuraxial anesthesia for Cesarean delivery: what criteria dene the optimal technique? Anesth Analg 2009;109:13703. 21. Rucklidge MW, Paech MJ. Limiting the dose of local anaesthetic for caesarean section under spinal anaesthesia has the limbo bar been set too low? Anaesthesia 2012;67:34751. 22. Ginosar Y, Mirikatani E, Drover DR, Cohen SE, Riley ET. ED50 and ED95 of intrathecal hyperbaric bupivacaine coadministered with opioids for cesarean delivery. Anesthesiology 2004;100: 67682. 23. Carvalho B, Durbin M, Drover DR, Cohen SE, Ginosar Y, Riley ET. The ED50 and ED95 of intrathecal isobaric bupivacaine with opioids for cesarean delivery. Anesthesiology 2005;103:60612. 24. Ferne R, Braveman FR, Scavone BM, Wong CA, Santos AC. Obstetrical anesthesia. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC, editors. Clinical anesthesia. 6th Ed. Philadelphia: Lippincott Williams & Wilkins; 2009: Chapter 43 25. Tsen LC. Anesthesia for obstetric care and gynecologic surgery. In: Longnecker DE, Brown DL, Newman MF, Zapol WM, editors. Anesthesiology. New York: MacGraw-Hill Medical; 2008: Chapter 61. 26. Birnbach DJ, Browne IM. Anesthesia for obstetrics. In: Miller RD, editor. Millers anesthesia. 7th Ed. Philadelphia: Elsevier; 2010.. Chapter 69. 27. Goy RW, Yoong CS, Sia AT, Koay CK, Shen L. The median effective dose of intrathecal hyperbaric bupivacaine is larger in the single-shot spinal as compared with the combined spinal epidural technique. Anesth Analg 2005;100:1499502. 28. Ithnin F, Lim Y, Sia AT, Ocampo CE. Combined spinal epidural causes higher level of block than equivalent single-shot spinal anesthesia in elective cesarean patients. Anesth Analg 2006;102: 57780. 29. Horstman DJ, Riley ET, Carvalho B. A randomized trial of maximum cephalad sensory blockade with single-shot spinal compared with combined spinal-epidural techniques for cesarean delivery. Anesth Analg 2009;108:2405.

References
1. Cyna AM, Andrew M, Emmett RS, Middleton P, Simmons SW. Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cochrane Database Syst Rev 2006;18(4): CD002251. 2. Ko JS, Kim CS, Cho HS, Choi DH. A randomized trial of crystalloid versus colloid solution for prevention of hypotension during spinal or low-dose combined spinal-epidural anesthesia for elective cesarean delivery. Int J Obstet Anesth 2007;16:812. 3. Ngan Kee WD, Khaw KS, Ng FF. Prevention of hypotension during spinal anesthesia for cesarean delivery: an effective technique using combination phenylephrine infusion and crystalloid cohydration. Anesthesiology 2005;103:74450. 4. Ngan Kee WD, Lee A, Khaw KS, Ng FF, Karmakar MK, Gin T. A randomized double-blinded comparison of phenylephrine and ephedrine infusion combinations to maintain blood pressure during spinal anesthesia for cesarean delivery: the effects on fetal acid-base status and hemodynamic control. Anesth Analg 2008;107:1295302. 5. Ben-David B, Miller G, Gavriel R, Gurevitch A. Low-dose bupivacaine fentanyl spinal anesthesia for cesarean delivery. Reg Anesth Pain Med 2000;25:2359. 6. Vercauteren MP, Coppejans HC, Hoffmann VL, Saldien V, Adriaensen HA. Small-dose hyperbaric versus plain bupivacaine during spinal anesthesia for cesarean section. Anesth Analg 1998;86:98993. 7. Choi DH, Ahn HJ, Kim MH. Bupivacaine-sparing effect of fentanyl in spinal anesthesia for cesarean delivery. Reg Anesth Pain Med 2000;25:2405. 8. Kang FC, Tsai YC, Chang PJ, Chen TY. Subarachnoid fentanyl with diluted small-dose bupivacaine for cesarean section delivery. Acta Anaesthesiol Sin 1998;36:20714. 9. Teoh WH, Thomas E, Tan HM. Ultra-low dose combined spinal epidural anesthesia with intrathecal bupivacaine 3.75 mg for cesarean delivery: a randomized controlled trial. Int J Obstet Anesth 2006;15:2738. 10. Kaya S, Karaman H, Erdogan H, Akyilmaz A, Turhanoglu S. Combined use of low-dose bupivacaine, colloid preload and wrapping of the legs for preventing hypotension in spinal anaesthesia for caesarian section. J Int Med Res 2007;35:61525.

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30. Moodley J, Chairman. Saving mothers 2005-2007. Fourth Report on Condential Enquiries into Maternal Deaths in South Africa 2005-2007. National Committee for the Condential Enquiries into Maternal Deaths. 31. Reynolds F, Seed PT. Anaesthesia for Caesarean section and neonatal acidbase status: a meta-analysis. Anaesthesia 2005;60: 63653. 32. Ngan Kee WD, Lee A. Multivariate analysis of factors associated with umbilical arterial pH and standard base excess after Caesarean section under spinal anaesthesia. Anaesthesia 2003;58: 12530. 33. Bijker JB, van Klei WA, Kappen TH, van Wolfswinkel L, Moons CJ, Kalkman CJ. Incidence of intraoperative hypotension as a function of the chosen denition: literature denitions applied to a retrospective cohort using automated data collection. Anesthesiology 2007;107:21320. 34. Klo hr S, Roth R, Hofmann T, Rossaint R, Heesen M. Denitions of hypotension after spinal anaesthesia for caesarean section:

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literature search and application to parturients. Acta Anaesthesiol Scand 2010;54:90921. Pedersen H, Santos AC, Steinberg ES, et al. Incidence of visceral pain during cesarean section: the effect of varying doses of spinal bupivacaine. Anesth Analg 1989;69:469. McNaught AF, Stocks GM. Epidural volume extension and lowdose sequential combined spinal-epidural blockade: two ways to reduce spinal dose requirement for caesarean section. Int J Obstet Anesth 2007;16:34653. Arzola C, Wieczorek PM. Efcacy of low-dose bupivacaine in spinal anaesthesia for Caesarean delivery: systematic review and meta-analysis. Br J Anaesth 2011;107:30818. Schnider TW, Minto CF, Bruckert H, Manderna JW. Population pharmacodynamic modeling and covariate detection for central neural blockade. Anesthesiology 1996;85:50212.

35.

36.

37.

38.