2012 Gerard W. Ostheimer Lecture – What’s new in obstetric anesthesia?

International Journal of Obstetric Anesthesia (2012) 21, 348–356 0959-289X/$ - see front matter c 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijoa.2012.08.005



REVIEW ARTICLE

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2012 Gerard W. Ostheimer Lecture – What’s new in obstetric anesthesia? A.J. Butwick Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA ABSTRACT The aim of the 2012 ‘‘What’s new in obstetric anesthesia?’’ review is to highlight important scientific and medical advances in the fields of obstetric anesthesiology, obstetrics and perinatology from literature published in 2011. This review will consider advances in the prevention and treatment of important obstetric and obstetric anesthesia-related morbidities, research relevant to the course of labor and electronic fetal monitoring, and advances in neuraxial analgesia and anesthesia for obstetric patients. c 2012 Elsevier Ltd. All rights reserved.



Keywords: Obstetrical Anesthesia; Obstetrics; Pregnancy complications

Introduction This review is an accompaniment to the honorary Gerard W. Ostheimer ‘‘What’s New in Obstetric Anesthesia?’’ lecture which is given at the Annual Meeting of the Society for Obstetric Anesthesia and Perinatology. The combined aims of the lecture and this review are to provide an overview of important scientific and clinical advances in the fields of obstetrics, obstetric anesthesiology, perinatology and allied medical disciplines relevant to the interdisciplinary care of the obstetric patient. In preparation for the lecture and this review, a systematic review of the 2011 medical literature was performed to identify key papers, which included a hand-search of the table of contents of 74 journals published from January 2011 to December 2011. Relevant clinical and scientific information published before or after 2011 was also considered. This review will highlight advances in the prevention and treatment of important obstetric morbidities, intrapartum fetal monitoring and progress in labor, and obstetric anesthesia-related morbidities and advances in neuraxial analgesia and anesthesia for obstetric patients.

Obstetric morbidities Important clinical, epidemiologic and analytic studies published in 2011 have enhanced current screening, Accepted August 2012 The 2012 Gerard W. Ostheimer Lecture presented at the Society for Obstetric Anesthesia and Perinatology 44th Annual Meeting, Monterey, CA, USA May 2012. Correspondence to: Alexander J. Butwick, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA. E-mail address: [email protected]

preventive and therapeutic approaches for a number of important obstetric morbidities.

Venous thromboembolism Recent mortality data indicate that venous thromboembolism (VTE) remains a leading direct cause of maternal death in well-developed countries. VTE was responsible for 10.2% of maternal deaths in the USA between 1998 and 2005,1 and 10.9% of all direct and indirect UK maternal deaths in the 2006–2008 triennium.2 From a public health standpoint, there is considerable interest in strategies to reduce the maternal mortality rate due to VTE in well-resourced countries. In the UK, implementation of national guidelines for screening at-risk women3 and more widespread thromboprophylaxis is speculated to have been instrumental in dramatically reducing the maternal mortality rate from VTE: 1.94 per 100 000 maternities between 2003 and 2005 to 0.79 per 100 000 maternities between 2006 and 2008.2 Pregnant women are known to be at increased risk of VTE compared to non-pregnant women,4 however, knowledge of the time-dependent changes in the maternal risk profile for VTE during pregnancy and the postpartum period is less certain. Virkus et al. performed a cohort study using four linked national registries in Denmark to investigate the incidence rates of VTE during pregnancy and the puerperium.5 The absolute risk of VTE among obstetric patients per 10 000 pregnant women years increased exponentially from 4.1 (95% CI 3.2–5.2) during 1–11 weeks of gestation, reached a peak of 60 (95% CI 47.2–76.4) in the week following delivery and decreased to 2.1 (95% CI 1.1–4.2) between 9 and 12 weeks after delivery. The importance of the early

A.J. Butwick postpartum period as an ‘at-risk’ period for VTE was also highlighted in a recent systematic review of epidemiologic studies investigating postpartum VTE.6 Jackson et al. reported that the risk for VTE for women during the first six weeks postpartum is 21.5–84 fold higher than for non-pregnant women of reproductive age.6 These data imply that prophylactic regimens for patients at high-risk for VTE should be considered during the early postpartum period. Although guidelines recommend postpartum thromboprophylaxis for women at moderate-to-high risk of VTE,3,7 recent studies have raised questions about the efficacy of low-dose thromboprophylaxis for these patients. In a retrospective cohort study of 91 ‘at-risk’ obstetric patients receiving low-dose low-molecular weight heparin (LMWH) (predominantly nadropin 2850 IU), Roeters van Lennep et al. reported that the incidences of antepartum and postpartum VTE were 1.8% (95% CI 0.4–9.2) and 7% (95% CI 2.9–6.7) respectively.8 All events occurred in women considered at high-risk for VTE who had received LMWH during the antepartum and postpartum periods. Unfortunately, this study was limited by the lack of a control group and objective diagnoses were not obtained for all reported episodes of VTE. A limited anticoagulant response may also occur with prophylactic doses of subcutaneous (s.c.) heparin. During elective cesarean delivery, Boyce et al. reported that s.c. heparin 7500 IU initiates only a minor hypocoagulable effect (assessed using thromboelastography with and without heparinase), with virtually undetectable anti-Xa levels measured up to 4 h post-heparin administration.9 In addition, the association between adverse surgical outcomes and post-cesarean enoxaparin thromboprophylaxis may be underappreciated. Ferres et al. observed that prophylactic enoxaparin use in at-risk women was associated with an increased risk of wound separation (adjusted OR 1.66, 95% CI 1.03–2.66).10 Clearly, population-wide multi-center studies are needed to prospectively investigate the risks vs. benefits and the cost-effectiveness of thromboprophylaxis in obstetric patients at low and high risk for VTE during the peripartum and postpartum periods. In 2011, the American College of Obstetricians and Gynecologists (ACOG) updated their practice bulletins for the screening and management of patients with inherited thrombophilias11 and for the prevention and management of venous thromboembolism in pregnancy.12 The joint release of these guidelines was well-planned as inherited thrombophilias, notably factor V Leiden mutation, prothrombin G20210A mutation, protein C deficiency; protein S deficiency are known to be associated with an increased risk of venous thromboembolism in pregnancy and the puerperium.13,14 In both guidelines, ACOG recommend that patients receiving prophylactic or therapeutic doses of LMWH should be converted to s.c. heparin at approximately 36 weeks of gestation to

349 permit safe induction of labor or scheduled cesarean delivery. For anesthesiologists who may be considering a neuraxial technique for anticoagulated obstetric patients, this recommendation is beneficial as s.c. heparin has a much shorter half-life than prophylactic or therapeutic LMWH.15 As a clinical consequence, no wait-period would be necessary after patients receive a prophylactic s.c. heparin dose before undergoing safe neuraxial block placement, whereas a wait-period of 12 h or 24 h would be needed for patients receiving prophylactic or therapeutic LMWH (based on guidelines from the American Society of Regional Anesthesia).16 Of note, ACOG and the American College of Chest Physicians suggest ‘intermediate’ LMWH or heparin dosing as an option for patients with low- or high-risk thrombophilia with a single prior episode of VTE.7,11 However, there is no current consensus on the safe timing of neuraxial block placement and epidural catheter removal for obstetric patients receiving ‘intermediate’ doses of LMWH or non-prophylactic s.c. heparin dosing (total daily dose >10 000 IU or >three times daily dosing).16

Preeclampsia It is well known that preeclampsia is associated with severe maternal and perinatal morbidity and mortality.17 In 2011, two important international prospective multicenter studies were published which incorporated sophisticated modeling for (a) predicting preeclampsia in healthy patients;18 and (b) predicting adverse maternal outcomes in patients with preeclampsia.19 Women often have combinations of different risk factors for preeclampsia, however, accurately predicting the degree of risk from combinations of clinical risk factors has proved challenging.20 Using multivariate logistic regression modeling with 10-fold cross validation, North et al. assessed 3572 healthy nulliparous women with a singleton pregnancy to investigate the risk profile of women who subsequently developed preeclampsia.18 The clinical factors at 14–16 weeks of gestation that were associated with an increased risk of preeclampsia were heterogeneous, and included: maternal age, mean arterial pressure, body mass index, family history of preeclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for >5 days. Factors associated with a reduced risk included: previous single miscarriage with the same partner, >12 months to conceive, high intake of fruit, cigarette smoking and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUROC) was 0.71 ± 0.002 (SD) which indicates moderate predictive performance; the model performance did not improve after accounting for uterine artery Doppler indices. Predicting adverse outcomes in patients with preeclampsia may have important value in reducing adverse obstetrical morbidity or mortality, however, previous modeling has proven unsuccessful for predicting adverse

350 outcomes after admission in patients diagnosed with preeclampsia.21 In a multicenter study assessing adverse maternal outcomes among preeclamptics, von Dadelszen et al. reported a 13% incidence of maternal morbidity or mortality among 2023 women admitted to tertiary care centers with preeclampsia.19 Using stepwise backward elimination for modeling and bootstrapping for internal validation, predictors of adverse outcomes included: gestational age, chest pain or dyspnea, oxygen saturation, platelet count, creatinine level and aspartate transaminase concentration. Surprisingly, headache and visual disturbance were not predictive of adverse outcome, and systolic and diastolic blood pressures were not found to be independent predictors (after adjustment). Nonetheless, the model had decent predictive performance (AUROC 0.88, 95% CI 0.84–0.92) for maternal adverse outcomes occurring within 48 h of the diagnosis of preeclampsia, which is often a clinically important period for maternal and fetal intervention. The results from these two prediction studies require external validation and subsequent studies of clinical impact. However, improvements in the risk stratification of obstetric patients at risk of preeclampsia or complications due to preeclampsia may lead to earlier and more strategic patient care as well as improved maternal outcomes.

Postpartum hemorrhage There has been increasing focus on system-level and institutional processes that influence the management of women who experience postpartum hemorrhage (PPH). Outcomes-based data from single institutions suggest that robust and intensive educational programs, structured treatment protocols and post-event peer review may individually or in combination lead to reductions in the incidence of severe PPH and hemorrhage-related maternal morbidity.22–24 However, it is unclear whether dissemination of similar educational programs spanning a network or region of hospitals results in similar improvements. A cluster-randomized controlled trial (Pithagore6 study) sought to assess the impact of a hospital-based structured educational program on reducing the incidence of PPH.25 In this study, 106 French maternity units were randomly assigned to receive a multifaceted educational program for improving hospital-wide PPH management (comprising outreach training, in-person educational reminders, and peer review) or a passively disseminated educational program. Disappointingly, the incidence of severe PPH in the maternity units that received the multifaceted educational program was not significantly different from that in ‘control units’ (1.64% ± 0.8 vs. 1.65% ± 0.96, respectively).25 In a secondary analyses of the Pithagore6 data, other interesting clinical and non-clinical (system/institutional) factors associated with severe PPH among women who had undergone vaginal delivery with

What’s new in obstetric anesthesia? atonic PPH have been identified.26 Delays either in administering uterotonic therapy (adjusted OR 1.86, 95% CI 1.45–2.38) or manual examination of the uterus (adjusted OR 1.83, 95% CI 1.42–2.35) of >20 min after bleeding onset were independently associated with an increased risk of severe PPH. Interestingly, epidural analgesia was associated with a reduced risk of severe PPH (adjusted OR 0.53, 95% CI 0.43–0.67). These data confirm that early treatment reduces the risk of severe PPH, and suggest that epidural analgesia may promote better patient tolerance of pelvic examination and/or early obstetric intervention during the early stage of bleeding. During the early phase of PPH, predicting which patients will respond to first-line treatment (such as uterotonic therapy, uterine massage) and which patients will require more invasive therapeutic intervention (such as interventional radiologic procedures, more surgical intervention) is often challenging. As a result, establishing clinical prediction models to identify patients at risk of invasive surgical or medical intervention for severe PPH has important obstetric and anesthetic value. Using separate patient cohorts for deriving and validating a prediction model, Gayat el al. identified five independent predictors for an advanced intervention for patients with severe PPH: abnormal placentation, prolonged INR >1.64, fibrinogen level <2 g/L, a detectable troponin level, and a maternal heart rate >115 beats/ min.27 The model for severe PPH had moderately good predictive performance (AUROC 0.8). Unfortunately, predictive factors were not assessed in non- or poorlyresuscitated patients during the early stages of severe PPH. In low-risk women undergoing elective cesarean delivery under spinal anesthesia, recent work indicates that only modest changes occur in the maternal coagulation profile during the perioperative period and that weak associations exist between thromboelastographic parameters and total estimates of blood loss.28 In contrast, the maternal coagulation profile can be more dramatically altered during the course of severe obstetric hemorrhage. There has been particular interest in the changes that occur in maternal fibrinogen levels during severe PPH. A landmark paper by Charbit et al. reported that, during the early stage of postpartum bleeding in 128 women, a fibrinogen level of <2 g/dL was a strong predictor for the development of severe PPH (positive predictive value 100%, 95% CI 71–100%).29 These findings have been supported by Cortet et al. in a secondary analysis of women with PPH post-vaginal delivery from the Pithagore6 study.30 After adjustment, the maternal fibrinogen level was independently associated with severe PPH: adjusted OR 1.9, 95% CI 1.16– 3.09 for fibrinogen levels between 2-3 g/dL, and 11.99, 95% CI 2.56–56.06 for fibrinogen levels <2 g/dL. A retrospective study also reported a significant negative association between the total estimated blood loss and

A.J. Butwick nadir fibrinogen levels in a cohort of 456 women experiencing severe PPH (r 0.48, P <0.01).31 This growing body of evidence supports the need for repeated measurements of maternal fibrinogen levels during the acute period of PPH. Future research will elucidate whether the early fibrinogen replacement for hypofibrinogenemia during the early stage of postpartum bleeding has value as a clinical measure for reducing the risk of severe PPH.32

Uterine atony For women undergoing cesarean delivery, research investigating optimal uterotonic regimens in the immediate postpartum period for preventing or treating uterine atony has an important bearing on maintaining quality standards for obstetric anesthesia practice.33–35 Although the use of oxytocin for initiating adequate uterine tone in women undergoing cesarean delivery has become standard practice, there have been surprisingly limited data assessing the value of an oxytocin infusion for maintaining adequate uterine tone. Sheehan et al. performed a multicenter randomized controlled study to assess the clinical impact of an oxytocin maintenance infusion (40 U over 4 h) vs. placebo infusion in 2069 healthy women undergoing elective cesarean delivery.36 Of note, all women received an oxytocin 5 U bolus after delivery as part of the study protocol. Similar proportions of patients in each study group experienced major obstetric hemorrhage (bolus and infusion 15.7% vs. bolus only 16%, P = 0.86). In contrast, women receiving an oxytocin bolus and infusion were less likely to receive an additional uterotonic agent compared to the bolus only group (12.2% vs. 18.4%, P <0.001). These data suggest that a prophylactic oxytocin infusion reduces the risk of patient exposure to rescue uterotonic agents for treating uterine atony during elective cesarean delivery. Carbetocin is a new, non FDA-approved, synthetic analog of oxytocin, and has been attracting interest as a possible alternative to oxytocin for prophylaxis against uterine atony due to its longer duration of action (40 min vs. 10–15 min, respectively).37 Carbetocin 100 lg has been shown to reduce the need for additional uterotonic therapy compared to oxytocin in women undergoing cesarean delivery.38–40 However, differences in the maternal hemodynamic profile in response to oxytocin vs. carbetocin are less clear. Moertl et al. performed a randomized trial to compare the hemodynamic effects of a bolus of oxytocin 5 U versus carbetocin 100 lg in 56 women undergoing elective cesarean delivery.41 Similar hemodynamic perturbance was observed in each study group (maximal increase in maternal heart rate 18 beats/min vs. 14 beats/min, and maximal decrease in systolic blood pressure 27 mmHg vs. 23 mmHg with oxytocin vs. carbetocin, respectively). Peak effects were observed for both drugs at 30–40 s after dosing. A variable but notable incidence of hypotension (21%–69%)

351 has been reported in other studies of carbetocin with doses ranging from 80–120 lg.42,43 Further studies assessing the minimal effective dose of carbetocin based on hemodynamic and uterotonic effects are warranted.

Intrapartum fetal monitoring The use of electronic fetal monitoring (EFM) is commonplace on labor and delivery units. Based on birth data from 2002, approximately 3.4 million fetuses (85% of approximately 4 million live births) in the US were assessed with EFM.44 However, a meta-analysis of 12 trials comparing EFM to fetal heart auscultation produced disappointing findings, and failed to show a reduced rate of perinatal death rates (RR 0.85, 95% CI 0.59–1.23) or cerebral palsy (RR 1.74, 95% CI 0.97– 3.11) with EFM.45 Only two trials in this meta-analysis were deemed to be high-quality, therefore there has been a need for robust, population-wide studies to assess the benefits of EFM. Chen et al. utilized US 2004 linked birth and infant death data from the National Center for Health Statistics to examine the association between EFM and early neonatal morbidity and mortality among a study cohort of 1.7 million singleton live births.46 The results appear to support the use of EFM in labor, as EFM was associated with significant decreases in the risk of early neonatal mortality (adjusted RR 0.5, 95% CI 0.44–0.57), infant mortality (adjusted RR 0.75, 95% CI 0.69–0.81), a reduced 5-min Apgar score <4 (adjusted RR 0.54, 95% CI 0.49–0.59), and neonatal seizures in high-risk pregnancies (adjusted RR 0.65, 95% CI 0.46–0.94). Unsurprisingly, the risks of an operative delivery (adjusted RR 1.39, 95% CI 1.34–1.42) or cesarean delivery for fetal distress (adjusted RR 1.81, 95% CI 1.74–1.88) were higher in the EFM group compared to the no EFM group. In order to reduce rates of emergency cesarean delivery, clinical measures to facilitate timely intrauterine resuscitation for the clinical management of acute fetal heart rate abnormalities need to be considered. In 2009, ACOG updated guidelines for fetal heart rate terminology and interpretation which incorporated a three-tier classification system.47 However, a study of inter-observer reliability among maternal–fetal medicine physicians for category I and II fetal traces was moderate (kappa = 0.45) and poor for category III traces (kappa = 0).48 Validation of this classification system is warranted, and a three-tier system may be insufficient in determining the fetal risk of adverse neonatal outcomes.49,50

Progress in labor Biexponential mathematical modeling is a sophisticated methodological approach to examine the influence of

352 demographic and clinical factors associated with progress in labor.51 More recently, this approach has been used to examine whether specific polymorphisms in the b2-adrenergic receptor (codons 16 (p.Arg16Gly) and 27 (p.Gln27Glu)) could influence the course of labor.52 Based on cervical dilatation in 103 nulliparous patients, patients expressing the CC allele at position 27 on the b2 adrenoceptor gene (b2AR27) transitioned from latent to active labor at 3.92 cm (95% CI 2.95–4.5 cm) vs. 2.73 cm (95% CI 1.85–3.60 cm) for patients with CG or GG alleles at this gene. In a separate model, Asian ethnicity also predicted slower labor progress, therefore the CC allele at b2AR27, which is common in Asian women, may explain this ethnic disparity in labor progress. Increased weight and African-American women experienced slower latent labor, and neuraxial analgesia was also associated with slower labor progress. In a separate study, linear associations between labor progress and b2AR genotype in 401 patients undergoing vaginal delivery were assessed.53 Patients with Arg/Arg16 homozygosity had significantly slower rates of labor progress than other genotypes (Arg/ Gly16 or Gly/Gly16): mean ± SD rates 0.64 ± 0.03 cm/h, vs. 0.8 ± 0.02 cm/h respectively. Using approaches incorporating linear and non-linear mixed-effects modeling, we will continue to gain a greater understanding of the interplay between intrapartum, genotypic and anesthetic factors on labor progress and perinatal outcomes.

Advances in obstetric neuraxial analgesia and anesthesia Pregnancy and local anesthetic potency Important potency differences for neuraxial local anesthetics may exist between pregnant women, non-pregnant women and men for intrathecal bupivacaine. Recent work indicates that pregnant women are more susceptible to motor block than non-pregnant women. Zhan et al. reported that the ED50 of intrathecal bupivacaine for motor block was higher in non-pregnant women undergoing gynecologic surgery compared to pregnant women undergoing elective cesarean delivery: 4.51 mg (95% CI 4.27–4.76) vs. 3.96 mg (95% CI 3.83–4.08), respectively; potency ratio 1.14.54 In a similar study by Camorcia et al., the ED50 for motor block with intrathecal bupivacaine was significantly different for men (6.9 mg, 95% CI 5.2–8.6 mg), non-pregnant women undergoing orthopedic surgery (5.2 mg, 95% CI 4.5–5.8 mg), and pregnant women undergoing elective cesarean delivery (3.4 mg, 95% CI 2.9–4.0 mg).55 As we gain more knowledge in this field, it is likely that a more tailored approach for the dose selection of neuraxial local anesthetics will be necessary to account for the differential effects of both sex and pregnancy on local anesthetic pharmacokinetics and pharmacodynamics.

What’s new in obstetric anesthesia?

Neuraxial labor analgesia The use of programmed intermittent epidural bolus (PIEB) regimens for the maintenance of labor epidural analgesia has continued to attract interest, yet optimal PIEB settings on electronic epidural infusion devices, notably the epidural bolus volume and intermittent dosing interval, remain unclear. Wong et al. compared three different PIEB regimens among 190 nulliparous patients receiving combined spinal-epidural labor analgesia: 2.5 mL every 15 min (2.5/15); 5 mL every 30 min (5/ 30); and 10 mL every 60 min (10/60).56 The epidural solution used to provide maintenance of labor analgesia was 0.0625% bupivacaine with fentanyl 1.95 lg/mL. The adjusted bupivacaine consumption per hour was decreased in patients receiving the ‘highest volume-longest bolus interval’ regimen (10/60) compared to the groups receiving smaller volumes and longer intervals (5/30 and 2.5/15): median [interquartile range] 8.8 mg [8.0–9.7] vs. 10 mg [9.3–10.8] and 10.4 mg [9.6–11.2], respectively (P = 0.005). However, these small differences in bupivacaine consumption between groups did not result in clinically relevant or statistically significant between-group differences in actual and derived measures of analgesic quality, which included: number of patient-controlled epidural analgesia requests, number of manual bolus doses, cumulative fentanyl doses and area under the pain score versus time curves. For patients receiving neuraxial labor analgesia, minimizing motor block is important for optimizing satisfaction and ambulation, and for decreasing the risk of instrumental delivery. However, previous studies of labor epidural PIEB regimens have not assessed maternal motor function as a primary outcome measure. Capogna et al. performed a randomized controlled study in 145 nulliparous patients in early labor (cervical dilatation <4 cm) to assess maternal motor block comparing continuous epidural analgesia (CEA) at an infusion rate of 10 mL/h vs. a PIEB regimen using a 10 mL bolus/h.57 Both regimens used 0.0625% levobupivacaine with sufentanil 0.5 lg/mL with patient-controlled epidural analgesia. Motor block and instrumental delivery were less common with PIEB compared to CEA (2.7% vs. 37%, P <0.001 and 7% vs. 20%, P = 0.03, respectively). In this study, the rate of instrumental delivery in the CEA group was higher than expected, which is in contrast to data published from a recent meta-analysis that reported an instrumental rate of 12.7% among nulliparous patients receiving epidural analgesia in early labor.58 Research incorporating important obstetric and intrapartum confounders is needed to formally assess the strength of association between PIEB and CEA with instrumental delivery. With the introduction of epidural pumps with PIEB programming functionality into clinical practice, further investigations are needed to assess analgesic efficacy and delivery outcomes associated with these state-of-the-art epidural labor analgesia regimens.

A.J. Butwick

Radiologic and ultrasonographic studies Previous research using magnetic resonance imaging (MRI) found that introduction of saline into the epidural space is known to reduce the pre-injection lumbosacral cerebrospinal fluid (CSF) volume, with CSF volume reductions dependent on epidural injection volume.59 In addition, for patients receiving spinal anesthesia, an inverse correlation has been reported between lumbosacral CSF volume and peak sensory block level.60 However, these studies were investigated in non-pregnant patients, and the effect of epidural saline on anatomic changes in epidural and CSF volumes in pregnant women has been somewhat uncertain. Using MRI, Higuchi et al. compared the effect of epidural saline 10 mL on neuraxial anatomy in pregnant and non-pregnant women.61 In pregnant women, epidural saline resulted in a greater reduction in CSF volume, less leakage from intervertebral foraminae and less coating of the dural sac than in non-pregnant patients, which may be due to inward pressure from the retroperitoneal area in pregnant patients. Based on these findings, one would expect that pregnant patients receiving spinal anesthesia incur more cephalad spread after expansion of the epidural space with saline (using combined spinal–epidural anesthesia) or local anesthesia (after a failed epidural top-up). However, a recent randomized controlled trial by Loubert et al. investigating the effect of epidural volume extension on the spread of intrathecal bupivacaine in patients undergoing combined spinal-epidural anesthesia for cesarean delivery did not support this assumption.62 In this study, patients who received a combined spinal–epidural anesthetic (comprising hyperbaric spinal bupivacaine 7.5 mg + epidural volume extension with saline 5 mL) had similar sensory block heights to patients receiving combined spinal–epidural anesthesia with either 7.5 mg or 10 mg hyperbaric spinal bupivacaine without epidural volume extension.62 Greater epidural expansion from larger volumes of epidurally-administered local anesthetic is more likely in patients receiving epidural top-ups for intrapartum cesarean delivery compared to patients receiving a combined spinal–epidural technique with loss-of-resistance to saline. As a consequence, patients who experience a failed epidural top-up for cesarean delivery may be at greater risk of developing a high spinal with standard doses of intrathecal local anesthetic.63 More studies are needed to investigate the volume-dependent and time-dependent effects of epidural volume expansion of local anesthesia agents injected into the intrathecal space, including sensory block heights and anesthesia onset times. Two ultrasound studies published in 2011 have provided important data to confirm that clinical assessment of the intercristal line – the imaginary line that connects the superior aspects of the iliac crests – is not analogous to demarcation with ultrasonography landmarks or the L4–5 interspace, which is traditionally thought to cross

353 the intercristal line.64,65 Lee et al. observed that clinicians’ estimates of the intercristal line were in general higher than the ultrasound measurement (1 level higher 23% of the time and >1 level higher 25% of the time), with clinicians’ estimates of the spinal level for the intercristal line agreeing with ultrasound measurement in only 23% of all assessments.64 Margarido et al. confirmed that the intercristal line determined by palpation in 45 patients was higher than the L4–5 interspace (confirmed by ultrasound) in 100% of all assessments.65 Of note, clinical assessments were performed by experienced anesthesiologists in both studies. Although ultrasonographic examination of the lumbar spine is not currently recommended by national societies as a standard of care technique before neuraxial block, only time will tell if consensus guidelines will be revised to encourage the use of this technology as part of standard obstetric anesthetic practice to reduce the risk, albeit small, of neurologic injury due to neuraxial blockade.66,67

Epidural-associated fever and maternal/perinatal morbidity The etiology and mechanisms that result in maternal fever in patients receiving labor epidural analgesia remain uncertain. One theory that has gained interest among researchers is that maternal fever results from a noninfectious inflammatory process, evidenced by increases in maternal cytokine levels, and that labor epidural analgesia either initiates or exacerbates this maternal temperature rise.68–70 To substantiate this putative association, Riley et al. compared rates of placental infection (using placental cultures and polymerase chain reaction analysis) and the maternal inflammatory response in women receiving epidural labor analgesia vs. no epidural analgesia.71 Intrapartum fever was more common in women receiving epidural labor analgesia compared to no epidural (22.7% vs. 5%, P = 0.009). The risk of epidural-associated fever was higher in patients with elevated IL-6 levels (>11 pg/mL) at admission compared to women with non-elevated IL-6 levels (RR 2.3, 95% CI 1.2–4.4). However, similar rates of placental infection were observed in both groups (4.7% vs. 4%, respectively, P >0.99). These data support a non-infectious inflammatory theory for explaining epidural-associated maternal fever, and suggests that epidural analgesia may result in maternal fever among women with an ‘activated’ immune system. In contrast, a recent prospective study by Frolich et al. suggest that non-anesthetic factors (body mass index and time from rupture of membranes to delivery) influence positive maternal temperature change in labor, and did not observe an epidural effect on the rate of change in maternal temperature during labor.72 Epidural-associated maternal pyrexia may also negatively impact on neonatal outcomes, and it is possible that intrauterine inflammation may be an etiologic factor. In a retrospective study of 3209 low-risk nulliparous

354 women, Greenwell et al. observed that maternal pyrexia was associated with a number of clinically relevant adverse neonatal outcomes.73 Compared to women with a maximal intrapartum temperature of 37.5°C, women with the highest maximal intrapartum temperatures (>38°C) were at significantly increased risk of prolonged neonatal hypotonia >15 min (adjusted OR 3.1), assisted ventilation (adjusted OR 2.1), 5-min Apgar <7 (adjusted OR 4.8), and early onset neonatal seizures (adjusted OR 6.5). Recent evidence also indicates that epidural labor analgesia may be associated with an increased risk of intrauterine inflammation, including: histologic chorioamnionitis and funisitis,71,74 however, intrauterine inflammation has been found to be more strongly associated with several obstetric factors, including nulliparity and the duration of labor.74 Although the results of these studies are associative as opposed to causative, these findings are particularly concerning as there is mounting evidence from animal models that intrauterine inflammation leads to neonatal neurologic injury. In a study using term mice, intrauterine inflammation induced with lipopolysaccharide resulted in neuronal injury with delayed neurotoxicity coupled with fetal brain inflammation.75 A similar study in term and pre-term mice found that fetal neuronal injury can occur in the absence of maternal inflammation, suggesting that subclinical placental inflammation is a key factor inducing a fetal immune response and subsequent injury to the fetal brain.76 Prospective studies are needed to fully assess whether intrapartum and perinatal factors influence or nullify the association between labor epidural analgesia and maternal pyrexia. In addition, robust mechanistic research is warranted to assess whether epidural labor analgesia specifically induces intrauterine inflammation sufficient to impair fetal neurodevelopment.77,78

Postdural puncture headache An epidural blood patch is recognized as the gold standard treatment for obstetric patients who develop a postdural puncture headache (PDPH) after unintentional dural puncture with an epidural needle.79 Unfortunately, the optimal volume of blood for the successful treatment of PDPH has remained uncertain, which has led to considerable variation in clinical practice in terms of the volume of blood injected for a therapeutic blood patch.80 Paech et al. performed a multicenter randomized controlled study to compare the therapeutic effect of three different volumes (15 mL, 20 mL, 30 mL) of autologous blood for an epidural blood patch in 121 women diagnosed with an unintentional PDPH.81 In this study, the incidence of partial or complete headache relief was similar among all study groups (61%, 73% and 67% respectively). Headache relief, assessed by postpatch headache pain scores, was worse after an epidural blood patch with 15 mL compared to either 20 mL or

What’s new in obstetric anesthesia? 30 mL of autologous blood. However, the rate of periprocedural back pain increased with increasing volumes of autologous blood, which likely resulted in a reduced number of patients receiving the allocated volume in the 20 mL and 30 mL groups (81% and 54%) compared to the 15 mL group (98%). Based on these findings, 20 mL of blood is reasoned to be the target volume to be injected for an epidural blood patch. However, the medium and long-term effects of epidural blood patch on symptom resolution, headache recurrence and patient satisfaction needs further evaluation.

Conclusion This review highlights important published research which impacts on the interdisciplinary care of lowand high-risk obstetric patients during the antepartum, peripartum and postpartum periods. Preventive strategies and therapeutic interventions continue to attract interest as key mechanisms for reducing the rate and severity of adverse maternal and perinatal outcomes. Furthermore, important new information on neuraxial labor analgesia and anesthesia for cesarean delivery will hopefully lead to quality improvements in obstetric anesthesia practice and the intrapartum management of the laboring patient. The author of this review applauds all investigators that have published important research in 2011 related to the science and clinical practice of obstetric anesthesia.

Acknowledgements The author wishes to thank the Society for Obstetric Anesthesia and Perinatology for being invited to present the Gerard W. Ostheimer Lecture in 2011. The author would also like to sincerely thank all members of the Division of Obstetric Anesthesia at Stanford University School of Medicine, and Dr. Paloma Toledo, Dr. Jill Mhyre, Dr. Lawrence Tsen, Dr. Roshan Fernando and Ms. Stephanie Hsi for their support and input. The author also wishes to express his gratitude to Ms. Lindsey Hayford and other members of his family for their unprecedented support and motivation during the periods of literature review, lecture preparation, and manuscript writing.

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