Journal Reading

Cardiovascular Alterations in the Parturient Undergoing Cesarean Delivery With Neuraxial Anesthesia
Pembimbing

Dr. M. Gusno Rekozar, Sp An Oleh Andre Ferryandri S 030. 08. 025

Kepanitraan Klinik Anestesi Rumah Sakit Otorita Batam Periode 18 Juni 21 Juli 2012 Fakultas Kedokteran Universitas Trisakti

LEMBAR PENGESAHAN
Journal Reading Ilmu Anestesi dengan judul :

Cardiovascular Alterations in the Parturient Undergoing Cesarean Delivery With Neuraxial Anesthesia

Nama NIM

: :

Andre Ferryandri S 030. 08. 025

Telah diterima dan disetujui oleh pembimbing Dr. M. Gusno Rekozar, Sp.An pada :

Hari Tanggal

: :

Sebagai salah satu syarat dalam mengikuti dan menyelesaikan Kepaniteraan Klinik Ilmu Anestesi Di Rumah Sakit Otorita Batam

Batam, Juli 2012

.. Dr. M. Gusno Rekozar, Sp.An

Cardiovascular Alterations in the Parturient Undergoing Cesarean Delivery With Neuraxial Anesthesia
Abstract and Introduction
Abstract
Sewaktu melahirkan melalui sectio caesaria dengan anestesi neuroaxial, hemodinamik si ibu berubah akibat pemberian cairan intravena, onset masa blok, dan sewaktu kelahiran bayi. Derajat perubahan hemodinamik ini dipengaruhi oleh beberapa faktor yang saling berinteraksi, seperti perubahan anatomi dan fisiologi saat kehamilan, faktor ibu, dan faktor janin. Selain itu, faktor comorbid, teknik neuroaksial, banyaknya kehilangan darah dan cairan, serta tatalaksana pengobatan juga berpengaruh. Saat ini faktor-faktor yang mempengaruhi hemodinamik, teknik anestesia, cara mencegah dan mengatasi hipotensi,akan dibahas untuk melihat perubahan kardiovaskuler pada saat partus melalui sectio caesaria dengan anestesia neuroaxial.

Introduction
Rasio partus melalui sectio caesaria telah meningkat dari 4,5 % (1965) mejadi 32,3 % di tahun 2008..[1] di banyak negara berkembang, penggunaan anestesi neuroaxial (epidural, spinal maupun kombinasi keduanya) sangat banyak digunakan. Karakter ibu dan janin, fator comorbid, perubahan anatomi dan fisiologi saat kehamilan, tatalaksana obat dan cairan, serta dampak dari pembedahan dan anestesi akan berpengaruh besar terhadap respons kardiovaskular. Derajat perubahan saat kehamilan dan partus sectio akan diuji. Dengan pengetahuan di ilmu kedokteran, kita akan mengevaluasi perubahan kardiovaskular, termasuk partus dengan preeklampsia ataupun kehamilan multifetal. Akhirnya, metode untuk mencegah dan mengatasi hipotensi akibat teknik spinal akan dibahas.

Cardiovascular Changes During Pregnancy

Pregnancy is associated with a 20% decrease in systemic vascular resistance (SVR), [6] which likely triggers the reninangiotensinaldosterone system to retain sodium and increase plasma volume. This increase in plasma volume exceeds a simultaneous increase in red blood cell mass, resulting in a lower hemoglobin level than in the nonpregnant state.[7] Plasma volume increases 50% over prepregnant values by 32 weeks gestation (Table 1).[8] SVR decreases to 30% below pre-pregnancy values by 20 weeks gestation; this change is reflected in a decrease in mean arterial pressure (MAP) and an increase in heart rate (HR) of 15 beats/min.[9] Overall arterial compliance increases from pregnancy onset until second trimester, then decreases from the second trimester through the remainder of the pregnancy.[10] Cardiac output (CO) increases by 30 to 60% until approximately 32 36 weeks gestation.[1115] Throughout pregnancy, pulmonary vascular resistance decreases, pulmonary blood flow increases, and pulmonary mean arterial pressures remain unchanged.[16] With supine positioning after 20 weeks gestation, the gravid uterus can compress the vena cava, reducing cardiac output, and compress the aorta proximal to the uterine artery further compromising uterine blood flow. A more in-depth review of the hemodynamic changes of pregnancy has been previously published. [17]

Hemodynamic Measurement Techniques in Pregnancy

The acquisition of hemodynamic data in the obstetric population has proven challenging. Although heart rate, heart rhythm and blood pressure can serve as imprecise indicators of cardiac output, the desire for more direct measurement has resulted in the application of a number of devices and modalities during pregnancy. Once performed for the sake of research alone, invasive hemodynamic monitoring, such as central venous,[18] pulmonary artery[19,20] and cardiac catheterization[21] in normal healthy parturients, is no longer considered acceptable. As a consequence, the studies referencing invasive hemodynamic data from a flow-directed, thermistor-tipped pulmonary artery catheter are unlikely to be repeated or directly compared with more contemporary measurement techniques. A recent editorial describes the advantages and disadvantages of the various noninvasive CO measurement techniques available.[22] With these limitations, the CO data from parturients undergoing CD with neuraxial techniques are presented (Table 2 & Table 3). In 1915, measurement of CO during pregnancy was performed utilizing a gas-based, dye-dilution technique with nitrous oxide or acetylene.[23] These measurements were believed to be inaccurate due to the wide variations (primarily increases ranging from 45 to 85%) in CO.[23] Pulmonary artery (PA) catheterization, which provided measurements based on the Fick principle, were performed during the 1940 and 1950s and provided accurate, albeit invasive, CO measurements.[21] In the 1960s, the dye dilution technique improved with the use of photometric dyes; dye concentrations are now determined by comparing a radial arterial blood sample with another measurement obtained via transillumination of the capillary bed of the ear. From these measurements, CO is calculated [13] and these measurements are considered relatively accurate. Table 2 & Table 3 illustrate CO during CD with neuraxial anesthesia including data obtained with this photometric dye dilution technique. Introduced in the 1960s, echocardiography can reliably calculate CO, although the results are based on, and therefore may be affected by, a number of assumptions. Stroke volume (SV) can be calculated by 2D and 3D echocardiography (2DE and 3DE) or by Doppler methodology. Several modalities exist to determine SV with 2DE. The area/length method assumes that the left ventricle (LV) is a cylindrical structure. LV volume is then calculated in systole and diastole by measuring the area (cm2) and the longitude (cm) of the cylinder. The obtained SV is then multiplied by the recorded HR to calculate the CO. Because pregnancy is associated with dilation of the LV, assumptions regarding the shape of the LV may be inaccurate and 2DE CO calculations may overestimate SV in late pregnancy.[24] A more robust 2DE modality is the 'method of disks', in which 20 'disk-shaped' measurements from the four- and two-chamber views of the left ventricle in systole and diastole are obtained and added together. An additional method for SV and CO calculation is based on the Doppler principle. It also assumes the 'cylinder' hypothesis; in this case the cylinder is the left ventricular outflow tract (LVOT). This method involves measuring the cross-sectional area of the LVOT (cm2) and the distance traveled by the blood during a heart beat (cm), and is obtained by measuring the velocity of systolic blood flow in the LVOT (cm). The ideal signal must be obtained to provide accurate measurement and is thus operator-dependent. SV is then calculated as a function of velocity over time, and multiplied by the recorded HR to calculate the CO. Measurements with this technique have been compared with the gold standard of pulmonary artery catheter thermodilution and have been validated in the pregnant state.[25] The data displayed in Table 2 & Table 3 that were obtained with this technique are considered quite accurate. Newer 3DE modalities are rapidly replacing 2DE in research and clinical applications for their superior accuracy and reproducibility.[2633] Furthermore, 3DE can mitigate the errors inherent to 2DE by eliminating foreshortening and avoiding geometric assumptions. An additional advantage of 3DE is that it is not reliant on correct image orientation at acquisition and the associated geometric

assumptions. The risk of foreshortening the right ventricle can be reduced, [30] which may be of particular benefit to the parturient with congenital heart disease or whose right ventricle is strained secondary to increased CO or increased pulmonary vascular resistance. [31] 3DE speckle tracking algorithms, which track the motion of speckles within the scan volume, further improve the visual geometric border detection of the ventricle, an inherent limitation in determining the shape and size of the ventricle.[34] This modality shows good intra- and inter-observer reliability, as well as testretest reliability for routine evaluation of ejection fraction and left ventricular volumes. [29] 3DE direct volumetric and speckle-tracking methods appear to provide comparable and reproducible results of ventricular volume and function, and are both feasible options for routine clinical practice. [32,33] In 1966, impedance cardiography was introduced in which changes in the electrical impedance across the thorax or whole body throughout the cardiac cycle were analyzed; from these measurements, CO is calculated. However, CO obtained by impedance cardiography correlates poorly with thermodilution measurements during CD[20] and during pregnancy in the presence of hypertensive diseases.[35] The overall accuracy of this technique in healthy term pregnancies has therefore been questioned.[36] Despite this, the method may be valuable for producing noninvasive, continuous data to detect CO trends.[37,38] Consequently, in Table 2 & Table 3, the data obtained through this technique[39,40] may not be as accurate as those obtained through other techniques. Modern devices have been developed that continuously measure CO using information derived from an arterial line such as the FloTrac (Flo Trac/Vigileo, Edwards Lifesciences, CA, USA), PiCCO (Pulsion Medical Systems AG, Munich, Germany) and LiDCO (PulseCO system, LiDCO Ltd, Cambridge, UK). The LiDCO device can be used with a peripheral venous and a radial arterial line and has the advantage of measuring beat-to-beat CO measurements, making it an excellent tool for measuring trends. A study employing bioimpedance and LiDCO measurements in the same patient found similar trends in changes in CO in response to spinal anesthesia and vasopressor administration.[41] A recent study also found acceptable agreement between thermodilution and LiDCO measurement immediately postpartum in pre-eclamptic patients.[42] Although studies have been performed that evaluate the clinical application of these devices, [43] further validation in pregnancy is necessary.

Hemodynamic Changes During Cesarean Delivery With Neuraxial Anesthesia

Hemodynamic changes during CD with neuraxial anesthesia occur during prehydration, block onset and birth. The greatest hemodynamic changes occur with block onset, which can lead to maternal hypotension, decreased uterine blood flow, maternal nausea and vomiting and, potentially, fetal compromise. Studies documenting the changes that occur with prehydration, block onset and birth are generally not designed to show statistical significance between events and, consequently, only selected values and trends can be discussed. Furthermore, there are a myriad of confounding factors including patient positioning, vasopressor administration, and local anesthetic solutions containing epinephrine that make these data difficult to analyze.
Prehydration/Cohydration
Hydration prior to neuraxial placement ('prehydration') or at the time of neuraxial block administration ('co-loading') is performed to correct hypovolemia and prevent hypotension after the initiation of neuraxial anesthesia.[44,45] The type of fluid (colloid vs crystalloid), the overall volume administered, the timing in relation to neuraxial blockade and the speed at which it is delivered all affect the efficacy of hydration in preventing hypotension. Neither prehydration nor co-loading can reliably prevent hypotension following neuraxial blockade,[4649]although other benefits may be realized; an increase in

maximal uterine artery blood flow has been observed with prehydration despite the absence of maternal MAP increases.[50] It has been suggested that the prevention of neuraxial anesthesia-induced hypotension is dependent on a fluid bolus sufficient enough to significantly increase intravascular volume, and subsequently CO.[51] Rapid administration of fluid in term parturients prior to neuraxial techniques does increase CO; however, the response is dependent on alterations in HR and SV that are quite variable. One study demonstrated that the administration of 1 l of lactated Ringers (LR) solution 15 min prior to neuraxial anesthesia increased CO by 20% (from 6.50 to 7.83 l/min), with the HR increasing from 77.6 to 81.9 bpm and the SV increasing from 84.2 to 95.4 ml.[52] A second study, using LR solution in a mean volume of 805 ml as prehydration, observed a 10% increase in CO (from 7.01 to 7.70 l/min) with a relatively stable HR (8382 bpm) but a significant increase in SV from 84 to 95 ml.[53] A similar study using 1 l of LR as prehydration resulted in an 11% increase in CO (5.25.8 l/min), an unchanged HR and a significant increase in SV from 63.3 to 70.5 ml.[54] A final study using 10 ml/kg of 6% hydroxyethyl starch (HES) as prehydration noted an increase in CO (cardiac index increasing 12% from 3.2 to 3.6 l/min/m2) and HR (7489 bpm), but a decreasing stroke index from 42.2 to 40.2 ml/m2.[40] Summarizing these studies, an increase in CO is observed with prehydration; however, the relative contributions of HR and SV are variable. The magnitude of CO increase is related to the fluid type, as well as the amount of hydration. Furthermore, the amount of fluid that remains intravascular may be associated with the incidence of hypotension. In a study comparing 1.5 l LR to 0.5 l HES to 1 l HES as prehydration prior to neuraxial blockade for CD, Ueyama and colleagues demonstrated that the amount of prehydration that remains intravascular (as measured by indocyanine green blood concentration monitored though noninvasive pulse spectrophotometry) is significantly correlated to the increase in CO; moreover, the incidence of hypotension was reduced in the group with the greatest increase in CO. [51] The authors demonstrated that in the 1.5 l LR, 0.5 l HES and 1.0 l HES groups, the volume of infused solution remaining in the intravascular space was 0.43 0.20 l, 0.54 0.14 l and 1.03 0.21 l, respectively; and the increase in CO was 11% (from 5.4 1.0 to 6.0 1.0 l/min), 15% (from 5.4 1.0 to 6.2 0.6 l/min) and 43% (from 5.1 1.0 to 7.3 1.1 l/min), respectively. The percentage of blood volume increase significantly correlated to the increase in CO (r2 = 0.838; p < 0.001). The incidence of hypotension after spinal anesthesia was 75% in the 1.5 l LR group, 58% for the 0.5 l HES group and only 17% for the 1.0 l HES group. In summary, 1.0 l of HES preload increased the intravascular volume and CO significantly more effectively than 1.5 l LR or 0.5 l HES; the incidence of 1 h post spinal hypotension was also reduced in this group. Overall, colloid solutions have been found to be more effective than crystalloid solutions in prehydration to prevent hypotension,[55] especially when at least 1 l of HES is used.[51] However, the use of colloid solutions prior to uterine evacuation and subsequent autotransfusion has been questioned by some, with the risk of potential pulmonary edema, allergies to colloidal solutions and the costs of the solutions cited.[56] Interestingly, recent studies have demonstrated that initiating a rapid infusion of crystalloid at the time of neuraxial blockade administration (i.e., 'co-loading') is as effective as prehydration with crystalloid in preventing hypotension; [45,57]however, when colloid is used as a coload versus for prehydration, there are no differences in the incidence of hypotension or vasoactive medications use.[48,58] Therefore, crystalloid solutions are more beneficial in preventing hypotension when used as a co-load instead of as prehydration, whereas colloid solutions can be as beneficial when used in either of these time frames. As a result of these studies, the use of a rapid co-load of crystalloid solution through a moderately large intravenous line during performance of a neuraxial technique for CD is a viable option.

Neuraxial Anesthesia Onset: Spinal

Spinal anesthesia is the most common anesthetic employed for elective CD. It provides a rapid, symmetrical, dense motor and sensory block, and allows the parturient to be awake for the birth of her baby. However, the hemodynamic changes that occur with the induction of spinal anesthesia are common and often profound.

Contribution of Arterial & Venous Peripheral Resistance

When spinal anesthesia is administered for CD, a rapid onset block of the lumbosacral and thoracic dermatomes occurs. The resulting preganglionic sympathetic blockade of the thoracic spine likely leads to relatively unopposed parasympathetic tone in the vasculature and, as a result, arterial and venous dilation. In general, it is thought that the level of the sympathectomy extends two to six dermatomal levels above the sensory block when measured by skin temperature changes.[59] Some experts have held that the hemodynamic effects of this relative sympathectomy on venodilation supersedes that of arterial dilation, because 75% of the body's blood is contained within the venous system and the arteries maintain greater autonomous tone.[60] As a consequence, overcoming the loss in preload has historically been an important strategy in maintaining CO when treating post-spinal hypotension. However, the observation that neither prehydration nor co-loading can reliably prevent hypotension following neuraxial blockade[4649] underscores that the role of venodilation may have been historically overemphasized. Furthermore, it has been suggested that if CO is maintained, total peripheral resistance should decrease by only 15 18% in normovolemic healthy patients, even with a relative sympathectomy.[60] However, data from parturients undergoing spinal anesthesia for CD have demonstrated a decrease (from baseline) in SVR in the range of 2631%,[40,52,61] begging the question of whether arterial vasodilation plays a greater role than previously anticipated. Finally, more recent studies specifically looking at the arterial circulation[41,62,63] have led experts to believe that it is possible that the role of preload in spinal hypotension has been overemphasized, [64] and "in the fluid replete parturient undergoing elective cesarean delivery, moderate spinal hypotension (20% decrease from baseline) primarily reflects decreased systemic vascular resistance". [65]

Contribution of Cardiac Output Variability

There is a wide variation in CO alterations when the spinal block is being established (Table 2). Using a dye dilution technique, Ueland et al. demonstrated a 35% decrease in CO when a spinal anesthetic was performed (tetracaine 710 mg with epinephrine 200 mcg) without prehydration, and the pregnant patient placed in the supine position.[66] By contrast, utilizing the beat-to-beat CO measurements provided by bioimpedance, Tihtonenet al. observed an immediate 11% increase in CO when 10 ml/kg colloid prehydration was given, hyperbaric bupivacaine 12 13.5 mg was administered, the patient was positioned in left uterine displacement, and a mean ephedrine dose of 0.53 mg/kg was provided.[40] The prehydration, left uterine displacement and ephedrine used in the latter study could have resulted in the CO differences observed. However, other studies utilizing both bioimpedance and LiDCO measurement techniques have confirmed this immediate increase in CO observed after induction of spinal anesthesia, even when phenylephrine, and not ephedrine, is administered.[41,63] Other factors that affect CO include, but are not limited to, prehydration, maternal positioning during and after the block, height and density of the block, presence of hypertensive disorders of pregnancy, gestational age, the number of gestations, the presence of labor, the prophylactic or therapeutic use of vasoactive substances, and the complex system of vascular tone and reactivity unique to each individual woman. Direct and indirect cardiac output measurements are infrequently performed during a typical cesarean delivery. Instead, fetal heart rate activity is often correlated to a range of noninvasive blood pressure measurements to give an indication of the adequacy of uteroplacental blood flow. Following the

removal of fetal heart rate monitors for skin sterilization of the abdomen, systolic blood pressure (SBP) is typically maintained within 20% of baseline values, or above a SBP of 100 mmHg (a common research definition of hypotension). Hypotension is typically poorly tolerated in parturients, often resulting in nausea, vomiting and lightheadedness. Spinal-induced hypotension in parturients undergoing CD is frequent, with reported incidences ranging from 17 to 95%.[51,67] The associated maternal and fetal morbidity and mortality associated with hypotension have investigators seeking clinically feasible and reliable ways to predict which parturients are at greatest risk.[6870] Maternal HR variability as a measure of autonomic nervous system activity appears promising in predicting hypotension risk.[7174] The most effective strategies for prevention of spinal-induced hypotension include prehydration with a sufficient amount of colloid[51] or co-loading with sufficient crystalloid,[45] positioning the parturient for surgery in the left uterine displacement position,[75] using a lower dose of intrathecal bupivacaine,[63,76 78] and administering prophylactic vasoactive agents such as ephedrine or phenylephrine. [63,79,80] Each of these strategies will be reviewed, with their relative efficacy summarized (Box 1).

Contribution of Block Height

One factor affecting hemodynamic changes at the onset of spinal anesthesia is block height. Typically, the higher the thoracic level of intrathecal block, the greater the hemodynamic effect. [81] The height of a spinal block is associated with the dose and baricity of the local anesthetic. Doses of bupivacaine ranging from 4.5 to 15 mg intrathecal bupivacaine have been described as adequate for CD, but the higher doses have resulted in greater decreases in arterial blood pressure in both nonpregnant[82] and pregnant patients.[83] To maintain adequate blood pressure for uteroplacental blood flow, multiple studies have sought to evaluate the lowest dose of intrathecal local anesthetic that can provide adequate anesthesia for CD.[63,76,78,84,85] An excellent review of such studies has been previously published. [86] The addition of opioids allows for lesser intrathecal local anesthetic dosing, and often lesser hemodynamic effects, while still allowing for adequate anesthesia.[84] The data comparing hyperbaric to isobaric bupivacaine are confounding; for example, hyperbaric (vs isobaric) bupivacaine 6.6 mg combined with sufentanil 3.3 mcg demonstrated lesser hemodynamic effects.[87]Alternatively, a similar study showed no differences in hemodynamic changes when hyperbaric versus isobaric bupivacaine 9 mg, combined with fentanyl 20 mcg, were used.[88]

Contribution of Heart Rate

Some studies indicate limited HR changes as a result of spinal anesthesia.[40,52,61,89] However, it is not uncommon to initially see an increase in HR with induction of spinal anesthesia. [63] This is likely from preservation of the baroreceptor response and the initial dilation of vasculature associated with spinal anesthesia. Subsequently, if the sympathetic block travels high enough, HR slowing may occur with a reduction in sympathetic output from the cardioaccelerator fibers located at the T1 through T4 levels. Because achieving a T4 sensory level is frequently the goal for CD anesthesia, a sympathetic blockade of the cardioaccelerator fibers may occur. However, significant bradycardia occurs in less than 2% of all cases.[90] Because CO is the product of HR and SV, it is important to note that as HR decreases, CO may also decrease, depending on whether alterations in SV can compensate for the change. This may be especially relevant during the onset of neuraxial anesthesia because venodilation results in decreased preload and an inability to increase SV to compensate for a decreased HR. Significant bradycardia may be a cause of cardiac arrest under spinal anesthesia in otherwise healthy patients.[9193] Although these cases may result from cardioaccelerator fiber blockade, other cardiac mechanisms are more likely responsible. A sudden decrease in preload activates intrinsic cardiac

receptors such as baroreceptors in the right atrium, mechanoreceptors in the left ventricle, or receptors in cardiac pacemaker cells leading to a decrease in HR; this mechanism is supported by the observation that HR decreases in transplanted hearts after spinal anesthesia. [94] In summary, the effect of intrathecal local anesthetic on HR most often depends upon the height of the block; blocks extending to the first through fourth thoracic sympathetic spinal levels affect the cardiac acceleration fibers and potentially cause bradycardia. A study has shown that increased doses of intrathecal hyperbaric bupivacaine increase the likelihood of bradycardia.[76]

Neuraxial Anesthesia Onset: Epidural

Epidural anesthesia provides lesser hemodynamic alterations than spinal anesthesia for CD. A metaanalysis including ten trials and 751 parturients indicated that patients who received spinal, versus epidural, anesthesia for CD were more likely to require treatment for hypotension with a relative risk of 1.23 (95% CI: 1.001.51).[95] The results of this meta-analysis also demonstrated a slower onset time for epidural anesthesia, which perhaps allows compensatory mechanisms to mitigate the evolving sympathetic block. Studies examining hemodynamic changes with the induction of epidural anesthesia show decreases in SVR and MAP,[39,96]increases in HR,[39,89] decreases in SV,[39,89,96] and both minimal decreases[89,96] or increases[39,97,98] in CO. The addition of epinephrine to the local anesthetic affects maternal hemodynamics. A single study showed that the addition of 5 mcg/ml of epinephrine to bupivacaine decreased maternal diastolic pressure when measured by M-mode echocardiography.[99] Uterine blood flow and systolic pressure remained unchanged.

Neuraxial Anesthesia Onset: Combined Spinal Epidural

An alternative to a single-shot spinal or an epidural technique is a combined spinal epidural (CSE) technique. A CSE technique allows the anesthesiologist to place an initial lower dose of local anesthetic in the intrathecal space, because if the intrathecal block is inadequate, then an epidural catheter would be present to dose. Although one study found no difference in CO or the incidence of hypotension regardless of whether 5 or 10 mg intrathecal bupivacaine was administered during a CSE,[54] as discussed earlier, multiple other studies have shown that decreasing doses of intrathecal local anesthetic decreases rates and degrees of spinal hypotension.[86] A low-dose CSE technique has been described in four high-risk cardiac patients, in which an intrathecal dose of 45 mg of heavy bupivacaine, along with 2025 mcg fentanyl was administered. This was subsequently followed by the slow loading of epidural local anesthetic to achieve a T4 surgical level.[100] The purported benefits of the low-dose CSE technique include a slower-onset of the neuraxial block, which may allow the anesthesiologist to maintain preload and afterload during the onset, while still achieving the greater block reliability of intrathecal local anesthetic administration. Further investigation is needed to determine the hemodynamic benefit of such techniques.

Delivery of the Fetus

Fetal delivery is associated with dramatic hemodynamic changes. As the uterus is evacuated, aortocaval compression is relieved and an autotransfusion of uterine blood occurs as the uterine muscle involutes to a contracted state. This increase in cardiac preload typically results in an increase in CO through an increase in both HR and SV. A decrease in SVR can result in an unchanged MAP.[40,96,101] These hemodynamic alterations are believed to exist for approximately 10 min [40] prior to resolution to predelivery values. The increase in CO at the time of fetal delivery varies significantly, with a range of less than 10%,[98] to as much as 61% (from baseline) and 140% (from post-block

values).[66] The latter values were originated in a study where uterine displacement was not used, likely exaggerating the removal of uterine aortocaval compression upon delivery.

Contribution of Blood Loss

The mean blood loss during CD of a singleton fetus historically was estimated to be as high as 1 l,[102] but more recently (using a hemoglobin extraction test before and after cesarean) has been found to be approximately 440 ml with a wide range of variability (135 1000 ml).[103] Additional blood loss can result from peripartum bleeding, uterine atony or injury, or placental abnormalities. Blood loss and resuscitation can significantly affect hemodynamic values. Blood loss reduces circulating volume, most often resulting in decreased preload, stroke volume, CO and MAP. In healthy parturients, MAP may remain normal until over 1500 ml of blood are lost, making hypotension a late sign of hemorrhage.[104] When blood loss is replaced with crystalloid or colloids sufficient to maintain normovolemia, decreased blood viscosity and anemia can result in increased CO. A healthy parturient may tolerate such physiologic alterations as long as red cell mass maintains adequate oxygencarrying capacity to the tissues.

Contribution of Uterotonic Agents

Uterotonic agents administered to prevent blood loss immediately after delivery affect maternal hemodynamics. Oxytocin has a direct relaxation effect on vascular smooth muscle, causing a decrease in systolic and diastolic blood pressure related in part to the dose and rate of administration.[105] Consequently, it has been recommended that anesthesia providers administer oxytocin in smaller amounts, which have proven to be efficacious for restoring uterine tone, and not as a bolus dose.[106] A recent case series used pulse wave analysis (PulseCO system, LiDCO Ltd, Cambridge, UK) to follow MAP, SVR and CO in six cesarean deliveries.[101] Upon administration of 5 units of oxytocin, a decrease in MAP was associated with a decrease in SVR and an increase in CO, SV and HR. Interestingly, a different study showed that a second bolus of oxytocin 5 units produced hemodynamic effects as well, but to a lesser degree than the initial bolus. [107] It is possible that the sympathetic blockade of neuraxial anesthesia may exacerbate the decrease in SVR associated with oxytocin administration.[108] Methylergonovine maleate (Methergine), a sympathomimetic -agonist, causes intense venous and arterial vasoconstriction that can result in significant hemodynamic effects. As such, this agent should be used with caution in parturients with preexisting hypertension, pregnancy-induced hypertension or preeclampsia. Moreover, because such cardiovascular effects are frequently related to the route and speed of administration, intramuscular administration is recommended. Even intramuscular administration, however, can cause an elevation in SBP in 20% of recipients with a duration of several hours.[109] Carboprost tromethamine (15-methyl prostaglandin F2 or Hemabate) is a uterotonic agent that causes systemic vasodilation, which may result in hypotension and a reflex elevation in HR. More concerning, Hemabate can cause both arterial and venous pulmonary circulation vasoconstriction with elevations in pulmonary arterial pressure and wedge pressure, and an overall change in the pattern of regional pulmonary blood flow.[19]Consequently, Hemabate is administered intramuscularly in an attempt to mitigate these side effects. There is currently little data as to the hemodynamic effects of misoprostol (Cytotec), a synthetic E1 prostaglandin analogue that can be administered rectally or buccally to produce uterine contractions.

Patient Populations With Variations in Hemodynamic Responses

Preeclampsia
Baseline maternal hemodynamic parameters in preeclampsia differ from those in a healthy pregnancy. The majority, but not all,[110,111]studies have found preeclampsia to be a low CO state accompanied by high SVR.[40,112114] Because preeclampsia progresses in a unique way in individual pregnancies and is frequently accompanied by comorbid conditions such as renal disease or chronic hypertension, there are no formulas to indicate how each individual's hemodynamic profile will respond to interventions, such as neuraxial anesthesia. Treatment with magnesium, tocolytics or antihypertensive medications further alters the hemodynamic state. Traditionally, the epidural technique was considered the neuraxial anesthetic of choice for CD in severe preeclampsia, due to the demonstration that lesser hemodynamic changes would be observed, when compared with a spinal technique.[115,116] However, recent, prospective studies have challenged this belief, indicating that the frequency and severity of hypotension associated with spinal anesthesia was less in preeclamptic women than in healthy women.[117119] Furthermore, some prospective and retrospective studies have shown no significant differences in hemodynamic shifts when spinal and epidural local anesthetic techniques for CD have been compared. [120122] Moreover, some of these studies have indicated that the hypotension produced was short-lived, easily treated and did not affect neonatal outcomes.[123] One study showed insignificant changes in uterine artery velocity waveforms when SBP was maintained at 80% baseline,[116] and another observed clinically insignificant CO changes following spinal anesthesia in severe preeclampsia. [62] Therefore, one author has concluded, "spinal anesthesia in stable and non-coagulopathic severely preeclamptic women is a reasonable alternative to epidural block, especially in emergency situations and particularly if it avoids the use of general anesthesia".[123]

Multifetal Gestation
Multifetal gestation introduces a number of hemodynamic derangements. Twin gestations are associated with a 10% greater increase in maternal blood volume[124] and a 20% greater increase in CO than a singleton pregnancy.[125] The diastolic blood pressure of parturients with twin gestations is associated with a lower nadir during the second trimester and greater increases as the third trimester progresses when compared with a singleton pregnancy. [126] Aortocaval compression is more common because of the greater uterine size, and blood loss with delivery is greater. Because of these exaggerated hemodynamic variables, parturients with multifetal gestations were believed to experience greater hemodynamic instability during CD under neuraxial anesthesia. However, a recent prospective study observed that parturients with multifetal gestation undergoing spinal anesthesia for CD did not have a greater incidence of hypotension or vasopressor requirements in comparison with parturients with singleton gestations.[127]

Parturient With Cardiac Disease

Up to 3% of deliveries are complicated by maternal heart disease. The presence of intracardiac shunting, cyanosis, left heart obstruction, and decreased left or right heart function will affect the hemodynamics that occur during cesarean delivery under neuraxial anesthesia. Some cardiac lesions (e.g., mitral stenosis, aortic stenosis, aortic coarctation or right-to-left shunting) could lead to significant decompensation with the SVR reduction associated with pregnancy and with the onset of neuraxial anesthesia for cesarean delivery. At times, general anesthesia may be indicated. If neuraxial anesthesia is the anesthetic of choice, maintenance of hemodynamic stability employing the techniques as described in Box 1 is important.

Interventions to Prevent or Treat Post-neuraxial Anesthesia Hypotension

Maternal Positioning & Other Mechanical Interventions
Maternal positioning has been shown to affect hemodynamic changes following induction of spinal anesthesia. The full lateral position, which minimizes uterine aortocaval compression with term gestation, allows for greater CO than the supine position.[96,128] The supine position in parturients following the induction of spinal anesthesia results in significant decreases in SV, CO and MAP. [66]The 'left uterine displacement' (LUD) position tilts the parturient's abdomen and pelvis at least 15 degrees off the midline by placing a wedge under the right buttock; this position shifts the gravid uterus off of the aorta and vena cava.[129,130] Although a significant improvement in CO can be observed relative to the full supine position,[128,131] LUD does not completely decompress the aorta and inferior vena cava and further CO increases may be observed in the full lateral position.[128,131] Therefore, if significant hypotension occurs in the LUD position, greater tilting of the parturient can be employed. It is important to note that experts do question "the exact contribution of tilt to reducing hypotension in spinal anesthesia" and call for more research on various contributing factors of hemodynamic changes associated with spinal anesthesia for CD.[64] Patient positioning for the administration of the neuraxial anesthetic technique may influence the maternal blood pressure response, but it may depend on the dose of agent used. In a study comparing the seated versus left lateral positions for administration of a CSE technique (spinal hyperbaric bupivacaine 12 mg with fentanyl 10 mcg, a greater degree of hypotension and vasopressor requirements were observed in the seated position.[132]However, in a similar study of parturients undergoing a CSE with hyperbaric bupivacaine 6.6 mg with sufentanil 3.3 mcg, less ephedrine was used when the CSE was performed in the seated, versus left lateral, position.[133] Of note, this may be related to the lower cephalad spread achieved in the seated position, which ultimately resulted in a greater need for epidural supplementation. As such, the use of the left lateral position may be of benefit for traditional dosing for spinal anesthesia for CD; however, the seated position may be better for low-dose dosing when lesser hypotension and vasopressor requirement is desired and an epidural is present for potential supplementation. Leg wrapping, leg elevation, thromboembolic stockings, inflatable splints, inflatable boots and Trendelenburg positioning have been evaluated as a means of increasing central blood volume and decreasing the incidence of hypotension. A qualitative systematic review of these interventions indicated that leg wrapping and inflatable splints may modestly decrease the incidence of hypotension, but inflatable boots, leg elevation and Trendelenburg positioning appears ineffective.[134]

Vasopressors
Healthy pregnant women have a diminished response to vasopressor administration, which can result in relatively greater dosage requirements than nonpregnant patients. However, ephedrine, phenylephrine and dopamine can all prevent spinal anesthesia-induced hypotension better than placebo,[135138] which has encouraged some practitioners to utilize prophylaxis instead of treatment only, to mitigate the effects of hypotension. The selection of a vasopressor for the prophylaxis or treatment of spinal hypotension has been a subject of a number of investigations and several current comprehensive reviews. [139,140] Recent studies have indicated that neuraxial anesthesia, particularly spinal anesthesia, may be associated with decreased fetal umbilical cord pH readings.[141143] Historical evidence that vasopressors with predominant -adrenergic stimulation resulted in uteroplacental vasoconstriction [144147] led many anesthesiologists to avoid phenylephrine. Ephedrine, in contrast to -agonists, demonstrated greater

selectivity of systemic over uterine blood vessel constriction, [148] and was shown to improve maternal blood pressure and uteroplacental blood flow during spinal anesthesia. [149,150]Ephedrine was subsequently considered the vasopressor of choice to prevent or treat hypotension during neuraxial anesthesia for CD. However, recent evidence has suggested that previous concerns regarding uteroplacental vasoconstriction with the use of phenylephrine may have been overstated, whereas the detrimental effects of ephedrine to the fetus may have been understated.[151] The concern with ephedrine in the obstetric population is an association with fetal acidosis and decreases in fetal base excess,[151154] possibly in a dose-dependent manner.[155] In 104 parturients undergoing spinal anesthesia for elective CD randomized to receive an infusion of phenylephrine or ephedrine,[151] fetuses exposed to ephedrine demonstrated significantly lower pH and base excess, and significantly higher umbilical arterial and venous partial pressure CO 2, lactate, glucose and norepinephrine concentrations. Most interesting, the mean umbilical venous to maternal artery (UV/MA) plasma concentration ratios were significantly greater in the ephedrine group (1.13 vs 0.17), indicating ephedrine's greater ability to cross the placenta. In addition, the umbilical artery to umbilical venous (UA/UV) plasma concentration ratios were also significantly greater with ephedrine (0.83 vs 0.71), indicating that ephedrine likely undergoes less early metabolism and redistribution in the fetal plasma. The greater presence in fetal circulation thus results in an increase in fetal metabolism. Multiple recent studies have indicated that phenylephrine is more effective with lesser fetal acid base alterations than ephedrine when used either as prophylaxis or treatment for hypotension in both elective and nonelective cesarean deliveries.[153,156] A randomized double-blinded comparison study of phenylephrine and ephedrine, and their combinations, indicated that decreasing proportions of phenylephrine were associated with worse hemodynamic control and fetal acid-base status.[157] The weight of the evidence for phenylephrine use for neuraxial anesthesia-induced hypotension during CD has now appeared to equal 'the burden of proof'.[158]However, in high-risk patients with significant hypertensive disease of pregnancy, comorbid conditions affecting placental physiology, or, in the cases of emergency CD, with impaired or at-risk fetuses, there are insufficient data to support its safety, and there may be some cause for concern.[159] Further investigations will be necessary to determine the role of -adrenergic agonists versus other vasopressor agents in these settings. The efficacy of prophylactic phenylephrine in preventing spinal hypotension is undoubted. A prophylactic phenylephrine infusion, particularly when combined with crystalloid co-hydration, is highly effective in maintaining hemodynamic stability. Ngan Kee and colleagues observed that an intravenous infusion of phenylephrine 100 mcg/min titrated with blood pressure readings carried out each minute nearly eliminated hypotension (defined as SBP <80% baseline) in nonlaboring parturients undergoing spinal anesthesia for elective CD.[160] Although hypotension occurred in 15 subjects (28.3%; 95% CI: 18.041.6%) in the maintenance fluid group (n = 55), only one subject (1.9%; 95% CI: 0.39.9%) experienced this in the rapid infusion crystalloid group (n = 57). Determining the precise dosing regimen for phenylephrine to consistently prevent spinal hypotension while minimizing episodes of undertreatment (hypotension and/or nausea) or over-treatment (hypertension and/or bradycardia) has been recently extensively studied. [80,157,160163] One study indicates that a fixed rate of 75 or 100 mcg/min phenylephrine is associated with more episodes of hypertension (than placebo or rates of 25 or 50 mcg/min) and a 100 mcg/min infusion was associated with episodes of sinus bradycardia requiring treatment with glycopyrrolate. [164] Citing a study that shows that bolus phenylephrine reduces maternal CO in close correlation to maternal HR,[41] other experts feel that phenylephrine can be administered in bolus doses titrated to maintain a stable HR. This, in turn, will maintain an adequate SVR to maintain a stable maternal MAP.[65]

Conclusion
Variables that contribute to the hemodynamic changes observed in parturients undergoing CD with neuraxial anesthesia include hydration; maternal positioning during and after the block; the block type, height and density; the presence of hypertensive disorders of pregnancy; gestational age; the number of gestations; the presence of labor; and the prophylactic or therapeutic use of vasoactive substances. The most effective strategies for prevention of neuraxial-induced hypotension include prehydration with a sufficient amount of colloid or co-loading with sufficient crystalloid or colloid, positioning the parturient for surgery in the left uterine displacement position, using a lower dose of intrathecal bupivacaine, and most notably, administering a prophylactic vasoactive agent such as phenylephrine. An understanding of how each contributing variable contributes to the overall hemodynamic picture will assist the anesthesiologist in predicting, preventing or treating hemodynamic changes that occur during cesarean delivery with neuraxial anesthesia. Mitigating these hemodynamic alterations may ultimately improve the safety and side-effect profile for the mother undergoing cesarean delivery and her baby.

Expert Commentary
Over the past 10 years, clinician-scientists have artfully performed a series of clinical studies that have assisted the clinician in preventing neuraxial anesthesia-induced hypotension. Although left uterine displacement has been utilized for decades, the mode of hydration has changed from administration of a fluid bolus prior to initiation of neuraxial anesthesia, to simply co-loading fluid as the neuraxial technique is being performed. Lower doses of intrathecal local anesthesia supplemented with opioid are now being used and phenylephrine has replaced ephedrine as the vasopressor of choice. The phenylephrine infusion regimens are now widely employed clinically, with clinicians experiencing far fewer episodes of post-neuraxial anesthesia-induced hypotension.

Five-year View
Advances in invasive, and particularly noninvasive, methods of CO measurement will allow improved monitoring of the parturient undergoing CD. In the next 5 years, these methods of monitoring CO will undergo further evaluation, validation and application in research and clinical environments. Improved hemodynamic monitoring should allow better understanding, titration and timing of vasopressor and fluid regimens in the parturient undergoing cesarean delivery. Ultimately, this may mitigate some of the hemodynamic variations associated with neuraxial techniques and improve known and unknown maternal and fetal parameters associated with favorable outcomes.