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Trends in Anaesthesia and Critical Care 3 (2013) 166e170

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Trends in Anaesthesia and Critical Care

journal homepage: www.elsevier .com/locate/ tacc

REVIEW

Control of blood pressure during spinal anaesthesia for caesarean section

Hon Sen Tan a, Ban Leong Sng b,*

aDuke-NUS Graduate Medical School, SingaporebDepartment of Women’s Anaesthesia, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

Keywords:Blood pressureVasopressorSpinalAnaesthesiaCaesarean section

* Corresponding author.E-mail addresses: Sng.Ban.Leong@kkh.com.sg, blsn

2210-8440/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.tacc.2013.02.010

s u m m a r y

Maternal hypotension during caesarean delivery under spinal anaesthesia may lead to adverse maternaland neonatal outcomes. Vasopressors commonly administered include phenylephrine and ephedrine.Phenylephrine (alpha-1 agonist) is now an established 1st line vasopressor compared to ephedrine(alpha- and beta-agonist) as it has rapid onset, is efficacious and titratable. Over.administration ofphenylephrine may result in reactive hypertension. Ephedrine may cause increased foetal acidosis fromincreased placental transfer with increased foetal metabolism and oxygen consumption. Recent advancesin vasopressor algorithms and delivery systems, together with non-invasive haemodynamic (bloodpressure, cardiac output) monitoring may lead to refinement in the management of hypotension whilstreducing reactive hypertension.

� 2013 Elsevier Ltd. All rights reserved.

1. Introduction

Maternal hypotension during spinal anaesthesia for caesareandelivery is an extremely common clinical problem.1 Severe intra-operative hypotension poses significant consequences to bothmother, such as nausea, vomiting, headaches,2 and neonate in theform of foetal acidosis and neurological injury resulting in weakrooting and suckling reflexes.3,4 Despite being a focus of researchand controversy for more than three decades, no strategy defini-tively prevents its occurrence. Strategies to counteract maternalhypotension include non-pharmacological methods such as intra-venous hydration, lower limb bindings and compression, left-lateral tilt and pharmacological methods, by administration of va-sopressors. Despite the latest Cochrane review concluding that nosingle method consistently eliminates maternal hypotension,5

recent years have seen exciting developments in automatedclosed-loop vasopressor dosing systems that promise to improveefficacy and reliability in maternal haemodynamic control. Thepurpose of this review is to summarize and evaluate the latestdevelopments.

2. Pharmacological management of hypotension

The severe limitations in the efficacy of non-pharmacologicalstrategies5 often mandate the use of vasopressors, however, thechoice of vasopressor had been a subject of debate. The ideal

gdr@yahoo.com.sg (B.L. Sng).

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vasopressor should be inexpensive, efficacious, able to improvematernal and uteroplacental haemodynamics with minimalplacental transfer and adverse effects, and is easily titratedwith fastonset and short duration of action. Obviously such a vasopressordoes not exist although ephedrine and phenylephrine have well-established safety and efficacy profiles and are used by most ob-stetric centres worldwide, and is hence the focus of this review.

2.1. Ephedrine

A non-selective sympathomimetic, ephedrine exerts its pre-dominant vasopressor effect via indirect release of noradrenalinefrom sympathetic nerve terminals, which mainly stimulates b1-adrenoceptors and increases cardiac output.

The use of ephedrine originated from the sheep model, withevidence that b-adrenergic agonists resulted in less uterine arteryvasoconstriction and hence, better maintenance of uterine bloodflow and foetal pH compared to a-agonists.6 Subsequent researchdiscovered that ephedrine possesses greater selectivity for systemicvessels with relative sparing of uterine arteries,7 perhaps due toelevated levels of endothelial nitric oxide synthase8 and lack ofdirect sympathetic innervation of uterine arteries.9 This findingwas confirmed by Ngan Kee et al. who found that ephedrine use inhumans was associated with higher umbilical vein oxygen partialpressure (PO2) compared to phenylephrine (selective a-agonist),presumably reflecting a reduction in placental blood flow with thelatter.10,11 Furthermore, ephedrine restored foetal cardiovascularhaemodynamics to baseline values in the sheep model,12 and mayeven prevent foetal late decelerations.13 Hence, ephedrine was

H.S. Tan, B.L. Sng / Trends in Anaesthesia and Critical Care 3 (2013) 166e170 167

adopted as the vasopressor of choice in obstetrics, where it has seenwidespread use for decades with minimal adverse maternal andneonatal outcomes. Its effectiveness as a vasopressor has beensummarized in recent reviews.5,14

Nonetheless, ephedrine possesses several notable shortcom-ings, leading to some concerns in recent years. Its limited effi-cacy14,15 and susceptibility to tachyphylaxis with a mean half-life of15 min16 translates to greater dosages required to maintain bloodpressure and a concomitant increase in adverse effects. Ephedrinehas been associated in a dose-related manner with foetal acidosisand decreased base excess17e20 along with elevated lactate andcatecholamine levels,10 possibly due to its high placental transfer10

exerting an increase in foetal metabolism17,21,22 via b1-adrenergicstimulation of brown fat.23 This hypothesis was corroborated byobservations of decreased PO2 and increased PCO2 veno-arterialgradients,11,17 suggesting that ephedrine resulted in increased ox-ygen utilization, and not decreased oxygen delivery. Furthermore,the discovery of an association between the b2-adrenergic receptorhaplotype and foetal acidosis evinces the possibility of geneticsusceptibility to significant acidosis even with small doses ofephedrine.24 However, the clinical significance of these findings isunclear, as most studies failed to demonstrate an adverse outcomeor drop in APGAR scores, though the studied population tendedtowards healthy, elective cases, with little research done on high-risk pregnancies. A recent meta-analysis demonstrated an associ-ation between foetal acidosis and poor outcomes, by showing afour-fold increase in neonatal mortality and a two-fold increase inmorbidity resulting from umbilical artery pH < 7.20.25 Severalstudies have reported that ephedrine use is associated with alowered mean umbilical arterial pH of 7.18 to 7.27.15,26,27 Further-more, it is possible that accelerating foetal metabolism decreasesthe oxygen supply-to-demand ratio in the foetus, which may beclinically evident only in the presence of factors predisposing toadverse neonatal outcomes, such as placental insufficiency or pre-eclampsia.

Also, the predominant b-adrenergic effect of ephedrine not onlyfails to address vasodilation occurring during spinal anaesthesia,but further increases maternal cardiac stress through its chrono-tropic and inotropic effects. Moreover, the haemodynamic profile ofephedrine is not optimal for use in obstetric anaesthesia. Ephedrinepossesses a relatively delayed onset of action, with a maximumeffect observed at 89.8 s compared to 61.8 s for phenylephrine.28

This, in combination with its longer duration of action, makesephedrine harder to titrate in cases of rapid and precipitous bloodpressure changes that often occur during spinal anaesthesia,potentially resulting in sustained abnormal blood pressures andfurther compromising maternal and neonatal outcomes.

2.2. Phenylephrine

For decades, a-adrenergic agonists such as phenylephrine wascontraindicated in obstetrics due to its potential adverse effects onuteroplacental flow observed in the sheepmodel (vide supra), but isnow gaining increasing acceptance and use. This revival is attrib-uted to studies in the past two decades and summarized in a recentmeta-analysis.29 Although there were no significant differences inincidences of hypotension, reactive hypertension, and APGARscores detected between phenylephrine and ephedrine, phenyl-ephrine was associated with significantly higher pH and baseexcess. This finding may be due to phenylephrine’s lesser extent ofplacental transfer10 and lack of metabolic stimulation in the foetus.Furthermore, there was no conclusive evidence of phenylephrineimpairing uterine blood flow in the two available studies utilizingDoppler velocimetry; one trial found an increase in vascularresistance in uterine and umbilical vessels,30 while the other

reported no significant difference.27 This discrepancy betweenearly experiments on the sheep model and subsequent humanstudies may be explained by difficulties in extrapolating resultsobtained from animal models to the vastly different physiology ofhumans.31e34

Furthermore, phenylephrine resulted in a lower incidence ofmaternal intraoperative nausea and vomiting,35 perhaps attribut-able to its faster onset and shorter duration of action, making foreasier dose-titration and minimized hypoperfusion to cerebrumand gut, thus avoiding activation of the vomiting centre36 andrelease of emetogenic substances.37 Moreover, phenylephrinedirectly addresses the vasodilation that occurs with spinal anaes-thesia by a-adrenoceptor stimulation; does not appear to sufferfrom the tachphylaxis seen in ephedrine; and offers greater po-tency e equipotent dose of ephedrine is 83:1.38 These character-istics results in lower doses of phenylephrine required and feweradverse maternal and neonatal effects.

However, phenylephrine is commonly associated withdecreasing maternal cardiac output (CO) and heart rate, sometimesnecessitating the use of anticholinergic drugs.27 Stewart et al.studied the effects of three phenylephrine infusion rates (25, 50,100 mg min�1) in caesarean section under spinal anaesthesia andreported a linear dose-dependant reduction in maternal CO, but thedifferences were small compared to inter-patient differences inbaseline CO.39 Gelman and Mushlin noted that 25% of total vascularvolume is stored as an “unstressed” reservoir within splanchnicorgans, which is converted to “stressed” (actively circulating) vol-umewith venoconstriction by a1-adrenergic agonists.40 In addition,this reservoir exists in parallel with the systemic circulation, andlocal venoconstriction would have little influence on total vascularresistance.41 Thus, it appears that phenylephrine increases cardiacpreload and CO, but at higher doses, it is unclear if the observeddrop in CO stems from excessive venoconstriction restrictingvenous return, or is actually due to baroreceptor-mediated increasein vagal tone. The former implies excessive phenylephrine dosing;while anticholinergics may be beneficial in the latter.

With the current movement towards “goal-directed therapy”,one must not forget that the target physiologic parameter is oxygendelivery, and not blood pressure or CO, which are merely surrogatemeasures of perfusion. Unfortunately, it is unclear howwell CO andblood pressure correlate with uteroplacental perfusion. Robsonet al. suggested that CO correlates better with uteroplacentalperfusion than blood pressure.42 The concern that phenylephrine-mediated drop in CO might decrease uteroplacental perfusion hasbeen addressed by Ngan Kee et al., who concluded that there waslittle change in uterine blood flow (as determined by uterine pul-satility) with the use of metaraminol, an a1-adrenergic agonistwhich depresses maternal heart rate (and presumably CO) in asimilar fashion as phenylephrine.19 Hence, further research isrequired to (1) determine the effects of phenylephrine-induceddecreases in maternal CO on uteroplacental perfusion, and (2) thebest surrogate parameter for uteroplacental perfusion.

2.3. Ephedrine or phenylephrine?

Twometa-analyses were published comparing ephedrine versusphenylephrine use during caesarean section under spinal anaes-thesia. Lin et al.43 analysed 15 trials and found no differences in theincidence of maternal hypotension and umbilical artery pH valueswith prophylactic use of ephedrine or phenylephrine. However,when used to treat intraoperative hypotension, phenylephrine wasassociated with higher umbilical arterial and venous pH values,although there was no difference in the incidence of maternal hy-potension. These results largely corroborate that of Veeser et al.,29

who found that as a treatment modality, ephedrine was associated

H.S. Tan, B.L. Sng / Trends in Anaesthesia and Critical Care 3 (2013) 166e170168

with poorer neonatal pH and base excess, but with similar in-cidences of maternal hypotension and reactive hypertension,umbilical artery PCO2, and APGAR scores as phenylephrine. Phen-ylephrine has been shown to be superior to ephedrine in bothneonatal (favourable acid-base values, less placental transfer) andmaternal (reduced nausea/vomiting) outcome measures. Further-more, phenylephrine has a much faster onset and shorter durationof action compared to ephedrine, making it easier to titrate and abetter choice for usewith the advent of recent closed-loop real-timemonitoring systems.

3. Vasopressor administration

While the debate on which vasopressor to use during caesareansection rages on, few studies have attempted to address the optimalway of administering vasopressors, with most focused onphenylephrine-based regimens.

3.1. Bolus versus infusion

A recent double-blinded randomized trial44 comparing infusionversus bolus regimens of phenylephrine found no difference in themaximum change in cardiac output, incidences of hypo/hyperten-sion, heart rate, nausea, vomiting, umbilical blood gases, andAPGAR scores. Interestingly, phenylephrine infusionwas associatedwith higher total doses administered and poorer blood pressurecontrol during the first 6 min after spinal anaesthesia e a timewhen the block is evolving and the parturient is at greatest risk forwide swings in blood pressure.

3.2. Prophylactic versus reactive administration

Burns et al. reported that 93% of obstetric anaesthetists usedephedrine prophylactically.45 This practise is not supported by ev-idence elicited from randomized trials, which showed either nodifference in the incidence and severity of hypotension,46 orimprovement only with high doses (30 mg ephedrine given pro-phylactically), which not only failed to eliminate hypotension, butwas associated with reactive hypertension in 50% of the partici-pants.15 When used reactively, by definition, maternal blood pres-sure would have dropped to a certain extent, and therefore, largerdoses of ephedrine in a short timespan may be required to restoreblood pressure, with the attending effects of increased foetalmetabolism and acidosis. Furthermore, the association of b-adre-noceptor haplotype to acidosis with ephedrine use24 does notfavour empiric doses of prophylactic vasopressors.25

Ngan Kee et al. showed that rapid crystalloid infusion combinedwith pre-emptive infusion of phenylephrine at 100 mg min�1

administered when maternal blood pressure was equal or belowbaseline decreased the incidence of hypotension, minimum-recorded BP and heart rate, and total doses of phenylephrineused.47 However, this regimen resulted in 47% of parturientsdeveloping hypertension. Clearly, the optimal “trigger point” ofmaternal blood pressure (below which phenylephrine would beadministered) needs to be determined.

4. Non-invasive blood pressure measurements

The current standard of care at many centres for elective andemergency caesarean sections involves oscillometric blood pres-sure monitoring of the brachial artery at one to 5 min intervals. Arecent study comparing continuous non-invasive BP monitoringversus oscillometricmeasurements at 3min intervals in parturientsundergoing caesarean section under spinal anaesthesia reportedthat standard monitoring missed 36% of hypotensive episodes,

failed to detect lower blood pressures picked up by continuousmonitoring, and showed inferior discrimination of acidotic(pH < 7.3) neonates.48 Therefore, continuous blood pressuremonitoring may detect hypotensive episodes earlier, thus permit-ting prompt treatment.

Several devices exist on the market now, based on the “volume-clamped” method described by Penaz in 1973. The technique in-volves measurement of blood volume in a finger via infraredplethysmography, which is fed back to a pneumatic pump con-nected to a proximal inflatable cuff. The cuff is then inflated withthe precise pressure needed to keep the blood volume in the fingerconstant. Since the blood volume is constant, there is no differencebetween the cuff and intra-arterial pressure, and BP can bemeasured in real time. A decade later, the Finapres system wasdeveloped,49 which was succeeded by the Finometer and Portapres(Finapres Medical Systems, Netherlands), and Nexfin (BMEye BV,Netherlands) devices. These systems utilize PhysioCal, an algorithmthat periodically recalibrates the system by tracking the diameter ofthe artery to account for changes in smooth muscle tone, but withthe attending effect of interruptingmeasurements for short periodsof time.50 In 2006, an Austrian group refined the Penaz principlewith the VERIFI algorithm,51 which is found in CNAP Monitor 500(CNSystems Medizintechnik AG, Austria) and CNAP Smart Pod(Draeger Medical, Germany). The VERIFI algorithm permits unin-terrupted long-term continuous blood pressure measurements bycontinuously analysing characteristics of the pulse wave.51

Several of these devices have even integrated the ability to es-timate cardiac output, stroke volume, stroke- and pulse-pressurevariations, and systemic vascular resistance via arterial pulsewave analysis,52e55 but it should be noted that global CO may notreflect regional uteroplacental perfusion, and hypotension andadverse outcomes can occur despite elevated CO.56 Accuracy andprecision have always been a point of concern. CNAP devices haverecently been validated in two prospective trials that showed goodagreement with intra-arterial measurements, and equally impor-tant, reliable detection of fast blood pressure changes and hypo-tensive episodes.57,58 However, a trial by McCarthy involving 61parturients in caesarean section under spinal anaesthesia found aslightly poorer correlation of CNAP to oscillometric measure-ments,59 which may be explained by the reported poor agreementbetween oscillometric and intra-arterial BP measurements.60 Theaccuracy and precision of non-invasive BP as measured by Nexfinhas been shown to correlate well with intra-arterial measure-ments,61 and its cardiac output data has been validated against bothTTE62 and Pulse-induced Contour Cardiac Output (PiCCO) trans-cardiopulmonary thermodilution methods.63 Blood pressure mea-surements produced by Portapres have been validated againstinvasive measurements in the aortic arch,64 though CO measure-ments were not as precise when compared to thermodilution.65

Finometer fared poorer in terms of blood pressure accuracy innormotensive, hypertensive, and pre-eclamptic parturients asmeasured by ascultation,66 as well as CO measurements comparedto indicator dilution technique.67

5. Advances in closed-loop feedback systems

The advent of microprocessor-controlled infusion pumps per-mits the integration of BP measurements into a closed-loop systemfor automatic vasopressor infusion. Such a system may achievebetter blood pressure regulation by use of complex algorithms thatminimize response time, overdosing, and fluctuation, as well asfreeing the anaesthetist to concentrate on other patient care re-quirements. An ideal controller achieves the setpoint with minimaldelay, deviation from the setpoint, and overshoot, thus producing astable output over time. As physiologic systems have little tolerance

H.S. Tan, B.L. Sng / Trends in Anaesthesia and Critical Care 3 (2013) 166e170 169

for rapid fluctuations or deviations from target, the controller mustmeet very strict performance criteria to prove clinically useful.

One can think of such closed-loop systems as a three-linkchain comprising (1) haemodynamic measurement device (input),(2) microprocessor-based control unit, and (3) vasopressor(s) anddosing system (effector), with the effectiveness of the entire systemdependant on the integrity of the weakest link. Currently, the inputand effector components exist separately in an open loop, with theanaesthetist closing the loop by performing analysis of the inputdata and managing the effector.

The first link requires a device that measures haemodynamicparameters of the patient and exports the data to the micropro-cessor controller unit. The ideal device suitable for routine obstetricuse should be non-invasive, permitting “hands-free” operation,quick to set up, and provide continuous, accurate and precisehaemodynamic data. Of the devices discussed above, the mostsuitable are those measuring BP from finger arteries such as CNAPand Nexfin. This technology avails several key advantages e BPmeasurements are non-invasive and continuous, some models arecapable of estimating cardiac output and other haemodynamicparameters, set up is rapid and the operation is “hands-free” withlittle operator training required. While oscillometric BP monitorsare non-invasive, already in widespread use, and afford “hands-free” operation, intermittent measurements result in fewer in-stances of hypotension detected and delays in treatment, and Dyeret al. hypothesised that CO may be a better surrogate measure ofuteroplacental perfusion than blood pressure.68 Nonetheless, itsuse in closed-loop systems has shown a reduced incidence of hy-potension, less blood pressure fluctuation, and fewer required in-terventions, with no change in clinical outcomes compared tomanual infusion.69

The second link in the chain represents the control algorithm.Specific to obstetric blood pressure management, only basic on-off70,71 and simple proportional69 algorithms have been utilized todate. It should be noted that while basic pharmacokinetic princi-ples still apply, maintaining blood pressure requires accounting fordynamic parameters such as cardiac output, evolving spinalblockade, aortocaval compression, surgical manipulation, etc. Inessence, this represents a constantly-shifting target that compli-cates the existing problems of pharmacokinetics, which must bedealt with by the control system to successfully maintain BP.

The final link in the chain is the effector component, consistingof vasopressor(s) and the dosing system. With respect to theformer, phenylephrine was used in preliminary trials evaluatingclosed-loop systems by Ngan Kee et al.,69,70 due to minimal risk ofneonatal acidosis and properties favouring easy titratability (fastonset, short duration of action). However, themain adverse effect ofphenylephrine is maternal bradycardia, which often necessitatedstopping phenylephrine administration or treatment with vago-lytics. However, it is possible for parturients to be both bradycardicand hypotensive, and for whom further phenylephrine adminis-tration is contraindicated e a situation that happens in 22% ofparturients.71 One solution involves phenylephrine as the mainvasopressor and switching to ephedrine in instances where hypo-tension and bradycardia occurred simultaneously.71

So how effective are closed-loop systems compared to standardof care? A preliminary trial by Ngan Kee et al.70 used oscillometricBP measurements at 1-min intervals and an on-off algorithm thatactivated phenylephrine infusion (100 mg min�1) when maternalblood pressure was equal to or below the baseline. They reportedthe incidence of hypotension as only 13.2%, but 37.7% had one ormore episodes of hypertension. Another recent study69 utilizedoscillometric BP input, but this time, a simple proportional algo-rithm regulated the infusion of phenylephrine (0e100 mg min�1).Compared to the on-off algorithm that activated phenylephrine

infusion (100 mg min�1) at or below baseline blood pressure, pro-portional infusion reported significantly decreased interventionsrequired tomanage BP, but similar incidences of hypo/hypertensionand clinical outcomes. A preliminary study performed by Sia et al.71

utilized non-invasive continuous blood pressure monitoring (CNAP)input to an on-off algorithm that activated 100 mg boluses ofphenylephrinewhen BP fell below 90% of the baseline, but switchedto ephedrine when the parturient was both hypotensive and bra-dycardic (heart rate less than 60 bpm) to actively treat both con-ditions simultaneously. There was a 65% incidence of hypotensionand an 11% incidence of hypertension. It appears that reactivelytreating hypotension (initiating treatment when blood pressurewas below 90% of baseline) compared to Ngan Kee’s pre-emptivetreatment (administering vasopressors at baseline) reduced reac-tive hypertension, but increased the risk of hypotension.

6. Conclusions

Although the choice of vasopressor still remains controversial,recent evidence has suggested that phenylephrine is a good choicewith pharmacologically appropriate action and rapid treatment ofhypotension due to spinal anaesthesia. The administration ofephedrine may cause increased foetal metabolism leading toacidosis, however, ephedrine may be more appropriate if maternalhypotension and bradycardia occurs simultaneously. The use ofnovel vasopressor dosing algorithms and the advent of non-invasive continuous monitoring have improved the managementof hypotension, though blood pressure end-points may not be theonly outcome in the treatment of hypotension. With recent non-invasive cardiac output monitoring to reflect uteroplacentalperfusion, future research in this area should explore the use ofcontinuous monitoring and more dynamic algorithms of vaso-pressor delivery.

Conflict of interest

The authors do not have any conflict of interest.

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