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Hypotensionduringspinalanaesthesiaforcaesareansection:Implications,detectionpreventionandtreatment

ARTICLEinFETALANDMATERNALMEDICINEREVIEW·MAY2006

DOI:10.1017/S0965539506001756

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TheChineseUniversityofHongKong

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TheChineseUniversityofHongKong

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TheChineseUniversityofHongKong

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Fetal and Maternal Medicine Review 2006; 17:2 1–27 C© 2006 Cambridge University Pressdoi:10.1017/S0965539506001756

HYPOTENSION DURING SPINAL ANAESTHESIA FORCAESAREAN SECTION: IMPLICATIONS, DETECTIONPREVENTION AND TREATMSENT

KIM S KHAW, WARWICK D NGAN KEE AND SHARA WY LEE

Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of WalesHospital, Shatin, Hong Kong, China

INTRODUCTION

Regional anaesthesia is preferred by most anaesthetists for the majority of caesareansections.1 The major advantage of regional anaesthesia is the avoidance of maternalmorbidity and mortality associated with general anaesthesia. The importance of thiscan be seen in the most recent Report of Confidential Enquires into Maternal Deaths2

in which it was reported that of the direct maternal deaths attributed to anaesthesia, allsix were associated with difficulties during general anaesthesia. Although a numberof regional anaesthesia techniques are available, spinal anaesthesia is particularlypopular because it is fast, easy to perform and provides excellent intraoperativeanalgesia.

However, spinal anaesthesia can be associated with a number of problems, includinghypotension and its sequelae. The year 2002 marked the centenary of the firstsuccessful use of spinal anaesthesia for caesarean section by Hopkins who used itfor a patient with placenta praevia. It is noteworthy that the technique was almostabandoned in its infancy because of problems associated with severe hypotension,which were exacerbated by the availability of only rudimentary monitoring and lack ofawareness of the effects of vasodilatation and aortocaval compression. Many patientssuccumbed to hypotension-related problems, resulting in an audited increase in thematernal mortality rate when spinal anaesthesia was used.3 The difference was soapparent that spinal anaesthesia was actively discouraged.

Fortunately, there have been many refinements in the management of spinalanaesthesia over the past several decades that have greatly improved its safety andacceptability. In particular, improvement in the understanding and management ofhypotension has been a major advance. Additionally, the advent of small-gauge pencil-point needles has greatly reduced the risk of post dural puncture headache.4 Thus,

Kim S Khaw, Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Princeof Wales Hospital, Shatin, Hong Kong, China.

2 KS Khaw, WD Ngan Kee and SW Lee

in the UK, spinal anaesthesia is used for the majority of elective and about half ofemergency Caesarean deliveries.

However several controversies remain. The optimal techniques for prevention andtreatment of hypotension are often debated. Furthermore, because of an associationbetween spinal anaesthesia and increased risk of fetal acidosis, it has been argued thatfrom the point of view of fetal wellbeing, spinal anaesthesia should not be regarded asthe optimal technique for Caesarean section.5–7

The purpose of this review is to provide a background to the problem of hypotensionduring spinal anaesthesia for Caesarean section and describe recent advances in itsdetection, prevention and treatment.

PHYSIOLOGY OF HYPOTENSION AND HAEMODYNAMIC DISTURBANCE

Spinal anaesthesia is produced by the injection of local anaesthetic, often togetherwith an opioid adjunct, into the subarachnoid space, with the objective of blockingconduction in afferent sensory fibres that transmit pain impulses to the brain.However, conduction block from local anaesthetics is non-specific and preganglionicfibres to the sympathetic chain are also affected, resulting in sympathetic block andhypotension which can cause hypoperfusion of the uterus and placenta. The extent towhich the sympathetic chain is blocked is related to the degree of cephalad spread oflocal anaesthetic in the subarachnoid space.8 In pregnant women, greater sensitivityto local anaesthetics results in higher blocks, and compounded by the effects ofaortocaval compression, hypotension occurs with greater frequency and severity.There is also an increase in sympathetic versus parasympathetic activity9 whichpredisposes to a greater degree of peripheral vasodilation. Epidural blockade producesa similar extent of sympathectomy, but there is a lower incidence and severity ofhypotension since the rate of onset of sympathectomy is slower, allowing more timefor cardiovascular compensation.

To understand how spinal anaesthesia affects the cardiovascular system, it isimportant to understand the basic principles of cardiovascular physiology. Bloodpressure (BP) is determined by the following equation:

Mean arterial pressure(MAP)

= Cardiac output(CO)

× Systemic vascular resistance(SVR)

Cardiac output CO is the volume of blood pumped by the heart per minute,and is equal to the product of the heart rate (HR) and stroke volume (SV), thelatter of which is determined by preload, afterload and contractility. During spinalanaesthesia, hypotension occurs as a result of a decrease in SVR and/or CO. Theoverall haemodynamic effects can be divided into three main categories:

Hypotension during spinal anaesthesia for caesarean section 3

The effects on preload

Starling’s law of the heart states that the force of contraction of the cardiac musclefibres is directly proportional to their initial resting length, or preload. Stretchingsensitizes the myofibrils to calcium and increases the force of cardiac contraction. Inthe intact heart, preload is determined by the end-diastolic volume which is dependenton venous return. The sympathectomy that accompanies spinal anaesthesia results invenodilatation which causes pooling of blood peripherally and reduces venous returnand preload. The decrease in preload reduces CO and thus contributes to hypotension.Clinically, left ventricular end diastolic volume cannot easily be measured, andpreload is assessed by measuring central venous pressure (CVP) or the pulmonaryartery wedge pressure.

The effects on afterload

Afterload is the resistance against which the left ventricle must contract and isdetermined mainly by the systemic vascular resistance (SVR). SVR is dependentlargely on arteriolar vasomotor tone which is decreased by the sympthectomycaused by spinal anaesthesia. Vasodilatation and a decrease in SVR occurs whichcontributes to hypotension. Although vasodilatation may improve peripheral bloodflow, it may also cause shunting which can result in regional tissue hypoxia.Initially, vasodilatation may lead to an increase in CO due to improvement in cardiacperformance but excessive vasodilatation invariably leads to hypotension.

The effects on the heart

Direct effects on the heart include effects on HR and contractility, the pumpingability of the heart. The effect of the sympathetic nervous system on the heart is toincrease both HR and contractility. These actions are opposed by parasympatheticinnervation via the vagus nerve. Sympathetic block from high spinal anaesthesiacan affect cardiac function and reflexes in several ways. An increase in baroreceptorsensitivity has been shown to occur in pregnancy, and HR can increase secondary toa reflex baroreceptor-mediated response to hypotension.10 Conversely, HR may alsodecrease either directly from a decrease in cardiac sympathetic stimulation resultingfrom block of sympathetic outflow from the upper thoracic segments, or indirectlyvia the Bainbridge reflex. The Bainbridge reflex describes an increase in HR secondaryto the stretch of the right atrium caused by increased venous return. Although itsimportance is controversial, during spinal anaesthesia, as venodilatation causes adecrease in right atrial filling, the HR may decrease. In clinical practice, the actualclinical response seen in patients is variable, and depends on the complex interactionof all of these factors.

4 KS Khaw, WD Ngan Kee and SW Lee

MONITORING AND DETECTION OF HYPOTENSION AND HAEMODYNAMIC DISTURBANCES

Definition and incidence of hypotension

The various haemodynamic parameters of the cardiovascular system interact directlyand indirectly to produce hypotension during spinal anaesthesia. The result is areduction in all the indices of the arterial BP. Definitions for hypotension duringCaesarean section vary. Although the use of mean arterial pressure to definehypotension is physiologically logical, traditionally, most studies have been basedon changes in systolic BP (SBP). In practice, it is common for anaesthetists tomake decisions according to changes in SBP. Accordingly, common definitions ofhypotension include a proportional decrease of SBP (e.g. < 70–80% of baseline) or adecrease in SBP below an absolute value (e.g. < 90–100 mmHg). Although its exactincidence varies according to definition and technique, it is estimated that hypoten-sion occurs in up to 80% to 100% of patients who have spinal anaesthesia for electiveCaesarean section.

Monitoring and detection

Standard recommended monitoring for Caesarean section performed under regionalanaesthesia includes continuous ECG, pulse oximetry and BP at 1-min cyclingtogether with continuous fetal heart monitoring until commencement of surgery.11

During spinal anaesthesia for Caesarean section, a range of simultaneous haemo-dynamic disturbances may occur. Inadequately treated, these may have detrimentalmaternal and fetal effects. Therefore, the development of methods and strategies formonitoring haemodynamic parameters is important. Because of historical limitationsin the methods that are available for haemodynamic monitoring, most studies andclinical recommendations have been based on changes in maternal BP. Arguably,however, monitoring of CO and uterine blood flow may be the more appropriateparameters to monitor to ensure fetal wellbeing. For example, in the presence ofundetected aortocaval compression, the adequacy of uterine perfusion cannot beconfirmed based solely on measurements of BP and HR alone which may be normal.12

Placental perfusion can be compromised without evidence of maternal hypotension,as maternal physiology preferentially preserves cerebral and cardiac circulation aheadof placental perfusion. Because of this, we will describe some of the available methodsfor monitoring BP and other haemodynamic parameters, including discussion of theiradvantages and limitations.

Maternal heart rate monitoring

The use of ECG and pulse oximetry enables the early detection of changes inmaternal HR that occur as a direct result of a high spinal anaesthesia, or secondary

Hypotension during spinal anaesthesia for caesarean section 5

to cardiac compensation and treatment for hypotension. In addition, the pulseplethysmographic trace from the pulse oximeter will detect early changes in peripheralperfusion secondary to hypotension. However, patient movement, shivering, and useof electrical diathermy can cause interference to the signals.

Invasive blood pressure measurements

Direct intra-arterial monitoring

Direct intra-arterial monitoring is the gold standard for BP measurement. Changesin circulatory status may occur rapidly after induction of spinal anesthesia. Use ofdirect intra-arterial monitoring allows accurate beat-to-beat measurement of BP. Thus,changes in BP can be rapidly detected and treatment given before a prolonged period ofuterine hypoperfusion occurs. Moreover, additional information can be derived fromshape of the arterial waveform, such as the stroke volume, myocardial contractility,resistance and compliance of the arterial vasculature, enabling earlier prediction ofpotential hypotension. The intra-arterial signal is also less vulnerable to interferenceand is largely unaffected by patient movement and shivering.

However, it is difficult to justify placement of intra-arterial catheters routinely inuncomplicated patients. This is an invasive procedure that requires more complicatedset up and calibration, and has the potential risk of thrombosis and ischaemiccomplications. Therefore, the use of direct intra-arterial monitoring is normallyreserved for patients with cardiac disease or other conditions where rapid and accurateassessment of BP is important.

Non-invasive blood pressure measurements

Non-invasive measurements of BP is the traditional and most widely used tool formonitoring haemodynamic disturbances from spinal anaesthesia. Intervals betweenBP measurements should be small (eg. every 1 min during the early phase of spinalanaesthesia) since the onset of hypotension may be rapid.

Auscultatory methods (mercury or anaeroid sphygmomanometer)

This is the commonly used method in the ward and delivery unit as a bedsideprocedure. Auscultatory measurement involved placing a cuff over the upper armwhich is inflated to above the systolic pressure when the pulse will no longer bepalpable. Then a stethoscope is placed distal to the cuff, which is slowly releasedat ∼3 mmHg per heart beat, until the onset of the Korotkoff sounds signalling thesystolic pressure, and muffling or disappearance signalling the diastolic pressure.13,14

However it is labour intensive and errors arise when the cuff pressure is releasedtoo rapidly. Automated systems using ultrasonic detection of the Korotkoff sounds

6 KS Khaw, WD Ngan Kee and SW Lee

and arterial wall movement, or photoplethysmograhic detection of arterial flowwere developed. However, these automated BP measurements never achieved thewidespread popularity of the oscillometric BP systems.

Oscillometric methods

This system is similar to auscultatory method but the detection of the systolic, meanand diastolic pressure is based on detection of the oscillation of pressure in the cuffitself. The first large increase and decrease in oscillation occur at systolic and diastoliccuff pressure respectively. Mean arterial pressure is denoted by the largest oscillationwith the lowest cuff pressure. Automated oscillometric measurements of BP are thestandard method of monitoring used in most operating theatres and measurementscorrelate well with invasive intra-arterial measurements.15–17 However, commonproblems encountered with using cuff oscillometric measurement of BP includes thesusceptibility to movement and interference, especially when patients shiver duringspinal anaesthesia.

Non-invasive continuous finger arterial blood pressure monitor (Finapres)

Finapres is the acronym for Finger Arterial Pressure. The device is a non-invasivecontinuous finger arterial BP monitor, based on the vascular unloading technique,developed by Jan Penaz and Karel Wesseling.18,19 It measures the arterial pressurewaveform of the finger using an inflatable finger cuff controlled by a servo pneumaticsystem. This enables simple non invasive continuous finger arterial pressure moni-toring in the clinical setting that produces output measurements similar to thatof an intra-arterial catheter. The performance of this method of arterial pressuremeasurement has been evaluated in a large number of studies.20 Although absolutemeasurements were not within the acceptable limits for clinical usage, it does providereliable tracking of beat-to-beat changes of arterial pressure which would makes itsuitable for monitoring for detection of hypotension in awake patient anaesthetizedunder spinal anaesthesia (Figure 1).

Continuous arterial tonometry (Avidenz)

Another device coming to the market is the Avidenz, a continuous non-invasiveBP monitoring system based on arterial tonometry. Using a pulse-sensing modulepositioned over the radial artery at the wrist, the arterial waveforms and BP are directlytransduced non-invasively. Preliminary studies showed good correlation between theAvidenz and intra-arterial catheters for the displayed arterial waveforms and readingsfor systolic, diastolic and mean BP and pulse rate.21 This device may be ideal formonitoring for hypotension after spinal anaesthesia although there have been fewclinical reports of its use to date.

Hypotension during spinal anaesthesia for caesarean section 7

Figure 1 Systolic blood pressure measurements from an automatic oscillometric NIBP cuff and a Finometershowing episodes of hypotension during the onset of spinal anaesthesia. The Finometer was able to detecteach hypotensive episode approximately 1 minute earlier than oscillometric NIBP.

Cardiac output monitoring

Cardio output may be impaired during spinal anaesthesia despite adequate correctionof BP using vasopressors.22 However, the utility of directing therapy towardsmaintenance of CO rather than BP is undetermined. Nonetheless, with progressivevasodilation during the onset of spinal anaesthesia, a drop in BP as a result of thedecreased SVR may trigger a compensatory reflex increase in CO which may initiallyminimize the extent of the decrease in BP. If early CO changes can be detected, thismay facilitate the early timing of therapy such as vasopressors to limit or minimizehypotension.

In practice, CO is seldom monitored, mainly because most available methods formeasurement have been invasive. However, a number of non-invasive techniqueshave been described and with advances in technology these are becoming morereliable. Several instruments are available that can be applied to patients havingspinal anaesthesia. These include pulse contour analysis using finometry, impedancecardiography and Doppler cardiography.

Non-invasive continuous finger arterial plethysmography (Finometer)

As mentioned previously, the Finapres provides beat-to-beat measurement of real timechanges in the BP. Recent improvement in technology incorporates a contour analysisalgorithm based on the Modelflow method, enabling the derivation of stroke volumeand CO.23 Tracking changes in CO from the pre-anaesthetic changes provides evenmore clinically useful beat-to-beat information on the haemodynamic disturbance

8 KS Khaw, WD Ngan Kee and SW Lee

and changes beyond what can be detected by simple measurement of BP. Potentially,this enables the prediction of impending hypotension, which can be anticipated inpatients under spinal anaesthesia.

Impedance cardiography

Impedance cardiography applies Ohm’s relationship to the thorax to allow changes involtage (�V) and impedance (�Z) detected by a high frequency harmless microcurrentto be translated into haemodynamic parameters of cardiac function. Ejection of blood,a strong conductor of current, from the heart into the great vessels contributes tothe changes in thoracic electrical impedance. Impedance cardiography has manyobvious practical advantages, being non-invasive and safe. Acquisition of derivedparameters continuously on a beat-to-beat basis permits real time monitoring.Furthermore, the data acquisition process is passive, and the data are reproducible,and stable as a trend monitor. There are over 200 studies in the literature validatingimpedance cardiography measurements of CO,24 and several comprehensive meta-analyses of these studies have found overall correlations (r) of 0.85.24–27 Although,impedance cardiography has demonstrated satisfactory reliability and reproducibility,interference of signals from shivering or surgical diathermy can be a problem.

Doppler ultrasound cardiography

Doppler-based ultrasound cardiography is one of the most promising non-invasivetechniques for monitoring CO. Based on the Doppler shift in signal, the velocityof the blood flow is derived, and SV can be calculated based on the ejection timeand cross-sectional area from the Doppler waveform.28 Good correlation has beendemonstrated between the CO measured by oesophageal or suprasternal Doppler andsimultaneously by thermodilution and Fick methods. However, this technique ishighly operator-dependent, taking up to a few minutes for each measurement, andalso the parameters are not continuously measured. Monitoring in an awake patientalso may induce some degree of discomfort and sometimes deep breathing, swallowingand neck movements interfere with measurements.

Derived physiological parameters

Heart rate variability

Analysis of HR variability has been shown to be potentially useful for predicting whichpatients are most at risk of hypotension.29,30 Using power spectral analysis of HRvariability as an indicator of autonomic balance, Hanss et al.29 found that parturientswith higher baseline sympathetic activity experienced more severe hypotensionduring spinal anaesthesia. Because of the problem in processing and evaluating this

Hypotension during spinal anaesthesia for caesarean section 9

parameter, it remain unclear as to whether this will prove to be a clinically usefultool.31

Pulse transit time

Pulse transit time (PTT) measures the interval from the electrical activity to thephysical pulse in the periphery (for example from the ‘R’ wave of the ECG to the pulseupstroke on a pulse oximeter trace). PTT may provide rapidly available beat-to-beatcardiovascular information when conditions change quickly as during obstetric spinalanaesthesia. The greater part of the measured PTT indicates vascular elastance whichdetermines the pulse wave velocity, and has also been used previously to infer changesin autonomic activity32 and arterial pressure.33 The pressure–volume relationship ofarteries is non-linear, and as pressure decreases, elastance and pulse wave velocitydecrease and PTT is prolonged. The value of this non-invasive technology has beenassessed recently in obstetric patients receiving spinal anaesthesia.34

Management of hypotension

Management of hypotension during regional anaesthesia in obstetrics has traditionallybeen based on the results of animal experiments in pregnant ewes that were performedmainly under general anaesthesia in the 1960s and 1970s. In particular, these studiesshowed that large doses of vasopressors caused vasoconstriction in the uteroplacentalcirculation which could result in fetal hypoxia. This led to an emphasis on non-pharmacological methods of management of hypotension and the establishment ofephedrine as the vasopressor of choice in obstetric patients. However, the results ofrecent clinical research have questioned the traditional teaching and are having amajor influence on the way that we manage hypotension during spinal anaesthesia inobstetrics.

Non pharmacological methods

Non-pharmacological methods for preventing hypotension have been historicallypopular because of concern that vasopressors might have detrimental effects onuteroplacental circulation. Some authors recommended that vasopressors shouldnot be used at all until non-pharmacological methods had failed to maintain BP.35

Many non-pharmacological methods have been described but all have the commonshortcoming of limited efficacy.

Patient positioning

The use of left uterine displacement to prevent aortocaval compression is a routinein obstetric anaesthesia that is supported by history and tradition. It was in the

10 KS Khaw, WD Ngan Kee and SW Lee

1950s that Holmes originally suggested occlusion of the inferior cava by the graviduterus, compounded by a reduction of vasomotor tone, as the mechanism of suddencirculatory collapse during Caesarean section under spinal anaesthesia.36,37 Followingthe suggestions by Holmes, Crawford demonstrated the importance of lateral tiltin a series of 150 cases of Caesarean section under general anaesthesia, whenhe found blood gases and Apgar scores were better when left lateral tilt wasapplied.38

Placing the patient in the full left lateral position after spinal injection has beenshown to be associated with less hypotension or improved CO compared with thetilted supine position.39 During surgery, although Crawford recommended the useof 15 degrees lateral tilt, there is no clear evidence to support use of any particularangle of tilt and the optimal degree of tilt is still unknown. Bamber and Dresner40

studied 33 women during the third trimester in seven positions including full lateral,supine and various degrees of right and left table tilt. Apart from the full left lateralposition in which the patients’ cardiac output was significantly higher, they foundno benefit whatsoever between the untilted supine position, and the different tiltedpositions ranging from 2.5 to 12.5 degrees. Similarly, Matorras41 compared 204 womenundergoing emergency Caesaraen section of whom 30 received spinal anaesthesiaand found no benefit from a 20 degree table tilt compared with the supine position.A meta-analysis by Wilkinson42 found no significant difference in the incidence oflow Apgar scores, severe neonatal depression or fetal acidosis when lateral tilt wasused.

There is probably marked individual variability in the susceptibility to aortocavalcompression, and it is likely that only a small proportion of women undergoingCaesarean section will have it severe enough to benefit from lateral table tilt. Thisis fortuitous, since it has been shown that most anaesthetists overestimate theamount of tilt that they use during surgery.43,44 It would be useful to be able toidentify patients likely to suffer from aortocaval compression. Kinsella reported thatmothers were more prone to hypotension if prior to spinal anaesthesia they hadtachycardia in the supine position and tended to adopt a posture with their kneesbent to improve venous return.45 However, because of a high incidence of falsenegatives with such non-specific signs, its predictive value was too low to be clinicallyuseful.

Mechanical compression of lower limbs

The main mechanical method described is lower limb compression by elastic orpneumatic stockings or wrappings. All these methods aim to maintain BP byincreasing venous return to the heart46 by minimizing venous pooling of blood inthe legs or increasing the resistance of the peripheral circulation. This augmentscirculating volume and has been shown to reduce the incidence of hypotension.

Hypotension during spinal anaesthesia for caesarean section 11

However, this technique has not gained popularity, probably because it has limitedefficacy and is not viewed as convenient.

Intravenous fluid prehydration (“Preload”)

Crystalloids

Intravenous prehydration is the most popular non-pharmacological method employedfor prevention of hypotension. The rationale for prehydration is to maintain oraugment cardiac preload and CO and thus prevent or attenuate hypotension. Ifthe requirement for vasopressor drugs can be reduced, the risk of consequentuteroplacental vasoconstriction may be decreased. Common practice is to infuseapproximately 1–2 litres or 10–20 ml/kg of lactated Ringer’s solution or normal salinewhile the patient is being prepared for regional anaesthesia.

Early studies describing prehydration had impressive results and thus it becameestablished as an accepted standard of care.47 However, more recent studies haveshown that this does not reliably prevent hypotension and patients are still likelyto require rescue vasopressors. In the first paper to seriously question the efficacyof crystalloid prehydration, Rout et al.48 randomized 140 patients to receive eitherno prehydration or 20 ml/kg of crystalloid. Prehydration reduced the incidenceof hypotension only modestly from 71% (95% CI 58–81.8%) to 55% (95% CI43.4–66.4%), with both groups having the same severity, timing or duration ofhypotension. Subsequently, many reports have described that prehydration with10–30 ml/kg of crystalloid has little or no effect on the incidence of hypotensionand vasopressor requirement.49 Hence, the routine use of crystalloid prehydration isquestionable. Its poor efficacy probably reflects rapid redistribution and short clinicalhalf life. Timing appears to be crucial, and rapid crystalloid infusion of 20 ml/kggiven immediately after spinal injection (“cohydration”) is associated with lesshypotension and vasopressor requirement compared with prehydration before spinalinjection.50,51

Colloids

In contrast to crystalloids, colloid solutions have a longer intravascular half lifeand are more effective than crystalloids in reducing the incidence as well as theseverity of hypotension. Recent studies have described the use of albumin, gelatinsand hetastarch solutions, some in combination with crystalloids.44,50,52–58 Using15 ml/kg of 5% albumin, hypotension was prevented and better condition of thebaby was reported53 and when 500 ml of 6% hetastarch was used to supplementcrystalloid preload, the incidence of hypotension was halved from 85% to 45%.52

However, colloids are expensive and have potential risks of allergic reactions, disease

12 KS Khaw, WD Ngan Kee and SW Lee

transmission and fluid overload which limits general acceptance in routine clinicalpractice.

PHARMACOLOGICAL METHODS FOR MANAGEMENT OF HYPOTENSION

Modification of spinal technique

The use of the combined spinal-epidural (CSE) technique enables smaller intrathecaldoses to be used with the option of topping up the epidural catheter if the block isinadequate. Using this approach the incidence of hypotension and the vasopressorrequirement can be reduced.59 However, because of the smaller dosage, there is a riskof the patient experiencing intraoperative breakthrough pain, if epidural top ups arenot given in a timely fashion. There is some evidence that slow intrathecal injectionand use of plain anaesthetic solutions to slow the onset of spinal anaesthesia maydecrease the incidence of hypotension.60

Vasopressors

Basic pharmacology

Vasopressors drugs increase BP by increasing SVR (by vasoconstriction) and/or byincreasing CO (by increasing contractility and HR). Normally they are given intra-venously but intramuscular, and rarely, oral administration have also been described.The haemodynamic effects of vasopressors are related to their interaction withreceptors in the cardiovascular system. The receptors most relevant to the effectof vasopressors are adrenoceptors which are classified as � or �. The �-adrenoceptorsare subdivided into �1 and �2 subtypes and the major subtypes of �-adrenoceptorsassociated with haemodynamic control are �1 and �2.61 Recently, a �3 receptor hasbeen identified which is more involved with metabolic effects. The physiologicalresponse to adrenoceptor stimulation depends on the location and the typeof receptors stimulated. Postsynaptic �1-receptors in peripheral vessels mediatevasoconstriction. Stimulation of postsynaptic �1-receptors in the heart increases HRand cardiac contractility. Postsynaptic �2-receptors in the vasculature mediate vaso-dilatation.

Choice of vasopressor

The choice of vasopressor for treatment of maternal hypotension from spinalanaesthesia is controversial.62 The main issues surround efficacy and haemodynamiceffects as well as the potential for adverse effects on uteroplacental blood flow andfetal acid-base status. Early animal studies recommended ephedrine as it caused less

Hypotension during spinal anaesthesia for caesarean section 13

reduction in uterine blood flow compared with alpha agonists. However, these earlystudies have been criticized as they used experimental animal models that had limitedapplicability to clinical practice in pregnant humans.

Ephedrine

Ephedrine is a mixed � and � receptor agonist. Its mechanism is both direct (binds andstimulates receptors) and indirect (causes release of noradrenaline from presynapticvesicles). Ephedrine causes an increase in cardiac contractility, HR, CO and systolicand diastolic BP.61

Ephedrine is a well-established drug that is readily available in most countries.Most anaesthetists are familiar with its use and reports of adverse clinical outcomesfor mother or baby from ephedrine are rare. Because early animal experimentsshowed that ephedrine maintained uterine blood flow better than other vasopressors,it became the standard drug for prophylaxis and treatment of spinal hypotensionin obstetric patients,63 a belief that remains firmly ingrained in the practice ofmany anaesthetists today. However, this has been questioned by recent clinicalstudies.

Several reasons have been proposed to explain why ephedrine increased BPwith minimal effect on uteroplacental blood flow in the early animal studies.Ephedrine increases BP mainly by increasing CO via indirect stimulation of cardiac �1

receptors with a smaller contribution from vasoconstriction. Since the uteroplacentalcirculation is largely devoid of direct sympathetic innervation, it is relativelyresistant to the vasoconstrictive effects of ephedrine.64 Compared with alpha agonists,ephedrine exhibited greater selectivity for constriction of systemic (femoral) bloodvessels compared with uterine blood vessels during pregnancy.65

Ephedrine has a slow onset of action and limited efficacy in prevention and treat-ment of hypotension.66,67 Large doses may be required which increases the chances ofunwanted effects. The pharmacological effects of ephedrine of increasing cardiac SVand HR do not address the pathophysiological vasodilatation of spinal anaesthesia.Acute tolerance to ephedrine develops and phenylephrine may need to be addedwhen ephedrine is ineffective or when a large dose has been given.68 When largedoses of ephedrine are used to restore BP, sustained increases above baseline mayoccur.69 Increased HR and contractility may increase myocardial oxygen demandand may lead to unpleasant palpitations, atrial and ventricular ectopic beats andtachyarrhythmias.70

An important concern about ephedrine in obstetrics has been the associationbetween its use and a dose-related depression of fetal pH and base excess.71–74

Metaanalysis showed that umbilical arterial pH is significantly lower with the useof ephedrine compared with phenylephrine (Figure 2).71 and a multivariate analysisshowed use of ephedrine to be a major factor predicting low umbilical arterial pHand base excess.74 When ephedrine is used aggressively in doses required to reliablyprevent maternal nausea and vomiting, very low values of umbilical arterial pH and

14 KS Khaw, WD Ngan Kee and SW Lee

Figure 2 Metaanalysis of trials comparing phenylephrine and ephedrine for management of hypotensionduring spinal anaesthesia for Caesarean section. Figure shows the effect of choice of vasopressor on umbilicalcord arterial pH. Data are mean difference with 95% confidence intervals. (Adapted from Lee A, Ngan KeeWD, Gin T71).

base excess are sometimes seen.67,72 This is an important limitation to the use ofephedrine.

How ephedrine depresses fetal pH and base excess more than other vasopressors isunknown. Since data from animal studies suggest that it exerts the least influence onuteroplacental blood flow, fetal hypoxia appears unlikely. An alternative explanationis a direct stimulating effect on fetal metabolism73,74 since ephedrine has metabolicstimulatory effects which has led to its use for weight loss75 and athletic performanceenhancement in adults.76 Metabolic stimulation is particularly noted in brownadipocytes and is thought to be mediated by stimulation of �-adrenoreceptors77

although the relative importance of the �1, �2 and �3 receptors has been debated.78,79

Ephedrine crosses the placenta and increases fetal catecholamine concentrations.80,81

An increase in umbilical arterial norepinephrine concentrations was shown tocorrelate with decreasing pH.80 Maternally-administered ephedrine increases fetalHR82 and in clinical practice, a fetal tachycardia can often be observed on thecardiotocograph when large doses of ephedrine are given before delivery. Supportinganimal evidence for a metabolic effect in the fetus is found in the observation that infetal lambs, � stimulation increased oxygen consumption and lactate concentrationsand decreased blood pH.83 In a clinical study, Cooper et al.73 showed that fetalacidaemia induced by ephedrine was associated with an increasing umbilical arterio-venous PCO2 difference; this is suggestive of increased CO2 production in the fetusand is evidence for an ephedrine-induced increase in fetal metabolic rate.

The clinical significance of the observation of fetal acidosis induced by ephedrineis still unclear, since evidence for a measurable clinical adverse effect is lacking.

Hypotension during spinal anaesthesia for caesarean section 15

Table 1 Maternal and neonatal outcome during spinal anaesthesia for caesarean section with infusion ofphenylephrine 100 µg/min titrated to different values of maternal systolic BP. Data are number (%), median[range] or mean (SD). (Adapted from: Ngan Kee WD, Khaw KS84).

Targeted maternal systolic blood pressure

80% of baseline(n = 25)

90% of baseline(n = 25)

100% of baseline(n = 25) P

Hypotension incidence 24 (96%) 18 (72%) 7 (29%) <0.001Total number of incidence of

hypotension5 [0–18] 2 [0–7] 0 [0–8] <0.001

Nausea or vomiting 10 (40%) 4 (16%) 1 (4%) 0.006Maternal bradycardia (heart

rate < 50 beats/min)5 (20%) 8 (32%) 3 (8%) 0.25

Uterine artery pH 7.30 (0.03) 7.30 (0.03) 7.32 (0.04) 0.036Uterine artery base excess

(mmol/l)−1.9 (2.4) −1.8 (1.7) −1.6 (2.7) 0.93

However, this does not necessarily mean that ephedrine-induced fetal acidosis isharmless as the majority of studies in this area have been performed in low-riskelective cases in which the neonatal outcome is expected to be good, regardless of thetechnique of anaesthesia. However, in the presence of conditions which may result inan adverse fetal outcome, the contribution of ephedrine may have clinical importance.Particularly, an increase in oxygen consumption caused by ephedrine may compoundobstetric causes of fetal hypoxia.

Phenylephrine

Phenylephrine is chemically related to adrenaline but pharmacodynamically similarto noradrenaline. It is a potent, rapidly-acting vasopressor with a short duration ofaction that selectively stimulates �1 adrenoreceptors with very little activity on the �1

adrenoreceptors of the heart. It increases systolic and diastolic BP in a dose-dependentmanner based purely on its �1 adrenoreceptor action.

Traditionally phenylephrine was reserved as a second-line drug for obstetricsbecause of concern about potential uteroplacental vasoconstriction. However, theserecommendations for practice were extrapolated from the results of the animalexperiments with few corroborating clinical data. These early studies, performedover 30 years ago, often used animals which were administered general ratherthan spinal anaesthesia and vasopressors were often titrated to increase BP abovebaseline values. This is a poor representation of treatment of hypotension inducedby spinal anaesthesia, when vasopressors are used to restore BP towards normalvalues. In fact, recent clinical studies have failed to show any evidence of adversefetal or neonatal effects when this class of drug is used in normal term pregnancy.

16 KS Khaw, WD Ngan Kee and SW Lee

Figure 3 Comparison of phenylephrine infusion and rapid crystalloid cohydration (Group 1) withphenylephrine infusion alone (Group 0) for preventing hypotension during spinal anaesthesia for caesareansection. Kaplan-Meier survival curve showing that the proportion of patients remaining not hypotensive untiluterine incision was greater in Group 1 versus Group 0 (P = 0.0002). The incidence of hypotensionwas 1.9% (95% confidence interval 0.3–9.9%) in Group 1. (Adapted from: Ngan Kee WD, Khaw KS,Ng FF50).

Since the pathophysiological basis of spinal anaesthesia-induced hypotension isvasodilatation, logically, it makes sense to use a vasoconstrictor. At doses titratedto maintain maternal BP near to baseline, the incidence of side effects such asnausea and vomiting in the mother can be reduced without any clinical evidenceof fetal acidosis84,85 (Table 1). Accordingly, phenylephrine has been the first-linevasopressor used in the authors’ practice for several years. To date, the only techniquethat has been shown to effectively prevent hypotension is the combination of aphenylephrine infusion at a high-dose with simultaneous rapid crystalloid infusion50

(Figure 3).However, some caution is appropriate with the use of phenylephrine. Few data

are available for its use in preterm, emergency, labouring or hypertensive patients,or in cases where there is preexisting fetal compromise. A reflex decrease in HRis common with phenylephrine which may occasionally require treatment withan anticholinergic drug.86 A decrease in CO may accompany the decrease in HRalthough the clinical importance of this is uncertain.87 Phenylephrine is commonlysupplied commercially as a 10 mg/ml preparation and care is required to avoid dosageand dilution errors.88 Some anaesthetists who are used to using ephedrine may be

Hypotension during spinal anaesthesia for caesarean section 17

Figure 4 Hypotension managed using phenylepherine infusion, commenced after the injection of spinalanaesthesia.

unfamiliar with the characteristics of phenylephrine. Compared with ephedrine, it hasgreater efficacy for increasing BP, thus excessive dosing may result in hypertension andreflex bradycardia. The short duration of phenylephrine means that it is best suitedto delivery by infusion (Figure 4) as intermittent bolus administration may producemarked fluctuations in BP (Figure 5). A recent study suggested that rostral spread ofspinal anaesthesia may be reduced when a phenylephrine infusion is used, but theclinical importance of this is undetermined.89

Metaraminol Metaraminol is a potent vasoconstrictor that acts both directlyon the �1 adrenoreceptor and indirectly by stimulating the release of endogenousnoradrenaline.61 At low doses metaraminol also stimulates the �1 adrenoreceptorsand has a positive inotropic effect, resulting in increase in contractility and CO. Bothsystolic and diastolic BP are increased with occasional reflex bradycardia. Similar tophenylephrine, infusion of metaraminol resulted in better fetal acid-base status withno difference in uterine artery pulsatility index compared with ephedrine.69 However,metaraminol is not available in all countries.

Combinations of vasopressors It is possible that using a combination of vaso-pressors may derive the benefits of the individual agents and address the deficiencyof the others. For example, in combination with phenylephrine, the positivechronotropic and inotropic effects of ephedrine may be useful to counter the reflexdecreases in HR and CO that phenylephrine may induce. Several authors have reported

18 KS Khaw, WD Ngan Kee and SW Lee

Figure 5 Hypotension in a patient managed with intermittent bolus doses of phenylepherine 100 µg. Notethat the ‘saw tooth’ pattern of blood pressure recordings.

the use of combination of phenylephrine and ephedrine together73,90,91 with a lowerincidence of maternal bradycardia and a lower incidence of nausea and vomiting.However, the optimal combination ratio is unknown and there is little evidence thatthis approach is superior to phenylephrine alone.73

Methods of using vasopressors

Use of vasopressors to prevent hypotension (prophylactic vasopressors)

Although vasopressors unquestionably have a role in the treatment of hypotension,their prophylactic use is more controversial. With an incidence of up to 90%–100%, hypotension during spinal anaesthesia for caesarean section it almost aninevitable complication. Spinal anaesthesia has a very rapid onset and the motheris particularly vulnerable to hypotension in this period until delivery of the baby.Therefore, the prophylactic use of vasopressors to prevent hypotension, particularlythat occurring in the first few minutes after intrathecal injection, is logical. However,there is controversy about the efficacy, choice, route and timing of prophylacticvasopressors as well as the potential for adverse maternal and fetal effects. Because theincidence of hypotension is smaller in patients who are in labour and in patients withpreeclampsia, there is less support for the use of prophylactic vasopressors in thesepatients.

Hypotension during spinal anaesthesia for caesarean section 19

Figure 6 Risk of benefit (prevention of hypotension) compared with risk of harm (reactive hypertension)for doses of ephedrine between 0 and 30 mg. Baseline risk of hypotension was assumed to be 80% and ofhypertension 11%. The threshold at which benefit and harm are equal is at 14 mg.

Intramuscular injection

This route of administration has the advantage of simplicity; however it is unusualfor anaesthetists in general to use this route of administration of drugs. Withintramuscular administration, as well as patient discomfort, variable absorptionmeans there may be uncertainty about the onset of effects. Many studies haveshown this route to be of limited efficacy or reliability, with significant variabilityin the onset of effect. While intramuscular doses of ephedrine in doses of 25–50 mgdid not adequately prevent hypotension, in some cases hypertension was induced.Phenylephrine in doses of 2–4 mg has also been described. Although some studieshave shown a reduction in the incidence and severity of hypotension, this is notconsistent, indicating that efficacy is variable and dose-related. Although reactivehypertension was described in early studies, this was not confirmed in later studies.Lower umbilical cord blood pH has been reported with intramuscular ephedrine whichappears to be dose-related.

Intravenous boluses of vasopressors

Bolus intravenous injection of vasopressor is simple and avoids the extra effort andtime needed to set up an intravenous infusion. Use of prophylactic boluses ofephedrine is common practice by some anaesthetists. However, application ofquantitative analysis methodology showed a significant dose-response relationshipfor preventing hypotension but also showed that dose was directly related to reactivehypertension and inversely related to umbilical arterial pH.92 By plotting the absoluterisk difference for hypotension and hypertension against dose (Figure 6), it was foundthat the largest dose for preventing hypotension where a small benefit outweighs the

20 KS Khaw, WD Ngan Kee and SW Lee

risk of reactive hypertension was 12 mg. At this dose, the number-needed-to-treat(NNT) was 8.8 (95% CI: 5.5 to 24.5) and the number-needed-to-harm (NNH) was9.4 (95% CI: 4.7 to 27.9). Doses greater than 12 mg did not eliminate hypotension,but caused reactive hypertension (at 30 mg the ratio of harm to benefit was almost 2to 1) and a decrease in umbilical arterial pH; conversely with doses less than 12 mgthere was only a small reduction in the risk of hypotension. The conclusion was thatprophylactic intravenous bolus ephedrine was not recommended.

Intravenous infusion of vasopressors

Intravenous infusion of vasopressors ideally requires the use of an infusion pumpalthough a simple system can be quickly set up by injecting a bolus into an intravenousfluid bag. Infusions of ephedrine,66 metaraminol,69;93 phenylephrine84;85 and mixturesof ephedrine and phenylephrine73,90 have been described, however, there is a risk offetal acidosis if ephedrine is used.69,71,73 If phenylephrine or metaraminol are used,decreases in maternal HR are common but this is usually baroreceptor-mediated andresolves on cessation of vasopressor administration, although an anticholinergic drugmay occasionally be required. Conversely, with ephedrine very high maternal HRmay occur which may be undesirable in some patients. Recently it was shown thatan infusion of phenylephrine even in high doses (100 µg/min) did not cause fetalacidosis84,85 and that the optimal regimen appeared to be to titrate phenylephrine asrequired to achieve values of maternal BP near to baseline84 (Table 1). This effectivelyreduced maternal symptoms without causing adverse effects in the fetus. Mixture ofphenylephrine and ephedrine have also been described and shown to result in betterfetal acid-base status compared with ephedrine alone.73 Although this approach maybe useful to reduce the incidence of maternal bradycardia, available data show a greaterincidence of nausea and vomiting and no improvement in fetal blood gases comparedwith phenylephrine alone and so it was not recommended.73

Vasopressors in the complicated parturient

Preeclampsia

The optimal anaesthetic technique for Caesarean section in preeclamptic womenremains controversial, but recent studies have suggested that spinal anesthesia canbe safely used. Previously, there has been concern that because of the intravascularvolume contraction from the severe vasoconstriction in preeclampsia, the sympathec-tomy from spinal anaethesia could result in catastrophic hypotension. There arenow several studies to show that this is not the case and spinal anaesthesia inseverely preeclamptic patients may even result in a lower incidence of hypotensioncompared with normotensive patients.94–99 Preeclamptic patients have a reducedintravascular volume, leaky capillary membranes and a low albumin concentrationwhich predisposes them to pulmonary oedema. However, poor renal perfusion from

Hypotension during spinal anaesthesia for caesarean section 21

a low CO state may lead to oliguria. Strict fluid management, sometimes guidedby measurement of central venous or pulmonary artery occlusion pressure, may berequired. The optimal vasopressor in patients with preeclampsia is undertermined.

Cardiac disease

A full discussion of the anaesthetic management of parturients with cardiac diseaseis beyond the scope of this review. Increasingly, regional anaesthesia is now beingused in cases where general anaesthesia would previously have been consideredmandatory.100,101 For example, patients with stenotic valvular lesions or cyanoticcardiac diseases are traditionally considered the most at risk from the haemodynamicdisturbance of regional anaesthesia. However, with improvements in haemodynamicmonitoring techniques, as well as an emphasis on controlling or limiting the onset ofblock, regional anaesthesia is becoming more accepted as an alternative. In particular,the CSE technique has gained popularity in many centres. Use of CSE permits the useof a smaller dose of spinal drug followed by fractionated epidural top up if required.Changes in BP are thus likely to be slower and less severe than during single-shotspinal anaesthesia. For management of hypotension, ephedrine may cause undesirabletachycardia and phenylephrine given as small boluses or infusion is probably a betterchoice in these circumstances.

SUMMARY

Most women who have Caesarean section will receive spinal anaesthesia. Hypoten-sion is the most common problem, and requires prompt treatment to avoid maternalsymptoms and fetal acidosis. Rapid detection of hypotension will minimize theperiod of untreated hypotension, and non-invasive BP measurements cycled at 1-min intervals is recommended. New non-invasive monitors are now capable ofmeasuring BP on a beat-to-beat basis and monitors that measure parameters suchSV, CO or SVR have potential to play a predictive role in anticipating and preventinghypotension. Non-pharmacological prophylaxis of hypotension is popular, but theclinical efficacy and practicality of procedures such as leg wrapping is questionable.Crystalloid prehydration is a common ritual despite its lack of efficacy. Colloidsolutions are more effective but there are limitations to their use. Recent research hasaddressed the controversy about the choice and use of vasopressor. Although use ofephedrine is supported by history, it has limited efficacy and there are concerns aboutits propensity to cause fetal acidosis. Evidence from recent clinical trials suggeststhat concerns about uteroplacental vasoconstriction caused by phenylephrine areunfounded and this is the authors’ drug of choice. Suggested infusion and bolusregimens for prevention of hypotension are shown in Figure 7. Aggressive use ofphenylephrine to maintain maternal BP near to baseline values reduces maternalsymptoms without causing fetal acidosis. A combination of phenylephrine infusion

22 KS Khaw, WD Ngan Kee and SW Lee

Figure 7 Suggested regimens for prevention of hypotension.

and simultaneous intravenous fluid loading can reduce the incidence of hypotensionnear to zero, thus addressing a perennial problem that has plagued spinal anaesthesiain obstetrics for over a hundred years.

LEARNING POINTS

1 Hypotension during SA occurs frequently 55%–90%2 Crystalloid preload is ineffective and colloid is better3 Ephedrine has poor efficacy in preventing hypotension4 Side effects of ephedrine includes maternal tachycardia and fetal acidosis5 Phenyephrine is more efficient for treating and preventing hypotension6 Phenyephrine may cause maternal bradycardia but does not cause fetal acidosis

Hypotension during spinal anaesthesia for caesarean section 23

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