Br. j. Anaesth. 1995 Critchley 373 8

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British Journal of Anaesthesia 1995; 74: 373-378

Hypotension during subarachnoid anaesthesia: haemodynamiceffects of ephedrineL. A. H. CRITCHLEY, J. C. STUART, F. CONWAY AND T. G. SHORT

SummaryWe have compared the haemodynamic effects ofephedrine alone with ephedrine and colloid for thetreatment of hypotension produced by sub-arachn oid anaesthesia in 30 patients aged 60-90 yrwith fractures of the neck of femur. Group onereceived ephedrine as an initial bolus dose of0.2 mg kg~1 followed by an infusion of0.5 mg kg"1 hr1. Group two received ephedrine andcol loid (polygeline, Haemaccel) 8 m l k g - 1 . Ifnecessary, up to three rescue bolus doses ofephedrine (0.1 mg kg"1) and then colloid solution(8 ml kg"1) were given to maintain systolic arterialpressure (SAP) at > 75% of baseline. Arterialpressure was measured by automated oscillo-tonometry, central venous pressure (CVP) by amanometer and cardiac index (Cl), stroke index(SI) and heart rate (HR) by transthoracic electricalbioimpedance. Systemic vascular resistance index(SVRI) was derived. In patients receiving ephedrineonly, SVRI, CVP and SIdecreased and HR increased(P < 0.0001). Five patients in this group requiredcolloid, the effect of which was to restore CVP,increase Cl and SI, and decrease HR (P


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374 British Journal of Anaesthesiafacturing Ltd, Irvine, CA, USA). It was connectedto the patient according to the manufacturer'sinstructions [5]. The method used to derive cardiacoutput has been presented previously [6, 7 ]. Datawere indexed to the patient's body surface area andthe average of 16 beats recorded. The variablesrecorded were cardiac index (CI), stroke index (SI)and HR. Using custom-made software, these datawere acquired continuously by an IBM-compatiblelap-top computer onto a spreadsheet file (MicrosoftExcel, Version 4.0) for later analysis. Arterialpressure and TEB data were collected for 3-5 minbefore the patient was turned to the lateral positionfor subarachno id pu ncture an d continued for at least25 min afterwards. CV P measurements were madebefore turning the patient and at 5-min intervalsafter starting the subarachnoid block.Using blocked randomization with sequentiallynumbered sealed forms, patients were allocated toone of two treatment regimens for hypotension:ephedrine alone or ephedrine combined with acolloid infusion. Immediately after injection ofbupivacaine, all patients received ephedrine as aninitial bolus of 0.2 mg kg"1 followed by an infusion of0.5 mg kg"1 h" 1. In the colloid group a rapid infu-sion of 3.5 % polygeline 8 ml kg"1 (Haemaccel,Behringwerke, Marburg, Germany), given over2-4 min, was commenced immediately after injectionof bupivacaine. We aimed to maintain SAP > 75 %of the value before block. If SAP decreased belowthis limit on two consecutive readings, the patientreceived a rescue bolus dose of ephedrine0.1 mgkg"1 . If the third rescue bolus was unsuc-cessful, the patient was given po lygeline 8 ml kg"1and the infusion rate of ephedrine doubled.The level of sensory loss to pinprick was assessed30 min after subarachnoid block by an independentobserver who was blind to the treatment regimen.When data collection was completed, anaesthesiawas continued according to standard practice andsurgery allowed to start.D A T A A N A L Y S I S A N D S T A T I S T I C SStatistical analysis was performed on a Macintoshcomputer (Apple Computer, Inc, CA, USA) usingthe software package Statview 4.02 (AbacusCo ncep ts, In c). Patient characteristics, total dose ofephedrine and the incidence of rescue treatment inthe two treatment groups were compared usingStudent 's t test or chi-square test as appropriate.Patients were classified as hypertensive if they had abaseline S A P > 160 mm H g or if they were receivingregular treatment for hypertension. The sensorylevels of the block were treated as non-parametricdata and were compared using a Mann-Whitney Utest. The haemodynamic data collected before sub-arachnoid block were averaged to give the baselinevalues, which were compared between the twotreatment groups using Student's t test.

When analysing the haemodynamic changes dur-ing subarach noid block, those patients who receivedrescue colloid in the ephedrine only group wereexcluded from the main group and analysed sep-arately.

SVRI was calculated using the formula:S V R I = ( M A P - C V P ) x 8 0 / C I

where MAP = mean arterial pressure and CVP wassubstituted for right atrial pressure.Continuously recorded haemodynamic data wereaveraged for each 1-min interval during the first25 min of subarachnoid block. T hese data werecompared within each treatment group and betweentreatment groups using analysis of variance forrepeated measures (ANOVA-RM). The times aftercommencing the block at which the changes in eachvariable became significant (P < 0.05) were deter-mined by performing multiple paired Student's ttests.Th e magnitude of the haemodynamic changes thatoccurred during subarachnoid block for each vari-able was calculated by comparing the percentagechanges with baseline for each 1-min interval afterthe block and then taking the mean value for the10-25-min period after the block. For CVP nu-merical difference rather than percentage change wasused. Th e m agnitude of the haemodynamic changesthat occurred after rescue with ephedrine boluseswas calculated in a similar ma nner by com paring the2-4-min period after rescue with the 2-min periodbefore. Comparisons were made using Student's ttest. P < 0.05 was considered significant and resultsare given as mean (SD).The power of the study was examined using thestandardized difference on the magnitude of thechanges in SAP before the design demanded in-tervention. A 25% change from a mean systolicpressure of 150 (S D 30) mm H g indicated that 15patients in each group would b e sufficient to detect asignificant difference at a power of 0.8.ResultsFifteen patients were studied in each group. Patientdata, characteristics of the subarachnoid block andbaseline haemodynamic data are shown in tables 1and 2. The two groups were similar in age, weight,height, ASA status, sex distribution, level of sensoryblock at 30 min and baseline haemody namic

Table 1 Patient characteristics, volume of bupivacaine, thesensory level (thoracic dermatome) to pinprick after 30 min ofsubarachnoid block and dose of ephedrine administered over30 min in patients given ephedrine only or ephedrine andcolloid to prevent hypotension during subarachnoid block(mean ( S D or range) or number). ** P < 0.01 between groups

Age (yr)Weight (kg)Height (cm)Sex (M/F)ASA status ( I I / I I I )HypertensiveBupivacaine 0.5 %(ml)Sensory level (T)Ephedrine dose(mg)

Ephedrine only(" = 15)79 (65-93)47(6)154 (10)3/1213/272.7 (0.2)

5(3-9)28 (19-43)**

Ephedrine and colloid(n = 15)74(60-89)49(11)155 (8)6 / 911/472.8 (0.3)

5(3-7)23 (16-35)**

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Ephedrine during subarachnoid anaesthesia 375Table 2 Baseline haemodynamic variables (mean (SD)) inpatients treated with ephedrine only or ephedrine and colloid toprevent hypotension during subarachnoid block. SAP =Systolic arterial pressure, MAP = mean arterial pressure, SVRI= systemic vascular resistance index, CVP = central venouspressure, CI = cardiac index, SI = stroke index and HR =heart rate. No significant differences between groups

SAP (mm Hg)MA P (mm Hg)SVRI (dvn s cm"5 m" 2)CVP (cm H 2O )CI (litre min-1 m 2 )SI (ml rrr2)HR (beat min"1)

Ephedrine only( = 15)150(29)106(18)2869 (942)4.5 (2.5)3.1 (0.8)35(8)88(10)

Ephedrine andcolloid( = 15)

155 (30)109(19)3172(841)5.9(1.9)2.8 (0.9)32(12)91 (16)

Table 3 Percentage changes (A) or num erical difference (Diff.)(mean (SD)) compared with baseline values for haemodynamicvariables, for the established effects of subarachnoid block inthe two treatment groups (10-25 min). Results from patientsrequiring rescue colloid in the ephedrine only group arepresented separately. SAP = Systolic arterial pressure, MAP =mean arterial pressure, SVRI = systemic vascular resistanceindex, CVP = central venous pressure, CI = cardiac index, SI= stroke index and HR = heart. *P < 0.05, **P < 0.01compared with baseline values

ASAP (%)AMAP (%)ASVRI (%)Diff. CVP(cm H 2O )ACI (%)ASI (%)A H R ( % )

Ephedrine only

( = 10)- 1 8 ( 1 3 ) * *- 1 7 ( 7 ) * *- 1 7 ( 1 5 ) * *-2.8(2.4)**

4(14)- 1 8 ( 9 ) * *27 (12)**

Rescue colloid( = 5)- 2 6 ( 1 1 ) * *- 2 7 ( 9 ) * *- 4 2 ( 1 0 ) * *0.5(1.5)

25 (10)**16(12)*9(6)*

Ephedrine andcolloid( = 15)- 1 3 ( 1 4 ) * *- 1 8 ( 1 5 ) * *- 2 7 ( 1 3 ) * *0.5 (2.4)

13(19)**5(15)9(10)**

variables. Significantly more patients received rescuetreatment in the ephedrine only group (chi-square:P < 0.005). Rescue treatm ent w as used in 11patientsin this group and in three patients in the ephedrineand colloid group. Patients in the ephedrine onlygroup received more ephedrine during the 30-minstudy period (P = 0.01).Fourteen hypertensive patients were included inthe study. In the ephedrine only group, one patientwas receiving a beta blocker and in the ephedrineand colloid group two patients were receivingcalcium channel blockers and two patients thiazidediuretics. Hypertensive patients were distributedevenly between the treatment groups, includingthose patients that required rescue colloid.Five patients in the ephe drine only group received,in addition to ephedrine boluses, rescue treatmentfor hypotension with i.v. polygeline 8 ml kg"1, whichwas started between 10 and 20 min after the block.Patient data and baseline haemodynamic variables inthese patients were similar to those of the otherpatients in the study, with the exception of CI (3.8(0.9)) which was greater than the baseline values ineach of the two main treatment groups (P < 0.05).Haemodynamic data from these five patients are

shown separately from the two main treatmentgroups (table 3 , fig. 1). Haemodynamic changes aftersubarachnoid block are shown in figure 1. Themag nitude of these effects between 10 and 25 min ispresented in table 3.ANOVA-RM of the haemodynamic data for theephedrine only group, excluding those patients whorequired rescue colloid, showed significant decreasein SAP, M A P, S VR I, CVP and SI and an increase inHR (P < 0.0001). These changes became significant(P < 0.05) after 6 min for SA P, M A P and SV R I,after 5 min for C VP , after 1 min for SI and after2 min for HR. No significant change occurred in CI.ANOVA-RM of the haemodynamic data for theephedrine and colloid group showed significantdecreases in SAP, MAP and SVRI and increases inCVP, CI, SI and HR (P < 0.0001). These changeswere significant (P < 0.05) after 9 min for SAP, after5 min for M A P, after 2 min for S VR I, after 5 min forCVP, between 3 and 12 min for C I, between 4 a nd10 min for SI and after 1 min for HR. When thehaemodynamic data between the two groups werecompared using ANOVA-RM, there were nosignificant differences in the degree of decrease inSA P, M A P, and SVR I. In the ephedrine only group,CVP and SI were significantly lower and HR wassignificantly higher tha n in the ephedrin e and colloidgroup (P < 0.05).

ANOVA-RM of the haemodynamic data for thefive patients that required rescue colloid showed thatafter sub arachnoid block and before rescue treatm entthere were significant decreases in SA P, M A P,SVR I and CV P and an increase in HR (P < 0.0001).Th ese changes were significant (P < 0.05) after5 min for SAP, after 1 min for M A P, after 2 min forSV R I, after 5 min for CV P and after 3 min for H R .There were no significant changes in CI or SI. Afteradm inistration of rescue colloid, significant increasesoccurred in CVP, CI, SI and a decrease in HR(P < 0.0001). N o significant changes o ccurred inSA P, MAP or SVRI. When haemodynamic datafrom these five patients were compared with datafrom the two main treatment groups using AN O VA -R M , there w ere significant differences in all haem o-dynamic variables except SVRI (P < 0.01).

Bolus doses of rescue ephedrine (O.lmgkg"1)were given on 19 occasions to 14 patien ts. T he effectwas to increase S A P by 5 (5) %, MA P by 5 (5) % an dSV RI by 4 (5)% (P < 0.01). N o significant effectsoccurred in CI, SI or HR.Discuss ionWe found that ephedrine alone, in doses of 20-40 mg, was inadequate for treatment of hypotensionin one-third of our patients. This was becauseephedrine caused only a small increase in SVRI anda large increase in H R . C VP decreased but this couldbe corrected by infusion colloid. T he com bination ofephedrine and colloid caused an increase in CI, amajor factor in maintaining SAP in this group.

TEB provided a simple, non-invasive method ofassessing changes in stroke volume and cardiacoutput. It has been shown to follow pharmaco-logically induced changes in stroke volume with a


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37 6 British Journal of Anaesthesia160-

5 10 15Time (min) 2 5 10 15Time (min) 20 25Figure 1 Mean (SEM) haemodynamic variables at baseline (0 min) and during the first 25 min of subarachnoidblock for the two groups of patients, including those patients in the ephedrine only group that required rescuecolloid. = Eph edrine only ; = ephedrine and colloid; = rescue colloid.

coefficient of variation of 7.8 % [8] and has been usedsuccessfully in several studies to measure changes instroke volume and cardiac outpu t during b oth spinaland general anaesthesia [4,9-12]. Non-invasivearterial pressure recorded at 1-min intervals wassufficiently accurate to measure the changes in SAP.Individual readings have been shown to have a 1 0 % variability [13] and in order to minimizeerrors, treatment was started only after two con-secutive low readings.W e chose to study elderly patients requiringemergency surgery for traumatic femoral headfractures. Appropriate treatment of hypotensionduring subarachnoid block is clinically important inthis group because of the high postoperative mor-bidity and mortality [14, 15]. W e also found th at thisgroup was highly susceptible to hypotension [16].H oweve r, all patients in the presen t study were giveni.v. fluids before operation and were haemo-dynamically stable before surgery. The dose regimen

for ephedrine was based on the findings of previousstudies. An initial bolus was given so that atherapeutic concentration could be attained rapidlyand an infusion was used in order to improve thecontrol over dosage and to prevent unnecessaryepisodes of hypertension.Greene and Brull have extensively reviewed theliterature on hypotension during subarachnoid block[3]. They concluded that the main mechanisminvolved was sympathetic block causing arterial andvenous dilatation. Arterial dilatation results indecreases in total peripheral resistance and SAP ofup to 30%. However, venous dilatation can causesevere hypotension as a result of a decrease in venou sreturn and cardiac output. They considered thatrestoring venous filling pressure by fluid ad-ministration or headdown tilt was the most importantmethod of treatment and that it was more appropriateto use a vasopressor that increased cardiac output inaddition to total peripheral resistance.


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Ephedrine during subarachnoid anaesthesia 377In previous studies of elderly patients receivingsubarachnoid block, Coe and Revanas found thatpreloading was ineffective in preventing hypotensionin 60% of healthy elderly patients with blocks abovethe seventh thoracic dermatome and recommendedthe use of ephed rine [17]. Hem mingsen, Poulsen andRisbo found that elderly ASA II and III patients

were particularly at risk of hypotension and alsorecommended the use of ephedrine [18]. Previously,we also found that ephedrine was more effective thanpreloading but not as effective as the alpha agonistmetaraminol [4]. These studies support the use ofephedrine in treating hypotension during sub-arachnoid block and the present study is the first, toour knowledge, to demonstrate how ephedrine exertsits effect.We found significant decreases of up to 42 % inSVRI following subarachnoid block. These de-creases were not treated adequately by the eph edrineboluses or infusion. Bolus doses of 0.1 mg kg 'increased SVRI but by only 5 %. Ephedrine vaso-constricts the arterial and venous systems, andstimulates the heart. A rterial vasoconstriction resultsfrom stimulation of alpha adrenergic receptors.However, the beta2 adrenergic activity of ephedrineresults in vasodilatation of blood vessels, the mostprominent effect being on skeletal muscle. Thevarious vascular beds respond differently to alphaand beta2 stimulation and to what extent vaso-dilatation opposes vasoconstriction when ephedrineis used is unreported. However, the coexistence ofarterial vasodilatation may account for our findingthat ephedrine had only a limited ability to increaseSVRI. It is also possible that tachyphylaxis wasresponsible for the limited response or that doses ofephedrine used in the study were too low, albeitsimilar to those used in previous studies.When ephedrine was used alone to treat hypo-tension, CVP and SI decreased. In a previous studywe found decreases in CVP of 2.5 cm H 2O and SIof 7-13% when SAP was decreased by 25% [16]and Greene and Brull also reported decreases inCVP of 1.5-2.0 cm H 2O in adult patients aftersubarachnoid block [3]. These decreases are similarto those in the present study and support ourfindings that eph edrine does not prevent the decreasein venous filling pressure during SAB. Ephedrineboluses also had no dem onstrable effect on C VP andS I. Hence, ephedrine appears to have no significantaction as a venoconstrictor during subarachnoidblock in elderly patients in the doses used in thepresent study.When ephedrine was used in combination withcolloid solution, either treatment or rescue, CIincreased by 13-25%. The increased in CI was animportant factor in maintaining SAP, as neitherephedrine nor colloid increased SVRI significantly.Administration of colloid seemed to play an im-portant role in enabling CI to increase, as decreasesin CVP were prevented and venous filling pressureand end-diastolic volume were maintained. In agree-ment with the findings of our previous study [16],polygeline 8 ml kg 1 proved to be a suitable volume.In the ephedrine and colloid group, the increase inCI was caused in part by the 9% increase in HR.

H owever, SI increased also despite a small change inCVP and hence the increase in SI cannot beaccounted for purely by an increase in end-diastolicvolume. It seems most likely that SI increased as aresult of an increase in contractility resulting fromthe inotropic effect of ephedrine.Previously, we have found that HR increased by8-13% in elderly patients when SAP decreased by25 %. The increase in HR was related to the severityof hypotension and returned to baseline on cor-recting the venous filling pressure with colloidsolution [16]. T his finding c ontradicted the review ofthe subject by Greene and Brull, who reported thatH R decreases during SA B [3]. In the present study,significant increases in HR occurred, especially inthe ephedrine only group, where HR increased by2 6 % , and administration of colloids, whether treat-ment or rescue, reduced this increase to 9 %. Thesefindings probably demonstrate the chronotropicaction of ephedrine. Reilly commented on theundesirability of using vasopressors that causetachycardia, especially in patients with coronaryartery disease because of the risk of precipitatingmyocardial ischaemia [19]. In the ephedrine onlygroup, the increase in HR of 26% would beundesirable in some patients.

Our findings demonstrate that fluid loading withcolloid has an important part to play when ephedrineis used to prevent hypotension during subarachnoidblock. We found that ephedrine in the doses used inthe study had only limited action as a peripheralvasoconstrictor and relied on its ability to increasecardiac outpu t in order to maintain S A P. T his abilitywas enhanced by fluid loading. In patients withsevere ischaemic heart disease or renal disease, whereincreases in cardiac output or fluid volume areundesirable, hypotension would be treated moreappropriately with an infusion of a pure peripheralvasoconstrictor.

References1. Macrae AF, Wildsmith JAW. Prevention and treatment ofhypotension during neural block. British Journal of An-aesthesia 1993; 70: 672-680.2. Atkinson RS , Rushman GB , Alfred Lee J. S pinal anaesthesia:intradural; extradural. In: Atkinson RS, Rushman GB,Alfred Lee J, eds. A Synopsis of Anaesthesia, 10th Edn.Bristol: Wright, 1987; 662-721.3. Greene NM , Brull SJ. Th e cardiovascular system. In : GreeneN M , Brull SJ , eds. Physiology of Spinal Anaesthesia, 4th Edn.Baltimore: Williams and Wilkins, 1993; 85-177.4. Critchley LA, Short TG, Gin T. Hypotension duringsubarachnoid anaesthesia: haemodynamic analysis of threetreatments. British Journal of Anaesthesia 1994; 72: 151-155.5. BoMed Ltd. Prepare the patient. In: BoMed Ltd, ed.NCCO M3 - R7 S Cardiodynamic Monitor Operator's Manual.Irvine, CA 92718, USA: BoMed Ltd, 1991; 15-17.6. Bernstein D P. A new stroke volume equation for thoracicelectrical bioimpedance: theory and rationale. Critical CareMedicine 1986; 14: 904-909.7. Kubicek WG, Kottke J, Ramos MU, Patterson RP, WitsoeDA, Labree JW, Remole W, Layman TE, Schoening H,Garamela J T . The Minnesota impedance cardiograph-theoryand applications. Biomedical Engineering 1974; 9: 410-416.8. Thomas SH. Impedance cardiography using the Sramek-Bem stein metho d: accuracy and variability at rest and duringexercise. British Journal of Clinical Pharmacology 1992; 34:467^176.9. Critchley LA, Critchley JA, Gin T. Haemodynamic changes


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378 British Journal of Anaesthesiain patients undergoing laparoscoptc cholecystectomy:measurement by transthoracic electrical bioimpedance.British Journal of Anaesthesia 1993; 70: 681-683.10. Sanders DJ , Jewkes CF , Sear JW , Verhoeff F, Foex P.Thoracic electrical bioimpedance measurement of cardiacoutput and cardiovascular responses to the induction ofanaesthesia and to laryngoscopy and intubation. Anaesthesia1992; 47: 736-740.11. Vohra A, Thom as A N, H arper N J, Pollard BJ. N on-invasivemeasurement of cardiac output during induction of an-aesthesia and tracheal intubation: thiopentone and propofolcompared. British Journal of Anaesthesia 1991; 67: 64-68.12. Vohra A, Kumar S, Charlton AJ, Olukoga AO, Boulton AJ,M cL eod D . Effect of diabetes mellitus on the cardiovascularresponses to induction of anaesthesia and tracheal intubation.British Journal of Anaesthesia 1993; 71: 258-261.13. Hutton P, Dye J, Prys-Roberts C. An assessment of theDinamap 845. Anaesthesia 1984; 39: 261-267.

14. McL aren AD , Stockwell MC , Reid VT . Anaesthetictechniques for surgical correction of fractured neck of femur.Anaesthesia 1978; 33: 10-14.15. Davis FM , Woolner DF , Frampton C. Prospective, multi-centre trial of mortality following general or spinal anaesthesiafor hip surgery in the elderly. British Journal of Anaesthesia1987; 59: 1080-1088.16. Critchley LA , Stuart JC, Short TG , Gin T . H aemodynamiceffects of subarachnoid block in elderly patients. BritishJournal of Anaesthesia 1994; 7 3: 464-470.17. Coe A J, Revanas B. Is crystalloid p reloading useful in spinalanaesthesia in the elderly? Anaesthesia 1990; 45: 241-243.18. Hemmingsen C, Poulsen JA , Risbo A. Prophylactic ephedrineduring spinal anaesthesia: double-blind study in patients inASA groups IIII. British Journal of Anaesthesia 1989; 63 :340-342.19. Reilly CS. Regional analgesia and myocardial ischaemia.British Journal of Anaesthesia 1993; 71 : 467-468.


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