4g / 5min1g/h

eclamptic seizure

The management of severe pre-eclampsia/eclampsia. RCOG Guideline. 2006. Magnesium sulphate is the therapy of choice to control seizures. A loading dose of 4 g should be givenby infusion pump over 5–10 minutes, followed by a further infusion of 1 g/hour maintained for 24 hoursafter the last seizure.

Recurrent seizures should be treated with either a further bolus of 2 g magnesium sulphate or anincrease in the infusion rate to 1.5 g or 2.0 g/hour.

Do not leave the woman alone but call for help, including appropriate personnel such as theanaesthetist and senior obstetrician. Ensure that it is safe to approach the woman and aim toprevent maternal injury during the convulsion. Place the woman in the left lateral position andadminister oxygen. Assess the airway and breathing and check pulse and blood pressure. Pulseoximetry is helpful.1,31 Once stabilised, plans should be made to deliver the woman but there is noparticular hurry and a delay of several hours to make sure the correct care is in hand is acceptable,assuming that there is no acute fetal concern such as a fetal bradycardia.The woman’s conditionwill always take priority over the fetal condition.

Magnesium sulphate is the therapy of choice and diazepam and phenytoin should no longer be used as first-line drugs.32 The intravenous route is associated with fewer adverse effects.Although a trial in Bangladesh33 has shown no significant reduction in recurrent seizures whenusing only a loading dose as opposed to the standard regimen, further studies would be neededbefore this practice could be recommended, as this finding may relate to body size.The seizurerates were 3.96% in loading versus 3.51% in standard regimen (P > 0.05). Magnesium toxicity isunlikely with these regimens and levels do not need to be routinely measured. Magnesiumsulphate is mostly excreted in the urine. Urine output should be closely observed and if it becomes reduced below 20 ml/hour the magnesium infusion should be halted. Magnesiumtoxicity can be assessed by clinical assessment as it causes a loss of deep tendon reflexes andrespiratory depression. If there is loss of deep tendon reflexes, the magnesium sulphate infusionshould be halted. Calcium gluconate 1 g (10 ml) over 10 minutes can be given if there is concernover respiratory depression.

In the collaborative eclampsia trial,32 a further bolus of 2 g magnesium sulphate was administeredfor recurrent seizures. An alternative is to increase the rate of infusion of magnesium sulphate to1.5 g or 2.0 g/hour. If there are repeated seizures then alternative agents such as diazepam orthiopentone may be used, but only as single doses, since prolonged use of diazepam is associatedwith an increase in maternal death.32 If convulsions persist, intubation is likely to be necessary toprotect the airway and maintain oxygenation.Transfer to intensive care facilities with intermittentpositive pressure ventilation is appropriate in these circumstances.

5.4 How should fluid balance be managed?

Fluid restriction is advisable to reduce the risk of fluid overload in the intrapartum and postpartumperiods. In usual circumstances, total fluids should be limited to 80 ml/hour or 1 ml/kg/hour.

Over the last 20 years, pulmonary oedema has been a significant cause of maternal death.3 This has oftenbeen associated with inappropriate fluid management. There is no evidence of the benefit of fluidexpansion34 and a fluid restriction regimen is associated with good maternal outcome.1 There is no evidencethat maintenance of a specific urine output is important to prevent renal failure, which is rare.The regimeof fluid restriction should be maintained until there is a postpartum diuresis, as oliguria is common withsevere pre-eclampsia. If there is associated maternal haemorrhage, fluid balance is more difficult and fluidrestriction is inappropriate.

RCOG Guideline No. 10(A) 6 of 11

Evidencelevel Ib

Evidencelevel IV

Evidencelevel Ia

A

A

C

ACOG Simulations Consortium – Eclampsia Learning Objectives

1

1.0 Risk Factors Level 1 (Declarative Knowledge) 1.1The learner will be able to state the following most common risk factors for eclampsia without references and with 100% accuracy including:

• Nulliparity • Family history of preeclampsia • Preeclampsia in a previous pregnancy • Smoking • Diabetes mellitus • Multiple gestation • Chronic hypertension • Obesity • Low socioeconomic status • Advanced maternal age (> 35 years-old) • African-American race

1.1.2 The learner will be able to state the following contraindications/cautions with the use of magnesium with 100% accuracy including:

• Contraindicated with myasthenia gravis,

• Use with caution with ca channel blockers may produce hypotension

• Concomitant use of muscle relaxants can cause prolonged paralysis 1.1.3 The learner will be able to state the following risk factors for magnesium sulfate toxicity

• decrease uo or cr >1.0

• magnesium level > = decreased dtrs

• magnesium level > = respiratory arrest

• magnesium level > = cardiac arrest 1.1.3 The learner will be able to state treatment for reversal of magnesium toxicity

• Calcium gluconate 1 gram

• Alert anesthesia staff

• Apply supplemental oxygen if pulse oximetry less than 95%

ACOG Simulations Consortium – Eclampsia Learning Objectives

7

• Pulmonary edema • Intracerebral hemorrhage, • Cardiac arrest • Liver rupture • Transient blindness

6.2.2.2 Fetal complications

• Fetal heart rate decelerations • Fetal acidosis

6.2.3 During a simulated scenario, the learner will be able to state how to manage the anesthesia needs of the patient, without references and with 100% accuracy, including the following:

• Have anesthesia available to monitor the patient’s airway 6.2.4 During a simulated scenario the learner will be able to demonstrate how to manage the patient after the seizure has stopped, without references and with 100% accuracy, including the following:

• Administer magnesium sulfate (2gm/hr IV continuous infusion) (pre-mixed) • Administer medications to control hypertension if severe hypertension present

(> 160/110) • Continuously monitor the fetal heart rate and consider intervention (delivery

by cesarean section) if decelerations do not resolve within approximately 10-15 minutes)

• Plan to move towards delivery (route of delivery dependent on gestational age / cervical examination / fetal status)

Level 3 (Clinical Performance)

6.3.1 The learner will be able to demonstrate the following knowledge in a clinical context, without references and with 100% accuracy, including the following:

6.3.1.1 Monitoring requirements and interventions • Maternal pulse oximetry • Continuous toco and FHR monitoring • Obtain IV access if it is not available • Provides supplemental oxygen

6.3.1.2 Patient positioning and safety

• Patient should be placed to lateral decubitus position • Rails should be put up on bed and potentially padded

1.1.1.3 Medications

6.3.1.3.1 Medications to control seizure • Magnesium sulfate 6 grams IV over 15-20 minutes (pre-mixed)

ORIGINAL ARTICLE

Blood pressure assessment and first-line pharmacologicalagents in women with eclampsia

A.T. Dennis,a,b,c E. Chambers,a,b,c K. Serangd

aDepartment of Obstetrics and Gynaecology, bDepartment of Pharmacology, University of Melbourne, Victoria,Australia, cDepartment of Anaesthesia, The Royal Women’s Hospital, Melbourne, Victoria, Australia, dDepartment ofAnaesthesia, Angliss Hospital, Melbourne, Victoria, Australia

ABSTRACTBackground: Eclampsia is a life-threatening complication of pregnancy. Timely blood pressure assessment and administration ofmagnesium sulphate are essential management. In this retrospective single-centre study we examined the timing and magnitude ofmaternal blood pressure before eclampsia, and whether magnesium sulphate was administered as the first agent for treatment.Methods: We conducted a five-year review of eclampsia in a tertiary referral obstetric hospital. Using data from electronic birthingrecords and hospital coding (ICD-10AM) we identified patients with the diagnostic criteria for eclampsia and assessed patientcharacteristics, blood pressure and pharmacological treatment.Results: There were 33812 births from July 2008 to June 2013 with 19 cases of eclampsia (1:1780). Patients were 32 ± 5.9 years ofage, 36 ± 3.9 weeks of gestation, 63% were nulliparous and all had a singleton pregnancy. Antepartum eclampsia occurred in 74%.In the four hours before a fit, 47% of patients had blood pressure recorded, of whom 78% were hypertensive. Magnesium sulphatewas administered as first therapy in 47% of patients but it was not given to any patient transferred to hospital by ambulance. Of thepatients who fitted antenatally, 86% underwent caesarean section, of whom 25% received neuraxial anaesthesia.Conclusions: Our study highlights the need for vigilance when managing pregnant women with hypertension, especially in the thirdtrimester as eclampsia is most likely preceded by raised blood pressure. It also highlights the need for timely commencement ofmagnesium sulphate in the community and during transfer to hospital for the treatment of eclampsia, and for prevention ofeclampsia in hospital when thresholds for severe preeclampsia are met.

!c 2015 Elsevier Ltd. All rights reserved.

Keywords: Eclampsia; Preeclampsia; Caesarean section; Magnesium sulphate; Blood pressure; Anaesthesia

Introduction

Eclampsia is an uncommon but serious complication ofpregnancy. It is associated with a high case fatality andcomplication rate.1 Eclampsia is defined as convulsionsin addition to preeclampsia with no pre-existing neuro-logical dysfunction.2 There is a clear consensus in the lit-erature that the morbidity and mortality associated withthis disorder can be avoided by adequate and timely pro-vision of treatment, including magnesium sulphate.3

Without treatment, eclampsia is a leading cause ofmaternal and neonatal morbidity and mortality with

most injury being associated with the seizures that markthe onset of the disease. Timely provision of preventativetherapy including magnesium sulphate, should com-mence before the onset of seizures in women at risk ofeclampsia.2,4–7 However, it is difficult to predict who willdevelop eclampsia as some women are normotensivebefore seizures.

We performed a study to determine the incidence ofeclampsia, the initial pharmacological management ofwomen with eclampsia and the relationship betweenthe recording of and magnitude of blood pressure(BP) before the initial seizure. We did this for tworeasons: first, we had observed that women transferredfrom the community with a diagnosis of eclampsiawere not routinely given magnesium sulphate; andsecond, we thought the reason why women were con-sidered to be normotensive before a seizure was thattheir BP had not been measured at an appropriate timebefore the fit thereby masking the development ofhypertension.

Accepted January 2015

Presented in part at The Obstetric Anaesthetists’ Association AnnualMeeting, Dublin, May 2014.Correspondence to: Alicia Dennis, Royal Women’s Hospital, LockedBag 300, Corner Flemington Road and Grattan Street, Parkville,Victoria 3052, Australia.E-mail address: alicia.dennis@thewomens.org.au

International Journal of Obstetric Anesthesia (2015) 24, 247–2510959-289X/$ - see front matter !c 2015 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.ijoa.2015.01.007

www.obstetanesthesia.com

Int J Obstet Anesth. 2015;24(3):247–51.

caesarean section which was performed under generalanaesthesia in 9/12 (75%) of cases; the main reason forchoosing general anaesthesia was reduced consciousstate after the seizure. When patients with eclampsiawere transferred to hospital by ambulance, nonereceived magnesium sulphate as first-line therapy. Oneneonate was stillborn at home minutes before the onsetof the seizure. Of the five (26%) neonates requiring

respiratory support, three (16%) required trachealintubation. Maternal length of stay in either a highdependency unit (HDU) or intensive care unit (ICU)varied from 12 h to four days. One woman suffered aliver laceration and a placental abruption. There wereno anaesthetic complications and no maternal deaths.

Discussion

We have demonstrated that eclampsia continues to be aserious obstetric complication in a large tertiary referralhospital in a high-income country, occurring in one in1780 births. Coding errors remain a serious problem inidentifying cases. We have shown that most women donot have their BP recorded in the four hours precedingthe seizure but when they do, the large majority arehypertensive. Our study demonstrated that magnesiumsulphate is only administered to approximately 50% ofeligible women and of those with eclampsia transferredto hospital by ambulance, none received it as first-linetherapy.

The incidence of eclampsia in our study is higher thanthat reported in the UK of 2.7:10000 births9 and his-torical Australian data,10 but similar to the reportedincidence of eclampsia cases in Australia.11 In Australia,a falling rate of preeclampsia matched by an increasingrate of eclampsia has been observed. This is in line withthe World Health Organisation estimates but differsfrom the USA and Canada which report a steady rateof cases:11 the reason for this situation is unclear.Improvement in antenatal care has been credited withreducing the rate of preeclampsia but why the numberof cases of eclampsia is unchanged or increased overthe same timeframe remains unclear.11

Most cases of eclampsia occurred in the antenatalperiod, a number that appears consistent across studies.There were two cases of late (>48 h after delivery) post-partum eclampsia in our study.12–14 The USA has seenincreasing rates of postpartum eclampsia,15 with rates

Table 1 Demographic and obstetric data of 19 patientswith eclampsia

Age (years) 32 ± 5.9Body mass index (kg/m2) 28 ± 7.2 [20–45]Nulliparous 12 (63%)Gestation at booking (weeks) 17 ± 4.4Booking systolic blood pressure (mmHg) 110 ± 9.0Booking diastolic blood pressure (mmHg) 65 ± 7.5Previous preeclampsia 3 (16%)Comorbidities

Asthma 3Anaemia 2Type-2 diabetes mellitus 2Depression 2Essential hypertension 2Migraine 1Hypothyroidism 1

Data are mean ± SD, [range] or number (%).

Table 2 Characteristics and pharmacological therapy of19 patients with eclampsia

Diagnosis of preeclampsia before seizure 10 (53%)Antepartum eclampsia 14 (74%)Gestation at seizure (weeks) 36 ± 3.9Seizure at home (ambulance transfer) 7 (37)Seizure out of hospital 8 (42)*

Blood pressure recorded in the four hoursbefore seizure

9 (47)!

Systolic blood pressure in previous fourhours (mmHg)

158 ± 30.3!

Diastolic blood pressure in previous fourhours (mmHg)

93 ± 16.2!

Hypertension in the previous four hours 7 (78)!

Time taken to record blood pressure afterseizure (min)

11.7 ± 8.89

First systolic blood pressure after seizure(mmHg)

155 ± 25.6

First diastolic blood pressure after seizure(mmHg)

98 ± 16.7

Hypertension following seizure 14 (74%)Magnesium sulphate bolus and infusion as

initial therapy9 (47%)

Benzodiazepine as initial therapy 4 (21%)No initial therapy given 6 (32%)

Data are mean ± SD or number (%).*One patient fitted in car on wayto hospital. !Nine patients had their blood pressure measured in fourhours before seizure. Of patients who had their blood pressurerecorded in four hours before seizure, 7/9 (78%) were hypertensive.

Table 3 Delivery details of 19 patients with eclampsia

Time from seizure to delivery in patientswho fitted before delivery (min)

170 ± 212.9

Caesarean delivery in patients who fittedbefore delivery

12 (86%)*

General anaesthesia for caesarean delivery 9 (75%)Reasons for general anaesthesia

Reduced conscious state 7 (78%)Recurrent seizures 1 (11%)Maternal request 1 (11%)Neonates requiring respiratory support 5 (26%)Admission to intensive care unit! 5 (26%)Admission to high dependency unit§ 19 (100%)

Data are mean ± SD or number (%).*Of 14 patients who fitted beforedelivery, 12 (86%) had caesarean delivery. !Also required a highdependency unit step-down stay. §Including high dependency man-agement on birthing suite.

A.T. Dennis et al. 249Int J Obstet Anesth. 2015;24(3):247–51.

140-150 / 80-100

after stabilisation of the mother

ANAESTHESIAfor caesarean section

! CLINICAL INVESTIGATIONSAnesthesiology 2008; 108:802–11 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Hemodynamic Changes Associated with Spinal Anesthesiafor Cesarean Delivery in Severe PreeclampsiaRobert A. Dyer, F.C.A. (S.A.),* Jenna L. Piercy, F.C.A. (S.A.),† Anthony R. Reed, F.R.C.A.,† Carl J. Lombard, Ph.D.,‡Leann K. Schoeman, F.C.O.G. (S.A.),§ Michael F. James, Ph.D."

Background: Hemodynamic responses to spinal anesthesia(SA) for cesarean delivery in patients with severe preeclampsia arepoorly understood. This study used a beat-by-beat monitor of cardiacoutput (CO) to characterize the response to SA. The hypothesis wasthat CO would decrease from baseline values by less than 20%.

Methods: Fifteen patients with severe preeclampsia con-sented to an observational study. The monitor employed usedpulse wave form analysis to estimate nominal stroke volume.Calibration was by lithium dilution. CO and systemic vascularresistance were derived from the measured stroke volume,heart rate, and mean arterial pressure. In addition, the hemo-dynamic effects of phenylephrine, the response to delivery andoxytocin, and hemodynamics during recovery from SA wererecorded. Hemodynamic values were averaged for defined timeintervals before, during, and after SA.

Results: Cardiac output remained stable from induction of SAuntil the time of request for analgesia. Mean arterial pressureand systemic vascular resistance decreased significantly fromthe time of adoption of the supine position until the end ofsurgery. After oxytocin administration, systemic vascular resis-tance decreased and heart rate and CO increased. Phenyleph-rine, 50 !g, increased mean arterial pressure to above targetvalues and did not significantly change CO. At the time ofrecovery from SA, there were no clinically relevant changesfrom baseline hemodynamic values.

Conclusions: Spinal anesthesia in severe preeclampsia wasassociated with clinically insignificant changes in CO. Phenyl-ephrine restored mean arterial pressure but did not increasematernal CO. Oxytocin caused transient marked hypotension,tachycardia, and increases in CO.

ONLY since 1995, when the first randomized trial on theuse of regional versus general anesthesia for cesarean

delivery in severe preeclampsia was published,1 has spi-nal anesthesia (SA) been considered an option in thishigh-risk group of patients. As recently as 1998, an edi-torial recommended that epidural anesthesia is prefera-ble to SA for cesarean delivery,2 even if the patient hasnot received epidural anesthesia in labor. Many recentstudies suggest that SA is safe in the absence of contra-indications to regional anesthesia.3–6 Some studies haveshown less hypotension and lower vasopressor require-ments than during SA in healthy parturients. One inves-tigation found less hypotension during SA in severe pre-eclamptics than in preterm women in whom fetalweights were similar.4 This eliminated the possibilitythat the more minor degree of hypotension was due to alesser degree of aortocaval compression in preeclampticpatients. Nevertheless, hypotension and placental under-perfusion remain a risk,7 and SA may be associated withmore neonatal acidosis than general anesthesia.8

Most studies have used heart rate (HR) and bloodpressure measurements as surrogate markers of maternalcardiac output (CO). Although pulse and blood pressuremeasurements are of value in assessing the safety of ananesthetic technique, the true goal of SA for cesareandelivery is to maintain maternal CO and uteroplacentalblood flow. In healthy patients, the maximum change inCO has been shown to correlate better with uteropla-cental blood flow than upper arm blood pressure.9 Fur-thermore, in severe preeclampsia, an increased systemicvascular resistance (SVR) could render blood pressure apoor indicator of CO, but the information available onsuch patients during SA is scanty. It was therefore de-cided to investigate CO changes during SA for cesareandelivery in severe preeclampsia. Our hypothesis was thatSA would result in a clinically insignificant change in COin these patients, other than at the time of oxytocinadministration. Also studied were the hemodynamic re-sponses to vasopressors and to delivery and oxytocin. Inaddition, an assessment was made of the hemodynamicsof recovery from SA.

Ultimately, a better understanding of the perioperativehemodynamic changes could contribute to a reductionin perioperative pulmonary edema, renal dysfunction,eclampsia, and neonatal morbidity.

Materials and Methods

Fifteen patients were recruited to this prospective ob-servational study of the hemodynamics of SA for cesar-

This article is accompanied by the following two EditorialViews: Langesæter E: Is it more informative to focus on car-diac output than blood pressure during spinal anesthesia forcesarean delivery in women with severe preeclampsia? ANES-THESIOLOGY 2008; 108:771–2; Pauca AL: Pressure wave analysisis useful to understand the pathophysiology of preeclampsia,but perhaps not the rapid changes during cesarean delivery.ANESTHESIOLOGY 2008; 108:773–4.

!

* Associate Professor, † Senior Specialist Anesthesiologist, " Professor andHead, Department of Anesthesia, § Senior Specialist Obstetrician and Gynecolo-gist, Department of Obstetrics and Gynecology, University of Cape Town.‡ Director, Biostatistics Unit, Medical Research Council, Cape Town, South Africa.

Received from the Department of Anesthesia, University of Cape Town, CapeTown, South Africa. Submitted for publication May 5, 2007. Accepted for pub-lication December 6, 2007. Support was provided solely from institutional and/ordepartmental sources. Presented in part at the Annual Meeting of the ObstetricAnaesthetists’ Association, Sheffield, United Kingdom, June 7–8, 2007.

Address correspondence to Dr. Dyer: D23 Department of Anesthesia, Univer-sity of Cape Town and New Groote Schuur Hospital, Anzio Road, Observatory,Cape Town 7925, South Africa. robert.dyer@uct.ac.za. This article may be ac-cessed for personal use at no charge through the Journal Web site, www.anesthesiology.org.

Anesthesiology, V 108, No 5, May 2008 802

Anesthesiology. 2008;108(5):802–11.

measurements, and considering the test for the associa-tion between the indicator for a CO decrease of morethan 20% from baseline and the time indicator, a Fisherexact test indicated no significant association (P !1.000).

Mean changes from baseline values in HR, MAP, SV,CO, and SVR, together with 95% confidence intervals atall time intervals, for the cohort of 15 patients, areshown in figures 2A–E.

Figure 3 shows ensembles of the responses of the 15patients to oxytocin (HR, MAP, SV, CO, and SVR). Indi-vidual responses are shown as thin gray lines, and theensemble average is depicted as a superimposed thickblack line.

A total of 10 patients received phenylephrine, 8 beforeand 6 after delivery. The median (range) doses beforeand after delivery were 50 (0–150) and 0 (0–150) !g,respectively. Seven patients required ephedrine, and 1developed tachyphylaxis, necessitating a change tophenylephrine, as dictated by the protocol. The median(range) dose of ephedrine was 0 (0–45) mg. Vasopressoruse is summarized in table 3.

Immediately before the first administration of phenyl-ephrine, i.e., when MAP was 20% below baseline values,SVR was significantly lower than baseline measurements.CO and HR were not different from baseline at this time(table 4). The administration of phenylephrine was asso-ciated with a significant increase in MAP and SVR, and asignificant decrease in HR, but SV and CO were notsignificantly changed from values immediately beforephenylephrine use (table 5). There was a trend toward adecrease in CO. The mean (SD) times to peak effect ofthe first, second, and third doses were 28.3 (4.2), 39.6(30.0), and 24.6 (3.2) s, respectively. The infrequent useof ephedrine precluded a detailed analysis of the use ofthis vasopressor.

Data relevant to the neonate include the following:The mean (SD) uterine incision to delivery time was54.4 (29.2) s. The mean (SD) neonatal weight was1,697 (520) g. The median (range) Apgar score at 1min was 9 (7–9), and that at 5 min was 9 (9 –10). Themedian (range) umbilical arterial pH and mean (SD)base deficit were 7.28 (7.19 –7.31) and "3.1 (1.9) mM,respectively.

2

4

6

8

10

12

14

Baseline Sitting Spinal Supine L Tiltdelivery

OxytocinPeak

End surg Recovery

Time Intervals

Card

iac

Out

put (

L/m

in)

Skin Uterine Post-

-40

-30

-20

-10

0

10

20

30

40

0 1 2 3 4 5 6 7 8 9 10 11 12

CO c

hang

e fro

m b

asel

ine

(%)

Baseline Sitting Spinal Supine L Tilt Skin Uterine Post-Delivery

End Surg Recovery

A

B

Fig. 1. (A) Cardiac output measurementsfor each patient at each time interval.Baseline ! baseline measurements aver-aged after calibration of cardiac outputmonitor; sitting ! time from sitting upfor spinal anesthesia until induction ofspinal anesthesia; spinal ! time from in-duction of spinal anesthesia until patientsupine; supine ! time from adoption ofsupine position until left lateral tilt; L tilt !left lateral tilt (from tilt until skin inci-sion); skin ! time from skin incision un-til 30 s before uterine incision; uterine !30-s time period before uterine incision;postdelivery ! 30-s period from deliveryuntil administration of oxytocin; oxyto-cin peak ! time from administration ofoxytocin until peak effect on cardiac out-put; end surg ! 30-s time period beforeskin closure (end of surgery); recovery !5-min time period before request for an-algesia. (B) Percentage cardiac output(CO) change from baseline for individualpatients, at defined time intervals, as in A.Reference lines have been drawn at "and #20%.

806 DYER ET AL.

Anesthesiology, V 108, No 5, May 2008

Anesthesiology. 2008;108(5):802–11.

http://www.cats.rwth-aachen.de/Members/mb

Guidelines

Regional anaesthesia and patients with abnormalities ofcoagulationThe Association of Anaesthetists of Great Britain & IrelandThe Obstetric Anaesthetists’ AssociationRegional Anaesthesia UK

Membership of the Working Party: W. Harrop-Griffiths, T. Cook,1 H. Gill, D. Hill,2 M. Ingram,M. Makris, S. Malhotra, B. Nicholls,3 M. Popat, H. Swales2 and P. Wood

1 Royal College of Anaesthetists2 Obstetric Anaesthetists’ Association3 Regional Anaesthesia UK

SummaryConcise guidelines are presented that relate abnormalities of coagulation, whether the result of the administrationof drugs or that of pathological processes, to the consequent haemorrhagic risks associated with neuraxialand peripheral nerve blocks. The advice presented is based on published guidelines and on the known propertiesof anticoagulant drugs. Four separate Tables address risks associated with anticoagulant drugs, neuraxialand peripheral nerve blocks, obstetric anaesthesia and special circumstances such as trauma, sepsis and massivetransfusion..................................................................................................................................................................

This is a consensus document produced by expert members of a Working Party established by the Association ofAnaesthetists of Great Britain & Ireland, the Obstetric Anaesthetists’ Association and Regional Anaesthesia UK. It hasbeen seen and approved by the elected Councils/Committees of all three organisations.Accepted: 4 June 2013

• What other statements are available on this topic?Guidance publications on regional anaesthesia inpatients taking anticoagulant or thromboprophylac-tic drugs are widely available, two well-known guide-lines having been published by the American Societyof Regional Anesthesia and Pain Medicine (ASRA)[1] or adopted by the European Society of RegionalAnaesthesia and Pain Therapy (ESRA) [2].

• Why was this guideline developed?The available published guidance focuses on neur-axial blockade in patients receiving drug therapy

specifically aimed at modifying coagulation, butdoes not address non-neuraxial regional blockadeor patients with abnormalities of coagulation forother reasons. Currently available guidelines arelengthy and discursive, and do not lend themselvesto use in the acute clinical setting. The remit of theWorking Party that produced these guidelines wasto create a concise document that considered regio-nal anaesthesia of all forms and abnormalities ofcoagulation of both therapeutic and pathologicalorigins.

966 © 2013 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of The Association of Anaesthetists of Great Britain and Ireland.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Anaesthesia 2013, 68, 966–972 doi:10.1111/anae.12359

• How does this statement differ from existing guide-lines?Although based on the available guidance and onpublished pharmacokinetic and pharmacodynamicdata pertaining to anticoagulant drugs, this guid-ance is considerably more concise.

• Why does this statement differ from existing guide-lines?These guidelines were developed in order to makeuseful and concise guidance available to anaesthe-tists in the clinical setting.

Anaesthetists are often faced with the question ofwhether the risks of regional anaesthetic techniques areincreased when performed on patients with abnormalitiesof coagulation and, if so, whether they are so increasedthat the techniques should be modified or avoided.This is not only because the popularity of regionalanaesthesia is on the rise but also because the use ofanticoagulant drugs in the prevention of venous throm-boembolism is expanding, as is the number of differentdrugs in use. The serious complications of regional anaes-thesia in patients without abnormalities of coagulationare very rare indeed [3]. For example, in the thirdNational Audit Project (NAP3), the incidence of vertebralcanal haematoma after neuraxial blockade was 0.85 per100 000 (95% CI 0–1.8 per 100 000). The extent to whichthe risk of haemorrhagic complications is increased inpatients with abnormalities of coagulation is unquantifi-able, but likely to be small. The rarity of the complica-tions means that it is difficult to make accurateestimates of the incidence of complications related toabnormalities of coagulation, and therefore offeringpatients and clinicians advice on the basis of ‘hard data’is not possible, and is unlikely ever to become possible.We are therefore reliant on expert opinion, case reports,case series, cohort studies and extrapolations from drugproperties such as the time taken to achieve peakplasma levels and the known half-lives of drugs.

Published clinical guidance in relation to the riskassociated with regional anaesthesia in patientswith abnormalities of coagulation is often binary. Forinstance, it is often said that the performance ofneuraxial block in a patient with < 75 9 109.l!1 plateletsis not acceptable, whereas its performance in the pres-

ence of > 75 9 109.l!1 platelets is acceptable. However,there can be no relevant difference in risk or outcomeafter neuraxial blockade in two patients, one of whomhas a platelet count of 74 9 109.l!1 and the other76 9 109.l!1. Risk is a continuum that runs from ‘nor-mal risk’ to ‘very high risk’, and this guidance seeks toemphasise this point. This guidance must be inter-preted and used after consideration of an individualpatient’s circumstances. None of the advice in thisguidance should be taken as being prohibitive or indic-ative. An abnormality of coagulation – however severe– is always a relative contraindication to the use of aregional anaesthetic technique. However, there may becircumstances in which, although the use of a regionaltechnique for a patient with abnormal coagulation mayput the patient at significant risk as a result, the alter-native for this patient (often a general anaesthetic)may expose them to even greater risk. Experienced cli-nicians should be involved in decisions about whetheror not to perform a regional anaesthetic technique ona patient with abnormal coagulation, and the patientwith capacity should be given all the information he/she needs to make an informed choice.

Advice is often offered that if regional anaesthesiais to be considered in a patient with a known abnor-mality of coagulation, an ‘experienced anaesthetist’should perform the procedure. There are, of course, nohard data to support this suggestion. However, it isadvice that the Working Party supports. It is likelythat an experienced regional anaesthetist will needfewer attempts to gain block success, and it is likelythat the complications related to bleeding are in partrelated to the number of attempts at a block. It isreasonable to ask novices to perform their blocks onpatients at ‘normal risk’, reserving attempts in patientsat ‘increased risk’ for experienced clinicians.

Guidance is offered here in the form of fourTables, each with explanatory notes: Table 1 containsrecommendations related to drugs used to modifycoagulation; Table 2 suggests the relative risk relatedto the performance of neuraxial and peripheral nerveblocks in patients with abnormalities of coagulation;Table 3 indicates relative risks related to obstetricpatients; and Table 4 describes risks of regional anaes-thesia in special circumstances.

© 2013 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of The Association of Anaesthetists of Great Britain and Ireland. 967

W. Harrop-Griffiths et al. | Guidelines: patients with abnormalities of coagulation Anaesthesia 2013, 68, 966–972Anaesthesia. 2013;68(9):966–72.

B. Carvalho “it depends”

R. Dyer non-invasive

W. Ngan Kee arterial

A. Dennis arterial

K. Nelson non-invasive

L. Tsen “it depends”

M. van de Velde arterial

R. Smiley non-invasive

R. Fernando arterial

N. Lucas arterial

C. Elton arterial

ORIGINAL ARTICLE

A dose–response study of remifentanil for attenuation of thehypertensive response to laryngoscopy and tracheal intubationin severely preeclamptic women undergoing caesarean deliveryunder general anaesthesia

K.Y. Yoo,a D.H. Kang,a H. Jeong,a C.W. Jeong,a Y.Y. Choi,b J. Leec

a Department of Anaesthesiology and Pain Medicine, b Department of Pediatrics, c Department of Physiology,Chonnam National University Medical School, Gwangju, South Korea

ABSTRACTBackground: Remifentanil is known to attenuate the cardiovascular responses to tracheal intubation. We determined effectivedoses (ED50/ED95) of remifentanil to prevent the pressor response to tracheal intubation in patients with severe preeclampsia.Methods: Seventy-five women with severe preeclampsia were randomly allocated to one of five remifentanil dose groups (0.25,0.50, 0.75, 1.0, or 1.25 lg/kg) given before induction of anaesthesia using thiopental 5 mg/kg and suxamethonium 1.5 mg/kg. Sys-tolic arterial pressure, heart rate and plasma catecholamine concentrations were measured. Neonatal effects were assessed byApgar scores and umbilical cord blood gas analysis. A dose was considered effective when systolic arterial pressure did not exceed160 mmHg for more than 1 min following tracheal intubation.Results: Baseline systolic blood pressure and heart rate did not differ among the groups. The intubation-induced increases of heartrate and blood pressure were attenuated in a dose-dependent manner by remifentanil. ED50 and ED95 were 0.59 (95% CI 0.47–0.70) lg/kg and 1.34 (1.04–2.19) lg/kg, respectively. Norepinephrine concentrations remained unaltered following intubationbut increased significantly at delivery, with no differences between the groups. Apgar scores and umbilical arterial and venouspH and blood gas values were comparable among the groups. Two women each in the 1.0 and 1.25 lg/kg groups received ephed-rine for hypotension defined as systolic arterial pressure <90 mmHg.Conclusions: The ED95 of remifentanil for attenuating the hypertensive response to tracheal intubation during induction of anaes-thesia in severely preeclamptic patients undergoing caesarean delivery under general anaesthesia was 1.34 lg/kg.

!c 2012 Elsevier Ltd. All rights reserved.

Keywords: Caesarean; Remifentanil; Hypertension; Tracheal intubation; Preeclampsia

Introduction

Preeclampsia is a complex hypertensive disorder thatconstitutes a major source of morbidity and mortalityworldwide.1,2 It is characterized by endothelial dysfunc-tion, increased vascular resistance and impaired cerebralautoregulation.1 The cardiovascular response to tra-cheal intubation is also markedly exaggerated in thesepatients, with increases in systemic and pulmonary arte-rial pressures and pulmonary capillary wedgepressure.3,4

Although occurring only in a small proportion of pa-tients with severe preeclampsia, transient but severe

hypertension during tracheal intubation has been associ-ated with increased maternal intracranial pressure, cere-bral haemorrhage, and cardiac failure with pulmonaryoedema, resulting in increased morbidity and mortalityin both mother and baby.5 Moreover, an increase ofmaternal plasma catecholamine levels upon inductionof anaesthesia during caesarean delivery may potentiallydecrease uterine blood flow6,7 and hence adversely affectthe neonate.8,9 In particular, preeclampsia is associatedwith increased sympathetic activity with elevated plasmanorepinephrine levels.10 Thus, close control of stress re-sponses during anaesthesia for caesarean delivery is re-quired in patients with severe preeclampsia.

Remifentanil has a rapid onset with its maximum ef-fect at 1–3 min.11 It also has a short duration of action,which makes it the most suitable systemic opioid foruse in obstetric surgery.12,13 It has been shown toattenuate the increases in systolic arterial pressure

Accepted September 2012Correspondence to: Kyung Yeon Yoo, Department of Anaesthesiol-ogy and Pain Medicine, Chonnam National University Medical School8 Hak-dong, Gwangju 501-757, South Korea.E-mail address: kyyoo@jnu.ac.kr

International Journal of Obstetric Anesthesia (2013) 22, 10–180959-289X/$ - see front matter !c 2012 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.ijoa.2012.09.010

www.obstetanesthesia.com

women14,21 and those with severe preeclampsia15,16

having general anaesthesia for caesarean delivery. Inhealthy subjects, remifentanil 1 lg/kg given as a singlebolus was effective for attenuating the pressor re-sponse,14 while a bolus of remifentanil 0.5 lg/kg fol-lowed by a continuous infusion at 0.15 lg/kg/minuntil peritoneal incision was ineffective.15 In contrast,remifentanil 0.5 lg/kg given as a single bolus beforeintubation was effective in attenuating the pressor re-sponse in our previous study on severely preeclampticpatients,16 suggesting a greater efficacy of remifentanilin preeclamptic patients. This led us to perform adose–response study to establish an optimal dose ofremifentanil to control the pressor response. Our defi-nition of success was when SAP did not exceed160 mmHg for more than 1 min. This value has beenpreviously suggested as an important predictor of cere-bral haemorrhage and infarction in patients with severepreeclampsia and eclampsia.22

Ngan Kee et al.14 reported that two (10%) of 20neonates born to healthy mothers given remifentanil1 lg/kg as a single bolus showed respiratory depressionrequiring assisted ventilation and naloxone. Draisciet al.21 also reported three (14%) of 21 neonates bornto healthy mothers given a bolus of remifentanil0.5 lg/kg followed by a continuous infusion at0.15 lg/kg/min required tracheal intubation but recov-ered at 5 min without naloxone. Therefore, a major con-cern of the use of remifentanil during caesarean deliveryis its potential placental transfer, causing neonatal respi-ratory depression, although being transient in natureand corrected by ventilatory assistance with or withoutadministration of naloxone.

Fig. 2 Systolic arterial blood pressure (SAP) and heart rate(HR) measured before injection of remifentanil (R,t = !1.5 min), just before intubation (t = 0), maximumresponse within 1 min after intubation, and every 1 min for7 min after intubation. Values are mean ± sd. Tracheal intu-bation increased SAP (P = 0.0001) and HR (P = 0.03) lesswith increasing remifentanil dose.

Fig. 3 Dose–response curve for success of intravenousremifentanil in attenuating the pressor response to trachealintubation.

Fig. 4 Probit–log (dose) plot. A linear regression line wasfitted, and ED50 and ED95 values were calculated usingmaximum likelihood estimation. ED50 = 0.59 (95% CI 0.47–0.70) lg/kg, ED95 = 1.34 (1.04–2.19) lg/kg, r = 0.98, r2 = 0.96.

14 Remifentanil and intubation in preeclampsiaInt J Obstet Anesth. 2013;22(1):10–8.

1350 www.anesthesia-analgesia.org December 2014 Volume 119 Number 6

Copyright © 2014 International Anesthesia Research SocietyDOI: 10.1213/ANE.0000000000000424

Hypertensive disorders of pregnancy are the most common direct cause of maternal mortality in the United States, responsible for 15% of deaths.1

Cerebrovascular complications are the most common cause of major disability and death in preeclampsia/eclampsia; hypertension and cerebral hyperperfusion-related vas-cular shear stress and vasogenic edema are postulated to cause stroke, cerebral edema, and eclampsia.2,3 Preeclamptic women suffering stroke have a poor prognosis. A retrospec-tive case series published in 2005 reported <50% survival in which only a small percentage of surviving patients were not disabled.4 The American College of Obstetricians and Gynecologists guidelines recommend urgent treatment of systolic blood pressures exceeding 160 mm Hg or diastolic blood pressures exceeding 110 mm Hg.5,6 The Seventh and Eighth Confidential Enquiries into Maternal Deaths reports from the United Kingdom recommend treatment of systolic blood pressures exceeding 150 to 160 mm Hg, and emergent treatment of systolic blood pressures exceeding 180 mm Hg, to prevent intracranial hemorrhage.3,7

The cesarean delivery rate in the United States in 2012 was 32.8%8 and may be higher among patients with severe preeclampsia. Although the majority of cesarean deliveries are performed under neuraxial anesthesia, some patients receive general anesthesia for maternal or fetal indications. Laryngoscopy and tracheal intubation are often accompa-nied by increases in arterial blood pressure and heart rate,9–13 and such increases may enhance the risk of cerebrovascular or cardiovascular events in preeclamptic patients.2,3 Many strategies for controlling the hemodynamic response to laryngoscopy and intubation have been investigated in the general surgical population, with conflicting results. Fewer studies specifically address preeclamptic patients, and prac-tice among anesthesiologists varies widely.14

An ideal induction technique for this patient population would have fast, predictable onset, allowing for a safe rapid-sequence induction and tracheal intubation followed imme-diately by surgical incision. Ideally, drugs should be quickly cleared, cause no serious maternal side effects, have minimal placental transfer or no significant fetal/neonatal effects, and be widely available and stable at room temperature without the need for reconstitution or dilution. There is no perfect medication or technique, but some drugs have more favorable pharmacodynamic and pharmacokinetic profiles than others. This review focuses on drugs used to control the hypertensive response to laryngoscopy and tracheal intuba-tion in preeclamptic patients receiving general anesthesia.

β-Adrenergic Blocking DrugsDepending on structure, β-adrenergic antagonists have activity at either β-1 or β-2 receptors, with variable onset and duration of action. Blockade of β-1 receptors causes decreased heart rate, cardiac contractility, and arterial blood pressure. Only esmolol and labetalol have been studied in women with preeclampsia.

Esmolol is a selective β-1 antagonist with short onset time and elimination half-life (Table  1).a Esmolol prevents the hemodynamic response to laryngoscopy and intubation in nonpregnant patients when administered as an infusion (50 µg/kg/min) or as a bolus (100–200 mg), after induction with thiopental 3 to 6 mg/kg.15–18 The combination of esmolol 1 to 2 mg/kg and lidocaine 1.5 mg/kg before induction with thiopental 4 mg/kg decreased the hypertensive response to intubation compared with saline placebo in nonpregnant healthy women undergoing gynecologic surgery, whereas either drug alone did not.19 In a randomized, blinded, con-trolled trial of 80 preeclamptic women undergoing cesarean delivery after induction with thiopental 5 mg/kg, esmolol 2 mg/kg suppressed both heart rate and arterial blood pres-sure increases during airway manipulation compared with saline placebo, whereas esmolol 1 mg/kg required the addi-tion of lidocaine 1.5 mg/kg to be effective.20

Serious maternal side effects of esmolol are few, given its short half-life. However, transient maternal bradycardia or heart block can occur, and the drug should be used cau-tiously in patients with heart failure.

Many medications have been used to prevent the hypertensive response to the induction of gen-eral anesthesia and laryngoscopy in preeclamptic patients, with varying results. In this focused review, we summarize the available data and pharmacologic profiles of these drugs. Several dif-ferent drug classes may be used safely; however, magnesium bolus, lidocaine, calcium channel antagonists other than nicardipine, and hydralazine are not recommended. Further research is warranted into the hemodynamic impact of varying the induction drug dose or combining differ-ent classes of drugs. (Anesth Analg 2014;119:1350–6)

Prevention of Peri-Induction Hypertension in Preeclamptic Patients: A Focused ReviewMelissa Pant, MD, Robert Fong, MD, and Barbara Scavone, MD

From the Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois.Accepted for publication June 24, 2014.Funding: Internal.The authors declare no conflicts of interest.Reprints will not be available from the authors.Address correspondence to Melissa Pant, MD, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland MC 4028, Chicago, IL 60637. Address e-mail to melissa.pant@gmail.com.

FOCUSED REVIEWS IN OBSTETRIC ANESTHESIAE

aLexi Drugs Online. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6847. Accessed January 15, 2013.

CME

1354 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

E FOCUSED REVIEWS IN OBSTETRIC ANESTHESIA

Magnesium crosses the placenta, with fetal serum lev-els approximating maternal serum levels.72 Administered maternal magnesium is associated with both fetal and neonatal depression; a large retrospective review reported lower 1- and 5-minute Apgar scores and higher rates of tra-cheal intubation, hypotonia, and requirement for neonatal intensive care in neonates as maternal magnesium levels increased.73

Anesthesia Induction DrugsNumerous sedative–hypnotic drugs are used for induction; however, in obstetric anesthesia, historically thiopental and currently propofol are the most commonly used drugs. Ketamine and etomidate are used occasionally for induc-tion of anesthesia for cesarean delivery, but their hemody-namic profiles make them less attractive for prevention of hypertension during laryngoscopy and tracheal intubation. Thiopental is a barbiturate with onset time of 30 to 60 sec-onds, effect duration of 5 to 30 minutes, and elimination half-life of 3 to 8 hrs.a Thiopental crosses the placenta with a wide range of reported F/M ratios (0.4–1.1).26 Serious maternal side effects include depression of myocardial contractility and decrease in systemic vascular resistance, causing hypotension and tachycardia, or histamine release, causing bronchospasm. Thiopental is no longer available in the United States but was commonly used for induction of anesthesia until 5 years ago. Therefore, most studies of hemodynamic control during intubation in preeclamptic patients used thiopental, not propofol, as the induction drug.

Propofol is a general anesthetic with unknown mecha-nism of action, possibly due to γ-aminobutyric acid receptor agonism or glutamate receptor antagonism. Onset time is 30 to 60 seconds, effect duration 3 to 10 minutes, with an elimination half-life of 40 minutes.a The most serious mater-nal side effect of propofol is a decrease in systemic vascular resistance, causing hypotension. Propofol crosses the pla-centa with an F/M ratio range of 0.65 to 0.85.26 The primary neonatal side effect of both thiopental and propofol is seda-tion, the degree of which may vary depending on induction to delivery time and fetal and maternal protein binding. Neonatal outcomes after exposure to thiopental and pro-pofol were compared in several studies, with most studies showing comparable Apgar scores.74–78 In addition, 1 study found no difference in neurologic and adaptive capacity scores between the 2 drugs.77

Safety studies comparing thiopental with propofol in healthy women undergoing cesarean delivery showed lower blood pressures during and after tracheal intubation with propofol 2 to 2.5 mg/kg compared with thiopental 4 to 5 mg/kg.76–78 No investigation into varying the doses of thiopental or propofol has been done in healthy pregnant or preeclamptic patients. It is likely that both the timing and dose of induction drug significantly affect the hemo-dynamic response to laryngoscopy and tracheal intubation.

In summary, there is scant literature regarding optimal pharmacologic drugs for control of arterial blood pressure during the rapid-sequence induction of general anesthe-sia in preeclamptic women. There are no trials available that compare the medications used in current practice, in

particular with propofol as the induction drug, and there is insufficient evidence to support one drug as first-line ther-apy. It may be that a combination of drugs from different classes, along with a patient-specific dose of induction drug, leads to optimal hemodynamic stability. Given their favor-able pharmacologic profiles, wide availability, and predict-ability with few reports of serious maternal or neonatal effects, esmolol 1.5 mg/kg or NTG 2 µg/kg, combined with propofol 2 mg/kg, is used by the authors of this review, depending on maternal hemodynamic variables at the time of anesthesia induction. The effect duration of these drugs is short in neonates; therefore, their use should not preclude admission of otherwise healthy term infants to the general care nursery. Labetalol and remifentanil are also reasonable options in nonemergency situations for practitioners who are comfortable with their use. Nicardipine may be use-ful; however, data are lacking. Lidocaine, calcium channel blocking drugs other than nicardipine, hydralazine, and magnesium bolus are not recommended given their lack of efficacy and/or potential serious maternal or fetal side effects. In all cases, a neonatal resuscitation team should be present at delivery and made aware of any maternally administered medications. Further prospective trials com-paring these drugs and varying doses of anesthesia induc-tion drugs are needed. E

DISCLOSURESName: Melissa Pant, MD.Contribution: This author helped prepare the manuscript.Attestation: Melissa Pant approved the final manuscript.Name: Robert Fong, MD.Contribution: This author helped prepare the manuscript.Attestation: Robert Fong approved the final manuscript.Name: Barbara Scavone, MD.Contribution: This author helped prepare the manuscript.Attestation: Barbara Scavone approved the final manuscript.This manuscript was handled by: Cynthia A. Wong, MD.

REFERENCES 1. Berg CJ, Callaghan WM, Syverson C, Henderson Z. Pregnancy-

related mortality in the United States, 1998 to 2005. Obstet Gynecol 2010;116:1302–9

2. Gogarten W. Preeclampsia and anaesthesia. Curr Opin Anaesthesiol 2009;22:347–51

3. Lewis G (ed). The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: Reviewing Maternal Deaths to Make Motherhood Safer: 2003–2005. The Seventh Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH, 2007

4. Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe preeclampsia and eclampsia: a para-digm shift focusing on systolic blood pressure. Obstet Gynecol 2005;105:246–54

5. ACOG Task Force on Hypertension in Pregnancy. Hypertension in pregnancy: report of the American College of Obstetricians and Gynecologists’ task force on hypertension in pregnancy. Obstet Gynecol 2013;122:1122

6. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 125: chronic hypertension in pregnancy. Obstet Gynecol 2012;119:396–407

7. Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D, Harper A, Hulbert D, Lucas S, McClure J, Millward-Sadler H, Neilson J, Nelson-Piercy C, Norman J, O’Herlihy C, Oates M, Shakespeare J, de Swiet M, Williamson C, Beale V, Knight M, Lennox C, Miller A, Parmar D, Rogers J, Springett A. Saving Mothers’ Lives: reviewing maternal deaths to

1354 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

E FOCUSED REVIEWS IN OBSTETRIC ANESTHESIA

Magnesium crosses the placenta, with fetal serum lev-els approximating maternal serum levels.72 Administered maternal magnesium is associated with both fetal and neonatal depression; a large retrospective review reported lower 1- and 5-minute Apgar scores and higher rates of tra-cheal intubation, hypotonia, and requirement for neonatal intensive care in neonates as maternal magnesium levels increased.73

Anesthesia Induction DrugsNumerous sedative–hypnotic drugs are used for induction; however, in obstetric anesthesia, historically thiopental and currently propofol are the most commonly used drugs. Ketamine and etomidate are used occasionally for induc-tion of anesthesia for cesarean delivery, but their hemody-namic profiles make them less attractive for prevention of hypertension during laryngoscopy and tracheal intubation. Thiopental is a barbiturate with onset time of 30 to 60 sec-onds, effect duration of 5 to 30 minutes, and elimination half-life of 3 to 8 hrs.a Thiopental crosses the placenta with a wide range of reported F/M ratios (0.4–1.1).26 Serious maternal side effects include depression of myocardial contractility and decrease in systemic vascular resistance, causing hypotension and tachycardia, or histamine release, causing bronchospasm. Thiopental is no longer available in the United States but was commonly used for induction of anesthesia until 5 years ago. Therefore, most studies of hemodynamic control during intubation in preeclamptic patients used thiopental, not propofol, as the induction drug.

Propofol is a general anesthetic with unknown mecha-nism of action, possibly due to γ-aminobutyric acid receptor agonism or glutamate receptor antagonism. Onset time is 30 to 60 seconds, effect duration 3 to 10 minutes, with an elimination half-life of 40 minutes.a The most serious mater-nal side effect of propofol is a decrease in systemic vascular resistance, causing hypotension. Propofol crosses the pla-centa with an F/M ratio range of 0.65 to 0.85.26 The primary neonatal side effect of both thiopental and propofol is seda-tion, the degree of which may vary depending on induction to delivery time and fetal and maternal protein binding. Neonatal outcomes after exposure to thiopental and pro-pofol were compared in several studies, with most studies showing comparable Apgar scores.74–78 In addition, 1 study found no difference in neurologic and adaptive capacity scores between the 2 drugs.77

Safety studies comparing thiopental with propofol in healthy women undergoing cesarean delivery showed lower blood pressures during and after tracheal intubation with propofol 2 to 2.5 mg/kg compared with thiopental 4 to 5 mg/kg.76–78 No investigation into varying the doses of thiopental or propofol has been done in healthy pregnant or preeclamptic patients. It is likely that both the timing and dose of induction drug significantly affect the hemo-dynamic response to laryngoscopy and tracheal intubation.

In summary, there is scant literature regarding optimal pharmacologic drugs for control of arterial blood pressure during the rapid-sequence induction of general anesthe-sia in preeclamptic women. There are no trials available that compare the medications used in current practice, in

particular with propofol as the induction drug, and there is insufficient evidence to support one drug as first-line ther-apy. It may be that a combination of drugs from different classes, along with a patient-specific dose of induction drug, leads to optimal hemodynamic stability. Given their favor-able pharmacologic profiles, wide availability, and predict-ability with few reports of serious maternal or neonatal effects, esmolol 1.5 mg/kg or NTG 2 µg/kg, combined with propofol 2 mg/kg, is used by the authors of this review, depending on maternal hemodynamic variables at the time of anesthesia induction. The effect duration of these drugs is short in neonates; therefore, their use should not preclude admission of otherwise healthy term infants to the general care nursery. Labetalol and remifentanil are also reasonable options in nonemergency situations for practitioners who are comfortable with their use. Nicardipine may be use-ful; however, data are lacking. Lidocaine, calcium channel blocking drugs other than nicardipine, hydralazine, and magnesium bolus are not recommended given their lack of efficacy and/or potential serious maternal or fetal side effects. In all cases, a neonatal resuscitation team should be present at delivery and made aware of any maternally administered medications. Further prospective trials com-paring these drugs and varying doses of anesthesia induc-tion drugs are needed. E

DISCLOSURESName: Melissa Pant, MD.Contribution: This author helped prepare the manuscript.Attestation: Melissa Pant approved the final manuscript.Name: Robert Fong, MD.Contribution: This author helped prepare the manuscript.Attestation: Robert Fong approved the final manuscript.Name: Barbara Scavone, MD.Contribution: This author helped prepare the manuscript.Attestation: Barbara Scavone approved the final manuscript.This manuscript was handled by: Cynthia A. Wong, MD.

REFERENCES 1. Berg CJ, Callaghan WM, Syverson C, Henderson Z. Pregnancy-

related mortality in the United States, 1998 to 2005. Obstet Gynecol 2010;116:1302–9

2. Gogarten W. Preeclampsia and anaesthesia. Curr Opin Anaesthesiol 2009;22:347–51

3. Lewis G (ed). The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: Reviewing Maternal Deaths to Make Motherhood Safer: 2003–2005. The Seventh Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH, 2007

4. Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe preeclampsia and eclampsia: a para-digm shift focusing on systolic blood pressure. Obstet Gynecol 2005;105:246–54

5. ACOG Task Force on Hypertension in Pregnancy. Hypertension in pregnancy: report of the American College of Obstetricians and Gynecologists’ task force on hypertension in pregnancy. Obstet Gynecol 2013;122:1122

6. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 125: chronic hypertension in pregnancy. Obstet Gynecol 2012;119:396–407

7. Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D, Harper A, Hulbert D, Lucas S, McClure J, Millward-Sadler H, Neilson J, Nelson-Piercy C, Norman J, O’Herlihy C, Oates M, Shakespeare J, de Swiet M, Williamson C, Beale V, Knight M, Lennox C, Miller A, Parmar D, Rogers J, Springett A. Saving Mothers’ Lives: reviewing maternal deaths to

Anesth Analg. 2014;119(6):1350–6.

anti-hypertensive

Saving Lives, Improving Mothers’ CareLessons learned to inform future maternity care

from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009-2012

December 2014

Maternal, Newborn and Infant Clinical Outcome Review Programme

hyperkalemic cardiac arrestNSARD !

mmH

thierry.girard@unibas.ch