Anesthesiologic management of major obstetrical hemorrhage

Accepted Manuscript Anesthesiologic Management of Major Obstetrical Hemorrhage Pascal H. Vuilleumier, MD, Prof. Daniel Surbek, MD PII:

S2210-8440(15)30016-2

DOI:

10.1016/j.tacc.2015.10.009

Reference:

TACC 267

To appear in:

Trends in Anaesthesia and Critical Care

Received Date: 10 September 2015 Revised Date:

17 October 2015

Accepted Date: 18 October 2015

Please cite this article as: Vuilleumier PH, Surbek D, Anesthesiologic Management of Major Obstetrical Hemorrhage, Trends in Anaesthesia and Critical Care (2015), doi: 10.1016/j.tacc.2015.10.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Anesthesiologic Management of

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Major Obstetrical Hemorrhage

a) Department of Anesthesiology and Pain Medicine

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Bern University Hospital

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Pascal H. Vuilleumier, MDa, Prof. Daniel Surbek, MDb

Inselspital, and University of Bern, Bern, Switzerland

b) Department of Obstetrics and Gynecology Bern University Hospital

Corresponding Author:

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Inselspital, and University of Bern, Bern, Switzerland

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Pascal H. Vuilleumier, MD

Department of Anesthesiology and Pain Medicine Bern University Hospital

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Inselspital, Bern, Switzerland [email protected]

Keywords: Major obstetrical bleeding, postpartum hemorrhage, anesthesiologic management

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Abstract

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Postpartum hemorrhage (PPH) remains a considerable burden on maternal morbidity and

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mortality, accounting for 80% of severe maternal morbidity. Although a consensus on

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definitions on major obstetrical bleeding is lacking, postpartum blood losses greater than 500

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ml after vaginal delivery and 1000 ml after cesarean section is considered as postpartum

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hemorrhage; a blood loss greater than 2500 ml is considered as severe postpartum

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hemorrhage.

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The definition of major obstetrical hemorrhage (MOH) is a broader term characterizing

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antenatal or postpartal bleeding. Approximately only 10 % of MOH is predictable, as

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etiologies and risk factors leading to MOH are still poorly understood. This lack of

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predictability may result in delays for initiation of proper anesthesiologic management of

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MOH. The quantity of blood loss, combined to the rapidity in which blood loss happens in

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case of MOH remains an important challenge anesthesiologic teams otherwise usually face

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only in major vascular or trauma surgery.

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Preservation of maternal fertility is one of the major aims after maternal and neonatal

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resuscitation has been granted. Drugs used to increase uterine tone are reviewed in detail, as

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well as surgical measures available today.

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Fortunately lessons learned from trauma management have been implemented in major MOH

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protocols. Not only is maternal and neonatal well being the primary aim to keep in sight,

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preservation of fertility whenever possible is the next aim anesthesiologists are facing.

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Introduction PPH is generally defined as a blood loss equal to or greater than 500ml within the first

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24 hours after vaginal delivery, whereas severe PPH is defined by blood loss that

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exceeds 1000ml within 24 hours. Reviews and textbook chapters tend to differentiate

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between bleeding that occurs before delivery (antepartum) and immediately

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postpartum regarded as primary PPH, whereas any abnormal or excessive bleeding

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from the birth canal occurring between 24 hours and 12 weeks postpartum is regarded

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as secondary PPH.

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There is no universal consensus on the definition of what constitutes a major

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obstetrical hemorrhage (MOH) in terms of blood loss. The term of MOH is somewhat

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broader than PPH as it is used for both ante- and postpartum hemorrhage. The World

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Health Organization (WHO) has defined PPH as a blood loss greater or equal to 500

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ml within 24h after birth, while severe PPH is a blood loss greater or equal to 1000 ml

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in the first 24h postpartum [1].

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Different definitions and stages of blood loss have been proposed by different authors

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and organizations; overall though, severe PPH or MOH usually consider that blood

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loss was greater than 2000-2500ml (Table 1).

Epidemiology

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Postpartum hemorrhage (PPH) remains a leading cause of maternal peripartum

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morbidity and mortality, occurring in approximately 3.7 per 1000 births (95% CI 3.4-

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4.0) [2] and accounting for 80% of all maternal morbidity [3]. The 2006-2008 UK

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Saving Mother’s Lives survey reports a total direct and indirect maternal mortality

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related to pregnancy of 11.39 (95% CI 10.09-12.86) per 100,000 maternities. Nine direct deaths related to hemorrhage were reported in that period, ranking as the 6th cause of mortality in the UK, after sepsis, pre-eclampsia and eclampsia, thrombosis and thrombo-embolism, amniotic fluid embolism and early pregnancy deaths [4]. The

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Scottish and UK decline in bleeding-related maternal deaths, compared to an increase

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in the number of cases of major obstetrical hemorrhage in the same time, points to

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better management of hemorrhage. Nevertheless, substandard care is still a concern in

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66% of bleeding related causalities [4]. These figures are expected to be much higher 3

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in developing countries, where obstetric hemorrhage is the leading cause of maternal

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deaths [5].

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Etiology and Risk Factors The steady increase in PPH in the last decade is related to: •

Increasing maternal ages

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•

Increasing cesarean delivery rates

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Labor induction and augmentation

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•

Increasing serious comorbidities in parturients

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Uterine atony accounts for 79% of PPH [6]. Overall, all PPH etiologies may be

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summarized into four ‘T’ categories: [7]: •

Tonus: uterine atony, and any factor that increases uterine distention, an infection or an anatomical abnormality

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o Multiparity

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o Multiple gestation (twins, triplets,)

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o Macrosomia

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o Polyhydramnios

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o Prolonged induction of labor, and prolonged 2nd stage of labor

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o Tocolysis

o MgSO4-Infusion

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•

Trauma: genital tract injury (laceration) or uterine injury (uterine rupture or inversion)

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•

Tissue: abnormal placental detachment of the myometrium in the third stage

of labor, remaining placental tissue

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Thrombin: pre-existing or acquired coagulopathy

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Antenatal screening for PPH focuses on identifying risk factors for abnormal placental

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invasion (accreta, percreta and increta) including:

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•

High maternal age

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•

Previous uterine scar and in particular cesarean delivery 4

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•

Placenta praevia, particularly with previous cesarean section

Nevertheless PPH is predictable only in 10% of parturients [8]

Placental abruption

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1. Definition & Pathophysiology

An ischemic or traumatic lesion of the decidua results in decidual necrosis, vascular

6

disruption and bleeding. Blood may dissect along the decidual plane with ensuing

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placental separation and retroplacental accumulation of blood. Preterm complete or

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partial separation of the placenta from the uterus, compromising the feto-maternal

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interface [9].

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2. Epidemiology

The absence of physiologic transformation of the spiral arteries have been reported in

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over 58% of patients [9]. With an incidence of 3-10 per 10,000 births it accounts for

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11-14% of all perinatal deaths [10]. Risk factors are [9]:

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•

Maternal age > 35 y., OR 1.3-2.6

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•

Cocaine use, OR 3.9-8.6

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•

Tobacco use, OR 1.5-2.5

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•

Maternal hypertension, OR 1.8-2.4

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•

Hyperhomocysteinemia, OR 1.8-5.3

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•

Thrombophilia, OR 1.4-7.7

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•

Pregestational diabetes mellitus, OR 2.7

•

Uterine anomaly, OR 8.1

•

Previous CS, OR 1.3-2.4

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Placental abruption OR 3.2-25.8

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•

Preeclampsia, OR 1.9-2.5

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•

Intrauterine infection, OR 2.5-3.3

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•

Preterm premature rupture of membranes, OR 1.8-5.9

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•

Placenta praevia, OR 3.2-5.7

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3. Diagnosis Lower abdominal tenderness combined to vaginal bleeding is the most common

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presenting sign. Nevertheless vaginal bleeding may be absent in cases of concealed

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abruptions. Ultrasonography is a highly specific, although less sensitive means of

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diagnosis.

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4. Anesthesiologic caveats

Monitoring of maternal vitals, maternal volume status and fetal heart rate (FHR) are of

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prime importance, as the initial treatment may be either more focused on fetal

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resuscitation or maternal resuscitation. Volume status may be particularly difficult to

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assess in the case of a concealed abruption. Immediate and aggressive compensation

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of blood loss is mandatory. Depending on the FHR vaginal delivery may be tried by

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the obstetrician. In this situation, depending on coagulation and volume status, an

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epidural anesthesia may be performed.

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Placenta praevia 1.

Definition & Pathophysiology

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Abnormal low placement of placental tissue, partially or totally covering the cervical

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os. Further distinctions are made in regard of the distance of the placenta to the

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cervical os [11]:

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•

Total placenta praevia: completely covers the cervical os

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•

Partial placenta praevia: partially covering the cervical os

•

Marginal placenta praevia: close distance, but not covering the cervical os

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Low placenta: placental edge in close proximity of the cervical os

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In late pregnancy shearing forces on the lower part of the uterus engage on a relatively

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nonelastic placenta. Partial placental detachment and disruptment of the intervillous

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spaces with consecutive painless vaginal bleeding results. Antepartum bleeding is a

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strong predictor for preterm delivery [12].

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A short distance between cervical os and placenta seems to be an independent risk

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factor for MOH [13]. 6

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2.

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It is one of the leading causes of MOH complicating 0.5% of pregnancies [13]. Risk

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factors are:

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•

Prior uterine surgery (CS, Fibromas)

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Prior placenta praevia

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Multiparty

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Advanced maternal age

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•

Tobacco abuse

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Epidemiology

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A history of multiple CS increases the risk of hysterectomy in placenta praevia patients, but the type of placenta praevia has no effect on maternal outcome. Neonates

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with incomplete placenta praevia have lower Apgar scores than neonates with a

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complete one [14].

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3.

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After 20 weeks of gestation routine ultrasonography (US) is the mainstay of

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identification. Transabdominal or transvaginal US are well suited for the diagnosis.

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Bleeding is typically painless and cannot be predicted by US findings [15].

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Concomitant presence of placenta accreta must be considered in a placenta praevia.

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Magnetic resonance may help in equivocal accreta or percreta cases [16].

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4.

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Early in pregnancy a benign and spontaneously remitting vaginal bleeding may occur,

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Anesthesiologic caveats

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Diagnosis

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when more advanced the only presenting sign may be a dramatic MOH. A low or marginal placenta praevia diagnosed early in pregnancy is usually managed expectantly. The distance from cervical os to placenta often increases as the pregnancy progresses.

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In the third trimester clinical management mandates close surveillance by the

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obstetrician and the neonatologist. Maternal and fetal outcomes are best, when a CS

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delivery is scheduled at 36 to 37 gestational weeks, ideally 48h after steroid

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administration [17]. Obstetricians and anesthesiologists will consider facing severe 7

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MOH in this CS. Pre-anesthesia consultation and a preliminary hematologic work-up

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to determine blood group and eventual irregular antibodies will help to anticipate

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problems with the airway, coagulation and blood product substitution. A regional

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anesthesia may be a suitable option in an elective setting for an uncomplicated

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placenta praevia [11]. The threshold for a general anesthesia must remain low when

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the airway is predicted difficult, the patient is bleeding profusely or the hemodynamic

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situation is compromised. In these situations Ketamine at 0.5-2 mg/kg and Etomidate

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at 0.3 mg/kg have been safely used as induction agents.

Placenta accreta, increta, percreta

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1.

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Placenta accreta is referring to three different grades of abnormal placental attachment

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to the uterine wall [18]: •

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Placenta accreta: chorionic villi attach to the myometrium instead of being restricted to the decidua

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Definition & Pathophysiology

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•

Placenta increta: chorionic villi penetrate into the myometrium

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•

Placenta percreta: chorionic villi penetrate beyond the uterus

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Bleeding occurs, when delivery of an adherent placenta is attempted. Examples of

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complications include:

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•

Damage to local organs: bowel, bladder, ureters, uterus

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Rescue hysterectomy after ongoing MOH

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•

Damage to surrounding neurovascular structures

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Amniotic fluid embolism

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Disseminated intravascular coagulation

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Acute respiratory distress syndrome

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2.

Epidemiology

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The concept of iatrogenic etiology is supported by pathological and epidemiological

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studies [18]. The re-epithelialization defects over a previous CS scar, combined to

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worldwide increasing CS have steadily increased the placenta accreta rate. It is 8

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reported in 3/1000 deliveries in western countries [18]. Additionally in vitro

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fertilization is strongly linked to placenta accreta. Placenta accreta is the single most

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important factor for emergency hysterectomies, concerning as much as 33-50%

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parturients with adherent placenta [16].

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3.

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The history of previous uterine scars mandates a high degree of suspicion, in regard to

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a difficult antenatal diagnosis. Many cases are only diagnosed during CS. Doppler-US

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is the mainstay of antenatal diagnosis, with a good accuracy in at-risk parturients. In

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equivocal cases MRI imaging may provide additional diagnostic information [16].

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Diagnosis

4.

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Antenatal planning and multidisciplinary management with obstetricians,

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neonatologists, radiologists and hematologists in a tertiary care hospital has reduced

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maternal morbidity [19]. Backup to the obstetrician with general surgeons, urologists

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and vascular surgeons might be necessary, if surrounding anatomical structures such

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as ureter, bowel or liver are invaded. Direct hysterectomy also called scheduled

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cesarean hysterectomy, without prior attempt to separate the placenta from the uterus,

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may be the best choice in regard to mortality and morbidity for the mother [20]. Rarely

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removal of the uterus is impossible in regard to the extent of surrounding pelvic

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invasion. In these cases postoperative methotrexate and selective angiographic

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embolization are considered [18]. In known cases the timing of delivery must be

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matched to the fetal needs, between 34 and 36 weeks of gestation [21]. Uterine

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preserving techniques may be offered to parturients depending on the presentation,

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depth of invasion and the parturients desire of subsequent pregnancies. In these cases,

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Anesthesiologic caveats

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the uterus with the placenta is left in situ. Preemptive invasive radiological techniques with uterine artery balloon catheter placements, temporary internal iliac artery occlusion or intrauterine inflatable balloons are used with promising results. Recurrent bleeding, generalized infection and the need of a delayed hysterectomy must be kept in

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mind if the uterus with the placenta in situ is preserved . The gold standard remains a

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cesarean hysterectomy [18]. Specifically Anesthesiologists must specifically consider

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the following:

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•

Preoperative anesthesiology consult 9

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•

Preoperative blood type and crossmatch determination

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•

Anticipation of MOH and blood bank notification of possible MOH

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Anticipation of rescue hysterectomy

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Blood loss monitoring with early substitution of blood and coagulation factors

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•

Extended monitoring of the patient with invasive arterial blood pressure

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monitoring

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Cell salvage system

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Regional technique possible, with low threshold to conversion into a general

•

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anesthesia, if the airway anatomy is not considered difficult

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In the case of an expected difficult airway a general anesthesia performed under stable and controlled circumstances may be the safer choice

•

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Large venous access, consider high flow intravenous catheters for fluid

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resuscitation, in connection to a rapid infusion system and fluid warming

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device •

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Uterine atony

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Consider an ICU or PACU unit after surgery

1.

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Uterine atony is a failure of the simultaneous contraction of myometrial fibers and

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subsequent retraction of the uterus after the delivery of the placenta. The uterine

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contraction serves to halt the blood supply of 800 ml/min to the placental bed [22].

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2.

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Epidemiology

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Definition & Pathophysiology

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In 2004, 79% of PPH were caused by uterine atony [7]. Between 1994 and 2006, there was a 26% increase of PPH in the USA is primarily due to an increased incidence of uterine atony, now representing 2.4% of all US births [23]. It is the most prevalent cause of MOH. Identification of atony is of prime importance, because most atony

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cases occur unexpectedly.

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3.

Diagnosis

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Failure of uterine contraction after delivery, ongoing painless blood losses and a “soft”

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uterus are the presenting signs.

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4.

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Active management of the third stage of labor is the cornerstone to prevent uterine

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atony. It consists of administration of uterotonic drugs, early clamping of the umbilical

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cord and controlled traction on the umbilical cord [24]. Pharmacologic and obstetrical

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interventions are specified in the section management of expected MOH.

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Definition & Pathophysiology

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Trauma

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Anesthesiologic caveats

The third cause of PPH, vaginal and cervical lacerations tend to occur more commonly

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with [25]:

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Advanced maternal age

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Asian race

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Nulliparity

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High birth weight

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Episiotomy

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Instrumental delivery

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2.

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The overall incidence of serious lacerations (third and fourth degree perineal

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Epidemiology

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lacerations) tends to decrease due to a decreased episiotomy practice, as well as more liberal CS indications. 3.

Diagnosis

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Largely a diagnosis of exclusion in the presence of persistent vaginal blood loss.

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Retained placental products and uterine atony are usually considered first.

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4.

Anesthesiologic caveats 11

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Surgical management is the mainstay of treatment. Pelvic examination may be

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exquisitely painful, necessitating anesthesiologic interventions.

Retained products of conception Definition & Pathophysiology

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1.

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Three main types have been described after vaginal deliveries [26] •

Placenta adherens: failed contraction of the myometrium behind the placenta

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•

Trapped placenta: detached placenta trapped behind a closed cervix

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•

Partial placenta accreta

2.

Epidemiology

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The incidence varies in between 0.1-3.3 % of vaginal deliveries, and is roughly the

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second most important cause of PPH.

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3.

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Frequently associated to uterine atony, it is diagnosed primarily if an incomplete

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placenta has been delivered.

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4.

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Systemic oxytocin after manual removal of the placenta under anesthesia is the

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mainstay of treatment. Nitroglycerin may be transiently needed during the procedure

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in order to produce uterine relaxation. Umbilical vein oxytocin and prostaglandin

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Diagnosis

injections are being investigated [26], but do not seem promising.

Uterine inversion

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1.

Definition & Pathophysiology

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Rare but severe, its etiology is largely unknown but thought to be iatrogenic. The

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internal surface of the uterus becomes forced partially or completely through the

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uterine cervix [27]. 12

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2.

Epidemiology

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The incidence in a large Dutch study was 1/20312 vaginal deliveries [27].

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3.

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The diagnosis is clinically obvious and can readily be confirmed by ultrasound. The

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inversion is mainly complete, but may be incomplete in a small amount of cases.

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4.

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Immediate uterine reversion (Johnson’s maneuver) must be performed by the

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obstetrician in order to prevent severe blood loss and hemodynamic instability.

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General anesthesia is usually mandatory, as volatile halogenated agents usually

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Diagnosis

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Anesthesiologic caveats

provide satisfactory uterine relaxation to perform reversion. To help uterine reversion

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adjunct short-time tocolysis with nitroglycerin may also be used, the negative

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hemodynamic effects may be counterbalanced by vasopressors (phenylephrine,

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adrenaline or noradrenaline) [27, 28].

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Uterine rupture

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1.

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Defined as an anatomic separation of the uterine muscle it is a rare, although a

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catastrophic situation.

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2.

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Epidemiology

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Definition & Pathophysiology

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The overall incidence is 325/100’000 trials of labor [29]. The incidence of uterine rupture (UR) is subject to great variation. The single most important risk factor is a previous uterine scar. Another important risk factor is grand multiparity. Classical and low vertical post CS uterine scars are more prone to rupture compared to the

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transverse uterine incision. Induction of labor and an increasing number of previous

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CS deliveries may increase the uterine rupture risk [29].

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3.

Diagnosis

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Pain may be the most prominent clinical symptom when antepartum UR happens.

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Vaginal bleeding may or may not be noticed, as intraabdominal bleeding may occur.

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Intrapartum abdominal pain or a sudden absence of contractions is regarded as a red

4

flag for UR in the presence of uterine scars. The most important sign however is

5

severely abnormal fetal heart rate tracing (cardiotocography).

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4.

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Emergency laparotomy and full resuscitation readiness are the mainstays. A special

8

emphasis must be placed on patients with a previous CS attempting vaginal birth

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(TOLAC). In case of epidural analgesia clinical suspicion for uterine rupture should be

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Anesthesiologic caveats

high when frequent epidural dosing adjustments are needed [30] or unusual

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breakthrough pain, as an example in the shoulder, is reported [31].

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Coagulopathy, bleeding tendency

Two major factors influencing morbidity and mortality in pregnancy are found within

14

coagulation disorders: Thrombo-embolism and bleeding. Coagulation disorders

15

favoring bleeding may be inherited (eg: Hemophilia, von Willebrands’disease) or may

16

have been acquired during pregnancy (HELLP-syndrome). At its extreme bleeding by

17

itself induces a net loss of coagulation factors and platelets, resulting in a

18

coagulopathy. Hyperfibrinogenemia of pregnancy is a physiologic compensation

19

mechanism thought to compensate for normal blood losses occurring during

20

childbearing. Nevertheless this compensation mechanism is rapidly overwhelmed

21

when faced to severe blood loss. The major cause of MOH is uterine atony, itself

22

being the major cause of acquired coagulopathy. Hemodilution after overly aggressive

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crystalloid or colloid volume replacement are frequent causes of secondary coagulation failure [32]. Risk factors for MOH with coagulopathy are [32]:

26

•

Uterine atony and genital lacerations

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•

Abnormal placentation (praevia, accreta etc.)

28

•

HELLP syndrome

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•

Placental abruption

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•

Amniotic fluid embolism 14

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1

•

Anticoagulant use

2

•

Underlying bleeding disorders, inherited and acquired

Expected MOH

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Antepartum history taking and diagnostic procedures are of prime importance to

5

identify and stratify at risk parturients, nevertheless MOH mostly occurs without

6

warning [33]. The setup of special care plans and maternal counseling have gained

7

popularity with the implementation of national programs like the Saving Mothers’

8

lives survey [4]. The questions of where, when and how to deliver are crucial

9

questions regarding safety of baby and mother. Enough evidence now suggests that

10

morbidity and mortality of “at risk” parturients is lower in in tertiary care hospitals

11

[19].

12

In this section we will review all drugs and procedures that may be an option in at risk

13

MOH parturients:

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1 Uterotonic drugs

16

•

Oxytocin

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Also used for induction and augmentation of labor, it is the first-line treatment in

18

regard to prevention and treatment of PPH. The ED90 at which a satisfying uterine tone

19

is obtained after elective CS is 0.35 IU min-1 (95% CI 0.18-0.52 IU) [34]. Several

20

factors have to be considered in this regard. The study was performed in CS patients,

21

not being exposed to any oxytocin augmentation before; as augmentation is known to

22

decrease oxytocin sensitivity. This study was performed in patients without MOH risk

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factors, and finally the study outcome, subjective uterine palpation by an obstetrician, is not a validated measure [35]. Side-effects of oxytocin include hypotension, tachycardia, nausea and vomiting, headache and myocardial ischemia. Bolus application of oxytocin is not recommended anymore. •

Carbetocin

28

It is sold under trade names Pabal (Pabal ®, Ferring, Baar, Switzerland) and Duratocin

29

(Duratocin®, Ferring, Toronto, Canada). It is an analogue of oxytocin, with a similar 15

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action, i.e. a contraction of the uterus [36]. Oxytocin administration is usually

2

performed by continuous intravenous administration, due to a short context sensitive

3

half-life of approximately 4-10 minutes. Due to potentially severe side effects

4

associated with hypotension, oxytocin should not be administered as an iv bolus. The

5

synthetic oxytocin analogue carbetocin has shown effectiveness on uterine

6

contractions of four to five hours [37, 38], and the elimination half-time is of

7

approximately 40 minutes [39]. Carbetocin has a binding affinity to isolated

8

myometral plasma membranes in the same order of magnitude than oxytocin [40].

9

Carbetocin is registered for prevention of PPH in cesarean section. A single-dose

10

injection of 100 mcg IV is the standard recommended treatment. According to the

11

Swiss Drug Agency Swissmedic the side-effect profile of carbetocin is comparable in

12

frequency and severity to oxytocin. •

Methylergometrine

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Semi-synthetic ergot alkaloid and strong uterine stimulant, it has a direct action on the

15

smooth muscle of the uterus. It produces a sustained tetanic uterotonic effect, which

16

shortens the third stage of labor and decreases blood losses. Methylergometrine is

17

administered at a dose of 0.2 mg as intramuscular bolus; time to peak concentration is

18

0.41 h± 0.21h, IM bioavailability is 78%. This dose may be repeated after 2-4 h. As a

19

potent vasoconstrictor of smooth muscle cells, the side effects include systemic

20

vasoconstriction, tachycardia, hypertensive crisis, cerebral edema, and coronary

21

vasoconstriction. For this reason, iv methylergometrine has been deleted as an

22

essential drug from most PPH treatment protocols. Methylergometrine is absolutely

23

contra-indicated in hypertensive (including pre-pregnancy hypertension) or toxemic

24

patients, as well it is contraindicated in patients with increased intracerebral pressure

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and coronary artery disease [41]. •

Prostaglandin analogues

Uterine activity is mediated by estrogens, progesterone and prostaglandins (PG). The

28

human chorion produces mainly PGE2, the decidua mainly PGE2 and PGF2 α.

29

Prostaglandins cause direct myometrial contraction by acting as calcium ionophores.

30

Exogenous PG-administration is used in induction of labor, termination of pregnancy

31

and prevention of obstetrical bleeding [42]. 16

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1

Prostaglandin PGF2 α: Carboprost Carboprost stimulates myometrial contractions resembling labor contractions. It is

3

administered by IM injection of 0.25 mg, time to peak concentration is 0.5h.

4

Contraindications include asthma, hyper and hypotension, diabetes, hepatic and renal

5

disease. A black-box warning has been issued by the FDA, carboprost should only be

6

used in hospitals with “proper training, and appropriate surgical and intensive care

7

facilities”. Cases of pulmonary edema and dystonia have been reported [41]. Prostaglandin E1-analogue: Misoprostol

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Misprostol has been used as NSAID-induced gastric ulcer prophylaxis, as well as to

10

induce labor or abortion. The FDA-labeled indication is for NSAID-induced gastric

11

treatment and gastric ulcer prophylaxis only. Oral or sublingual misoprostol has shown

12

promising results as uterotonic agent [43, 44]. Administration may be sublingual, oral,

13

vaginal or rectal. Recent studies performed in India, Egypt and Libya did demonstrate

14

the efficacy of sublingual misoprostol. The advantage of that treatment is that it is

15

readily available, cheap and easy to administer. Side effects are fever and shivering

16

[45, 46]. Toxic shock syndromes, myocardial infarction and cardiac dysrhythmia have

17

been reported [41]. However, due to its lower efficacy as compared to oxytocine (in

18

the prevention of PPH) and to iv sulprostone (in the treatment of PPH), it is only

19

recommended in low resource settings or for treatment in non-severe PPH.

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Prostaglandin E1-analogue: Sulproston

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Sulproston has shown a great efficacy in treating MOH as second-line treatment. It is

22

administered as a continuous infusion, and is one of the most effective and therefore

23 24 25 26

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most important drugs in PPH treatment. In France an audit on 16 French maternities reported the use of sulproston in 84.4% persisting PPH [47]. Sulproston is administered at maximal rates of 8.3 µg/min, and maximal doses of 1500 µg/24h [48]. Sulproston has the strongest effect on uterine tonus and the most rapid onset compared

27

to oxytocin and methylergometrine, but many side-effects have been reported.

28

Common side effects are nausea, vomiting, diarrhea, headache, cutaneous flush,

29

shivering and hyperthermia. Serious cardiac and hemodynamic side-effects have been

30

described: Coronary vasospasms and myocardial infarction, cardiac dysrrhytmia,

31

pulmonary edema and cardiac collapse [49]. One case-report has linked concomitant 17

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noradrenaline and sulproston use with intracerebral bleeding [50]. Table 2 provides an

2

overview of uterotonic drugs.

3

2 Volume and Hematologic management of MOH

4

The optimal perioperative fluid replacement strategy remains a challenge for clinical

5

research and in daily practice. The situation of major blood losses occurring over a

6

very short period of time mandates anticipation and preemptive substitution of volume

7

and blood products in order to avoid two dreaded outcomes: dilutional coagulopathy

8

and hemodynamic collapse. MOH is a unique situation in regard to antenatal elevated

9

baseline cardiac output and fibrinogen, contrasting an already present dilutional

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1

anemia. Lessons learned from trauma surgery revealed in figure 1 certainly also apply

11

to the actual obstetrical standards in MOH. Uterine tamponade and the use of rFVII

12

are two examples among many [33].

13

Transfusion and substitution efficiency heavily relies on the timing of administration.

14

Routine underutilization of fresh frozen plasma, coagulation factors and calcium have

15

been sufficiently reported [51]. This is the reason why the mainstay of these

16

substitution strategies is to avoid entry into the vicious cycle of coagulopathy as

17

shown in figure 2.

18

Resuscitation protocols used for trauma regarding bleeding emergencies are relying on

19

several steps:

20

1. Initial crystalloid-colloid infusion to restore and maintain intravascular volume

21

2. Packed red blood cells (pRBC) to restore and maintain oxygen transport capacity

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and oxygenation

3. Platelets (PLT) to and maintain a hemostatic plug

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4. Substitution of clotting factors restoring and maintaining hemostasis

The indication to use blood products has to be controlled and led by laboratory tests, but when time matters they always seem too slow to obtain. Sometimes, treatment

27

(e.g. with tranexamic acid) must start before results are available. On a blood gas

28

analysis modern machines will be issuing hemoglobin and calcium results in a timely

29

manner. The complete overview of coagulation with PT/(a)PTT, INR, fibrinogen, and

30

thrombocytes needs approximately 30-40 minutes to be performed. Although its use

31

still is off-label in obstetric anesthesia, ROTEM® and TEG measures are point-of-care 18

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measures that are less time consuming, first results and trends being available after 5-

2

15 minutes [52].

3

Emphasizing is necessary, that most studies have been or still are conducted in trauma

4

and not in obstetric patients, and that many, although promising substances used in

5

regard to correction of coagulation disorders, are being used off-label. Some health

6

systems may be more permissive in their off-label use.

7

Recent literature supports the rationale of balanced administration of blood products

8

mimicking the composition of circulating blood, and hence transfusion of pRBC, FFP

9

and to a certain extent PLT in a unit-for-unit ratio. This is likely to both prevent and

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treat coagulopathy due to MOH [52, 53].

11

1. pRBC: Erythrocytes contribute to oxygen transport, but also to marginalization of

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10

platelets and functional responsiveness of activated platelets. The optimal

13

hematocrit for platelet-vessel wall interactions is not known, but may very well be

14

as above a hematocrit of 35%, beyond the transfusion level required for oxygen

15

transport [53].

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2. FFP: A stepwise reduction in mortality is observed with increasing FFP:pRBC ratios from 1:4 to 1:1 in trauma patients [54].

3. PLT: The relation of thrombocytopenia to increased morbidity and mortality is

19

well-established, as well as the improved survival in patient receiving most

20

platelets [53]. Highest survival in bleeding patients were those who received both,

21

high PLT:pRBC and high FFP:pRBC ratios [55]. 4. Fibrinogen: Coagulation factor I is an essential substrate for clot formation.

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Normal fibrinogen levels in nonpregnant patients are considered around 3g/l (95%

24

CI 1.45-3.48 g/l), rising to 5g/l by the end of pregnancy. Studies have shown that

25

the first fibrinogen level obtained during PPH predicts severity of PPH: the lower

26 27 28 29

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the fibrinogen, the more severe the PPH. Perinatally two independent studies identified a threshold of 2g/l, at which the risk of MOH was multiplied by 12 [56], or identified a positive predictive value for a 100% likelyhood of MOH [57]. Invitro and animal studies have shown that fibrinogen administration is able to

30

reverse dilutional coagulopathy [58]. This was confirmed in patients with severe

31

hemorrhage and dilutional coagulopathy [59]. One large RCT has been performed

32

in Denmark regarding the outcome of fibrinogen in MOH as initial treatment in

33

MOH [60]. During PPH with normal plasmatic fibrinogen level this RCT did not 19

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1

find evidence in favor of preemptive administration of 2g of fibrinogen [61].

2

Transfusion of fibrinogen remains an off-label indication, but is implemented in

3

many European MOH transfusion guidelines, and may be effective in patients with

4

low fibrinogen [62]. 5. Recombinant activated factor VIIa (rFVIIa): It is transforming fibrinogen to fibrin

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by inducing a thrombin burst on the activated platelets, independently of factors

7

VIII and IX. It is currently approved for congenital VII deficiency and hemophilia

8

A and B with inhibitors [53]. Off-label use of rFVIIa has started in MOH in early

9

2000, many case-reports have been published on that subject since then. Seriously contrasting the early euphorism about rFVIIa, its lack of efficacy as well as

11

thrombotic events were published in regard to bleeding trauma patients [63]. In

12

obstetrics, an off-label consensus is that rFVIIa is only considered when the patient

13

has been treated by uterotonics, uterine massage and surgical hemostasis, and has

14

been treated for hypothermia, acidosis, hypocalcemia, platelet and clotting factor

15

disorders or dysfunction. A prudent dose of 90 mcg/kg IV seems to be the

16

consensus starting dose in MOH [64]. rFVIIa’s major role remains in fertility

17

preservation while avoiding emergency hysterectomies during PPH, as well as for

18

hemostasis after hysterectomy, when conventional treatment has failed [65].

19

6. Factor XIII (FXIII): The fibrin-stabilizing factor is the key factor stabilizing the

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clot and positively influencing hyperfibrinolysis [57], as acquired Factor XIII

21

deficiency mainly results from trauma and major hemorrhage [66]. In trauma

22

patients a blind dose of Factor XIII may be attempted if laboratory studies are not

23

readily available [67]. There is actually no specific data on its use in MOH,

24

nevertheless has been implemented as off-label use in some local European MOH

25

guidelines.

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7. Prothrombin complex concentrate (PCC): This soluble powder provides vit. K. dependent coagulation factors. Depending on the production technique there are three factor (USA) or four factor (Europe) PCC’s. Its indications are treatment of prothrombin and factor X deficiencies, as well as emergent reversion of oral

30

anticoagulation. PCC’s might find a place in bleeding control, but further studies

31

are needed, its use is strictly off-label [59].

32

8. Tranexamic acid: It has shown efficacy in decreasing postpartum blood loss after

33

vaginal birth or CS, as well as lowering oxytocin use [68, 69]. Tranexamic acid is

34

given as an IV infusion of 1-2g over 30-60 minutes. TEG and ROTEM® may 20

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1

readily show fibrinolysis and reversal of fibrinolysis with tranexamic acid [32].

2

Tranexamic acid has been introduced widely in clinical protocols of PPH-

3

treatment, and due to its positive benefit-risk ratio and low costs it is being used

4

deliberately already in the early phase of PPH. 3 Therapeutic and preemptive Interventional radiology/embolization

6

Transcathether embolization of uterine arteries (UA) has been practiced in the

7

management of MOH as sole or adjunct therapy to hysterectomy. It is practiced when

8

bleeding continues despite hysterectomy, or as an alternative to hysterectomy for

9

fertility preservation. This technique is reserved to bleeding, but nevertheless

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5

hemodynamically stable patients. Identification of the bleeding vessel with contrast

11

allows embolization [33]. The disadvantage of this technique is the need of patient

12

transfer to interventional radiology units, that might be challenging during profuse

13

bleeding. Nevertheless, in the UK the RCOG recommends that all large obstetric

14

departments should implicate transport logistics between obstetrical and interventional

15

radiology departments in order to be ready for uterine artery embolization in case of

16

severe PPH.

17

Placement of prophylactic uterine artery catheters is performed prior to CS in

18

parturients with known placenta praevia and accreta.13 parturients with prophylactic

19

uterine artery balloons, placed under neuraxial block prior to CS in the radiology suite,

20

raised promising results. Of the 13 studied women, the balloons were inflated in 12

21

women. 8 women were not transfused, and no hysterectomy was necessary in that

22

group. The preliminary conclusion is that prophylactic UA balloons have the potential

23

to decrease maternal blood losses, nevertheless there is a risk of UA spasm during

25 26

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angiography, this may cause fetal compromise necessitating an emergency CS [70]. 4 Cell salvage

Cell salvage has become standard in several UK maternities, where the costs of

27

systematic cell salvage has been compared to the transfusion-related costs of pRBC. It

28

was long resisted to be used in obstetrics because of concerns regarding rhesus

29

immunization and amniotic fluid embolism [71]. Until today no complications

30

associated to cell salvage has been reported with the use of the Pall leucocyte filter

31

[72]. One large study in Liverpool lasting 6 years could demonstrate a significant 21

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advantage to, systematically set-up a cell salvage system in high and medium risk CS

2

[72]. Nevertheless, the theoretical possibility of red blood cell – isoimmunization due

3

to autologous transfusion of maternal RBC’s contaminated with fetal RBC’s cannot be

4

excluded.

5

5 Surgical measures

6

1. Fertility preserving surgical measures

7

Several surgical interventions are practiced to preserve fertility in the setting of MOH.

8

The options are listed in table 3 [73]. Recently, new surgical techniques of uterine

9

compression sutures have been introduced, which have been shown be be considerably

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1

successful [74, 75].

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2. Hysterectomy

13

Carried out as life-saving procedure in 10-24% of MOH, mortality per procedure is

14

actually reported between 0.6%-1%, end-organ dysfunction is reported in 16% [73] .

15

Importantly, from the moment when decision to perform hysterectomy is taken until it

16

is completed, considerable additional blood loss (1000 – 3000 ml) must be expected.

17

6 Assessment of coagulation using thromboelastography (TEG) or thromboelastometry

18

(ROTEM®)

19

The standard laboratory tests used in MOH (eg. PT, aPTT, INR, fibrinogen,

20

hemoglobin, platelets) are standard of care, but are of limited value in the clinical

21

assessment of clot formation and strength. TEG and ROTEM® are whole blood

22

analyzers, providing an evaluation of the kinetic in clot formation, stability and

24 25

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12

strength. Speed and patterns of change in strength and elasticity of the clot are measured and drawn as a graph over time. TEG/ROTEM® is able to detect and quantify the etiology of coagulopathies as [76, 77]:

26

•

Thrombocytopenia

27

•

Factor deficiency

28

•

Heparin effects

29

•

Hypofibrinogenemia

30

•

Hyperfibrinolysis 22

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Monitoring dynamic changes of coagulation by repeated TEG/ROTEM® measures is

2

thought to assist clinicians in improving management of major bleeding emergencies,

3

and at the same time to optimize the use of blood products, antifibrinolytics or

4

coagulation factors [77]. Reference values for ROTEM® have recently been published

5

for the obstetric population, but its use must be considered at most as a diagnostic aid

6

in MOH management [77, 78]. It must be emphasized that the use of TEG/ROTEM®

7

is not validated in regard to decision making if it is safe to administer neuraxial

8

anesthesia.

Unexpected MOH

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1

It has been shown that up to date, sub-standard care is still an issue in 66% of MOH

11

causalities [4]. Lessons learned led several authorities to implement guidelines for

12

MOH. Among others the California OB Hemorrhagic Toolkit [79], the WHO [1], and

13

the Scottish Royal College of Obstetricians and Gynecologists [80] published

14

guidelines including care and decision flowcharts. They provide a structured approach

15

to the treatment of the expected and unexpected MOH.

16

Anesthesiologists must keep important key points in mind when facing an unexpected

17

MOH:

18

1. Call for help!

19

2. Call the blood bank, declare a bleeding emergency and ask for blood products

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early, usually pRBC and FFP. In addition, procoagulants such as tranexamic acid,

21

fibrinogen concentrate (Haemocompletan®), rFVIIa (NovoSeven®) as well as

22

thrombocyte concentrate should be made readily available.

24 25 26 27

3. Venous access: Have several high-flow IV accesses

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4. Set-up and prepare cell-salvage systems, fluid warming systems and a heating blanket

5. Consider an anesthesiologic technique. a. Neuraxial blocks may be time consuming, and may compromise

28

hemodynamic stability. Nevertheless no airway management is needed

29

with a functional neuraxial block. Thresholds to convert a neuraxial

30

anesthesia to a general anesthesia must be kept low and done at first signs

31

of hemodynamic, neurologic or respiratory compromise. 23

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b. General anesthesia is always considered when maternal hemodynamic or

1

central nervous systems are compromised. Initial general anesthesia under

3

optimal conditions may be the best strategy if the patient has developed a

4

coagulopathy. Advanced airway skills are mandatory in order to manage a

5

potential difficult airway.

6

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6. Monitoring

7

The ASA standard monitoring, and considering anesthesia depth monitoring.

8

Emergency CS is considered high risk for perioperative awareness episodes.

9

Consider an arterial line in every bleeding patient. Large pulse pressure variations are early and reliable signs of hypovolemia. Arterial lines allow easy and fast

11

access for blood samples. 7. Volume management:

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10

13

Early and aggressive correction of hypovolemia and blood losses. Hemodilution,

14

hypothermia, acidosis and hypocalcaemia are the entry doors into iatrogenic

15

coagulopathy. Consider 1:1 pRBC to FFP ratios and early correction of

16

thrombocytopenia.

17 18

8. Constant monitoring of blood losses is mandatory, as laboratory results will always be available too late.

9. Communication with obstetricians and midwives is of prime importance

20

10. Save the mothers’ live first

Conclusion

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In the UK mortality related to hemorrhage in pregnancy has decreased from the 2003-

23

2005 to the 2006-2008 “Saving Mothers’ Lives” surveys [4], nevertheless sub-

24 25 26 27

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22

standard care still is an important issue today. The same has been shown in a large registry of maternal deaths in France [81]. Sub-standard care must be avoided by constant training of anesthesiological skills as well as interdisciplinary emergency collaboration training including obstetricians, anesthesiologists and midwifes.

28

Furthermore, implementation of guidelines that are readily available where MOH is

29

expected to happen, and high professional standards assuring the best-qualified care to

30

parturients are of utmost importance for patients safety in obstetrics.

24

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Acknowledgements The authors do not have any conflict of interest to declare.

1.

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Tables & Figures

Table 1: Definitions of Obstetrical Blood Loss

loss (ml)

500-1000

1000-1500

1500-2000

Compensated

Mild

Moderate

Stage 1 after CS Stage 1 after vaginal birth

Stage 2 if blood loss less than 1500 ml and continued bleeding

PPH after CS

Minor PPH

Major PPH

or unstable vitals after 2

[82]

[79]

PRBC or suspicion of DIC

MOH

Severe PPH

Major moderate

[2] [1]

Major severe

[83]

>2500 ml blood loss or: transfusion of ≥5 PRBC, or treatment of

[84]

coagulopathy

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PPH after vaginal birth

Severe

Stage 3 if blood loss >1500

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or vital signs instable

Reference

>2000

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Blood

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Quantification of Obstetrical Blood Loss

MOH: Major Obstetrical Hemorrhage, PPH: Postpartal hemorrhage, CS: Cesarean Section, PRBC: Packed Red Blood Cells, DIC: Disseminated Intravascular Coagulation

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Oxytocin

First line

Second line

treatment

treatment

Yes

Yes

Advantage

Disadvantage

Nausea, vomiting,

Inexpensive

hypotension, tachycardia

Carbetocin

Yes

No

Single administration

Methylergometrine

Yes

Yes

Single administration

Contra-indication

Hypotension

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Substance

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Table 2: Current uterotonic drugs used in MOH

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Expensive, not FDA approved

Hypotension

Major adverse effects

Dose

Route

10-20 IU/h

IV

Same as Oxytocin

100 mcg

IV

Hypertension

0.2mg

IM

0.250 mg

IM

Hypotension, NSTEMI, STEMI,acute lung edema

Eclampsia,

Hypertensive

preeclampsia, hypertension

Reactive airway

No

Yes

Single administration

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Carboprost

disease, Hypertension,

Pulmonary edema,

Kidney and Liver

bronchospasm, dystonia

disease

Oral, sublingual or rectal Yes

Yes

administration,

Not many studies

Caution when ischemic

performed

heart disease is present

inexpensive, photo and

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Misoprostol

Dysrrhythmia

200-600 mcg

Oral, Sublingual,

sublingual or rectal

Rectal

120-1500 mcg/h

IV

thermoresistant

No

Yes

Strong and fast effect on uterine tone

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Sulproston

Only continuous

administration, not FDA approved

Caution when ischemic

Hemodynamic and

heart disease is present

coronary side-effects

NSTEMI: Non ST-elevation myocardial infarction, STEMI: ST-elevation myocardial infarction, IU: International Units, mcg: Microgramms, IV: Intravenous

35

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Table 3: Non-definitive surgical measures

Technique

Success rate

Advantage

identification of failed Balloon tamponade

84%

cases, a negative “tamponade test” mandates laparotomy

Uterine compression sutures,

91.7%

eg. B-Lynch

If bleeding stops the suture is most probably effective

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The uterine artery is easily

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Easy insertion, rapid

accessible; it is a simple Internal iliac artery or uterine

84.6%

artery ligation

and low-risk technique. The internal iliaque artery

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ligation is more difficult to perform

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Adapted from Su et al. [73]

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Figure 1: Lessons learned from trauma surgery

Anesthesiologists

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Surgeons

Meanwhile hemostatic

the anatomical cause of

control resuscitation is

bleeding by non-definitive and

seeking early control of

definitive means

coagulopathy

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Prioritizing the early control of

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Legend: Adapted from Johansson et al. [53]

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Acidosis: Lactate, hemorragic shock

Hypothermia: Volume loss, radiation, non heated infusions

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Dilutional coagulopathy: Aggressive fluid management

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Hypocalcemia: Rapid FFP and pRBC infusion

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Figure 2. The vicious circle of coagulopathy

Legend: FFP: Fresh frozen plasma, pRBC: Packed red blood cells, Radiation: Radiation heat

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transfer

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Highlights •

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•

Major obstetrical bleeding is accounting for 80% of severe maternal morbidity. Preservation of maternal fertility has become one of the major aims after maternal and neonatal resuscitation. Insights gained in trauma anesthesiology have been implemented in major obstetrical bleeding protocols in the last years.

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•