• expert knowledge essential

basic pharmacological principles of such a therapy

- potential side effects and complications

… a professional challenge

First part of presentation: tocolytic therapy

• anesthesia: rarely involved in decision-making

taking care of pregnant women under tocolysis

- secondary preterm Cesarean delivery

• anesthesia: always involved in decision-making

… a professional challenge

Second part of presentation: uterotonic therapy

… teamwork: essential componentof safe patient care

taking care of pregnant women at risk of PPH

Cesarean delivery

manual removal of placenta

• expert knowledge as basis of a team approach

basic pharmacological principles of such a therapy

- potential side effects and complications

Factors determining uterine tone

Vercauteren M et al, Acta Anaesthesiol Scand 2009

Uterus contractility

Uterine contraction: contractile protein actomyosin

• Ca2+intracellular as determining factor

• myosin light chain kinase activity as determining factor

influx from extracellular compartment

- slow voltage-dependent calcium channels

release/reuptake from sarcoplasmatic reticulum

Ca2+ dependent myosin phosphorylation

Drugs affecting uterine contractility

Tocolytic substances• β-adrenergic drugs

• Calcium channel blockers

• Oxytocin antagonists

• Prostaglandin synthesis inhibitors (COX-1, COX-2)

• Magnesium sulphate• Nitroglycerine

fenoterol (Partusisten®), hexoprenaline (Gynipral®)

nifedipine (Adalat®)

atosiban (Tractocile®)

indomethacin (Indocid®, Elmetacin®)

Vercauteren M et al, Acta Anaesthesiol Scand 2009

Drugs affecting uterine contractility

Vercauteren M et al, Acta Anaesthesiol Scand 2009

Uterotonic substances→ induction/augmentation of labor→ prevention/treatment of postpartum hemorrhage (PPH)

• Oxytocin receptor (OXTR) agonistsoxytocin (Syntocinon®), carbetocin (Pabal®)

• ProstaglandinsPGE2/sulproston (Nalador®, Propess®) PGE1/misoprostol (Cytotec®)

• Ergot alkaloidsmethylergometrine or methylergonovine (Methergin®)

Neonatal morbidity extending to later life • cerebral palsy, sensory deficits, learning disabilities

• respiratory distress syndrome

at risk of

• preterm birth <37 completed weeks of gestation

A close look at patients receiving tocolytic therapy

Patients in preterm labor

preterm birth rate Europe 2005 6.2% (95%CI 5.8–6.7)

preterm birth rate worldwide 2005 9.6% (95%CI 9.1–10.1)

Neonatal mortality (<7 days of life)• unrelated to congenital malformations ∼ 28%

Beck S et al, Bull World Health Organ 2010

risk of life-long care if birth <28 weeks ∼ 10%

Prevention of prematurity as therapeutic goal

Implementation of beneficial clinical strategies

Improving neonatal survival

• fetal lung maturation: corticosteroid administration

• in utero transfer to a specialized care facility (NICU)

21 studies, 4269 infants RR (95%CI)

- respiratory distress syndrome 0.66 (0.59-0.73)

- cerebroventricular haemorrhage 0.54 (0.43-0.69)

- neonatal death 0.69 (0.58-0.81)

Roberts D et al, Cochrane Database Syst Rev 2006

- <26 weeks of gestation Sweden 1990-92 +3% per dayFinnström O et al, Acta Paediatr 1997

Revisiting the issues of tocolytic efficacy and indications

Metaanalysis of trials of tocolyis

Prophylactic tocolytic therapy for suspected fetal distress

Tsatsaris V et al, Obstet Gynecol 2001

Kulier R et al, Cochrane Database Syst Rev 2009

efficacy in delaying birth at least 48 h 1.52 (1.03-2.24)

efficacy in delaying birth over 34 wks 1.87 (1.11-3.15)

treatment discontinuation 0.12 (0.05-0.29)

no improvements in FHR abnormalities 0.26 (0.13-0.53)

reduction in uterine activity 0.07 (0.00-1.10)

• nifedipine with β-adrenergic therapy OR (95%CI)

• β-adrenergic drugs vs no treatment RR (95%CI)

• β-adrenergic drugs vs MgSO4

comparing

Risks and complications associated with tocolytic therapy

β-adrenergic therapy• tachycardia, arrhythmia, myocardial ischemia• pulmonary edema (≤24 hrs after discontinuation)

Ogunyemi D, Eur J Obstet Gynecol Reprod Biol 2007

risk factors OR (95%CI)

- spontaneous preterm labor 10.9 (1.3-90)

- tocolytic therapy 4.3 (2.3-8.4)

- corticosteroid therapy 2.3 (1.3-4.0)

- chorioamnionitis 2.7 (1.1-6.5)

Vercauteren M et al, Acta Anaesthesiol Scan 2009

fluid retention and metabolic effects- ADH ↑, aldosterone ↑, glucagon ↑, insulin ↑

Atosiban (oxytocin antagonist): a safer tocolytic ?

Worldwide atosiban vs beta-agonists study group, Br J Obstet Gynaecol 2001

Multinational multicenter double-blind randomized trial

Effectiveness

Safety

• preterm labor at 23 – 33 wks (n = 733)• atosiban vs β-agonists (ritodrine, salbutamol, terbutaline)• at least 18 hrs up to 48 hrs

• undelivered after 48 hrs (%) 88.1 : 88.9 after 7 days (%) 79.9 : 77.6

• age at delivery (mean [SD]) 35.8 [3.8] : 35.5 [4.1]*

• adverse cardiovascular events (%) 8.3 : 81.2*

• treatment discontinuation (%) 1.1 : 15.4*

Atosiban: can we afford it ?

Wex J at al, BMC Pregnancy and Childbirth 2009

Metaanalysis: 3 double-blinded, placebo-controlled trials

• cost per case German hospital drug purchase costs +treatment of associated adverse events

Outcomes

• start of tocolysis within 48 hrs of admissionatosiban vs β-agonist fenoterol (Partusisten®)

• efficacy (RR (95%CI)) 0.99 (0.94–1.04)

• cost savings with atosiban (G-DRG)18 hrs of atosiban tocolysis (€) 226 per case48 hrs of atosiban tocolysis (€) 71 per case

• incidence of adverse events ↓ 6 : 16 items*

scientific drawing of afetus in utero (1510-13)

Leonardo da Vinci (1452 – 1519)

2nd part of presentation

focus on the

postpartum period

Having a close look at uterotonic therapy

Out at last … after vaginal birth or Cesarean delivery • stimulation of uterine contraction (active management)• prevention of uterine atony and PPH

Oxytocin receptor (OXTR) agonists

Prostaglandins

Ergot alkaloids

• oxytocin (Syntocinon®), carbetocin (Pabal®)

• PGE2/sulproston (Nalador®) • PGE1/misoprostol (Cytotec®)

• methylergometrine (Methergin®)

Risks and complications of uterotonic therapyOxytocin (Syntocinon®)

Carbetocin (Pabal®)

• hemodynamic side effectsvasodilation, hypotension, tachycardia, nausea, vomitinghypovolemia, cardiac disease: cardiac arrest

• hormonal side effectsfluid retention, hyponatremia

• more hemodynamic stability ?• less hormonal side effects ?• a single 100 μg IV bolus as effective and more reliable

than a standard continuous infusion of oxytocin … ?Boucher M et al, J Perinatol 1998

Dosis sola facit venenum

Paracelsus (1493–1541)

Poison is in everything,and no thing is withoutpoison.

The dosage makes it eithera poison or a remedy.

Oxytocin: minimum effective intravenous bolus dose ?

Carvalho JCA et al, Obstet Gynecol 2004

Randomized, single-blinded study in healthy patients

• elective Cesarean delivery under spinal anesthesia (n=40)

• estimated response rates

ED97.1 0.5 IU

ED100 1.0 IU

0.2 1.00 0.60.4 0.8

response rate (%)10080604020

0

Oxytocin requirements

• ED90 0.35 IU (95%CI 0.18–0.52)

oxytocin dose (IU)

Oxytocin: minimum effective intravenous bolus dose ?

1086420

0.5 5.00 1.0 3.0

oxytocin dose (IU)

uterine tone (0-10)

2 min3 min6 min9 min

Butwick AJ et al, Br J Anaesth 2010

Uterine tone (UT)

Randomized double-blind placebo-controlled dose-range trial

• elective Cesarean delivery under spinal anesthesia (n=75)

Oxytocin bolus dose

• 0, 0.5, 1, 3, or 5 IU

• 0 (no UT) – 10 (optimal UT)• after 2, 3, 6, and 9 min• ED50/ED90 not determined

Oxytocin: minimum effective intravenous bolus dose ?

Balki M et al, Obstet Gynecol 2004

Oxytocin requirements*

1.5 3.50.5 2.52.0 3.0

probability of uterine response1

0.80.60.40.2

0

initial oxytocin dose (IU)

1.0

• ED90 2.99 IU (95%CI 2.32–3.67)

• loading dose

Randomized, single-blinded study

• C section for labor arrest under epidural anesthesia (n=30)

*biased coin up-down sequentialallocation scheme

LESS IS MORE

20

0• CO (L/min)

2000

0• SVR (dyn.s.cm-5)

150

0• HR, SV (mL)

200

0• BP (mm Hg)

0 90 180 270 360oxytocindelivery time (s)

Pulse power analysis for hemodynamic assessment

Changes in hemodynamics induced by a 5 IU oxytocin bolus

• spinal anesthesia for cesarean delivery

Archer TL et al, Int J Obstet Anesth 2008

oxytocin hemodynamic stability

Oxytocin in presence of hypovolemia: a disaster

5 IU 5 IU

CEMD 1997-1999, RCOG Press 2000

bloo

d pr

essu

re (m

m H

g)

200

180

160

120

100

80

60

40

20

0

Risks and complications associated with other uterotonics

• hypertension, coronary artery spasm, myocardial ischemia• cerebral artery spasm, ischemic cerebral injury• bronchospasm

contraindications: preeclampsia, hypertension …

• bronchoconstriction

• SVR ↓ + CO ↑hypotension, myocardial ischemia, arrhythmia … VF

nausea, vomiting, diarrhea, shivering, fever

Vercauteren M et al, Acta Anaesthesiol Scand 2009

PGE2/sulproston (Nalador®), PGE1/misoprostol (Cytotec®)

Ergot alkaloids (Methergin®)PGF2α (Minprostin® F2α) withdrawn from market : PVR ↑

‘Parturient’Emil Knöll, Basel

1889-1972