• 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