First part of presentation: tocolytic therapy

… a professional challenge

• anesthesia: rarely involved in decision-making

• expert knowledge essential

¾ basic pharmacological principles of such a therapy - potential side effects and complications

¾ taking care of pregnant women under tocolysis

- secondary preterm Cesarean delivery Second part of presentation: uterotonic therapy

… a professional challenge

• anesthesia: always involved in decision-making

¾ Cesarean delivery … teamwork: essential component

¾ manual removal of placenta of safe patient care

• expert knowledge as basis of a team approach

¾ basic pharmacological principles of such a therapy - potential side effects and complications

¾ taking care of pregnant women at risk of PPH Factors determining uterine tone

Uterus contractility

2+ •Caintracellular as determining factor

¾ influx from extracellular compartment - slow voltage-dependent calcium channels

¾ release/reuptake from sarcoplasmatic reticulum

• myosin light chain kinase activity as determining factor

2+ ¾ Ca dependent myosin phosphorylation

Uterine contraction: contractile protein actomyosin

Vercauteren M et al, Acta Anaesthesiol Scand 2009 Drugs affecting uterine contractility

Tocolytic substances • β-adrenergic drugs ® ® ¾ fenoterol (Partusisten ), hexoprenaline (Gynipral ) • Calcium channel blockers ® ¾ nifedipine (Adalat ) • Oxytocin antagonists ® ¾ atosiban (Tractocile ) • Prostaglandin synthesis inhibitors (COX-1, COX-2) ® ® ¾ indomethacin (Indocid , Elmetacin ) • Magnesium sulphate • Nitroglycerine Vercauteren M et al, Acta Anaesthesiol Scand 2009 Drugs affecting uterine contractility

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

• Oxytocin receptor (OXTR) agonists

® ® ¾ oxytocin (Syntocinon ), carbetocin (Pabal ) • Prostaglandins ® ® ¾ PGE2/sulproston (Nalador , Propess ) ® ¾ PGE1/misoprostol (Cytotec ) • Ergot alkaloids ® ¾ methylergometrine or methylergonovine (Methergin )

Vercauteren M et al, Acta Anaesthesiol Scand 2009 A close look at patients receiving tocolytic therapy

Patients in preterm labor at risk of • preterm birth <37 completed weeks of gestation

¾ preterm birth rate Europe 2005 6.2% (95%CI 5.8–6.7)

¾ preterm birth rate worldwide 2005 9.6% (95%CI 9.1–10.1) Neonatal mortality (<7 days of life) • unrelated to congenital malformations ∼ 28% Neonatal morbidity extending to later life • cerebral palsy, sensory deficits, learning disabilities

¾ risk of life-long care if birth <28 weeks ∼ 10% • respiratory distress syndrome Beck S et al, Bull World Health Organ 2010 Prevention of prematurity as therapeutic goal

Implementation of beneficial clinical strategies • fetal lung maturation: corticosteroid administration

¾ 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

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

- <26 weeks of gestation Sweden 1990-92 +3% per day Finnström O et al, Acta Paediatr 1997 Revisiting the issues of tocolytic efficacy and indications

Metaanalysis of trials of tocolyis comparing • nifedipine with β-adrenergic therapy OR (95%CI)

¾ efficacy in delaying birth at least 48 h 1.52 (1.03-2.24)

¾ efficacy in delaying birth over 34 wks 1.87 (1.11-3.15)

¾ treatment discontinuation 0.12 (0.05-0.29) Tsatsaris V et al, Obstet Gynecol 2001

Prophylactic tocolytic therapy for suspected fetal distress

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

¾ no improvements in FHR abnormalities 0.26 (0.13-0.53)

• β-adrenergic drugs vs MgSO4

¾ reduction in uterine activity 0.07 (0.00-1.10) Kulier R et al, Cochrane Database Syst Rev 2009 Risks and complications associated with tocolytic therapy

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

¾ 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) Ogunyemi D, Eur J Obstet Gynecol Reprod Biol 2007

¾ fluid retention and metabolic effects -ADH ↑, aldosterone ↑, glucagon ↑, insulin ↑ Vercauteren M et al, Acta Anaesthesiol Scan 2009 Atosiban (oxytocin antagonist): a safer tocolytic ?

Multinational multicenter double-blind randomized trial • preterm labor at 23 – 33 wks (n = 733) •atosiban vsβ-agonists (ritodrine, salbutamol, terbutaline) • at least 18 hrs up to 48 hrs Effectiveness • 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]* Safety • adverse cardiovascular events (%) 8.3 : 81.2* • treatment discontinuation (%) 1.1 : 15.4* Worldwide atosiban vs beta-agonists study group, Br J Obstet Gynaecol 2001 Atosiban: can we afford it ?

Metaanalysis: 3 double-blinded, placebo-controlled trials • start of tocolysis within 48 hrs of admission ® ¾ atosiban vs β-agonist fenoterol (Partusisten ) • cost per case German hospital drug purchase costs + treatment of associated adverse events Outcomes • efficacy (RR (95%CI)) 0.99 (0.94–1.04) • cost savings with atosiban (G-DRG)

¾ 18 hrs of atosiban tocolysis (€) 226 per case

¾ 48 hrs of atosiban tocolysis (€) 71 per case • incidence of adverse events ↓ 6 : 16 items* Wex J at al, BMC Pregnancy and Childbirth 2009

2nd part of presentation

focus on the postpartum period

scientific drawing of a fetus in utero (1510-13)

Leonardo da Vinci (1452 – 1519) 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 • oxytocin (Syntocinon®), carbetocin (Pabal®) Prostaglandins

® •PGE2/sulproston (Nalador ) ® •PGE1/misoprostol (Cytotec ) Ergot alkaloids • methylergometrine (Methergin®) Risks and complications of uterotonic therapy Oxytocin (Syntocinon®) • hemodynamic side effects

¾ vasodilation, hypotension, tachycardia, nausea, vomiting

¾ hypovolemia, cardiac disease: cardiac arrest • hormonal side effects

¾ fluid retention, hyponatremia Carbetocin (Pabal®) • 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

Poison is in everything, and no thing is without poison.

The dosage makes it either a poison or a remedy.

Paracelsus (1493–1541) Oxytocin: minimum effective intravenous bolus dose ?

Randomized, single-blinded study in healthy patients • elective Cesarean delivery under spinal anesthesia (n=40)

Oxytocin requirements response rate (%) 100 •ED90 0.35 IU (95%CI 0.18–0.52) 80 • estimated response rates 60 40 ¾ ED97.1 0.5 IU 20 ¾ ED 1.0 IU 100 0 0 0.2 0.4 0.6 0.8 1.0

Carvalho JCA et al, Obstet Gynecol 2004 oxytocin dose (IU) Oxytocin: minimum effective intravenous bolus dose ?

Randomized double-blind placebo-controlled dose-range trial • elective Cesarean delivery under spinal anesthesia (n=75)

Oxytocin bolus dose uterine tone (0-10) • 0, 0.5, 1, 3, or 5 IU 10 8 Uterine tone (UT) 6 2 min • 0 (no UT) – 10 (optimal UT) 4 3 min 2 6 min • after 2, 3, 6, and 9 min 0 9 min •ED50/ED90 not determined 0 0.5 1.0 3.0 5.0

Butwick AJ et al, Br J Anaesth 2010 oxytocin dose (IU) Oxytocin: minimum effective intravenous bolus dose ?

Randomized, single-blinded study • C section for labor arrest under epidural anesthesia (n=30)

Oxytocin requirements* probability of uterine response 1 •ED90 2.99 IU (95%CI 2.32–3.67) 0.8 • loading dose 0.6 0.4 0.2 * biased coin up-down sequential 0 allocation scheme 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Balki M et al, Obstet Gynecol 2004 initial oxytocin dose (IU) LESS oxytocin IS MORE hemodynamic stability

Changes in hemodynamics induced by a 5 IU oxytocin bolus • spinal anesthesia for cesarean delivery

Pulse power analysis for hemodynamic assessment 20 •CO (L/min) 0 2000 •SVR (dyn.s.cm-5) 0 200 • BP (mm Hg) 0 150 • HR, SV (mL) 0 0 90 180 270 360

Archer TL et al, Int J Obstet Anesth 2008 delivery oxytocin time (s) Oxytocin in presence of hypovolemia: a disaster

5 IU 5 IU 200 180 160 120 100 80 60 40 blood pressure (mm Hg) (mm blood pressure

20 CEMD 1997-1999, RCOG Press 2000 0 Risks and complications associated with other uterotonics

® ® PGE2/sulproston (Nalador ), PGE1/misoprostol (Cytotec ) •SVR ↓ + CO ↑

¾ hypotension, myocardial ischemia, arrhythmia … VF nausea, vomiting, diarrhea, shivering, fever • bronchoconstriction ® PGF2α (Minprostin F2α) withdrawn from market : PVR ↑ Ergot alkaloids (Methergin®) • hypertension, coronary artery spasm, myocardial ischemia • cerebral artery spasm, ischemic cerebral injury • bronchospasm

¾ contraindications: preeclampsia, hypertension …

Vercauteren M et al, Acta Anaesthesiol Scand 2009

‘Parturient’ Emil Knöll, Basel

1889-1972