Anesthesia and tocolytic / uterotonic therapy in obstetrics Prof

Anesthesia and tocolytic / uterotonic therapy in obstetrics Prof

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
¾
manual removal of placenta
… teamwork: essential component
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
• Ca2+intracellular 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
¾
Ca2+ 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
¾ no improvements in FHR abnormalities
RR (95%CI)
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 vs β-agonists (ritodrine, salbutamol, terbutaline)
• at least 18 hrs up to 48 hrs
Effectiveness
• undelivered after 48 hrs (%)
after 7 days (%)
• age at delivery (mean [SD])
88.1 : 88.9
79.9 : 77.6
35.8 [3.8] : 35.5 [4.1]*
Safety
• adverse cardiovascular events (%)
• treatment discontinuation (%)
8.3 : 81.2*
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
¾
¾
60
40
ED97.1 0.5 IU
20
ED100 1.0 IU
0
0
Carvalho JCA et al, Obstet Gynecol 2004
0.2
0.4
0.6
oxytocin dose (IU)
0.8
1.0
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
Uterine tone (UT)
8
6
2 min
3 min
6 min
9 min
• 0 (no UT) – 10 (optimal UT) 4
• after 2, 3, 6, and 9 min
• ED50/ED90 not determined
Butwick AJ et al, Br J Anaesth 2010
2
0
0
0.5
1.0
3.0
5.0
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
• ED90 2.99 IU (95%CI 2.32–3.67)
• loading dose
1
0.8
0.6
0.4
*biased
0.2
coin up-down sequential
0
0.5 1.0 1.5 2.0 2.5 3.0 3.5
allocation scheme
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
• CO (L/min)
• SVR (dyn.s.cm-5)
• BP (mm Hg)
• HR, SV (mL)
20
0
2000
0
200
0
150
Archer TL et al, Int J Obstet Anesth 2008
0
0
90
delivery
180
oxytocin
270
360
time (s)
Oxytocin in presence of hypovolemia: a disaster
200
5 IU 5 IU
blood pressure (mm Hg)
180
160
120
100
80
60
40
20
0
CEMD 1997-1999, RCOG Press 2000
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