UTEROTONICS: A CONCERN FOR THE ANESTHETIST? Thursday 7th November 2013 SAOA, Lausanne N.Roten Departement of Anesthesia, Geneva PROBLEMS MAY HAPPEN.. PLAN
Regulation of the uterin contraction Main uterotonics – Ocytocin (Syntocinon®) – Carbetocin (Pabal®) – Prostaglandins • Sulprostone (Nalador®) • Misoprostol (Cytotec®) – Ergotamin (Methergin®)
Undesirable cardiac events with uterotonics The facts How to prevent and to deal with
FUNCTIONNAL ANATOMY OF UTERUS AND CERVIX
Uterus Uterin body: 70% non striated muscle Cervix: Non striated muscle (25-16-6%) Collagen fibers Matrix REGULATION OF UTERIN ACTIVITY NEJM 1999, NORWITZ STRUCTURAL AND BIOCHEMICAL MODIFICATIONS
Gap junctions (NEJM 1984, At the end of pregnancy Huszar)
More gap junctions More ocytocine and Pg receptors Activation of Ca++ channels
MOLECULAR EVENTS IN THE UTERIN CONTRACTION
Regulation of free Role of Ca++ intracellular Ca++
Free intracellular Ca++ Ocytocin Pg Activation myosin light chain kinase C-AMP (β2 agonist) Actine+ Antagonist of Ca++ myosinactomyosin Antagonist of ocytocin R
Contraction
OCYTOCIN
Uterin contraction Milk ejection
Onset of action: 2-3 min Half-life: 10-15 min STIMULATION/INDUCTION OF LABOUR WITH OCYTOCIN
FDA black box warning Incorrect use of ocytocin 50% of the amount of money paid in obstetrical claims (AJOG 2009, Clark) Therapeutic index not predictable Fetal pH 1/α nb of CU (AJOG, 2007 Bakker) Fetal oxygenation compromised if >5 CU/10min (AJOG, 2008, Simpson KR) Risk of uterin rupture Always use the lowest dose and titrated to the desired effect
LOSS OF SENSITIVITY OF OCYTOCIN R PHANEUF, J OF REPRODUCTION AND FERTILITY 2000,120; 91-7
When admnistred continously the binding sites for ocytocin decrease
Uterin atony
RISK OF UTERIN ATONY WITH EXPOSURE TO AN INFUSION OF OCYTOCIN (GROTEGUT ET AL, AJOG 2011; 204; 56; E1-6)
12’476 births 671 PPH 109 transfused (54 uterin atony) Ocytocin infusion during labour = risk factor whatever the delivery mode MAIN SECONDARY EFFECTS Maternal: Fetal: Hypotension Hypercinesiafeta Tachycardia l asphyxia Arrythmias Myocardial ischemia* Flushing Headaches Nausea Uterin rupture (hyperkinesia) Hyponatremia
PPH PREVENTION AFTER VB (WHO 2012, SHELDON BMC PREGNANCY AND CHILDBIRTH 2013, VOL 13, 46
Active management of third stage: Ocytocin 5-10 UI iv/im Second choice if ocytocine not available: misoprostol, ergometrin, BOLUS OR INFUSION? (THOMAS, BJA 2007; 98(1); 116-19) BOLUS OR INFUSION? OCYTOCIN IN THE CS: HOW MUCH?
Sartain, BJA 2008,101(6) 822-6 (BUTWICK, BJA 104(3), 338-43 PROPOSITION FOR A RULE OF « 3’S » (EDITORIAL L.TSEN IJOA 2010,19,243-5)
For CS: 3 UI rapid infusion (not bolus) 3min observation Inadequate tonus: 3 UI more (two times 3x3 UI) Perfusion continue de 3 UI/1000ml à 100ml/h 3 rescue uterotonics: Ergométrine PG (carboprost-misoprostol) TAKE HOME MESSAGES FOR OCYTOCIN
1st choice in preventing PPH after VB: 5 UI Always use a small infusion (no bolus) CS: the efficient dose for prevention probably between 0,35-5 UI Risk of desensitization of the myocyte if prolonged used Other utertotonics remain efficient Main adverse maternal effects= cardiovascular Fetal distress if overstimulation of labour CARBETOCIN (PABAL®) ( RATH, EUR J OBST &GYNECOL&REPRODUCTIVE BIOLOGY, 2009;147, 15-20)
Synthetic analog of ocytocin Onset: 2min ½ vie 60 (iv) to 120 (im) min Iv (compendium CH), im (litterature): 1 dose of 100µg One indication in Switzerland: PPH prevention after CS Utilisation : environ 23 pays (Canada depuis 1997)
CARBETOCINE IN CS AT RISK FOR PPH(DE ANGEL-GARCIA, VALUE HEALTH 2006; 9(6); A254
Carbetocin iv (n=77) 5 UI ocytocin iv (n=75)
8% atony in carbetocin group 19% ocytocin group(p<0,0001)
FURTHER RESEARCHES NEEDED
Difficulty of research Why?
Methodology N RCT Common definitions of PPH Common algorithm Common anaesthetic techniques LES PROSTAGLANDINES MISOPROSTOL AND PREVENTION OF PPH Miso > placebo Valuable alternative if: Ocytocin not available No iv line Cold storage not possible Low price Onset: oral(8’), vaginal (20’), rectal (100’) Sustained effect: 3-4h
Lancet 2006,368;1248-53 Lancet 2001,358; 689-95 Cochrane 2007 IJGO, 2007;99 (suppl 2); 198-201 MISOPROSTOL AND TREATEMENT OF PPH AFTER VB (WINIKOFF, LANCET 2010 ,375, 210-16)
Misoprostol sublingual 800µg /ocytocine 40 UI iv over 15 min Primary outcomes: Active bleeding controlled 20 min post UT: ocytocine faster (2min) Transfusion or drop of Hb > 30G/l: more often in the misoprostol group TAKE-HOME MESSAGES FOR MISOPROSTOL
Give it p.os Better than pacebo (prevention or ttt): valuable alternative if ocytocin not available Less efficient ocytocin for ttt of PPH in VB Main secondary effect: fever and shivering Forget rectal or vaginal route of administration
SULPROSTON (NALADOR®): PGE2 ANALOG
Strictly iv (electrical infusion device) Onset: 4min ½ life: 8min Rise basal tonus and frequency of uterin contractions )> ocytocin Indication: 2nd line treatement of PPH SULPROSTON AND CARDIOVASCULAR COMPLICATIONS MECHANISM OF CARDIOVASCULAR COMPLICATIONS
Depending of the sub-type of PG R activated Vasodilatation (EP2-4) coronary arteries included: coronary steal Vasoconstriction (EP1-3) coronary arteries included: coronary spasm Rise in CO and cardiac and frequency
Pulmonary circulation: constriction/dilatation Hyperthermia BUT IS ONLY SULPROSTON THE GUILTY MAN/WOMAN? OTHER CONTRIBUTING FACTORS
Amines, stress, autres ut.toniques PPH AND MYOCARDIAL ISCHEMIA FACTORS LEADING TO ISCHEMIA TAKE-HOME MESSAGES FOR SULPROSTON Respect iv administration with electrical infusion device Correct contributiong factors to myocardial ischemia quickly: we are often « to late and not enough » Hypotension, tachycardia Hypovolemia Anemia Invasive cardiovascular monitoring early: 5 lead ECG and arterial line Follow troponines Follow cardiac function ERGOMETRIN TAKE-HOME MESSAGE FOR ERGOMETRIN
No iv admistration : 1 dose strictly im; sustained effect for many hours
Be careful when used in association with other uterotonics : coronary deleterious effects at risk
Be careful with other medical conditions: Maternal age Tobacco and cocaï abuse Anaemia, hypovolemia Hypertensive diseases,cardiopathies Stress NEW COOK BOOK AT HUG (MARCH 2013) Nalador®: 500µg in 250ml/NaCl 0,9% over 1h 250 µg (125ml) over 20min (=375 ml/h) 250 µg (125 ml) over 40min (=188 ml/h) 500 µg in 250 ml NaCl 0,9% over 5h50ml/h after 1st perfusion 3d dose (500 µg in 250 ml NaCl 0,9% ) over 12h (21ml/h) : depending on the needs Methergin ®: 0,2 mg im seulement si: Absence de CI: pathologies cardiaques et HTA Non réponse au Nalador après 20min Cytotec®: 2cp (400 µg ) per os; only if sulproston contraindicated