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 – Ocytocin (Syntocinon®) – (Pabal®) – • Sulprostone (Nalador®) • (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 ) Actine+  Antagonist of Ca++ myosinactomyosin  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  Hypercinesiafeta  Tachycardia l asphyxia  Arrythmias  Myocardial ischemia*  Flushing  Headaches  Nausea  Uterin rupture (hyperkinesia)  Hyponatremia

PPH PREVENTION AFTER VB (WHO 2012, SHELDON BMC PREGNANCY AND 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 (-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: 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  (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 5h50ml/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