Uterotonic Agents and… Intervention Radiology

1. Big Obstetric Bleeding Symposium Sigtuna, May 5-6, 2010 Uterotonic Agents and… Intervention Radiology Jose CA Carvalho, MD, PhD, FANZCA, FRCPC Director of Obstetric Anesthesia, Mount Sinai Hospital Professor of Anesthesia and Obstetrics and Gynecology, University of Toronto

2. Etiology4 “T”s Uterine atony 80%

5. Uterine Atony - Risk factors Uterine overdistension Polyhydramnios, multiple gestation,macrosomia Uterine muscle exhaustion Rapid/ prolonged/ induced/ augmented labor, high parity Intra-amniotic infection Chorioamnionitis, prolonged rupture of membranes Functional/anatomical distortion of uterus Fibroids, placenta previa, uterine anomalies

6. Oxytocin Stimulates OTR, increasing intracellular Ca++ Contracts the upper uterine segment predominantly Metabolized by enzyme oxytocinase Side effects: hypotension, arrhythmias, myocardial ischemia water intoxication, pulmonary edema, convulsions nausea/vomiting, flushing, headache

7. Ergometrine αagonist and serotoninergic effect Tetanic contraction of upper and lower uterine segments Side effects hypertension (less with methyl-ergonovine) coronary artery spasm, ICH nausea, vomiting

8. Carboprost 15- methyl analogue of the naturally occurring PGF2 Exact mechanism is unknown (direct action?, oxytocin levels?) Side effects nausea, vomiting, diarrhea bronchospasm, flushing, pyrexia hypertension and headache Contraindications cardiac, pulmonary, renal or hepatic disease

9. Misoprostol PGE1 analogue Acts on prostaglandin receptors Rapid de-esterification to misoprostolic acid Side effects pyrexia, shivering, nausea/vomiting, diarrhea more common with oral/sublingual

10. Oxytocin

12. Misoprostol (PGE1)ACOG800-1000 g PR Carboprost (PGF2α) SOGC/ACOG 0.25 mg IM/ IMM q 15-90 min Maximum 8 doses (2 mg)

13. Prophylactic oxytocin for the third stage of labour Oxytocin appears to be beneficial for the prevention of postpartum hemorrhage. However, there is insufficient information about other outcomes and side-effects… Cotter A et al. Cochrane Database of Systematic Reviews 2001, Issue 4. Oxytocin agonists for preventing postpartum hemorrhage There is insufficient evidence that intravenous carbetocin is as effective as oxytocin. Carbetocin is associated with reduced need for additional uterotonic agents, and uterine massage. There is limited comparative evidence on adverse events. Su LL et al. Cochrane Database of Systematic Reviews 2007, Issue 3.

14. Prophylactic use of ergot alkaloids in the third stage of labor Prophylactic intramuscular or intravenous injections of ergot alkaloids are effective in reducing blood loss and postpartum hemorrhage, but adverse effects include vomiting, elevation of blood pressure and pain after birth requiring analgesia, particularly with the intravenous route of administration. Liabsuetrakul T et al. Cochrane Database of Systematic Reviews 2007, Issue 2.

15. Prophylactic ergometrine-oxytocin versus oxytocin for the third stage of labor The use of ergometrine-oxytocin appears to be associated with a small reduction in the risk of PPH when compared to oxytocin for blood loss between 500-1000 ml. Maternal side-effects, including elevation of diastolic blood pressure, vomiting and nausea, are more common with ergometrine-oxytocin as compared to oxytocin alone. Thus, the advantage of a reduction in the risk of PPH needs to be weighed against the adverse side-effects. McDonald SJ et al. Cochrane Database of Systematic Reviews 1997, Issue 2. Revised 2003

16. Prostaglandins for prevention of postpartum hemorrhage Misoprostol orally or sublingually shows promising results when compared to placebo in reducing blood loss after delivery. As side-effects are dose-related, research should be directed towards establishing the lowest effective dose for routine use, and the optimal route of administration. Neither intramuscular prostaglandins nor misoprostol are preferable to conventional injectable uterotonics as part of the management of the third stage of labor, especially for low-risk women. Gülmezoglu AMet al. Cochrane Database of Systematic Reviews 1997, Issue 4. updated May 23. 2007

17. Uterine response to Oxytocin • Receptors to oxytocin increase in pregnancy; max @ term @ labor • There is a finite number of oxytocin receptors in the uterus • Oxytocin infusion during labor down-regulates receptors

18. ED90 of Oxytocin at Cesarean Deliveries Elective Labor Arrest EBL: 693 ± 487 ml EBL: 1178 ± 716 ml Carvalho JCA, et al. Obstet Gynecol 2004; 104: 1005-10. Balki M et al. Obstet Gynecol 2006, 107:45-50

19. Desensitization of Oxytocin Receptors in Human Myometrium Culture % of OTR responding to OT as a function of OT pretreatment Control cells  Cells Pretreated with OT Robinson C et al. Am J Obstet Gynecol 2003, 188: 497-502

20. Desensitization of OTR in Rats (isolated myometrial strips)

21. Pre-exposure to oxytocin decreases response to oxytocin in rat myometrium Magalhaes JK et al. Reprod Sci 2009;16:501-8 Magalhaes et al. Reproductive Sciences 2009; 5:501-508

22. Reprod Sci 2010;17:269-77

23. Prostaglandin F2alpha In in-vitro (tissue bath), the contractile responses of the term pregnant uterus to oxytocin are different in augmented laboring and non-augmented laboring/non-laboring women--there is significant oxytocin desensitization in augmented laboring tissue.

24. Oxytocin and uterine tone Effect of increasing dose Oxytocin 5, 10, 15, 20 IU @ 1 IU/min Sarna MC et al. Anesth Analg 1997; 84: 753-6

25. Intravenous Oxytocin vs Ergometrine-Oxytocin in Cesarean Deliveries for Labor Arrest Ergot-Oxytocin Oxytocin p-value (n=24) (n=24) Estimated Blood Loss (ml) 1218±716 1299 ±774 0.72 Additional “study” solution (%) 21 57 0.01 Rescue carboprost (%) 8 9 0.97 Tachycardia (%) 13 17 0.64 Hypotension (%) 21 26 0.67 Hypertension (%) 4 17 0.14 Nausea (%) 42 9 0.01 Vomiting (%) 25 4 0.05 Balki M et al. Br J Obstet Gynaecol, 2008;115 :579-84

26. Vasculature Animal Data Oxytocin Heart Oxytocin receptors ANP Endotelial cells NO vasodilatation Smooth muscle cells vasoconstriction Progress in Brain Research 2002; 139:281

27. Cardiovascular effects of oxytocin 1st trimester Secher NJ. Acta Obstet Gynecol Scand 1978, 57: 97-103

28. Oxytocin at Cesarean Delivery: Hemodynamic Consequences 5 IU Bolus vs Infusion (5 min) MAP Changes 5 s interval Pulse Rate Changes 5 s interval Thomas JS et al. Br J Anaesth 2007; 98:116-9

29. What do I do? • Oxytocin: 20 IU/ 1000 ml crystalloid 0.5-3.0 IU fast infusion, followed by 40 milliunits/min • Ergometrine: 0.2 mg added to oxytocin drip • Carboprost: 0.25 mg IM (IMM) 15-90 min. max 8 doses • Misoprostol: 1000 mcg PR

30. Now, and the future… Discuss and revise guidelines Look for the “ideal” intravenous prostaglandin?

31. New SOGC Practice Guidelines 2009 Carbetocin 100 µg IV bolus over 1 minute should be used instead of continuous infusion of oxytocin in elective CS Carbetocin: long acting analog of oxytocin (half life 40 minutes as opposed to 3-17 minutes) Ergonovine can be used for prevention of PPH, but should be considered 2nd choice because of side effects… Carboprost is not mentioned… Leduc D et al. JOGC 2009; 980-981

32. Etiology of PPH Uterine Atony Placentary tissue Lacerations of the Inferior Genital Tract Uterine Rupture Uterine Inversion Placenta Acreta/Increta/Percreta Coagulopathy

33. Incidence of Placenta Previa according to the Number of Cesarean Sections If previa, incidence of acreta % Incidence of Previa % Number of Previous CS Irving FC et al. Surg Gynecol Obstet 64:178-200

34. skin bladder uterus

35. Placenta Increta/PercretaPlacenta left in situ, Histerectomy 4 months post-partum AX T1 FS + Gad AX T2

36. Surgical Interventions Uterine tamponade Uterine artery ligation Internal iliac artery (hypogastric) ligation Hysterectomy Uterine suture techniques (B-Lynch 1997)

37. catheter femoral artery Uterine artery

38. Conservative management at CS LABOUR & DELIVERY: Lines, Epidural, Foley catheters INTERVENTIONAL SUITE: Pre-op I.R catheter placement, for use after delivery: - balloons can be inflated after delivery of fetus, if necessary OPERATING ROOM: CS with vertical skin incision Intra-operative ultrasound to define upper placental edge Classical CS to above upper placental edge Ligate cord and aim to leave placenta in-situ RETURN TO INTERVENTIONAL SUITE: Electively embolize postoperatively RETURN TO LABOUR & DELIVERY Post-op care and IR catheters removed next day

39. Arteriogram confirms catheter position before CS

40. Right uterine artery arteriogram following CS, pre embolization

41. Post-embolization, 2nd order branches are no longer present, indicating total occlusion. Note eflux to other branches of internal iliac artery

42. Not diagnosed antenatally: Massive blood transfusion (> 20 unit) Hysterectomy Damage to bladder etc ICU admission, ARDS etc 10% maternal death If diagnosed antenatally: Probably no transfusion Often no hysterectomy Usually no bladder lesion No ICU admission No maternal deaths Morbidly adherent placenta

43. Antenatal Referral for Conservative Management of the Uterus Mount Sinai Hospital 2003-2009 55 patients over the past 6 years 15 are proven percretas – opposed to possible accretas etc. Conservative management successful in 50% of the time, but creates postoperative problems such as AVMs at placental site We are increasingly keener on elective cesarean-hysterectomy 90% of women did not need transfusion and the only woman who had a large transfusion had it after our only life-threatening complication: rupture of an iliac vessel during an inflation of the balloon post-op