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 Big Obstetric Bleeding Symposium Sigtuna, May 5-6, 2010

Etiology 4 “T”s Uterine atony 80%

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

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

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

Carboprost 15- methyl analogue of the naturally occurring PGF2  Exact mechanism is unknown (direct action?, oxytocin levels?) 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

Misoprostol PGE 1 analogue Acts on prostaglandin receptors Rapid de-esterification to misoprostolic acid Side effects pyrexia, shivering, nausea/vomiting, diarrhea more common with oral/sublingual

Oxytocin SOGCACOGBNF Bolus5 IU IV 10 IU IM/IMM (Alternate route IM, IMM) 5-10 IU slow IV followed by Infusion10-20 IU/L10-40 IU/L5-30 IU/ 500 ml at a rate sufficient to control uterine atony

Ergometrine SOGCACOG 0.25 mg IM/ mg IV Repeat q 5 min Max 5 doses (1.25 mg) 0.2 mg IM (IMM) q 2-4 h

Misoprostol (PGE1) ACOG  g PR Carboprost (PGF2α) SOGC/ACOG 0.25 mg IM/ IMM q min Maximum 8 doses (2 mg)

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.

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.

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 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

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

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

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

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

Desensitization of OTR in Rats (isolated myometrial strips)

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

Reprod Sci 2010;17:269-77

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. Prostaglandin F2alpha

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

Intravenous Oxytocin vs Ergometrine-Oxytocin in Cesarean Deliveries for Labor Arrest Ergot-OxytocinOxytocin p-value (n=24) (n=24) Estimated Blood Loss (ml)1218± ± Additional “study” solution (%) Rescue carboprost (%) Tachycardia (%) Hypotension (%) Hypertension (%) Nausea (%) Vomiting (%) Balki M et al. Br J Obstet Gynaecol, 2008;115 :579-84

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

Cardiovascular effects of oxytocin Secher NJ. Acta Obstet Gynecol Scand 1978, 57: st trimester

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

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

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

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 2 nd choice because of side effects… Carboprost is not mentioned… Leduc D et al. JOGC 2009;

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

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

bladder uterus skin

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

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

catheter femoral artery Uterine artery

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 Conservative management at CS

Arteriogram confirms catheter position before CS

Right uterine artery arteriogram following CS, pre embolization

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

Morbidly adherent placenta 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

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 Antenatal Referral for Conservative Management of the Uterus Mount Sinai Hospital