Which of these medications is commonly used to control postpartum bleeding related to uterine atony?

A. Uterine Atony

Uterine atony is responsible for the majority of PPH cases. Failure of the uterine smooth muscle to contract and constrict to create “living ligatures” around the spiral blood vessels in the placental bed12 can lead to rapid blood loss. This blood loss can be significant because there is approximately 700 ml of blood per minute flowing through the term uterus.13 Predisposing factors for uterine atony include overdistension of the uterus, chorioamnionitis, dysfunctional labor (e.g., protracted active phase, secondary arrest of labor, or prolonged second stage) or prolonged use of oxytocin, grand multiparity, and administration of MgSO4.13,14

Uterine Atony

Uterotonics

Postpartum uterine atony can occur immediately after delivery or several hours later. If the atony persists, risk of significant postpartum hemorrhage and maternal morbidity are both increased. Initial prevention of uterine atony includes bimanual uterine massage and administration of oxytocin as either a continuous IV infusion or in small (e.g., 3 Units) repeated doses (Table 37.6). Rapid IV bolus administration is associated with vasodilation, hypotension, and tachycardia. Consequently, even small doses should be administered over at least 30 seconds.86 Frequent communication between the anesthesiologist and obstetric provider in the postpartum period is critical to determining if additional uterotonics are required. Each uterotonic agent has unique side effects and considerations that may pose a contraindication when certain patient comorbidities exist.

OXYTOCIC AGENTS

The primary treatment for uterine atony is the use of uterotonic medications. Oxytocin is the first choice for both the treatment and prophylaxis of uterine atony. Prophylactic oxytocics reduce the risk of postpartum hemorrhage by about 60%. Oxytocin is typically administered by intravenous infusion, with 20 to 40 units added to 1 L of carrier fluid. It can cause vasodilatation and hypotension if administered by bolus. If this alone is unsuccessful, ergot alkaloids are second-line medications for the treatment of uterine atony. Both ergonovine and methylergonovine produce tetanic uterine contractions, most likely mediated by α-adrenergic receptors. The usual dose is 0.2 mg intramuscularly. Effects are observed within a few minutes and last several hours. These agents may cause extreme hypertension, especially in hypertensive patients or those receiving concomitant vasopressor therapy. Such ergot-induced hypertension may be severe enough to cause intracranial hemorrhage, stroke, or seizures.

If these methods fail to relieve uterine atony, 15-methyl prostaglandin F2α can be used to treat refractory cases. However, it may cause bronchospasm and alter lung ventilation-perfusion ratios, causing hypoxemia. The usual dose is 250 μg administered intramuscularly or intramyometrially. It can be repeated every 15 to 30 minutes, but the total dosage should not exceed 2 mg. Misoprostol, another prostaglandin, has been investigated for safety and efficacy in the treatment of postpartum hemorrhage. A dose of 1000 μg per rectum has been shown to be effective for severe postpartum hemorrhage unresponsive to standard uterotonic agents. Recently, several case reports have described the successful use of recombinant factor VIIa (20 to 40 μg/kg) in patients with severe, refractory postpartum hemorrhage.

Blue Cohosh

Blue cohosh is indicated when there is dysmenorrhea owing to uterine atony. It was popular among the Eclectics, and continues to be used by herbalists as a uterine tonic, promoting effective uterine contractions and relieving spasticity, in conjunction with uterine spasmolytic.150,158 Blue cohosh is an emmenagogue, and uterotonic. The quinolizidine alkaloids N-methylcysteine and sparteine are believed to responsible for caulophyllum's oxytocic, stimulatory effect on the uterine muscle.154 Its steroidal saponins, caulosaponin, caulosapogenin, and caulophyllosaponin also may have an effect on the uterus. It typically constitutes only a small fraction (i.e., 20%) of a formula owing to its potential hypertensive activity and toxicity.

Massive Transfusion Protocol in Other Medical Scenarios

Severe hemorrhage accompanying obstetric complications, including placenta previa, uterine atony or rupture, and DIC, can lead to a hysterectomy, loss of future reproductive capacity, and/or loss of the mother, child, or both. Postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide with 140,000 deaths per year. PPH is seen in 5%–15% of all births and 3.7/1000 pregnancies. Its incidence has increased twofold over the last decade with no known increase in risk factors. Massive PPH has been defined as >500 mL blood loss after a vaginal delivery or >1000 mL blood loss following a caesarian delivery. Coagulation factors during pregnancy increase up to 10-fold over the nonpregnant state. However, if fibrinogen were at nonpregnant levels it could be considered critically low in the pregnant state. For each decrease of 100 mg/dL in fibrinogen the risk of PPH increases 2.6-fold. For PPH prevention the use of cryoprecipitate or fibrinogen concentrates is being studied, and thus far it has been shown to be of benefit. In the obstetric setting, waiting until fibrinogen reaches 150–200 mg/dL, as in most MTP initiations, will essentially guarantee 100% chance of a massive postpartum hemorrhagic bleed in this obstetric setting. The odds ratio for PPH with fibrinogen 200–300 mg/dL is 1.90 (1.16–3.09). This ratio increases to 11.99 (2.56–56.05) for fibrinogen <200 mg/dL. With this information, transfusion of cryoprecipitate when fibrinogen level approaches 200 mg/dL is more protective in the obstetric patient to avoid maternal mortality. When a patient has PPH, initial therapy involves treatment with oxytocin, followed by prostaglandins, and finally intrauterine balloon tamponade. TEG has aided in blood component transfusion support in these emergent cases. In addition, cell savers, fibrinogen concentrates, cryoprecipitate, TXA, and desmopressin have also been used in the treatment of PPH. The goal is to keep Hgb >8 g/dL, platelet count >75 × 109/L, PT/PTT <1.5 times the normal, and fibrinogen >200 mg/dL. Optimization of MTP/MHP with early use of cryoprecipitate/fibrinogen concentrates continues to be investigated.4,28,57–66

In pediatric patients with trauma most protocols still initially use crystalloids at 20–40 mL/Kg as the preferred dose before instituting blood component infusion. When more than 30 mL/Kg RBCs have been infused emergently, MTP with a 1:1:1 ratio of RBC:FFP:platelets is instituted when the patient is over 30 Kg. On the contrary, when the pediatric patient is less than 30 Kg a ratio of 30:20:20 mL/Kg of RBC:FFP:platelets is recommended. Cryoprecipitate is also infused when fibrinogen is below 100 mg/dL. TXA is used early when a high-risk massive bleed is present at 15 mg/Kg and up to 1 g can be given intravenously. In adults, its use is best within 1 h of injury and no additional benefit is noted if given after 3 h, when it has been shown to be harmful.33,67 More importantly, predictors of need for MTP in children may need to be modified. The ABC model when applied in the pediatric setting was 29% sensitive. When this model was age adjusted, the sensitivity increased to only 65%. Additional studies will need to be performed to create better predictive models in children.13,67

In elderly patients, crystalloid use is limited to 20 mL/Kg. Fluid status can be evaluated with the use of echocardiography and pulse pressure measurements. When there is evidence of cardiac ischemia an Hgb level of 9 g/dL is desirable. A mean arterial pressure of >70 mm Hg to ensure adequate perfusion of the central nervous system (CNS) is also a goal in this scenario.41

When there is CNS trauma (i.e., TBI), the goals in MTP/MHP are also different. Instead of tolerating lower blood pressures to stabilize clots, a higher SBP is the goal. SBP lower than 90 mm Hg can lead to further CNS damage, and as a result, a goal of at least 90 mm Hg is more desirable. Moreover, due to the potential for end organ ischemia at lower RBC concentrations an Hgb goal of 9 g/dL is also set.3,13

In other surgical/medical scenarios various successes have been seen with MTP. In patients with ruptured abdominal aortic aneurysms (rAAA) the mortality decreased from 66% to 44%.22 Separately, another study of rAAA showed increased survival with cell saver technology and no increased benefit in reducing mortality with use of FFP.68 In the operating room, repair of rAAA using massive transfusion support improved the survival by decreasing the mortality from 80% to 30%. In these patients, repair of rAAA using endovascular aneurysm repair required less blood, but 55% of patients needed massive transfusions. Importantly, the ratio of blood components used in this repair process did not change the mortality of the procedure.69 Patients who have pelvic ring fractures had no additional benefit from MTP over standard component transfusion.70 Patients requiring transfusions in cardiothoracic, gastrointestinal tract, and hepatopancreaticobiliary bleeds tolerated higher ratio of FFP:RBC with no increase in 30-day mortality. High RBC:platelet ratio decreased the 48-h mortality, and at 30 days, no increased mortality was seen. Interestingly, cardiopulmonary patients who were on cardiobypass for greater than an hour benefited from platelet transfusions. Gastrointestinal tract bleeds requiring ≤5 units RBCs receive no additional benefit with concomitant FFP transfusion. Based on the aforementioned data it becomes clear that additional research is still needed to establish guidelines for appropriate blood component ratios in patients without trauma.22,71

Fourth Stage of Labor

Some consider the first hour after delivery of the placenta the fourth stage of labor. Risk of uterine atony is highest during this period. The patient should be watched carefully for excessive vaginal bleeding, an enlarging boggy fundus, and hypotension. Massage of the uterine fundus most often is sufficient to return it to a contracted state and stop bleeding. Oxytocin may be added to the IV fluids in doses of 20 or 40 units/L of fluid and the IV rate increased, or if no IV fluid is needed, 20 units of oxytocin can be given intramuscularly (IM). Alternately, methylergonovine (Methergine), 0.2 mg, can be given IM every 20 minutes if the mother is not hypertensive. Finally, if no resolution to bleeding, 250 μg of prostaglandin F2α (Hemabate) can be given IM every 15 to 20 minutes as needed for up to 3 doses.

Delivery of the Infant and Maternal Management

Before umbilical cord clamping and delivery, coordination between the surgery and anesthesia teams is crucial to prevent uterine atony and excessive maternal hemorrhage. Because a decrease in the tocolytic agent, whether an inhaled or an intravenous agent, would result in increased uterine vascular resistance and decreased fetal oxygenation, reversal of the tocolysis must not occur before the umbilical cord is clamped. However, at clamping, a near-total reversal of tocolysis is required to limit uterine bleeding. This is best achieved with low-solubility halogenated inhaled anesthetics (e.g., desflurane). As the cord is clamped, the anesthetic agent is immediately discontinued and oxytocin is administered as a bolus followed by a continuous infusion and titrated to uterine response (e.g., 40 units oxytocin in 500 mL NS over 30 minutes, followed by 20 units over 8 hours). Additional uterotonic medications may be necessary and must be immediately available should uncontrolled maternal hemorrhage occur. These medications include methylergonovine, carboprost, and calcium carbonate. Blood products should also be available and administered if uncontrolled and persistent bleeding occurs. In cases of uncontrolled hemorrhage despite maximal drug therapy, a hysterectomy may be necessary. When maternal hemostasis has been achieved, uterine tone restored, and the placenta delivered, then low-dose inhaled anesthetic agents and nitrous oxide can be administered, provided that the mother is hemodynamically stable.

A separate team of neonatologists, anesthesiologists, and nurses should be available for the neonate because additional medications, blood products, and vascular access may be needed. A brief physical examination, confirmation of bilateral breath sounds, and hemodynamic stability must be ensured soon after delivery. In some instances, immediate surgical intervention is planned, necessitating entirely separate anesthetic, surgical, and nursing teams in an adjacent operating room as the maternal abdomen is closed.

Delivery of the Infant and Maternal Management

Before umbilical cord clamping and delivery, coordination between the surgery and anesthesia teams is crucial to prevent uterine atony and excessive maternal hemorrhage. Because a decrease in the tocolytic agent, whether it is an inhalational or an IV agent, would increase uterine vascular resistance and decrease fetal oxygenation, reversal of the tocolysis must not occur before the umbilical cord is clamped. However, at clamping, a near-total reversal of tocolysis is required to limit uterine bleeding. This is best achieved with an inhalational anesthetic with a low-solubility (e.g., desflurane). As the cord is clamped, the anesthetic is immediately discontinued and oxytocin is administered as a bolus followed by a continuous infusion and titrated to uterine response (e.g., 40 units oxytocin in 500 mL of normal saline solution over 30 minutes, followed by 20 units over 8 hours). Additional uterotonic medications may be necessary and must be immediately available should uncontrolled maternal hemorrhage occur.230 These medications include methylergonovine, carboprost, and calcium carbonate. Anticipation of massive and rapid maternal hemorrhage is essential. Appropriate IV access (e.g., rapid infusion catheters, introducer sheaths) with a rapid infusion device in place for blood product administration may be lifesaving, should uncontrolled and persistent bleeding occur. In cases of uncontrolled hemorrhage despite maximal drug therapy, a hysterectomy may be necessary. When maternal hemostasis has been achieved, uterine tone restored, and the placenta delivered, then a low-dose inhalational anesthetic and nitrous oxide can be administered, provided that the mother is hemodynamically stable.

A separate team of neonatologists, anesthesiologists, and nurses should be available for the neonate because additional medications, blood products, and vascular access may be needed. A brief physical examination, confirmation of bilateral breath sounds, and hemodynamic stability must be ensured soon after delivery. In some instances, immediate surgical intervention is planned, necessitating entirely separate anesthetic, surgical, and nursing teams in an adjacent OR as the maternal abdomen is closed.

Carboprost tromethamine — (Hemabate)