SCCM Resource Library-Pharmacologic Adjuncts in Obstetric Hemorrhage: First Line and Beyond

Video Transcription

Hello, I am Mary Jane Reed, and I will be speaking today on the pharmacological adjuvants in obstetrical hemorrhage, and I have no disclosures.  As noticed in the previous lecture, obstetrical hemorrhage is a leading cause of maternal death in the world, and is often the leading cause of death in resource-poor countries.  In today's lecture, we will discuss the risk factors for obstetric hemorrhage, summarize  pharmacological prophylactics, review pharmacologic adjuvants for obstetric hemorrhage, recognize contraindications to common medications used for obstetric hemorrhage.  Obstetrical hemorrhage causes has been addressed in the previous lecture in this section. Of note, good resuscitative efforts as well as some pharmacological adjuvants are helpful  in both prophylacting as well as treating obstetrical hemorrhage. Recognizing risk factors for obstetrical hemorrhage is important because this will help plan your  resuscitative efforts. As again suggested before, uterine atony, genital tract trauma, placental problems,  coagulopathies, sepsis, preeclampsia, acute fatty liver pregnancy, and bleeding tendencies are all risk factors for obstetrical hemorrhage.  In obstetrical hemorrhage, there are opportunities to intervene that may prevent or decrease significant bleeding.  It is important to remember that preparation and multidisciplinary team approach is crucial to maternal and fetal outcomes.  The points of opportunity can occur antenatally with treatment of anemia, active management of third stage of labor, early recognition of hemorrhage and treatment, which includes  resuscitation, mass transfusion, as well as uterotonics and transamic acid, and then of course a multidisciplinary maternity team.  Identification and treatment of antenatal anemia may be helpful in reducing perinatal blood loss. Anemia can be a cause and a consequence of postpartum hemorrhage.  A cohort study of Indian women noted that women with moderate or severe anemia had greatly increased risk of postpartum hemorrhage.  Women with moderate anemia, defined as 7-9.9 grams per deciliter of hemoglobin, had a 50% increase in postpartum hemorrhage, whereas those with severe anemia had a 10-fold increase.  A second study showed that anemic women experienced worse outcomes after postpartum hemorrhage.  An international survey of 275,000 women found that severe maternal outcomes after PPH were nearly three times more common in anemic than non-anemic women.  In the active management of the third stage of labor, the current gold standards for the uterotonic used for PPH prevention is oxytocin.  A further consideration of oxytocin prophylaxis is the optimal route of administration. Previously there had been thought that there was no clear benefit for intravenous over  intramuscular oxytocin in preventing excessive blood loss after a vaginal birth. However, two large studies recently done found that IV oxytocin to be more effective than  IM oxytocin, resulting in a 50% reduction in postpartum blood loss and a 70% reduction in blood transfusion requirement without increasing adverse effect.  At present, the use of oxytocin is standard in the active management of the third stage of labor, which includes controlled cord traction and delayed cord clamping.  In international units, IM or IV is recommended for prevention of postpartum hemorrhage for  all births by the WHO, however, caution must be had when giving an IV bolus as hypotension is a significant side effect.  Even a small dose of oxytocin given intravenously as a bolus over a short period of time can cause a rapid and transient drop in blood pressure.  This graph shows the precipitous drop of the mean arterial blood pressure when an IV bolus is given over 15 seconds versus an infusion given over 5 minutes.  Care must be taken to assure that oxytocin is not given too fast and cause a significant drop in patient's blood pressure.  In the prevention of postpartum hemorrhage, only one intratonic medication should be given. Carbintocin is the gold standard, but the following medications are also suggested by  the WHO's recommendations of 2018. When comparing carbintocin to oxytocin, there are similar desirable effects and carbintocin  likely superior in reducing postpartum hemorrhage greater than 500 cc. There is fewer use of additional uterine tonics and blood loss is less after delivery,  although there are no clear differences in undesirable effects. While on balance the effects probably favor carbintocin, the supply cost of carbintocin  is approximately 20 times that of oxytocin, thereby making oxytocin the primary choice. Misoprostol has similar desirable effects to oxytocin, but is less effective for reducing  severe postpartum hemorrhage of greater than 1000 cc. It causes more undesirable effects including nausea and vomiting, shivering, fever, and diarrhea.  However, it is cheaper, it is heat stable, and can be given orally and is probably acceptable  and feasible to use in the low resource environment because it can be given by trained lay personnel.  Although there are no clear differences in desirable effects with ergotamine derivatives  over oxytocin, more women are likely to experience nausea, vomiting, headache, and hypertension.  In fact, the drug should not be given or given very carefully in patients with known hypertension.  It also needs to be given by trained personnel so it is less favorable in low resource areas.  The combination drug of oxytocin plus ergotamine is similar to oxytocin in terms of desirable  outcomes and possibly more effective in preventing postpartum hemorrhage of greater than 500 cc.  It does, however, have more undesirable effects than oxytocin including nausea, vomiting, and diarrhea.  The balance overall favors oxytocin over this drug especially in women who have history of hypertension or there is an inability to screen for hypertension at the time of delivery.  Isoprestol plus oxytocin compared to oxytocin alone is probably superior for blood transfusion decrease and additional uterotonic use and blood loss.  It may possibly prevent more postpartum hemorrhage and result in a small mean change in hemoglobin level.  It is, however, associated again with more undesirable effects including nausea, vomiting, diarrhea, shivering, and fever.  The balance of effects favors oxytocin alone and it is limited in complexity of dosage when having to use two separate medications through different routes of administration.  So in summary, the World Health Organization postpartum hemorrhage prevention includes the algorithm if skilled healthcare personnel are available for injectable uterotonics.  If not, then isoprestol which can be given by lay health workers or trained community workers can be given PO or Porectum.  Other than that, the available uterotonics that are injectable, oxytocin is the uterotonic of choice or carburetosin if available.  The ergotamine derivatives, either in combination with oxytocin or in combination with themselves, can only be given to those patients who can be screened for hypertension.  Transamic acid is an antifibrillatic agent that inhibits plasmidogen activation and has been widely used for the treatment of bleeding and prevention of blood loss in trauma and  general surgery. The prophylaxis use of transamic acid reduces the incidence of minor postpartum hemorrhage  as well as major postpartum hemorrhage in those undergoing cesarean section. The concern for prophylaxis seems to be accepted for those women who are at high risk for postpartum  hemorrhage undergoing cesarean section. One gram IV of transamic acid after cord clamping. Contraindications are renal insufficiency as it is renally excreted, active thrombotic  events, and hypersensitivity to transamic acid. The half-life is two hours and adverse side effects include nausea and vomiting and in higher doses, seizure and thrombotic events.  In the active management of postpartum hemorrhage treatment, uterotonics are first and second line treatment as well as transamic acid, which we will go over.  Also, the avoidance of hypocalcemia during massive transfusion is imperative as it is part of the coagulation cascade.  Since far and away the leading cause of postpartum hemorrhage is uterine atony, uterotonics are first line treatment for this condition.  Oxytocin is the preferred drug of choice and when given for treatment, it works best when the patient has not received a prophylactic dose.  A slow bolus followed by continuous infusion of no more than 5 IU per minute will help avoid hypotension.  Although evidence for the ergotomy derivatives in postpartum hemorrhage treatment is scarce, it remains present in all major postpartum hemorrhage guidelines due to its efficiency  in prophylactic trials. It does, however, come with a high side effect profile, which we have talked about before, which includes hypertension and emesis.  As such, it is contraindicated in those patients with hypertensive comorbidities. It is also difficult to score and prone to degradation when exposed to heat and light,  resulting in reduced potency of up to 20% per month. Carboprost or hemepate is an injectable prostaglandin PGE2 that increases uterine contractility.  It is administered intramuscularly and can be used every 15 minutes for a maximum of 8 times for postpartum hemorrhage treatment.  Its most common side effect is diarrhea, nausea, and vomiting. Care needs to be taken when given an asthmatics as it can cause bronchospasm.  Current guidance suggests that carboprost should be administered as a final pharmacological  measure in those patients non-responsive to previous therapies prior to surgical intervention.  It is an expensive therapy requiring cold storage and therefore it is difficult to employ in low-resource settings.  There are no trials comparing carboprost with other therapeutics for postpartum hemorrhage treatment.  In women who have not received oxytocin prophylaxis, mesopristol is less effective than oxytocin as a first-line treatment for postpartum hemorrhage.  However, the differences are less following oxytocin prophylaxis.  Mesopristol treatment is therefore only recommended in low-resource settings where oxytocin is not available.  The use of emergency transemic acid has expanded since it was found to reduce mortality in bleeding trauma patients.  The recent 20,000 patient women's study has shown that compared to placebo, treatment with intravenous transemic acid reduces maternal death due to postpartum hemorrhage with no  increase in adverse effects. The overall benefits appear to be mainly in those undergoing laparotomy.  The women's trial showed that transemic acid was effective in all causes of postpartum hemorrhage.  One gram given IV initially with an additional gram given 30 minutes later for ongoing bleeding helped decrease maternal mortality.  The impact of the treatment, however, needs to be quick and within the first three hours. For every 15-minute delay, there was a 10% decrease in survival benefit.  In the case of oxytocin, laboratory studies have shown that repeated doses of oxytocin result in a decreased concentration of oxytocin receptors, a reduced oxytocin receptor binding  potential, and desensitization. All factors that impair the post-delivery effects of oxytocin on uterine contractility.  Current gold standard guidelines recommend the use of oxytocin both as a prophylaxis and then subsequently for treatment of primary postpartum hemorrhage.  Three studies have explored the use of successive oxytocin for prophylaxis at cesarean section and found no additional benefit of giving additional oxytocin in women already treated  with that drug. This has yet to be explored in vaginal birth or in cases of women given prophylaxis oxytocin  who then require further uterotonics for treatment of postpartum hemorrhage. However, these findings suggest that alternative uterotonics over that other than oxytocin  should be considered for postpartum hemorrhage treatment in women already given prophylaxis with oxytocin. Research is currently underway to assess this further.  Also consideration of combination drugs over oxytocin which has a short half-life as well  as final determination if transamic acid prophylaxis is appropriate in vaginal delivery in those patients who are at high risk for postpartum hemorrhage.  Thank you for your consideration.

Video Summary

In this video, Mary Jane Reed discusses pharmacological adjuvants in the treatment of obstetrical hemorrhage. Obstetrical hemorrhage is a major cause of maternal death worldwide, and it is important to recognize the risk factors and take appropriate measures to prevent and treat it. The lecture covers various pharmacological prophylactics and adjuvants, including oxytocin, carboprost, misoprostol, ergotamine derivatives, and transamic acid. Oxytocin is the preferred drug for preventing postpartum hemorrhage, given either intravenously or intramuscularly. Carboprost is an injectable prostaglandin that can be used as a last resort treatment for non-responsive cases. Misoprostol is a cheaper alternative to oxytocin, but less effective for severe postpartum hemorrhage. Ergotamine derivatives have similar effects to oxytocin but come with more side effects and should be avoided in patients with hypertension. Transamic acid is a promising adjuvant that reduces blood loss, but careful consideration is necessary due to potential side effects. The lecture concludes by discussing the use of repeated oxytocin doses and the need for further research in this area.

Asset Subtitle

Pharmacology, Obstetrics, Hematology, 2022

Asset Caption

Physiologic changes in blood volume and hemostasis that accompany pregnancy mitigate the risk of maternal hemorrhage; however, these adaptive mechanisms can be overcome in superimposed pathophysiologic states. Uterotonic and hemostatic adjuncts constitute the first line of defense in combatting postpartum hemorrhage. Familiarity with the indications, contraindications, and pharmacokinetics of these agents is critical for the continued successful management of hemorrhage in the ICU. Early recognition and management are therefore critical because failure to treat potential contributors to hemorrhage can lead to adverse outcomes.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Obstetrics

Knowledge Area Hematology

Knowledge Level Advanced

Membership Level Select

Tag Pharmacology

Tag Obstetrics

Tag Hemorrhage

Year 2022

Keywords

pharmacological adjuvants

obstetrical hemorrhage

oxytocin

carboprost

misoprostol

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