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Uterotonic Agents for Cesarean Delivery: All Rights Reserved

Uterotonic Agents for Cesarean Delivery: All Rights Reserved

A Supplement to MARCH 2018

The Frost Series #336 Continuing Medical Education

Uterotonic Agents for Cesarean Delivery: All rights reserved. Reproduction in whole or in part without permission is prohibited. Anesthetic Copyright Implications © 2018 McMahon and Publishing Side Effects Group unless otherwise noted.

PHYSICIAN CONTINUING MEDICAL EDUCATION: Accreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for and Penn State College of Medicine. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NURSING CONTINUING EDUCATION: Accreditation Statement: Postgraduate Institute for Medicine is accredited with distinc- tion as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Credit Designation: This educational activity for 1.0 contact hours is provided by Postgraduate Institute for Medicine. Designated for 0.7 contact hours of pharmacotherapy credit for Advance Practice Registered Nurses.

DISCLOSURE OF CONFLICTS OF INTEREST Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of RELEASE DATE: March 1, 2018 EXPIRATION DATE: April 30, 2019 this activity. All identified COIs are thoroughly vetted and resolved according to PIM policy. The existence or absence of COIs for everyone in a position to control content will be dis- WRITTEN BY closed to participants prior to the start of each activity. Stacey Duryea, DO Assistant Professor of Anesthesiology FACULTY DISCLOSURES Department of Anesthesiology and Perioperative Medicine Stacey Duryea, DO, and Sonia J. Vaida, MD, have no relationships with commercial inter- Penn State Health Milton S. Hershey Medical Center ests related to the content of this CME activity. Hershey, Pennsylvania The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests REVIEWED AND EDITED BY related to the content of this CME activity: Sonia Vaida, MD The following PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, Professor of Anesthesiology & Perioperative Medicine and and Gynecology PharmD, CHCP, Judi Smelker-Mitchek, RN, BSN, and Jan Schultz, MSN, RN, CHCP, hereby Vice Chair, Research state that they or their spouse/life partner do not have any financial relationships or rela- Director, Obstetric Anesthesia tionships to products or devices with any commercial interest related to the content of this Department of Anesthesiology and Perioperative Medicine activity of any amount during the past 12 months. Penn State Health Milton S. Hershey Medical Center The planners and managers from Penn State College of Medicine hereby state that they or Hershey, Pennsylvania their spouse/life partner do not have any financial relationships or relationships to prod- ucts or devices with any commercial interest related to the content of this activity of any TIME TO COMPLETE ACTIVITY: 1 hour amount during the past 12 months. TARGET AUDIENCE SPONSORSHIP This activity is intended for anesthesiologists and certified registered nurse anesthetists. This activity is jointly provided by Postgraduate Institute for Medicine and Penn State LEARNING OBJECTIVES College of Medicine. After completion of this activity, the reader should be able to: INSTRUCTIONS FOR PARTICIPATION 1. Describe the of Participants can download and print the course material in an easy to read printer-friendly 2. Indicate the recommended dose of oxytocin format, available through the boxed link at the top of the page. Participants must reflect 3. Recognize the side effects of oxytocin on the information presented, and then register to complete the exam and course evalua- 4. Indicate contraindications of methylergonovine and tion online before the expiration date at CMEZone.com/TheFrostSeries. 5. Choose the appropriate for the individual patient Because there is no commercial support subsidizing this activity, the certification fee for 2 I Anesthesiology News MARCH 2018

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CME/CE credit is $25. During the period March 1, 2018 through April 30, 2019, participants The content of this activity was developed by the faculty indicated herein under the super- must read the learning objectives and faculty disclosures and study the educational activity. vision of Postgraduate Institute for Medicine and assistance from Penn State University. Upon registering and successfully completing the post-test with a score of 75% or better Applied Clinical Education (ACE) is responsible for graphic design and distribution of the and the activity evaluation, your certificate will be made available immediately. activity via Anesthesiology News and CMEZone.com. All information included in this activ- ity is believed to be true and accurate at the date of publication. ACE makes no warranty, DISCLOSURE OF UNLABELED USE expressed or implied, with respect to the material contained herein. This educationalAll rights activity might reserved. contain discussion Reproduction of published and/or investigationalin whole uses or in part without permission is prohibited. of agents that are not indicated by the FDA. The planners of this activity do not recom- CONTACT INFORMATION mend the use of any agent outside Copyright of the labeled indications. © 2018 The McMahonopinions expressed inPublishing Questions Group regarding course unless content otherwise may be directed to noted.Dr. Sonia Vaida at svaida@ the educational activity are those of the faculty and do not necessarily represent the views pennstatehealth.psu.edu. Questions regarding continuing education may be directed to of the planners. Please refer to the official prescribing information for each product for [email protected]. discussion of approved indications, contraindications, and warnings. CALL FOR WRITERS DISCLAIMER If you would like to author a future installment of The Frost Series in Anesthesiology News, Participants have an implied responsibility to use the newly acquired information to enhance please send an email to Sonia Vaida, MD, at [email protected]. patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, med- STATEMENT OF NEED ications, or other courses of diagnosis or treatment discussed or suggested in this activity Administration of uterotonic agents can be associated with serious adverse effects. It is should not be used by clinicians without evaluation of their patients’ conditions and possi- important to strike a balance between achieving the desired uterotonic effect while mini- ble contraindications and/or dangers in use, review of any applicable manufacturer’s product mizing the risk for complications. This manuscript reviews side effects and complications information, and comparison with recommendations of other authorities. caused by commonly administrated during cesarean delivery.

Case 1: Oxytocin A 23-year-old primigravida at 35 weeks’ gestation, weighing bicuspid aortic valve at 4 years of age and has been followed 88 kg and measuring 165 cm in height, who has severe aortic by the cardiology service since childhood. She was scheduled stenosis was admitted to the labor and delivery unit in active to have her aortic valve replaced and had been advised against labor. The patient had been diagnosed with a congenital .

Due to severe aortic stenosis and fetal breech presentation, elec- The newborn was delivered 2 minutes after skin incision with tive cesarean delivery (CD) was planned at 37 weeks of pregnancy. Apgar scores of 3 and 6 at 1 and 5 minutes, respectively. An Physical examination showed a score of Mallampati class I, with 6 cm infusion of 10 IU of oxytocin in 500 mL of lactated Ringer’s solution thyromental distance and a grade 3/4 systolic murmur at the left ster- was started with an immediate decrease in blood pressure to nal border. The patient reported exertional orthopnea, and echogenic 85/45 mm Hg and heart rate increase to 124 beats per minute. findings were consistent with severe aortic stenosis: ejection fraction was refractive to repeated doses of of 100 of 48%, pressure gradient of 50 mm Hg across the valve, and an aortic mcg, totaling 500 mcg. at 8 mcg was administered as valve area of 0.9 cm2. an IV bolus, and the oxytocin infusion was stopped. Compared with previous studies, her condition was progress- The blood pressure and heart rate returned to baseline values, and ing. Electrocardiogram (ECG) showed sinus tachycardia (heart rate, no further uterotonic agents were administered. Before extubation, 112 beats/min) with left ventricular hypertrophy. Her blood pres- 100 mcg of remifentanil were administered for cough suppression and sure was 131/70 mm Hg. A 16-gauge IV catheter and arterial line were to avoid further hemodynamic changes. The patient was extubated, placed. Fetal heart monitoring showed a category 3 fetal heart trac- observed in the intensive care unit for 24 hours, and discharged from ing, and it was decided to proceed immediately with CD under gen- the hospital on postoperative day 4 with a recommended plan for eral anesthesia. surgical correction of the aortic stenosis. General anesthesia with rapid sequence induction was induced The severe hypotension in this patient was likely induced by with 100 mcg of remifentanil, 20 mg of etomidate, and 120 mg of high-dose oxytocin administration. Oxytocin-induced vasodilation succinylcholine, and maintained with a 50%/50% mix of oxygen/ causes reduction of the systemic vascular resistance, leading to to a minimum alveolar concentration (MAC) of 0.8, with an increase in the pressure gradient across the stenotic valve, and added . The patient’s blood pressure after intubation was worsening hemodynamics. Furthermore, tachycardia reduces the time 148/88 mm Hg and heart rate was 91 beats per minute with normal for cardiac filling, potentially causing ischemia. oxygenation and ventilation. MARCH 2018 Anesthesiology News I 3

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Introduction Oxytocin has a half-life of 10 to 15 minutes, and is metabolized by the Uterotonic agents are widely used to induce or augment labor placenta, kidney, and liver. and to prevent or treat postpartum hemorrhage secondary to uterine The dosage of oxytocin administered during CD is highly variable. atony. The most common uterotonic used during CD is oxytocin fol- As reflected by surveys of obstetricians and obstetric anesthesiolo- lowedAll by rights reserved. and . Reproduction Oxytocin administrationin whole or ingists, part higher without than necessary permission oxytocin isdoses prohibited. are still commonly used in is associated with serious adverse effects. clinical practice.7,8 Copyright © 2018 McMahon PublishingCarvalho Group et al, unlessusing logistic otherwise regression tonoted. analyze data obtained Oxytocin Review by a up-and-down coin allocation method, demonstrated that oxy- Oxytocin is a cyclic nonapeptide synthetized as a large precursor tocin doses as low as 0.35 IU are necessary to obtain adequate uter- by macrocellular neurons in the hypothalamus and stored in the neu- ine contraction when administered during elective CD in nonlaboring ral lobe of the pituitary gland. During transport to the pituitary gland, women.9 Sartain et al compared the efficacy of 2 with 5 IU, adminis- the precursor undergoes cleavage to an oxytocin–neurophysin com- tered as an IV bolus over 5 to 10 seconds, followed by an infusion of plex. When triggered by stimuli from the uterine cervix or vagina, the 10 IU per hour in elective CD. Oxytocin at 5 IU caused a significantly oxytocin–neurophysin complex is released into the systemic circula- higher heart rate with lower mean arterial pressure as well as an tion where the oxytocin becomes a free molecule binding to its recep- increased incidence of nausea and vomiting.10 tor to stimulate uterine myometrial contraction.1 Butwick et al reported an incidence of 47% hypotension in The oxytocin receptors belong to the G protein–coupled recep- patients receiving 5 IU of IV oxytocin, administered over 15 sec- tor family and are located in the uterine myometrial cell surface and onds, and adequate uterine tone 2 minutes after administration of decidual cells.2 The density and sensibility of the oxytocin receptors in 0.5 to 3 IU.11 Implementation of a “rule of threes” algorithm, reported the uterus increase progressively throughout the pregnancy, reaching by Kovacheva et al—using a bolus of 3 IU followed, if necessary, by a peak before delivery. The effect of oxytocin is limited by the number another bolus of 3 IU at 3 and 6 minutes—resulted in better uterine of receptors in the uterus rather than its concentration in the plasma. tone compared with an infusion of 30 IU in 500 mL.12 Prolonged, repeated administration of oxytocin causes desensi- Oxytocin Side Effects and Complications tization of uterine oxytocin receptors, leading to reduced response Hemodynamic Eff ects with repeated administration and therefore decreased efficacy.1,2 As Oxytocin administration can cause significant hypotension, tachy- a result, a significantly higher dose of oxytocin is recommended in cardia, increased cardiac output, myocardial ischemia, and arrhyth- patients with previous exposure to oxytocin during labor. Lavoie et al mias, especially when administered in large doses over a short period showed that the effective dose in 90% of parturients (ED90) for oxy- of time. The oxytocin-induced hemodynamic changes are dose tocin was 16.2 IU per hour for nonlaboring patients and 3 times higher dependent and generally well tolerated by healthy parturients; how- (44.2 IU/hour) for laboring patients.13 ever, administration of oxytocin may have serious consequences in Foley et al recommended two different protocols for oxytocin vulnerable patients. administration based on previous labor exposure to oxytocin: The “Confidential Enquiries Into Maternal Deaths” report, pub- 1. For nonlaboring patients with no oxytocin exposure: 18 IU per lished in 2001 and covering data from the United Kingdom between hour followed by 36 IU per hour if needed for and 1997 and 1999, mentions two deaths attributed to the administration 54 IU per hour if needed for continued atony. of oxytocin in severely hemodynamically compromised patients.3 Two 2. For patients with recent oxytocin administration: 36 IU per hour fatal cases attributed to oxytocin administration were also reported in followed by 54 IU per hour if needed, and another uterotonic for “Confidential Enquiries Into Maternal Deaths” in South Africa.4 continued atony.14 Transient electrocardiographic changes suggestive of myocar- In addition, receptor desensitization after prolonged oxytocin dial ischemia (ST changes) and chest pain have been attributed to administration can explain reduced hemodynamic changes after the administration of 10 IU of oxytocin intravenously, both in women administration of a second dose of oxytocin.15 undergoing elective CD under spinal anesthesia, as well as in healthy It is critical to strike a balance between achieving the desired nonpregnant, nonanesthetized women.5 A significantly higher inci- uterotonic effect while minimizing the risk for maternal complica- dence of ST changes was observed with a bolus of 10 IU (21.6%) tions. A recent prospective, double-blind study by Duffield et al compared with 5 IU (7.7%) within 3 minutes after administration, as showed that the uterine tone and estimated blood loss were similar recorded by a Holter monitor, in healthy parturients undergoing elec- after an oxytocin maintenance infusion of either 2.5 or 15 IU per hour, tive CD.6 after initial administration of 1 IU in women undergoing elective CD.16 Oxytocin-induced hypotension is attributed to nitric oxide–medi- The hemodynamic effects of oxytocin are summarized in Table 1 and ated peripheral vasodilation, negative inotropic effects resulting from other side effects are listed in Table 2. binding to the oxytocin cardiac receptors, and the release of atrial natriuretic peptide.4 Tachycardia is both compensatory to the hypo- Other Side Eff ects tension and induced by direct atrioventricular conduction alterations. Although oxytocin is structurally similar to and The onset of action is after 1 to 2 minutes following IV injection. may exhibit an antidiuretic effect, water retention and dilutional 4 I Anesthesiology News MARCH 2018

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are rare side effects, which occur mainly after prolonged Table 1. Oxytocin Hemodynamic Effects administration of a high dose in dextrose 5% in water.1,17 Oxytocin-induced pulmonary vasodilation with shunt exacerbation Blood pressure L was described by Nandhakumar and Silverman in a patient with pre- existing underlying pulmonary disease (primary ciliary dyskinesia).17 HeartAll rightsrate reserved. ReproductionK in whole or in part without permission is prohibited. Flushing due to oxytocin-induced vasodilation has an incidence as high Systemic vascular resistance Copyright © 2018 McMahonL Publishingas 62.5%. Group9 Oxytocin unless contributes otherwise significantly noted. to the increased incidence of nausea and vomiting during CD. Cardiac output K

Stroke volume K Summary • The quest to find the lowest effective dose of oxytocin to balance the effective reduction of postpartum hemorrhage with minimal side effects is continuing. • Hypotension and tachycardia during CD induced by large-dose rapid Table 2. Noncardiovascular Oxytocin Side Effects administration of oxytocin may incorrectly be attributed to hemody- namic changes caused by neuraxial anesthesia or blood loss. Nausea ± vomiting • Oxytocin doses less than 5 IU have proven to be as effective as higher doses in controlling . Flushing • Slow infusion of oxytocin is associated with fewer side effects. Headaches • A higher dose of oxytocin is recommended in patients with previous exposure to oxytocin during labor. Chest pain Second-Line Uterotonic Agents Hyponatremia/water intoxication (very rare) Second-line uterotonics are typically administered when oxytocin fails to achieve appropriate uterine tone. The most commonly used second- line uterotonics are methylergonovine maleate and carboprost tro- methamine.18 The side effects of methylergonovine and carboprost are summarized in Tables 3 and 4. Table 3. Methylergonovine Side Effects Analyzing a very large national data set that included data obtained from 357 hospitals, Bateman et al showed a large variability in second- line uterotonic use, based mainly on physician preferences, hospital cul- Nausea ± vomiting ture, drug availability, and cost. Overall, the frequency of second-line uterotonic use was 7.1%. The authors called for “defining optimal phar- Headaches macologic strategies for the management of uterine atony.”19 Coronary artery spams (very rare)

Peripheral vasoconstriction

Table 4. Carboprost Side Effects

Bronchospasm

Alteration of ventilation/perfusion ratios

Nausea ± vomiting

Flushing

Myalgias

Fever MARCH 2018 Anesthesiology News I 5

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Case 2: Methylergonovine Maleate A 26-year-old gravida 3, para 2 at 38 weeks’ gestation was significant for two vaginal deliveries, the second of which presented to the labor and delivery unit in active labor. The was complicated by a retained placenta and postpartum patient’sAll rights medical reserved.history was significant Reproduction for morbid in obesity, whole or in hemorrhage,part without for which permission she received is 4 prohibited.units of packed red blood with a body mass index of 45 kg/m2. Her obstetric history cells. Copyright © 2018 McMahon Publishing Group unless otherwise noted.

Her blood pressure at presentation was 140/90 mm Hg and heart rate Methylergonovine Side Effects was 87 beats per minute. Epidural analgesia was successfully initiated Methylergonovine is a semisynthetic that causes 1 hour after initial presentation, at 4 cm , and oxytocin tonic uterine contraction by acting on the uterine smooth muscle. It is a was administered for labor augmentation at that time. Ten hours after of -adrenergic, 5HT-1, and epidural placement, her cervix was dilated to only 5 cm and category 2 receptors, although the mechanism by which it causes uterine contraction fetal heart rate tracings were noted. is not completely understood.4 Ampules containing methylergonovine are The decision was made to proceed with CD. Epidural analgesia was very unstable and need to be refrigerated and not exposed to light. successfully augmented to epidural anesthesia with 20 mL of 2% lido- Frequent side effects of methylergonovine include headaches, nau- caine and 50 mcg of fentanyl. Bilateral T4 sensory level at light touch sea, vomiting, increased blood pressure, and vasoconstriction. Blood was confirmed. A healthy newborn was delivered with Apgar scores of 7 pressure increases by approximately 20% from baseline after intra- and 8 at 1 and 5 minutes, respectively. muscular (IM) administration. Significant vasoconstriction may occur, A bolus of 3 IU of oxytocin was administered and repeated after 3 especially after IV administration. After IM injection, vasoconstriction and 6 minutes due to increased postpartum bleeding. Uterine atony occurs 3 to 7 minutes after administration and lasts several hours.20 was noted, and uterine massage performed. Fifteen minutes after deliv- Methylergonovine-induced vasoconstriction has the potential to cause ery, the estimated blood loss was 1,200 mL, with a blood pressure of coronary artery spasm and . 120/67 mm Hg and heart rate of 93 beats per minute. There are several case reports of myocardial infarction after admin- Methylergonovine at 0.2 mg was administered intramuscularly. istration of ergot alkaloids in parturients.21,22 Although possible, Approximately 10 minutes after methylergonovine administration, the Bateman et al found that the risk for acute coronary syndrome and uterine tone significantly improved; however, blood pressure increased acute myocardial infarction after administration of to 198/120 mm Hg and heart rate decreased to 85 beats per minute. The is extremely small.23 Spitzer et al recently reported another complica- patient complained of severe headache and chest pain. at 20 tion associated with methylergonovine where a patient with congeni- mg was administered intravenously over 2 minutes with no decrease tal cardiomyopathy (left ventricular noncompaction) developed acute in blood pressure, followed by additional doses of 20 and 40 mg at after administration.24 Butwick et al examined 10-minute intervals, for a total cumulative dose of 120 mg. At the com- 1,335 women receiving either methylergonovine or carboprost during pletion of surgery, her blood pressure was 160/87 mm Hg and her chest CD to treat uterine atony unresponsive to oxytocin.25 They concluded pain had improved. A 12-lead ECG showed ST depression that resolved that hemorrhage-related morbidity—defined as intraoperative or post- 30 minutes after sublingual administration of nitroglycerin. She was operative blood transfusion, uterine or hypogastric artery ligation, or observed in the intensive care unit for 24 hours and then discharged hysterectomy—had a higher incidence in women receiving carboprost home 4 days after delivery. (17.4%) compared with methylergonovine (8.8%).25 The patient presented with several risk factors for uterine atony, including a history of previous postpartum hemorrhage, multiple ges- Summary tations, obesity, prolonged labor, and oxytocin administration. She had • Methylergonovine is an effective second-line uterotonic. no history of cardiovascular disease or pregnancy-induced hypertension • Methylergonovine should be avoided in patients with chronic hyper- before her labor; however, she presented with high blood pressure. Most tension, pregnancy-induced hypertension, coronary artery disease, likely, administration of methylergonovine precipitated a hypertensive and peripheral vascular disease, including Raynaud’s disease. crisis and temporary coronary vasospasm leading to ST changes. • IV administration should be avoided. 6 I Anesthesiology News MARCH 2018

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Case 3: Carboprost A 23-year-old primigravida at 38 weeks’ gestation presented 10 minutes of her arrival at the hospital. A rapid sequence to the labor and delivery unit with painful vaginal bleeding, induction using propofol and succinylcholine was used to induce uterineAll tenderness, rights reserved. and increased Reproduction uterine activity. inPlacental whole or ingeneral part without anesthesia. permission is prohibited. abruption was suspected, so the patient was taken for CD within Copyright © 2018 McMahon Publishing Group unless otherwise noted.

The newborn was delivered 2 minutes after skin incision with Apgar carboprost to a patient with asthma is a potential trigger for broncho- scores of 3 and 6 at 1 and 5 minutes, respectively. After delivery, her spasm. In addition, light general anesthesia with a lower MAC, due to blood pressure was 90/50 mm Hg with a heart rate of 120 beats per concerns of volatile agents inducing uterine atony, may have contributed minute and estimated blood loss of 1,500 mL. Anesthesia was main- to the bronchospasm. tained with a 50%/50% mix of oxygen/nitrous oxide and sevoflurane to Carboprost is a 15-methyl F2 alpha that is used as a MAC of 0.7. A bolus of 5 IU of oxytocin was administered intravenously a second-line uterotonic agent to stimulate uterine contractility. It is over 15 seconds, followed by a continuous infusion of 20 IU per hour. administered intramuscularly or may be injected directly into the myo- Uterine atony was diagnosed, and uterine massage performed by metrium, after careful aspiration, to avoid IV administration. The rec- the obstetric team. After an estimated additional 500 mL of blood loss, ommended initial dose is 250 mcg, with repeated doses at 15-minute 0.2 mg of methylergonovine was administered intramuscularly with no intervals, up to a total dose of 2 mg. Maximum plasma levels are reached effects on uterine tone. Carboprost at 250 mcg was then administered 20 minutes after IM administration.26,27 intramuscularly, followed by a second dose after 15 minutes. Blood loss Stimulation of gastrointestinal smooth muscles causes frequent nau- was replaced with 4 units of packed red blood cells. sea, vomiting, and diarrhea. The uterine tone improved significantly; however, the peak inspiratory Severe respiratory complications may result from stimulation of bron- pressure increased from 21 to 35-40 cm H2O. Along with the increase in chial smooth muscle, resulting in bronchospasm. It may also cause pul- peak airway pressures, there was a decrease in oxygen saturation to 89% monary vasoconstriction and alteration of ventilation/perfusion ratios, and an increase in end-tidal carbon dioxide to 56 mm Hg. Upon auscul- leading to pulmonary shunting.27,28 tation, diffuse wheezing was heard. Bronchospasm was diagnosed. Moderate increases in blood pressure can occur after IM administra- The patient was placed on a fraction of inspired oxygen of 1.0, and the tion, probably with no significant clinical implications. Other side effects concentration of sevoflurane was increased to a MAC of 1. Albuterol was reported after carboprost administration are flushing, myalgia, and administered via the endotracheal tube, and 25 mg of were fever.27 given intravenously. After achieving stable hemodynamic and respira- tory parameters, the patient was administered 100 mcg of remifentanil Summary intravenously to blunt cough reflexes and extubated successfully. • Carboprost is contraindicated in patients with bronchial asthma and pulmonary hypertension. Carboprost Side Effects • Nausea and vomiting are frequent side effects. Postoperatively, the patient reported a history of bronchial asthma • IV administration should be avoided. that was unknown before induction of anesthesia. Administration of MARCH 2018 Anesthesiology News I 7

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Conclusion Oxytocin, the most commonly used uterotonic, has a very well- not by vomiting during CD is multifactorial, including hypotension, opi- established role in preventing and treating postpartum hemorrhage dur- oid administration, and visceral manipulation. Uterotonics significantly ing CD and in the postpartum period. Given that its side effects are dose contribute to worsening of the symptoms. The optimal choice of an dependent,All rights the lowest reserved. effective oxytocin Reproduction dose providing uterinein whole con- or inuterotonic part without agent for thepermission individual patient, is prohibited. together with its administra- traction should be administered. Methylergonovine and carboprost are tion via the appropriate route and recommended dose, results in fewer effective second-line uterotonics. Copyright Intravenous © 2018 administration McMahon should bePublishing side effects Group and increased unless patient otherwise safety during noted. CD and the postpartum avoided for both methylergonovine and carboprost. Nausea followed or period. References 1. Smith JG, Merrill DC. Oxytocin for induction of labor. Clin Obstet Gynecol. 15. Langesaeter E, Rosseland LA, Stubhaug A. Haemodynamic effects of repeated 2006;49(3):594-608. doses of oxytocin during caesarean delivery in healthy parturients. Br J Anaesth. 2009;103(2):260-262. 2. Gizzo S, Patrelli TS, Gangi SD, et al. Which uterotonic is better to prevent the postpartum hemorrhage? Latest news in terms of clinical efficacy, side effects, and 16. Duffield A, McKenzie C, Carvalho B, et al. Effect of a high-rate versus a low-rate contraindications: a systematic review. Reprod Sci. 2013;20(9):1011-1019. oxytocin infusion for maintaining uterine contractility during elective cesarean delivery: a prospective randomized clinical trial. Anesth Analg. 2017;124(3):857-862. 3. Thomas TA, Cooper GM. Maternal deaths from anaesthesia. An extract from Why Mothers Die 1997–1999, the Confidential Enquiries Into Maternal Deaths in the United 17. Nandhakumar A, Silverman GL. Acute hypoxemia in a parturient with primary ciliary Kingdom. Br J Anaesth. 2002;89(3):499-508. dyskinesia following the administration of intravenous oxytocin: a case report. Can J Anaesth. 2013;60(12):1218-1221. 4. Dyer RA, van Dyk D, Dresner A. The use of uterotonic drugs during caesarean section. Int J Obstet Anesth. 2010;19(3):313-319. 18. Sumikura H, Inada E. Uterotonics and tocolytics for anesthesiologists. Curr Opin Anaesthesiol. 2016;29(3):282-287. 5. Svanström MC, Biber B, Hanes M, et al. Signs of myocardial ischaemia after injection of oxytocin: a randomized double-blind comparison of oxytocin and methylergometrine 19. Bateman BT, Tsen LC, Liu J, et al. Patterns of second-line uterotonic use in a during caesarean section. Br J Anaesth. 2008;100(5):683-689. large sample of hospitalizations for in the United States: 2007-2011. Anesth Analg. 2014;119(6):1344-1349. 6. Jonsson M, Hanson U, Lidell C, et al. ST depression at caesarean section and the relation to oxytocin dose. A randomised controlled trial. BJOG. 2010;117(1):76-83. 20. Spielman FJ, Herbert WN. Maternal cardiovascular effects of drugs that alter uterine activity. Obstet Gynecol Surv. 1988;43(9):516-522. 7. Mockler JC, Murphy DJ, Wallace EM. An Australian and New Zealand survey of practice of the use of oxytocin at elective caesarean section. Aust N Z J Obstet Gynaecol. 21. Lin YH, Seow KM, Hwang JL, et al. Myocardial infarction and mortality caused by 2010;50(1):30-35. methylergonovine. Acta Obstet Gynecol Scand. 2005;84(10):1022.

8. Orbach-Zinger S, Einav S, Yona A, et al. A survey of physicians’ attitudes toward 22. Tsui BC, Stewart B, Fitzmaurice A, et al. Cardiac arrest and myocardial infarction uterotonic administration in parturients undergoing cesarean section. J Matern Fetal induced by postpartum intravenous ergonovine administration. Anesthesiology. Neonatal Med. 2017:1-8. 2001;94(2):363-364.

9. Carvalho JC, Balki M, Kingdom J, et al. Oxytocin requirements at elective cesarean 23. Bateman BT, Huybrechts KF, Hernandez-Diaz S, et al. Methylergonovine maleate and delivery: a dose-finding study. Obstet Gynecol. 2004;104(5 pt 1):1005-1010. the risk of myocardial ischemia and infarction. Am J Obstet Gynecol. 2013;209(5):459. e1-459.e13. 10. Sartain JB, Barry JJ, Howat PW, et al. Intravenous oxytocin bolus of 2 units is superior to 5 units during elective caesarean section. Br J Anaesth. 2008;101(6):822-826. 24. Spitzer E, Weiner M, Beilin Y. Cesarean delivery in a parturient with left ventricular noncompaction complicated by acute pulmonary hypertension after 11. Butwick A, Coleman L, Cohen SE, et al. Minimum effective bolus dose of oxytocin methylergonovine administration for postpartum hemorrhage. A A Case Rep. during elective caesarean delivery. Br J Anaesth. 2010;104(3):338-343. 2015;4(12):166-168. 12. Kovacheva VP, Soens MA, Tsen LC. A randomized, double-blinded trial of a “rule of 25. Butwick AJ, Carvalho B, Blumenfeld YJ, et al. Second-line uterotonics and the risk of threes” algorithm versus continuous infusion of oxytocin during elective cesarean hemorrhage-related morbidity. Am J Obstet Gynecol. 2015;212(5):642.e1-642.e7. delivery. Anesthesiology. 2015;123(1):92-100. 26. Bygdeman M. of prostaglandins. Best Pract Res Clin Obstet 13. Lavoie A, McCarthy RJ, Wong CA. The ED90 of prophylactic oxytocin infusion Gynaecol. 2003;17(5):707-716. after delivery of the placenta during cesarean delivery in laboring compared with nonlaboring women: an up-down sequential allocation dose-response study. Anesth 27. Vallera C, Choi LO, Cha CM, et al. Uterotonic medications: oxytocin, methylergonovine, Analg. 2015;121(1):159-164. carboprost, . Anesthesiol Clin. 2017;35(2):207-219.

14. Foley A, Gunter A, Nunes KJ, et al. Patients undergoing cesarean delivery after 28. Hankins GDV, Berryman GK, Scott RT Jr, et al. Maternal arterial desaturation with exposure to oxytocin during labor require higher postpartum oxytocin doses. Anesth 15-methyl prostaglandin F2 alpha for uterine atony. Obstet Gynecol. 1988;72(3 Analg. 2017 Aug 30. doi: 10.1213/ANE.0000000000002401. [Epub ahead of print] pt 1):367-370. 8 I Anesthesiology News MARCH 2018

The Frost Series #336

Post-test Select the single best answer:

1. Oxytocin-induced hemodynamic changes include: 6. Oxytocin efficacy is reduced by: a. hypertension, tachycardia, and decreased cardiac output. a. previous exposure during prolonged labor. b.All hypotension rights andreserved. bradycardia, Reproduction with no change in cardiac in output. whole or in partb. without slow IV administration. permission is prohibited. c. hypertension, tachycardia, Copyright and increased © 2018 cardiac McMahonoutput. Publishingc. Group intramuscular unless (IM) administration. otherwise noted. d. hypotension, with no change in heart rate and cardiac output. d. bolus administration of 3 IU.

2. Oxytocin is synthetized in the: 7. Methylergonovine-induced vasoconstriction after IM administration a. pituitary gland. occurs after: b. hypothalamus. a. 1 minute, lasting several hours. c. pineal gland. b. 3-7 minutes, lasting several hours. d. placenta. c. 10 minutes after administration, lasting 30 minutes. d. 30 minutes after administration, lasting several hours. 3. Oxytocin-induced hypotension is attributed to all, except: a. nitric oxide–mediated peripheral vasodilation. 8. Side effects after methylergonovine administration include: b. negative inotropic effects. a. water intoxication. c. release of atrial natriuretic peptide. b. hyponatremia. d. histamine release. c. hypotension. d. nausea and vomiting. 4. What is the onset of action for oxytocin after IV administration? a. 1-2 minutes 9. Methylergonovine can be safely administered in patients with: b. 5 minutes a. Raynaud’s disease. c. 8 minutes b. gestational hypertension. d. 10-15 minutes c. gestational diabetes. d. chronic hypertension. 5. sensibility reaches a peak: a. during the second trimester. 10. Maximum plasma levels after IM administration of carboprost are b. at 31 weeks’ gestation. reached after: c. before delivery. a. 2 minutes. d. in the immediate postpartum period. b. 5 minutes. c. 20 minutes. d. 45 minutes.

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