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Uterotonic drug usage in Canada: a snapshot of the practice in obstetric units of university-affiliated hospitals

  • B. Thorneloe
    Affiliations
    Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, Canada
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  • J.C.A. Carvalho
    Affiliations
    Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, Canada

    Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Canada
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  • K. Downey
    Affiliations
    Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, Canada
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  • M. Balki
    Correspondence
    Correspondence to: Dr M. Balki, University of Toronto, Department of Anesthesia and Pain Management, Mount Sinai Hospital, 600 University Avenue, Room 19-104, Toronto, ON M5G 1X5, Canada.
    Affiliations
    Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, Canada

    Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Canada

    Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Canada
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Published:September 11, 2018DOI:https://doi.org/10.1016/j.ijoa.2018.09.002

      Highlights

      • The overall institutional survey response rate was only 52%.
      • There is a lack of a unified approach to the use of uterotonics in Canadian centers.
      • Two-thirds of respondents use oxytocin and one-third carbetocin initially.
      • The use of second line agents differs between obstetricians and anesthesiologists.
      • Canadian national guidelines and clinical practice show a discrepancy.

      Abstract

      Objective

      The objective of this study was to determine the pattern of uterotonic drug usage in obstetric units of university-affiliated hospitals in Canada.

      Methods

      This was a prospective observational study conducted in the form of an electronic survey. The target group consisted of chiefs or directors of Obstetrics and Anaesthesia at university-affiliated hospitals across Canada. The survey was sent out between November 2016 and January 2017, using the program ‘SurveyMonkey’. Data on institutional obstetric practices and usage of uterotonic agents were collected.

      Results

      The survey was sent to 92 obstetricians and anesthesiologists from 46 institutions, of which 33 clinicians from 24 institutions responded. About 65% of clinicians were unaware of the rate of postpartum hemorrhage in their institution. The first-line agent for vaginal deliveries was reported as oxytocin by 94% and carbetocin by 6% of physicians. For women at low-risk for postpartum hemorrhage when undergoing cesarean deliveries (CD), 66% reported oxytocin as the first-line uterotonic, while 34% reported carbetocin. For CDs at high-risk of postpartum hemorrhage, 60% of physicians reported oxytocin and 40% reported using carbetocin initially. The use of second-line uterotonics was also variable. The choice of uterotonic was mainly based on perceived efficacy and Society of Obstetricians and Gynaecologists of Canada guidelines.

      Conclusion

      There is a lack of a unified approach to the use of uterotonic drugs for postpartum hemorrhage management in Canada. To improve the management of postpartum hemorrhage due to uterine atony, an evidence-based approach to usage and consensus between obstetricians and anesthesiologists is warranted.

      Keywords

      Introduction

      In Canada and the United States, the incidence of severe postpartum hemorrhage (PPH) related to uterine atony appears to be on the rise, despite the use of oxytocin and other uterotonic agents.
      • Mehrabadi A.
      • Liu S.
      • Bartholomew S.
      • et al.
      Temporal trends in postpartum hemorrhage and severe postpartum hemorrhage in Canada from 2003 to 2010.
      • Kramer M.S.
      • Berg C.
      • Abenhaim H.
      • et al.
      Incidence, risk factors, and temporal trends in severe postpartum hemorrhage.
      This has resulted in an increase in the rates of blood transfusion and hysterectomy.
      • Kramer M.S.
      • Berg C.
      • Abenhaim H.
      • et al.
      Incidence, risk factors, and temporal trends in severe postpartum hemorrhage.
      Postpartum hemorrhage continues to be one of the leading causes of maternal morbidity and mortality worldwide.
      • Maswime S.
      • Buchmann E.
      A systematic review of maternal near miss and mortality due to postpartum hemorrhage.
      Uterotonic agents are used to prevent and treat PPH. Oxytocin, the most common first-line uterotonic, is routinely used in the third stage of labor for vaginal deliveries, as well as for elective and emergency cesarean deliveries (CD).
      • Dahlke J.D.
      • Mendez-Figueroa H.
      • Maggio L.
      • et al.
      Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines.
      Carbetocin, an oxytocin analogue, is also used instead of oxytocin in some countries, including Canada. In fact, the Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends carbetocin as the uterotonic agent of choice to prevent PPH at elective CD (1-B recommendation).
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      The SOGC also recommends its use for women delivering vaginally with one risk factor for PPH (1-B recommendation).
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      Second-line uterotonics are recommended if uterine atony persists despite prophylaxis or treatment with oxytocin or carbetocin.
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      • Bohlmann M.K.
      • Rath W.
      Medical prevention and treatment of postpartum hemorrhage: a comparison of different guidelines.
      • Royal College of Obstetricians and Gynaecologists
      Prevention and management of postpartum haemorrhage.
      • American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 183, October 2017: postpartum hemorrhage.
      These uterotonics include ergonovine maleate, carboprost and misoprostol. Recently, Bateman et al.
      • Bateman B.T.
      • Tsen L.C.
      • Liu J.
      • Butwick A.J.
      • Huybrechts K.F.
      Patterns of second-line uterotonic use in a large sample of hospitalizations for childbirth in the United States: 2007–2011.
      looked at patterns of second-line uterotonic usage for the treatment of uterine atony across the United States. They observed a surprisingly high level of inter-hospital variation that could not be explained by patient or hospital characteristics. There is also a wide variability in the current national and international guidelines for uterotonic usage in the management of PPH.
      • Dahlke J.D.
      • Mendez-Figueroa H.
      • Maggio L.
      • et al.
      Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines.
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      • Bohlmann M.K.
      • Rath W.
      Medical prevention and treatment of postpartum hemorrhage: a comparison of different guidelines.
      • Royal College of Obstetricians and Gynaecologists
      Prevention and management of postpartum haemorrhage.
      • American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 183, October 2017: postpartum hemorrhage.
      This suggests a lack of consensus for both first-line and second-line uterotonic utilization.
      The pattern of uterotonic drug usage in Canada is currently unknown and may be more varied and complex due to the presence of carbetocin as an alternative to oxytocin. The objective of this study was to determine the pattern of uterotonic usage in obstetric units of university-affiliated hospitals in Canada.

      Methods

      In Canada, no large databases exist to track usage of uterotonics in hospitals. Therefore, we conceived a prospective observational study in the form of a targeted, online survey. Research Ethics Board approval was obtained from Mount Sinai Hospital, Toronto, Canada (REB16-0239-E; September 26, 2016). Our target group consisted of chief obstetricians and directors of obstetric anesthesia (or chief anesthesiologists in lieu) at all 46 obstetric units of university-affiliated hospitals across Canada. Their email addresses were obtained via medical school/university hospital websites. If no email address was found or accessible, an administrative assistant at each respective university was contacted to obtain the email address of the chief of obstetrics and/or obstetric anesthesiology. In certain cases there were ‘interim chiefs’ and ‘co-chiefs’ of the departments, and referrals were made to the appropriate person in the institution to complete the survey. For this reason, a total of 109 surveys were sent out, to target 92 clinicians from 46 hospitals. An invitation letter explaining the study was sent via email to the practitioners, along with a link to the survey, which included the study questions integrated into the program ‘Survey Monkey’ (SurveyMonkey® Canada – Surveymonkey.com) (Appendix 1, supplementary file). The consent to participate was implied if the person contacted agreed to respond to the survey. The survey questions were phrased to aim mainly at institutional, rather than individual, clinical practice. The survey was distributed during the period November 2016 to January 2017. Three reminder emails were sent at approximately one week intervals from the initial send out date.
      Data collected consisted of institutional characteristics, use of oxytocin versus carbetocin in both vaginal and CD in women at low- and at high-risk for PPH; and use of second-line uterotonics. For the purpose of this study, the following risk factors for PPH were provided as a reference to responders of the survey: abruptio placentae, placenta previa, placenta accreta/increta/percreta, uterine rupture, polyhydramnios, fetal macrosomia, multiple gestation (twins/triplets), grand multiparity, preeclampsia, oxytocin induction/augmentation for prolonged period, infection (e.g. chorioamnionitis), morbid obesity (body mass index >40 kg/m2), instrumental delivery, bleeding disorders (pregnancy and non-pregnancy related), general anesthesia and previous history of PPH. Data were collected and integrated into Excel format for analysis. Data were summarised as proportions of respondents.

      Results

      The survey targeted 92 clinicians across all 46 university-affiliated hospitals in Canada. A total of 33 clinicians from 24 hospitals responded, giving us individual and institutional response rates of 36% and 52%, respectively. We received responses from all provinces except for Saskatchewan. Of the 33 respondents, 61% were anesthesiology specialists and 39% were obstetricians. The majority of the respondents had practice experience of more than five years in their area of specialty. Most participants (76%) reported CD rates of 21–30%, with a few (24%) reporting rates over 30%. Epidural rates were high across most institutions, with 42% of respondents reporting rates greater than 75%. The majority of clinicians (64%) were unaware of the rate of PPH in their institution (Table 1).
      Table 1Institutional obstetric data
      Overall (N=33)Anesthesiologists (N=20)Obstetricians (N=13)
      Duration of practice of responding clinicians (years)
      <51 (3.0)1 (5.0)0 (0)
      5–109 (27.3)9 (45.0)0 (0)
      10–2010 (30.3)5 (25.0)5 (38.5)
      >2013 (39.4)5 (25.0)8 (61.5)
      Number of deliveries/year
      2500–499917 (51.5)10 (50.0)7 (53.8)
      >500016 (48.9)10 (50.0)6 (46.2)
      Cesarean delivery rate
      21–30%25 (75.8)17 (85.0)8 (61.5)
      >30%8 (24.2)3 (15.0)5 (38.5)
      Epidural rate (%)
      <251 (3.0)1 (5)0 (0)
      25–503 (9.1)1 (5)2 (15.4)
      51–7515 (45.5)9 (45)6 (46.2)
      >7514 (42.4)9 (45)5 (38.5)
      Postpartum hemorrhage rate (%)
      <34 (11.8)3 (15.0)1 (7.7)
      >38 (23.5)1 (5.0)7 (53.8)
      Unknown21 (63.6)16 (80.0)5 (38.5)
      Values are n (%).

      First-line uterotonic agents

      Oxytocin was reported as the first-line uterotonic drug for vaginal delivery by 94% (31/33) of responders, and for low-risk and high-risk CD by 66% (21/32) and 60% (18/30) of responders, respectively. Carbetocin was reported to be the first-line agent for vaginal delivery by only 6% (2/33) of responders, but for low-risk and high-risk CDs by 34% (11/32) and 40% (12/30) of responders, respectively (Table 2).
      Table 2Use of first and second-line uterotonic drugs
      First-line uterotonic agentOverall (N=33)Anesthesiologists (N=20)Obstetricians (N=13)
      Oxytocin
      Vaginal31 (94)18 (90)13 (100)
      Low-risk CD21 (66)*11 (58)§10 (77)
      High-risk CD18 (60)*11 (61)§7 (58)
      Carbetocin
      Vaginal2 (6)2 (10)0 (0)
      Low-risk CD11 (34)*8 (42)§3 (23)
      High-risk CD12 (40)*7 (39)§5 (42)
      Second-line uterotonic agentOverall (N=29)Anesthesiologists (N=18)Obstetricians (N=11)
      Additional oxytocin17 (59)12 (67)5 (46)
      Additional carbetocin2 (7)1 (6)1 (9)
      Carboprost29 (100)18 (100)11 (100)
      Ergonovine maleate23 (79)13 (72)10 (91)
      Misoprostol23 (79)13 (72)10 (91)
      *N=32 for low-risk CD. *N=30 for high-risk CD. §N=19 for low-risk CD. N=18 for high-risk CD. Values are n (%). CD: Cesarean delivery.
      For vaginal deliveries, the most commonly used dose of oxytocin included a 5 IU intravenous (IV) bolus or 10 IU intramuscular bolus. For both low- and high-risk CD, most participants reported the use of an IV oxytocin bolus of 5 IU (range 3–10 IU) in their institutions, however, maintenance infusion rates post-bolus differed. Sixty-two percent (8/13) of obstetricians used oxytocin boluses in addition to an infusion, even for low risk CD. Rapid boluses were used for vaginal (30%) as well as both low- and high-risk CD (13%). Oxytocin boluses of 10 IU, either IV or intramuscularly, were used by 20% (4/20) of anesthesiologists and 38% (5/13) of obstetricians for vaginal deliveries. While for CD, 10% (2/20) of anesthesiologists and 38% (5/13) of obstetricians used 10 IU IV boluses. The dose of carbetocin ranged from 25 to 100 μg IV for almost all types of deliveries (Table 3).
      Table 3Mode of administration and doses of oxytocin and carbetocin at delivery by all practitioners
      Vaginal delivery (N=33)Low-risk CD (N=32)High-risk CD (N=30)
      OxytocinN (%)DoseN (%)DoseN (%)Dose
      IM (IU)5 (15.2)10 (5–10)0 (0)NA0 (0)NA
      IV bolus (IU)5 (15.2)5 (5–10)
      Represents IV bolus of oxytocin alone or with infusion.
      0 (0)5 (3–10)
      Represents IV bolus of oxytocin alone or with infusion.
      0 (0)5 (3–10)
      Represents IV bolus of oxytocin alone or with infusion.
      IV bolus + infusion8 (24.2)11 (34.4)9 (30.0)
      IV infusion (IU/L)11 (33.3)20 (20–40)10 (31.3)20 (20–60)9 (30.0)40 (20–40)
      IM + infusion2 (6.1)0 (0)0 (0)
      CarbetocinN (%)DoseN (%)DoseN (%)Dose
      IV bolus (μg)2 (6.1)100 (100–100)11 (34.4)100 (25–100)12 (40.0)100 (50–100)
      CD: cesarean delivery. IM: intramuscular. IV: intravenous. IU: international units. Dose expressed as median (range).
      * Represents IV bolus of oxytocin alone or with infusion.

      Second-line uterotonic agents

      The second-line uterotonic usage was highly variable, with the use of carboprost by all, and ergonovine and misoprostol each by 79% of responders (Table 2). Amongst the second-line drugs, carboprost was ranked as the top choice overall, followed by ergonovine by anesthesiologists and misoprostol by obstetricians. All responders used a carboprost dose of 250 μg, and a maximum of eight doses (range 2–8), with boluses given at least 15 minutes apart. For ergonovine, the doses used were 200–250 μg, either IV or intramuscular, with variable timing intervals between repeat doses, ranging from five minutes to four hours.

      Choice of drugs

      The top ranked reasons as to why clinicians chose their first or second-line uterotonic drugs were the agent’s perceived efficacy, the SOGC guidelines or obstetricians’ preference, and the convenience. There were nine institutions with paired responses from an anesthesiologist and an obstetrician. For the first-line uterotonic agent, the agreement between the responses of the anesthesiologists and the obstetricians was 81%, while for the second-line uterotonic agent, it was only 22%. For doses and routes of oxytocin administration, the agreement was 40%.

      Discussion

      To our knowledge, this is the first Canadian study using a survey to establish patterns of uterotonics usage in obstetric units of Canadian academic hospitals. Our findings suggest that oxytocin remains the predominant first-line uterotonic drug. Carbetocin was also found to be widely utilized in all types of deliveries, primarily in CD; however, its indications and doses were not consistent with SOGC guidelines.
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      The use of second-line uterotonic drugs was also highly variable and dependent upon the drug’s perceived efficacy and the obstetrician’s preference. These findings warrant a review of evidence-based literature and application of appropriate guidelines for consistency in the management practices across the country.
      Regarding oxytocin usage, our results are in keeping with previous surveys conducted in other countries that have confirmed great variability in oxytocin management between obstetricians and anesthesiologists;
      • Orbach-Zinger S.
      • Einav S.
      • Yona A.
      • et al.
      A survey of physicians' attitudes toward uterotonic administration in parturients undergoing cesarean section.
      the importance of implementing national guidelines for oxytocin use to improve patient safety and reduce side effects;
      • Marcus H.E.
      • Fabian A.
      • Lier H.
      • et al.
      Survey on the use of oxytocin for cesarean section.
      and a potential lack of robust evidence/research in the area of uterotonic management, as evidenced by a perception that oxytocin boluses and infusions are ‘low-risk’.
      • Sheehan S.R.
      • Wedisinghe L.
      • Macleod M.
      • Murphy D.J.
      Implementation of guidelines on oxytocin use at caesarean section: a survey of practice in Great Britain and Ireland.
      • Wedisinghe L.
      • Macleod M.
      • Murphy D.J.
      Use of oxytocin to prevent haemorrhage at caesarean section—A survey of practice in the United Kingdom.
      Our results further elucidate practices regarding second-line uterotonic usage, reflecting lack of consistency in drug choices and usage, similar to the findings in the United States.
      • Bateman B.T.
      • Tsen L.C.
      • Liu J.
      • Butwick A.J.
      • Huybrechts K.F.
      Patterns of second-line uterotonic use in a large sample of hospitalizations for childbirth in the United States: 2007–2011.

      Oxytocin

      Although it is common to use a 5 IU bolus IV for all types of deliveries, 10 IU boluses are also used. It may be reasonable to give a higher dose, up to 10 IU in patients at high-risk for PPH, or in the event of uterine atony, however, this dose should be given in aliquots of smaller doses.
      • Balki M.
      • Tsen L.
      Oxytocin protocols for cesarean delivery.
      Such doses are, however, not recommended for routine prophylaxis for vaginal and low-risk CD. These higher doses have been shown to produce a high rate of hypotension, tachycardia and dysrhythmia. Therefore, higher doses of oxytocin should be used with caution, especially in the presence of neuraxial blockade or hypovolemia secondary to PPH, where the side effects can be more pronounced.
      • Balki M.
      • Tsen L.
      Oxytocin protocols for cesarean delivery.
      What is more concerning is that our findings suggest that oxytocin 10 IU IV is used in vaginal deliveries despite a lack of routine cardiac monitoring or the presence of anesthesia personnel. Intravenous boluses of oxytocin 5–10 IU are also still commonly used for CDs, despite established evidence against it. The effective dose 90% (ED90) for an IV bolus of oxytocin is 0.35 IU (95% confidence interval (CI) 0.18 to 0.52 IU) at elective CD and 2.99 IU (95% CI 2.32 to 3.67 IU) at CD for labor arrest.
      • Carvalho J.C.
      • Balki M.
      • Kingdom J.
      • Windrim R.
      Oxytocin requirements at elective cesarean delivery: a dose-finding study.
      • Balki M.
      • Ronayne M.
      • Davies S.
      • et al.
      Minimum oxytocin dose requirement after cesarean delivery for labor arrest.
      Butwick et al.
      • Butwick A.J.
      • Coleman L.
      • Cohen S.E.
      • Riley E.T.
      • Carvalho B.
      Minimum effective bolus dose of oxytocin during elective Caesarean delivery.
      also suggested that doses between 0.5 and 3 IU are effective at elective CD and that a dose of 5 IU can no longer be justified. Oxytocin infusions are often used alone or in conjunction with IV boluses for elective CD and CD for labor arrest. Recently published evidence from a randomized controlled trial by Duffield et al.
      • Duffield A.
      • McKenzie C.
      • Carvalho B.
      • et al.
      Effect of a high-rate versus low-rate oxytocin infusion for maintaining uterine contractility during elective cesarean delivery: a prospective randomized clinical trial.
      confirms that high rate oxytocin infusion (15 IU/h) versus low rate (2.5 IU/h) at elective CD does not improve uterine tone or reduce PPH rate and that the lower maintenance rate may minimize oxytocin side effects. Women with prior exposure to oxytocin for labor augmentation or induction undergoing CD for labor arrest require a higher infusion rate (ED90 44.2 IU/h, 95% CI 33.8 to 55.6) compared to their non-laboring counterparts (ED90 16.2 IU/h, 95% CI 13.1 to 19.3).
      • Lavoie A.
      • McCarthy R.J.
      • Wong C.A.
      The ED90 of prophylactic oxytocin infusion after delivery of the placenta during cesarean delivery in laboring compared with nonlaboring women: an up-down sequential allocation dose-response study.
      The study by Lavoie et al.
      • Lavoie A.
      • McCarthy R.J.
      • Wong C.A.
      The ED90 of prophylactic oxytocin infusion after delivery of the placenta during cesarean delivery in laboring compared with nonlaboring women: an up-down sequential allocation dose-response study.
      illustrates that higher doses of oxytocin and more second-line uterotonics are required in women with labor arrest and previous oxytocin exposure. However, it is the opinion of the authors that these high oxytocin infusion rates (and therefore total doses) should be interpreted with caution. These doses are not the norm at our institution. Furthermore, the authors believe that more teaching regarding oxytocin pharmacology and its side effects should be provided to labor and delivery nurses, obstetricians and family doctors so that, in the setting of PPH prevention, the benefit may be maximized and side effects minimized.

      Carbetocin

      Carbetocin was used in vaginal deliveries as well as high-risk CD. This is despite no recommendations in SOGC guidelines for its use in high-risk CD.
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      The use of carbetocin at vaginal deliveries was reported in only 6% institutions, so significance and generalizability of this finding must be guarded. Carbetocin doses ranged from 25 to 100 μg. The product monograph for DURATOCIN™ recommends 100 μg, but the evidence suggests the ED90 for elective CD is 14.8 μg (95% CI 13.7 to 15.8) and that doses >100 μg may be required for CD after labor arrest (ED90 121 μg, 95% CI 111 to 130), but that such doses may induce arrhythmias and cannot be recommended.
      • Khan M.
      • Balki M.
      • Ahmed I.
      • Farine D.
      • Seaward G.
      • Carvalho J.C.
      Carbetocin at elective cesarean delivery: a sequential allocation trial to determine the minimum effective dose.
      • Nguyen-Lu N.
      • Carvalho J.C.
      • Farine D.
      • Seaward G.
      • Ye X.Y.
      • Balki M.
      Carbetocin at cesarean delivery for labour arrest: a sequential allocation trial to determine the effective dose.
      Carbetocin is not currently recommended by any national guideline other than that of the SOGC.

      Second-line uterotonics

      Our survey findings convey that second-line uterotonic usage for PPH management is also variable in Canadian centers. Use of carboprost, ergonovine maleate and misoprostol is based on clinician preference and experience more than evidence. This is akin to the ‘institution-based factors’ such as practitioner experience, preference and local hospital culture described by Bateman et al.
      • Bateman B.T.
      • Tsen L.C.
      • Liu J.
      • Butwick A.J.
      • Huybrechts K.F.
      Patterns of second-line uterotonic use in a large sample of hospitalizations for childbirth in the United States: 2007–2011.
      The doses of both carboprost and ergonovine were consistent with SOGC guidelines,
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      however, the frequency of administration of ergonovine maleate was quite varied. Additional carbetocin was used in the event of continued uterine atony despite lack of evidence or guideline recommendations.
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      • Royal College of Obstetricians and Gynaecologists
      Prevention and management of postpartum haemorrhage.
      • American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 183, October 2017: postpartum hemorrhage.
      Both obstetricians and anesthesiologists considered carboprost to be their first choice for a second-line uterotonic, however, we were surprised to find out that obstetricians chose misoprostol over ergonovine as their second choice second-line uterotonic, in the event of PPH. This could perhaps be because the management of obstetricians is geared towards vaginal delivery, while anesthesiologists consider parenteral routes in the setting of CD. Misoprostol has been shown to have significant side effects (cramping, hyperthermia, shivering, convulsions, diarrhea, fever) and has limited efficacy.
      • Quibel T.
      • Ghout I.
      • Goffinet F.
      • et al.
      Active management of the third stage of labor with a combination of oxytocin and misoprostol to prevent postpartum hemorrhage: a randomized controlled trial.
      • Winikoff B.
      • Dabash R.
      • Durocher J.
      • et al.
      Treatment of post-partum haemorrhage with sublingual misoprostol versus oxytocin in women not exposed to oxytocin during labour: a double-blind, randomised, non-inferiority trial.
      The advantage of ergonovine is that it can be given both IV and intramuscularly, as per the SOGC and the Royal College of Obstetricians and Gynaecologists (RCOG).
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      • Royal College of Obstetricians and Gynaecologists
      Prevention and management of postpartum haemorrhage.
      Also, ergonovine has been associated with a reduced risk of hemorrhage-related morbidity during CD as compared to carboprost.
      • Vallera C.
      • Choi L.O.
      • Cha C.M.
      • Hong R.W.
      Uterotonic medications oxytocin, methylergonovine, carboprost, misoprostol.
      Dose-response studies done in human myometrial samples from laboring and non-laboring women also show that ergonovine provides superior contraction compared to carboprost and misoprostol.
      • Balki M.
      • Erik-Soussi M.
      • Kingdom J.
      • Carvalho J.C.A.
      Comparative efficacy of uterotonic agents: in-vitro contractions in isolated myometrial strips of laboring and non-laboring women.
      Therefore we believe that ergonovine may be the best choice for a second-line uterotonic in the absence of contraindications such as hypertension or preeclampsia.

      Canadian Guidelines

      National guidelines are vital to the evidence-based practice of clinicians. Inconsistencies in societal guidelines continue to contribute to significant variations in the clinical uterotonic regimens used for vaginal and CD, whether elective or for labor arrest. Bohlmann et al.
      • Bohlmann M.K.
      • Rath W.
      Medical prevention and treatment of postpartum hemorrhage: a comparison of different guidelines.
      and Dalkhe et al.
      • Dahlke J.D.
      • Mendez-Figueroa H.
      • Maggio L.
      • et al.
      Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines.
      both elaborated on the substantial variation in medical approaches to PPH prevention and treatment, as well as resuscitation strategies, in various international guidelines. Postpartum hemorrhage remains one of the leading worldwide causes of morbidity and mortality.
      • Maswime S.
      • Buchmann E.
      A systematic review of maternal near miss and mortality due to postpartum hemorrhage.
      This is confirmed by the latest MBRRACE-UK report (2017), which found that death from hemorrhage has doubled from 2009–11 to 2013–15.
      This underscores the need for improved national and international uterotonic guidelines.
      The choice of first- and second-line agents for PPH in our survey was mainly based on the perceived efficacy and the SOGC guidelines or obstetrician’s preference. Interestingly, these particular guidelines are the only ones recommending carbetocin 100 μg in lieu of oxytocin, administered over one minute for elective CD or vaginal delivery, when there is one risk factor for PPH (not specified) (Appendix 2, supplementary file).
      • Dahlke J.D.
      • Mendez-Figueroa H.
      • Maggio L.
      • et al.
      Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines.
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      There is, however, more recent evidence that suggests smaller doses are equally effective in elective CD, while eight-times higher doses are required for CD during labor arrest.
      • Khan M.
      • Balki M.
      • Ahmed I.
      • Farine D.
      • Seaward G.
      • Carvalho J.C.
      Carbetocin at elective cesarean delivery: a sequential allocation trial to determine the minimum effective dose.
      • Nguyen-Lu N.
      • Carvalho J.C.
      • Farine D.
      • Seaward G.
      • Ye X.Y.
      • Balki M.
      Carbetocin at cesarean delivery for labour arrest: a sequential allocation trial to determine the effective dose.
      The SOGC recommended oxytocin dosing for medical management of established PPH is 10 IU intramuscular, 5 IU IV push, or 20–40 IU in 250 mL normal saline IV infusion at 500–1000 mL/h.
      • Dahlke J.D.
      • Mendez-Figueroa H.
      • Maggio L.
      • et al.
      Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines.
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      Although ergonovine doses and formulations differ between guidelines and countries,
      • Dahlke J.D.
      • Mendez-Figueroa H.
      • Maggio L.
      • et al.
      Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines.
      • Leduc D.
      • Senikas V.
      • Lalonde A.B.
      Society of Obstetricians and Gynecologists of Canada. SOGC Clinical Practice Guideline. Active Management of the third stage of labour: prevention and treatment of postpartum hemorrhage.
      • Royal College of Obstetricians and Gynaecologists
      Prevention and management of postpartum haemorrhage.
      • American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 183, October 2017: postpartum hemorrhage.
      in Canada ergonovine 0.25 mg is recommended via the intramuscular or IV route, repeated every two hours. The guidelines regarding carboprost administration are consistent across countries, with the recommendation of 0.25 mg intramuscularly (or intramyometrially in Canada), which can be repeated every 15 minutes to a maximum of 2 mg (eight doses).
      So where do we go from here? College and societal guidelines can have far reaching influence and impact both academic centers and small community hospitals alike. Therefore, it is of the utmost importance that these guidelines be consistent, concise and offer a clear message to practising clinicians. The authors feel that the SOGC guidelines, as well as their international counterparts from the American College of Obstetricians and Gynecologists (ACOG) and RCOG, are vital aids to evidence-based practice of clinicians. Therefore, the authors recommend that evidence from dose-finding studies in various patient populations and recent literature
      • Marcus H.E.
      • Fabian A.
      • Lier H.
      • et al.
      Survey on the use of oxytocin for cesarean section.
      • Sheehan S.R.
      • Wedisinghe L.
      • Macleod M.
      • Murphy D.J.
      Implementation of guidelines on oxytocin use at caesarean section: a survey of practice in Great Britain and Ireland.
      • Wedisinghe L.
      • Macleod M.
      • Murphy D.J.
      Use of oxytocin to prevent haemorrhage at caesarean section—A survey of practice in the United Kingdom.
      • Balki M.
      • Tsen L.
      Oxytocin protocols for cesarean delivery.
      • Carvalho J.C.
      • Balki M.
      • Kingdom J.
      • Windrim R.
      Oxytocin requirements at elective cesarean delivery: a dose-finding study.
      • Balki M.
      • Ronayne M.
      • Davies S.
      • et al.
      Minimum oxytocin dose requirement after cesarean delivery for labor arrest.
      • Butwick A.J.
      • Coleman L.
      • Cohen S.E.
      • Riley E.T.
      • Carvalho B.
      Minimum effective bolus dose of oxytocin during elective Caesarean delivery.
      • Duffield A.
      • McKenzie C.
      • Carvalho B.
      • et al.
      Effect of a high-rate versus low-rate oxytocin infusion for maintaining uterine contractility during elective cesarean delivery: a prospective randomized clinical trial.
      • Lavoie A.
      • McCarthy R.J.
      • Wong C.A.
      The ED90 of prophylactic oxytocin infusion after delivery of the placenta during cesarean delivery in laboring compared with nonlaboring women: an up-down sequential allocation dose-response study.
      be used to update such guidelines. Ideally the SOGC, RCOG and ACOG should consider working together to develop guidelines.
      Our study has significant limitations that should be recognized. Individualized institutional response rates of 36% and 52%, respectively, although in keeping with some other responses noted for surveys in the literature,are very low. Therefore, any conclusions drawn may not be generalizable, particularly to institutions outside Canada. However, the majorities of respondents were from large academic centers with annual delivery rates of more than 5000, and hence may provide a good overview of practices across the country. Survey methodology also has inherent survey and selection bias, as respondents’ practices are likely to differ from those who do not respond. Furthermore, anesthesiologists were over-represented when compared to their obstetrician respondent counterparts. This could be explained by the fact that the study was anesthesiology led, but other reasons could also be responsible.
      In conclusion, this study demonstrates the lack of a unified approach to first- and second-line uterotonic usage. It reveals a ‘snapshot’ of Canadian practice and needs to be interpreted in this light. An evidence-based approach to uterotonic usage, as well as the consensus of obstetricians and anesthesiologists, is warranted in order to improve the management of PPH due to uterine atony. Considering the variation in practice between-hospitals and between-subspecialists within each institution, institutional audits and standardization of care for prophylaxis and treatment of uterine atony are necessary. The use of consistent, evidence-based societal guidelines can help to bring uniformity to clinical practice. More research may be needed to provide further evidence before change to national guidelines.

      Acknowledgements

      We thank all anesthesiologists and obstetricians who participated in the survey.

      Disclosures

      This work was presented at the Society for Obstetric Anesthesia and Perinatology 49th Annual Meeting, Bellevue, WA May 10–14, 2017 and at the Canadian Anesthesiologists’ Society Annual Meeting, Niagara Falls, ON June 23–26, 2017.

      Funding

      Institutional. Mrinalini Balki was supported by Merit awards, Department of Anesthesia, University of Toronto , Canada.

      Competing interests

      No external funding and competing interests declared.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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