- Email: [email protected]
Outcomes after institution of a new oxytocin infusion protocol during the third stage of labor and immediate postpartum period
Correspondence
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stage of labor and immediate postpartum period. Int J Obstet Anesth 2013;22:194–9. George RB, McKeen D, Chaplin AC, McLeod L. Up-down determination of the ED90 of oxytocin infusions for the prevention of postpartum uterine atony in parturients undergoing Cesarean delivery. Can J Anesth 2010;57:578–82. Robinson C, Schumann R, Peisheng Z. Oxytocin-induced desensitization of the oxytocin receptor. Am J Obstet Gynecol 2003;188:497–502. Balki M, Cristian A, Parkes RK, Kingdom J, Carvalho JC. Oxytocin pre-exposure of pregnant rat myometrium reduces the efficacy of oxytocin but not ergonovine or carbaprost. Society of Obstetric Anesthesia and Perinatology Annual Meeting, Washington D.C., USA. 2009. A12. Balki M, Ronayne M, Davies S, et al. Minimum oxytocin dose requirement after caesarean delivery for labor arrest. Obstet Gynecol 2006;107:45–50. Rizvi F, Mackey R, Barrett T, McKenna P, Geary M. Successful reduction of massive postpartum haemorrhage by use of guidelines and staff education. BJOG 2004;111:495–8.
0959-289X/$ - see front matter
c 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijoa.2013.10.005
In reply
We thank Dr Elnour et al. for their interest in our article describing the institution of a new oxytocin protocol in the postpartum period.1 Surprising as it may seem, it is in fact common practice in the USA to administer oxytocin 10–40 units in 1 L of crystalloid at an unspecified and uncontrolled rate, often as quickly as possible. In fact, this was the practice in our hospital before the institution of the new protocol. However, we may have been unclear in our manuscript; we did not mean to imply that oxytocin administration was discontinued altogether when infusion of this first liter of crystalloid was finished. Rather, at that time, another liter of oxytocin-containing crystalloid was usually started, but at a slower, although still uncontrolled, rate and the infusion continued for several hours. It is therefore likely that patients in our pre-protocol group received oxytocin for a number of hours after delivery, and they probably received higher total doses of oxytocin, perhaps even for longer periods of time, than patients in the post-protocol group. Regarding the dosages called for in the protocol, Elnour et al. correctly point out that oxytocin requirement may be higher than those called for by George et al.2 in certain patient populations such as those who have been exposed to oxytocin for induction or augmentation of labor before cesarean delivery. In spite of basing our protocol on the George et al. doses, hemorrhage rates did not increase in the post-protocol patients. Elnour et al. correctly note that we did not measure total oxytocin doses in our two groups. It would
87 have been nearly impossible to do so in the pre-protocol group due to the uncontrolled manner in which oxytocin was administered. As described in our Appendix,1 patients in the post-protocol group received oxytocin at a slow rate (3.6 U/h) after the first hour until the fundus was firm or until the patient was transferred to the postpartum unit. The reasons behind the protocol’s success are most likely multifactorial. The protocol’s design mandated not only the dose of oxytocin but also called for the quick delivery of other uterotonic agents if atony continued. As Elnour et al. point out, staff education and training may also have played a role. Additionally, as mentioned in our article, there existed a higher proportion of hypertensive diseases of pregnancy in the pre- versus postprotocol population, and this may have biased results in favor of the post-protocol group, although it seems unlikely that the small decrease in hypertensive disease measured explains our results entirely. While Elnour et al. chose to focus on the total dose of oxytocin and the difficulty with interpreting hemorrhage rates in both groups, it is important to remember that the primary objective of protocol implementation was a reduction in the rate of oxytocin infusion since previous studies have shown the deleterious effects of rapidly infusing oxytocin in the third stage of labor.3–6 While admittedly there may have been other factors that impacted our incidence of hemorrhage, we were able to implement a safer, consistent way of administering third-stage oxytocin without adversely impacting postpartum hemorrhage rates. B. Scavone, K. Nunes Department of Anesthesia and Critical Care Department of Obstetrics and Gynecology University of Chicago IL, USA E-mail address: [email protected]
References 1. DaGraca J, Malladi V, Nunes K, Scavone B. Outcomes after institution of a new oxytocin infusion protocol during the third stage of labor and immediate postpartum period. Int J Obstet Anesth 2013;22:194–9. 2. George RB, McKeen D, Chaplin AC, McLeod L. Up-down determination of the ED90 of oxytocin infusions for the prevention of postpartum uterine atony in parturients undergoing cesarean delivery. Can J Anesth 2010;57:578–82. 3. Pinder AJ, Dresner M, Calow C, Shorten GD, O’Riordan J, Johnson J. Haemodynamic changes caused by oxytocin during caesarean section under spinal anaesthesia. Int J Obstet Anesth 2002;11:156–9. 4. Archer TL, Knape K, Liles D, Wheeler AS, Carter B. The hemodynamics of oxytocin and other vasoactive agents during neuraxial anesthesia for cesarean delivery: findings in six cases. Int J Obstet Anesth 2008;17:247–54. 5. Svanstrom MC, Biber B, Hanes M, Johansson G, Na¨shund U, Baifors EM. Signs of myocardial ischaemia after injection of oxytocin: a randomized double-blind comparison of oxytocin and
88 methylergometrine during caesarean section. Br J Anaesth 2008;100:683–9. 6. Jonsson M, Hanson U, Lidell C, Norde´n-Lindeberg S. ST depression at caesarean section and the relation to oxytocin dose. A randomised controlled trial. BJOG 2010;117:76–83. 0959-289X/$ - see front matter
c 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijoa.2013.10.005
QT interval prolongation following carbetocin in prevention of postcesarean delivery hemorrhage Carbetocin is a new synthetic analog of human oxytocin that is used in the prevention of postpartum hemorrhage during cesarean delivery.1 It is longer lasting than oxytocin;2 however, it decreases arterial blood pressure and increases heart rate in similar proportions. Oxytocin has been shown to cause a transient increase in the QT interval,3 and cause changes in T-wave morphology that may predispose to cardiac arrhythmia.4 These effects may be caused by a direct action on conduction tissue but may also be related to indirect sympathetic effects such as a decrease in arterial blood pressure and an increase in heart rate.3,5,6 This observational study assessed the electrocardiographic and hemodynamic effects of carbetocin administered during cesarean delivery. After umbilical cord clamping, an intravenous bolus of carbetocin 100 lg (PabalÒ, Ferring GmbH, Kiel, Germany) was administered over 10 s. A digital 12-lead electrocardiogram was obtained before induction of anesthesia, 3 min after stable anesthesia had been obtained, and then at 1, 2, 3, 5, 7, 10 and 15 min after carbetocin injection. The QT interval was measured semi-manually by a single observer and was corrected according to Fridericia’s correction formula (QTcf = QT/RR). Sample size was calculated in order to detect a QTcf change >10 ms using a b risk at 0.20. QTcf, RR intervals and arterial blood pressure were compared by ANOVA for repeated measures and, if significant, using post-hoc analyses. Among the 20 women enrolled (age: 31 ± 6 years, weight: 78 ± 14 kg), 85% underwent an elective procedure. Gestational age was 37 weeks and 3 days ± 7 days. Cesarean delivery was performed because of previous cesarean delivery (n = 7), placenta previa (n = 3), cervical dystocia (n = 2), twin pregnancy (n = 2), breech presentation (n = 2), intrauterine growth restriction (n = 2), fetal cardiac rhythm abnormality (n = 1) and HIV infection (n = 1). Spinal, combined spinal–epidural and epidural anesthesia were used in 10, five and five patients, respectively. Hyperbaric 0.5% bupivacaine was used in 15 cases, 2% lidocaine in four cases and both drugs combined in one case. Fifteen women required vasopressor
Correspondence support with ephedrine (n = 10, mean total dose 9 ± 11 mg) or phenylephrine (n = 7, mean total dose 60 ± 91 lg). Baseline hemodynamic characteristics before anesthesia were systolic blood pressure 134 ± 14 mmHg, diastolic blood pressure 79 ± 9 mmHg, heart rate 89 ± 14 beats/min and QTcf 403 ± 19 ms. Apgar scores were 10 in 75% [range 8–10] and 10 in 85% [range 9–10] at 1 and 5 min, respectively. Arterial blood gas measurement was obtained in 12 newborns: median pH was 7.31 [range 7.14–7.40]. Mean QTcf interval values over time are shown in Fig. 1. QTcf duration was significantly longer from the post-anesthesia measurement from 5 min until the last recorded value at 15 min after carbetocin administration. The maximal increase was observed at 7 min (+ 18 ± 4 ms, P = 0.01). Compared to the pre-anesthesia baseline measurements, all QTcf values were significantly prolonged with a maximal rise at 7 min (+ 30 ± 4 ms, P < 0.0001). No arrhythmia occurred during the study period. Carbetocin did not modify heart rate but was associated with a 19% drop of arterial blood pressure. Compared with post-anesthesia values, the nadir was found at 15 min after carbetocin administration: 23 ± 4 and 22 ± 3 mmHg for systolic and diastolic blood pressure, respectively (both P < 0.0001). Although this observational study lacked a control group, the observed QT prolongation and hemodynamic changes following carbetocin are likely to be drug-related. Firstly, the observed decrease in arterial blood pressure is close to that reported in previous studies, supporting external validity;7 secondly, data obtained in observational and placebo-controlled studies usually show similar drug-induced QT prolongation.8 However, we cannot exclude that the prolongation in QT interval might have been related to other QT prolonging factors. Apart from case
Fig. 1 Mean QTcf (±SD) during cesarean delivery. *P < 0.05 versus level after anesthesia.
2.
3.
4.
5.
6.
stage of labor and immediate postpartum period. Int J Obstet Anesth 2013;22:194–9. George RB, McKeen D, Chaplin AC, McLeod L. Up-down determination of the ED90 of oxytocin infusions for the prevention of postpartum uterine atony in parturients undergoing Cesarean delivery. Can J Anesth 2010;57:578–82. Robinson C, Schumann R, Peisheng Z. Oxytocin-induced desensitization of the oxytocin receptor. Am J Obstet Gynecol 2003;188:497–502. Balki M, Cristian A, Parkes RK, Kingdom J, Carvalho JC. Oxytocin pre-exposure of pregnant rat myometrium reduces the efficacy of oxytocin but not ergonovine or carbaprost. Society of Obstetric Anesthesia and Perinatology Annual Meeting, Washington D.C., USA. 2009. A12. Balki M, Ronayne M, Davies S, et al. Minimum oxytocin dose requirement after caesarean delivery for labor arrest. Obstet Gynecol 2006;107:45–50. Rizvi F, Mackey R, Barrett T, McKenna P, Geary M. Successful reduction of massive postpartum haemorrhage by use of guidelines and staff education. BJOG 2004;111:495–8.
0959-289X/$ - see front matter
c 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijoa.2013.10.005
In reply
We thank Dr Elnour et al. for their interest in our article describing the institution of a new oxytocin protocol in the postpartum period.1 Surprising as it may seem, it is in fact common practice in the USA to administer oxytocin 10–40 units in 1 L of crystalloid at an unspecified and uncontrolled rate, often as quickly as possible. In fact, this was the practice in our hospital before the institution of the new protocol. However, we may have been unclear in our manuscript; we did not mean to imply that oxytocin administration was discontinued altogether when infusion of this first liter of crystalloid was finished. Rather, at that time, another liter of oxytocin-containing crystalloid was usually started, but at a slower, although still uncontrolled, rate and the infusion continued for several hours. It is therefore likely that patients in our pre-protocol group received oxytocin for a number of hours after delivery, and they probably received higher total doses of oxytocin, perhaps even for longer periods of time, than patients in the post-protocol group. Regarding the dosages called for in the protocol, Elnour et al. correctly point out that oxytocin requirement may be higher than those called for by George et al.2 in certain patient populations such as those who have been exposed to oxytocin for induction or augmentation of labor before cesarean delivery. In spite of basing our protocol on the George et al. doses, hemorrhage rates did not increase in the post-protocol patients. Elnour et al. correctly note that we did not measure total oxytocin doses in our two groups. It would
87 have been nearly impossible to do so in the pre-protocol group due to the uncontrolled manner in which oxytocin was administered. As described in our Appendix,1 patients in the post-protocol group received oxytocin at a slow rate (3.6 U/h) after the first hour until the fundus was firm or until the patient was transferred to the postpartum unit. The reasons behind the protocol’s success are most likely multifactorial. The protocol’s design mandated not only the dose of oxytocin but also called for the quick delivery of other uterotonic agents if atony continued. As Elnour et al. point out, staff education and training may also have played a role. Additionally, as mentioned in our article, there existed a higher proportion of hypertensive diseases of pregnancy in the pre- versus postprotocol population, and this may have biased results in favor of the post-protocol group, although it seems unlikely that the small decrease in hypertensive disease measured explains our results entirely. While Elnour et al. chose to focus on the total dose of oxytocin and the difficulty with interpreting hemorrhage rates in both groups, it is important to remember that the primary objective of protocol implementation was a reduction in the rate of oxytocin infusion since previous studies have shown the deleterious effects of rapidly infusing oxytocin in the third stage of labor.3–6 While admittedly there may have been other factors that impacted our incidence of hemorrhage, we were able to implement a safer, consistent way of administering third-stage oxytocin without adversely impacting postpartum hemorrhage rates. B. Scavone, K. Nunes Department of Anesthesia and Critical Care Department of Obstetrics and Gynecology University of Chicago IL, USA E-mail address: [email protected]
References 1. DaGraca J, Malladi V, Nunes K, Scavone B. Outcomes after institution of a new oxytocin infusion protocol during the third stage of labor and immediate postpartum period. Int J Obstet Anesth 2013;22:194–9. 2. George RB, McKeen D, Chaplin AC, McLeod L. Up-down determination of the ED90 of oxytocin infusions for the prevention of postpartum uterine atony in parturients undergoing cesarean delivery. Can J Anesth 2010;57:578–82. 3. Pinder AJ, Dresner M, Calow C, Shorten GD, O’Riordan J, Johnson J. Haemodynamic changes caused by oxytocin during caesarean section under spinal anaesthesia. Int J Obstet Anesth 2002;11:156–9. 4. Archer TL, Knape K, Liles D, Wheeler AS, Carter B. The hemodynamics of oxytocin and other vasoactive agents during neuraxial anesthesia for cesarean delivery: findings in six cases. Int J Obstet Anesth 2008;17:247–54. 5. Svanstrom MC, Biber B, Hanes M, Johansson G, Na¨shund U, Baifors EM. Signs of myocardial ischaemia after injection of oxytocin: a randomized double-blind comparison of oxytocin and
88 methylergometrine during caesarean section. Br J Anaesth 2008;100:683–9. 6. Jonsson M, Hanson U, Lidell C, Norde´n-Lindeberg S. ST depression at caesarean section and the relation to oxytocin dose. A randomised controlled trial. BJOG 2010;117:76–83. 0959-289X/$ - see front matter
c 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijoa.2013.10.005
QT interval prolongation following carbetocin in prevention of postcesarean delivery hemorrhage Carbetocin is a new synthetic analog of human oxytocin that is used in the prevention of postpartum hemorrhage during cesarean delivery.1 It is longer lasting than oxytocin;2 however, it decreases arterial blood pressure and increases heart rate in similar proportions. Oxytocin has been shown to cause a transient increase in the QT interval,3 and cause changes in T-wave morphology that may predispose to cardiac arrhythmia.4 These effects may be caused by a direct action on conduction tissue but may also be related to indirect sympathetic effects such as a decrease in arterial blood pressure and an increase in heart rate.3,5,6 This observational study assessed the electrocardiographic and hemodynamic effects of carbetocin administered during cesarean delivery. After umbilical cord clamping, an intravenous bolus of carbetocin 100 lg (PabalÒ, Ferring GmbH, Kiel, Germany) was administered over 10 s. A digital 12-lead electrocardiogram was obtained before induction of anesthesia, 3 min after stable anesthesia had been obtained, and then at 1, 2, 3, 5, 7, 10 and 15 min after carbetocin injection. The QT interval was measured semi-manually by a single observer and was corrected according to Fridericia’s correction formula (QTcf = QT/RR). Sample size was calculated in order to detect a QTcf change >10 ms using a b risk at 0.20. QTcf, RR intervals and arterial blood pressure were compared by ANOVA for repeated measures and, if significant, using post-hoc analyses. Among the 20 women enrolled (age: 31 ± 6 years, weight: 78 ± 14 kg), 85% underwent an elective procedure. Gestational age was 37 weeks and 3 days ± 7 days. Cesarean delivery was performed because of previous cesarean delivery (n = 7), placenta previa (n = 3), cervical dystocia (n = 2), twin pregnancy (n = 2), breech presentation (n = 2), intrauterine growth restriction (n = 2), fetal cardiac rhythm abnormality (n = 1) and HIV infection (n = 1). Spinal, combined spinal–epidural and epidural anesthesia were used in 10, five and five patients, respectively. Hyperbaric 0.5% bupivacaine was used in 15 cases, 2% lidocaine in four cases and both drugs combined in one case. Fifteen women required vasopressor
Correspondence support with ephedrine (n = 10, mean total dose 9 ± 11 mg) or phenylephrine (n = 7, mean total dose 60 ± 91 lg). Baseline hemodynamic characteristics before anesthesia were systolic blood pressure 134 ± 14 mmHg, diastolic blood pressure 79 ± 9 mmHg, heart rate 89 ± 14 beats/min and QTcf 403 ± 19 ms. Apgar scores were 10 in 75% [range 8–10] and 10 in 85% [range 9–10] at 1 and 5 min, respectively. Arterial blood gas measurement was obtained in 12 newborns: median pH was 7.31 [range 7.14–7.40]. Mean QTcf interval values over time are shown in Fig. 1. QTcf duration was significantly longer from the post-anesthesia measurement from 5 min until the last recorded value at 15 min after carbetocin administration. The maximal increase was observed at 7 min (+ 18 ± 4 ms, P = 0.01). Compared to the pre-anesthesia baseline measurements, all QTcf values were significantly prolonged with a maximal rise at 7 min (+ 30 ± 4 ms, P < 0.0001). No arrhythmia occurred during the study period. Carbetocin did not modify heart rate but was associated with a 19% drop of arterial blood pressure. Compared with post-anesthesia values, the nadir was found at 15 min after carbetocin administration: 23 ± 4 and 22 ± 3 mmHg for systolic and diastolic blood pressure, respectively (both P < 0.0001). Although this observational study lacked a control group, the observed QT prolongation and hemodynamic changes following carbetocin are likely to be drug-related. Firstly, the observed decrease in arterial blood pressure is close to that reported in previous studies, supporting external validity;7 secondly, data obtained in observational and placebo-controlled studies usually show similar drug-induced QT prolongation.8 However, we cannot exclude that the prolongation in QT interval might have been related to other QT prolonging factors. Apart from case
Fig. 1 Mean QTcf (±SD) during cesarean delivery. *P < 0.05 versus level after anesthesia.