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Intravenous nitroglycerin for controlled cord traction in the management of retained placenta
International Journal of Gynecology and Obstetrics 112 (2011) 103–106
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Intravenous nitroglycerin for controlled cord traction in the management of retained placenta Shusee Visalyaputra a,⁎, Japarath Prechapanich b, Sukanya Suwanvichai a, Suwimol Yimyam a, Ladda Permpolprasert a, Pattipa Suksopee a a b
Department of Anesthesia, Siriraj Hospital, Mahidol University, Thailand Department of Obstetrics and Gynecology, Siriraj Hospital, Mahidol University, Thailand
a r t i c l e
i n f o
Article history: Received 25 May 2010 Received in revised form 16 August 2010 Accepted 29 October 2010 Keywords: Nitroglycerin Placenta removal Postpartum Retained placenta
a b s t r a c t Objective: To determine the effect of 200 μg of intravenous nitroglycerin in the release of retained placenta by controlled cord traction. Methods: In this randomized controlled study, 40 women with a placenta retained for 30 minutes received intravenously 200 μg of nitroglycerin or a normal saline solution before umbilical cord traction was initiated. The rates of successful removal of the retained placenta in the study (n = 20) and control (n= 20) groups were compared, as were blood pressure, pulse rate, blood loss, and adverse effects. Results: The placenta was released in only 15% and 20% of the participants in the study and control group, respectively. The remainder of the participants required general anesthesia and manual removal of the retained placenta regardless of group assignation. Blood pressure fell in significantly more women in the study group, but there were no differences in estimated blood loss or minor adverse effects. Conclusion: Intravenously administered nitroglycerin did not facilitate the release of retained placenta by umbilical cord traction. However, cord traction may be performed longer than 30 minutes to attempt releasing the placenta before operative manual removal is initiated. © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction With reported incidence rates of 2.0% or 3.3%, retained placenta is not an uncommon occurrence [1,2]. Its manual removal usually necessitates general anesthesia, which provides cervicouterine relaxation as well as analgesia. In 2009, in an effort to avoid the risks of complications arising from general anesthesia, including the risk of aspiration pneumonitis from difficult intubation [3], the WHO published guidelines for the management of postpartum hemorrhage and retained placenta [4]. These guidelines recommend injecting saline-diluted oxytocin into the umbilical vein. However a large, randomized, controlled trial recently reported that the injection had no clinically significant effect on the need to remove retained placenta manually [5]. The most commonly used pharmacologic nitrovasodilator, nitroglycerin (NTG), relaxes smooth muscle cells by releasing nitric oxide, which then stimulates cyclic guanosine monophosphate production and results in smooth muscle relaxation. The myometrium is known to synthesize nitric oxide for its own relaxation [6], and although NTG has been used mostly as a vasodilator in patients with angina pectoris or undergoing a hypertensive crisis, it has also been used in cases of uterine inversion or placental retention [7–13]. A wide majority of the
⁎ Corresponding author. Department of Anesthesia, Siriraj Hospital, Prannok, Bangkoknoi, Bangkok, Thailand 10700. Tel.: + 66 2 419 7990. E-mail address: [email protected] (S. Visalyaputra).
studies of the use of NTG for the release of retained placenta have been descriptive [7–9] or retrospective [10–12]. Only one was a randomized controlled trial of 1 mg of NTG administered sublingually in 24 women with retained placenta [13]. The present randomized controlled trial was conducted at Siriraj Hospital, a tertiary care center affiliated with the medical school of Mahidol University, Bangkok, Thailand. Its objective was to determine whether 200 μg of NTG, administered intravenously in 2 doses of 100 μg to prevent severe drug-induced hypotension, is more helpful than placebo when controlled traction is applied on the cord to release a retained placenta. 2. Materials and methods Since women with a retained placenta are in an emergency situation, obtaining written consent from them would be inappropriate and inadvisable. According to Guideline 29 of the 2008 revision of the Declaration of Helsinki regarding clinical trials, physicians may proceed without written consent in an emergency situation if this has been previously approved by a competent research ethics committee (the participant's consent to remain in the study should be obtained as soon as possible, however) [14]. The Ethics Committee of Siriraj Hospital approved our protocol, which stipulated that the informed verbal consent of conscious participants would be sufficient in emergency situations. The different types of retained placenta are associated with different clinical signs. A small and contracted fundus and a tight cervical os are
0020-7292/$ – see front matter © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2010.08.021
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signs of a trapped placenta, for example, and a soft and wide fundus suggests a placenta adherens [15]. However, these signs can be difficult to recognize and exploration by ultrasound has been suggested [16]. Since ultrasound is not used at our hospital to differentiate between types of retained placenta, we decided to recruit only women who had been diagnosed as having a retained placenta. The latter was defined as a placenta not delivered within 30 minutes after fetal delivery. The eligibility criteria were a singleton pregnancy with no cardiac, pulmonary, or other form of disease requiring treatment and a placenta retained for 30 minutes or longer following the vaginal delivery of the fetus. The exclusion criteria were pre-eclampsia, a gynecologic infection, a uterine scar, placenta accreta, a gestation less than 28 weeks, hypotension (defined as a systolic blood pressure b100 mmHg and a pulse rate N100 bpm), and umbilical cord disruption. Immediately following delivery of the fetus, in accordance with the routine management of vaginal delivery at Siriraj Hospital, 10 U of oxytocin in 1000 mL of 0.45% saline solution with 5% dextrose was administered intravenously to promote uterine contraction, at rates of 200–300 mL in the first few minutes and then of 100 mL/hour. If there were no signs of placental separation after 15 or 20 minutes, 5 more units of oxytocin were infused intravenously. If these 5 supplemental units did not provoke placental delivery, a Kelly clamp was attached to the cord as a visual way to indicate whether the placenta was being released, and controlled traction was applied to the umbilical cord (with countertraction applied to the uterine fundus to prevent uterine inversion). If the placenta was still retained 30 minutes after fetal delivery, an anesthesia team was called and manual removal was performed in the operating room. Once a diagnosis of retained placenta was made, 500 mL of a crystalloid solution was injected intravenously and pulse oximetry, an electrocardiogram, and noninvasive blood pressure monitoring were initiated. The women were approached at this time if they met the eligibility criteria. If they accepted, they were enrolled in the trial. Using the Research Randomizer program (made freely available by the Social Psychology Network at http://www.Randomizer.org), 40 successive eligible women with a retained placenta were randomized to a study or control group by the block-of-4 method, and their group assignation was enclosed in a numbered envelope. Those assigned to the study group received 200 μg of NTG intravenously, 100 μg at a time, in an amount of a normal saline solution (NSS) sufficient to fill a 10-mL syringe. Those assigned to the control group received 10 mL of NSS, also in 10-mL syringes. A nurse who did not participate in the remainder of the study opened the envelopes as needed and filled the syringes with the appropriate solutions outside the operating room. Neither the investigators who gave the injections and managed the participants’ blood pressure, nor the obstetricians who performed controlled cord traction, nor the study participants were aware of the syringe content. Before NTG or NSS was administered and cord traction initiated, 50 to 100 μg of fentanyl citrate (Fentanyl; Janssen-Cilag, Bangkok, Thailand) was given to all participants for analgesia and norepinephrine bitartrate (Levophed; Hospira, IL, USA) was administered intravenously to those with hypotension. This drug, which is supplied in 4-mL vials containing 4-mg doses (for a concentration, therefore, of 1 mg [or 1000 μg/mL]), was further diluted to 4 μg/mL in a 10-mL syringe. In the treatment group, the NTG used (David Bull Laboratories, Victoria, Australia) was supplied in 5-mL vials containing 25-mg doses in a solution. To achieve a concentration of 50 μg/mL, 1 mL (i.e. 5000 μg) of the vial solution was diluted in 9 mL of NSS to fill 10-mL syringes (to get 500 μg/mL). Then, 1 mL (500 μg) of the solution thus obtained was further diluted with 9 mL of NSS in another 10-mL syringe to get 50 μg/mL. The average time for NTG to take effect is 80 seconds [9]. Therefore, 80 seconds after the first 100 μg of NTG (or 2 mL of the solution) was injected, the obstetrician began to gently pull on the cord. If the placenta was not released within 1 minute and the participant was not in a state of hypotension, a second 100-μg
bolus from the same syringe was injected and cord traction was resumed for no longer than 2 more minutes. If the placenta was not released after 3 minutes of controlled cord traction, the procedure was considered to have failed. Oxytocin or ergometrine was administered to the participants in whom the procedure succeeded. The vital signs were recorded before the first NTG bolus and thereafter at 1-minute intervals for 5 minutes, at 2-minute intervals for 20 minutes, and then every 5 minutes for 30 minutes. Blood loss was evaluated by a nurse in the labor room after fetal delivery but prior to NTG administration, and also by the obstetricians in the operating room after manual placenta removal. The participants in whom the placenta could not be released after 3 minutes of controlled cord traction underwent general anesthesia and manual removal of the placenta. In a previous randomized study with 12 women, only 1 woman (about 10%) had her placenta successfully delivered by controlled cord traction [13]. Based on an expected difference in success rate of at least 50% (60% vs. 10%), we calculated that 20 participants per group were needed for a 2-sided type 1 error of 0.01 and 80% power. Statistical analyses were performed using SPSS software, version13.5 (SPSS, Chicago, IL, USA). Values are given as mean ± SD or number and percentage. The χ2 test or the Fisher exact test, as appropriate, was used to test differences in qualitative variables between the 2 groups. Because of unequal correlations among the repeated measurements, between-group comparisons of hemodynamic values observed 1, 2, 3, 4, 5, 7, and 9 minutes after initiation of the NTG treatment were performed using a linear mixed model with random intercept and slope. The number of minutes since treatment initiation was the independent variable. This model resulted in a linear regression equation for each group. P b 0.05 was considered statistically significant.
3. Results From January 1, 2008, to June 30, 2009, 47 women were to undergo manual removal of the placenta under general anesthesia. Of these, 5 were not approached because obstetricians had already applied controlled cord traction, 2 opted for immediate anesthesia and placenta removal, and the remaining 40 were recruited. The first traction caused cord disruption in 1 participant in each group, and the event was considered a failed outcome. One patient in the study group became severely hypotensive after the first 100-μg dose of NTG, with a systolic blood pressure of 70 mmHg, owing to uterine atony and massive hemorrhage. This event was considered a failed outcome. After the patient was treated with the rapid infusion of a crystalloid solution to prevent hypovolemic shock, followed by 26 μg of norepinephrine plus 0.2 mg of methylergometrine to increase blood pressure, she received 1 unit of packed red blood cells. The fourth failed outcome occurred in the placebo group, also because of hypotension from massive hemorrhage, in a woman who received 8 μg of norepinephrine and 2 units of blood. There were no significant differences between the 2 groups in demographic characteristics, estimated blood loss, amount of intravenous fluid used, or postoperative hematocrit values (Table 1); in success rates of placental removal by controlled umbilical cord traction; or in occurrence of adverse effects (Table 2). Only 3 participants (15%) in the study group and 4 participants (20%) in the placebo group underwent the controlled cord traction procedure successfully. The type of retained placenta was diagnosed by tactile judgment during manual removal in the remaining 33 participants. There were 6 women (18%), 3 in each group, with a trapped placenta and 27 women (82%), 14 in the study group and 13 in the placebo group, with a placenta adherens. In the study group, 3 women with a placenta adherens needed a second procedure because placental parts were incompletely removed during the first. One of these participants eventually underwent uterine curettage.
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Table 1 Patient characteristics, estimated blood loss, volume of intravenous fluid and dose of fentanyl used, and postoperative hematocrit in the 2 groups.a Variable
Study group (n = 20)
Placebo group (n = 20)
P value
Age, y Weight, kg Height (cm.) No. of abortions Gestational age, wk EBL before NTG or NSS injection, mL EBL after NTG or NSS injection, mL Volume of fluid infused before NTG or NSS injection, mL Volume of fluid infused after NTG or NSS injection, mL Fentanyl used, mg Postoperative hematocrit, %
28.4 ± 5.9 68.5 ± 11.2 157.1 ± 6.3 10 38.4 ± 2.1 217.5 ± 107.5 263.9 ± 178.9 528.9 ± 221.9
28.0 ± 6.2 66.6 ± 12.1 159.7 ± 6.1 5 37.5 ± 2.5 176.3 ± 87.2 230.6 ± 225.7 524.2 ± 276.8
0.85 0.61 0.19 0.19 0.45 0.20 0.63 0.95
788.9 ± 531.2
652.8 ± 394.9
0.39
45.0 ± 26.4 31.7 ± 4.7
47.4 ± 18.4 30.1 ± 4.6
0.75 0.29
Abbreviations: EBL, estimated blood loss; NSS, normal saline solution; NTG, nitroglycerin. a Values are given as mean ± SD unless otherwise indicated.
The blood pressure values noted 1, 2, 3, 4, 5, 7, and 9 minutes after initiation of the NTG treatment differed between the groups only at 1, 2, and 3 minutes. Systolic blood pressure differed at minutes 1 and 2 (P = 0.047 and P = 0.046, respectively) (Fig. 1) and diastolic blood pressure differed at minutes 1, 2, 3, and 4 (P = 0.003, P = 0.005, P = 0.01, and P = 0.03, respectively) (Fig. 2). However, there were no differences in pulse rates between the groups in the 10 minutes following treatment initiation (Fig. 3). 4. Discussion With success rates of 15% in the study group and 20% in the control group, 200 μg of NTG administered intravenously was ineffective in facilitating the release of a retained placenta. On the other hand, a significant drop in both systolic and diastolic blood pressure first occurred in the study group. We opted for 200 μg of NTG because, with 1 exception, it is the highest dose (the lowest being 50 μg) that has been successfully used in previous studies on the release of retained placentas [7,8,10,11]. In a 1989 study, Peng et al. [9] administered 500 μg of NTG intravenously in 15 women with a trapped placenta. We thought that a dose higher than 200 μg would increase the risk of severe hypotension in women with some degree of hypovolemia. The 3 main causes of retained placenta are placenta adherens (81%), trapped placenta (13%), and partial placenta accreta (6%) [15]. Placenta adherens occurs when contractions in the retroplacental myometrium are insufficient to completely release the placenta; a completely separated placenta becomes trapped in the presence of a constriction ring in the uterus or a closed cervix prevents its expulsion; and a partial placenta accreta occurs when a small area of the placenta remains firmly attached to the myometrium [15]. In our study, 6 women (18%) with a closed cervix required manual removal of the placenta, perhaps because they had both a closed cervix and some degree of placenta adherens. However, 3 women in the study group and 4 women in the placebo
Fig. 1. Sytolic blood pressure on admission (adm), 2 and 1 minutes (2b, 1b) before nitroglycerin injection (inj), and in the 30 minutes following the injection. Systolic blood pressure differed in the 2 groups only at minutes 1 and 2 after nitroglycerin injection (P = 0.047 and P = 0.046, respectively).
group were successfully treated by controlled umbilical cord traction. According to the WHO guidelines for the management of postpartum hemorrhage and retained placenta, in the absence of hemorrhage, 30 minutes may be allowed to pass following the 30 minutes allowed for the cord traction procedure before manual removal of the placenta, as spontaneous expulsion can still occur [4]. If more time had been allowed to pass, these 7 patients may have experienced a spontaneous release of the placenta. Peng et al. [9] reported the successful extraction of retained placentas in 15 patients treated with 500 μg of NTG intravenously. However, only women with a closed cervix were included in their study. DeSimone et al. [8] reported that intravenous doses of 50 to 100 μg of NTG had facilitated the manual extraction of retained placenta in 6 women with a contraction of the uterus around the umbilical cord. Reasons for the low success rate in our study may be that our patients were women scheduled for the immediate manual removal of a retained placenta, most often adherens, and that the adherens type needs to be manually separated from the myometrium even though the uterus and cervix may be fully relaxed. Weeks [15] also reported 81% of placenta adherens in 127 patients with retained placenta. Our results are not in agreement with those of the retrospective descriptive study by Lowenwirt et al. [11], who found that 50 to 200 μg of NTG injected intravenously facilitated placental release in 33 women
Table 2 Success and failure of placenta removal and adverse events in the 2 groups.a Variable
Study group (n = 20)
Placebo group (n = 20)
P value
Successful cord traction Severe hypotensionb Headache Palpitations Dizziness
3 2 1 1 1
4 (20) 2 (10) 0 (0) 1 (5) 1 (5)
0.63 0.96 0.32 0.97 0.97
a b
(15) (10) (5) (5) (5)
Values are given as number (percentage) unless otherwise indicated. Defined as a systolic blood pressure of 80 mm Hg or less.
Fig. 2. Diastolic blood pressure on admission (adm), 2 and 1 minutes before nitroglycerin injection (inj) (2b, 1b), and in the 30 minutes following the injection. Diastolic blood pressure differed significantly in the 2 groups at minutes 1, 2, 3, and 4 after nitroglycerin injection (P = 0.003, P = 0.005, P = 0.011, and P = 0.03, respectively).
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placenta. Because the success rate of cord traction was similar in the 2 groups, controlled cord traction should be tried longer than 30 minutes before the retained placenta is manually removed. Acknowledgments This study was supported by the research development fund of Siriraj Hospital and the Faculty of Medicine of Mahidol University, Thailand. Conflict of interest The authors have no conflicts of interest. References
Fig. 3. Pulse rate on admission (adm), 2 and 1 minutes before nitroglycerin injection (inj) (2b, 1b), and in the 30 minutes following the injection. There were no significant differences in pulse rate between the 2 groups.
with retained placenta; or with those of the prospective descriptive study by Chedraui and Insuasti [7], who successfully used the same doses of NTG in 30 patients with retained placenta; or with those of the small randomized controlled study by Bullarbo et al. [13], who compared the efficiency of 1 mg of NTG taken sublingually with placebo tablets. In that study, all 12 patients in the NTG group were successful delivery of a retained placenta by controlled cord traction, whereas only 1 patient was in the placebo group. However, the causes of retained placenta were not clarified in any of these 3 studies. The difference between the study of Bullarbo et al. [13] and ours is that these investigators used 10 supplemental intravenous units of oxytocin to promote placental separation before administering NTG tablets sublingually and applying controlled cord traction. It is therefore possible that the reason for the incomplete separation of the placenta in some of our patients could not have been corrected by the sole use of NTG. Whether, in addition to the routine dose, a dose of oxytocin injected intravenously before the intravenous or sublingual administration of NTG would help increase the success rate of umbilical cord extraction in women with retained placenta needs further study. The results of the present study do not support using umbilical cord traction following the intravenous administration of NTG for the release of retained placenta. The dilating effect of intravenous NTG on smooth vascular muscle, especially venous, is well known [17] and verified in this study, as blood pressure decreased within 4 minutes of the NTG injection, but NTG did not facilitate the release of retained
[1] Combs CA, Laros RK. Prolonged third stage of labour: Morbidity and risk factors. Obstet Gynecol 1991;77(6):863–7. [2] Dombrowski MP, Bottoms SF, Saleh AA, Hurd WW, Romero R. Third stage of labor: analysis of duration and clinical practice. Am J Obstet Gynecol 1995;172(4pt1): 1279–84. [3] Hawkins JL, Koonin LM, Palmer SK, Gibbs CP. Anesthesia-related deaths during obstetric delivery in the United States, 1979–1990. Anesthesiology 1997;86(2): 277–84. [4] WHO guidelines for the management of postpartum hemorrhage and retained placenta. Geneva: World Health Organization; 2009. [5] Weeks AD, Alia G, Vernon G, Namayanja A, Gosakan R, Majeed T, et al. Umbilical vein oxytocin for the treatment of retained placenta (Release Study): a double-blind, randomized controlled trial. Lancet 2010;375(9709):141–7. [6] Caponas G. Glyceryl trinitrate and acute uterine relaxation: a literature review. Anaesth Intens Care 2001;29(2):163–77. [7] Chedraui PA, Insuasti DF. Intravenous nitroglycerin in the management of retained placenta. Gynecol Obstet Invest 2003;56(2):61–4. [8] DeSimone CA, Norris MC, Leighton BL. Intravenous nitroglycerin aids manual extraction of a retained placenta. Anesthesiology 1990;73(4):787. [9] Peng AT, Gorman RS, Shulman SM, DeMarchis E, Nyunt K, Blancato LS. Intravenous nitroglycerin for uterine relaxation in the postpartum patient with retained placenta. Anesthesiology 1989;71(1):172–3. [10] Axemo P, Fu X, Lindberg B, Ulmsten U, Wessen A. Intravenous nitroglycerin for rapid uterine relaxation. Acta Obstet Gynecol Scand 1998;77(1):50–3. [11] Lowenwirt IP, Zauk RM, Handwerker SM. Safety of intravenous glyceryl trinitrate in management of retained placenta. Aust N Z J Obstet 1997;37(1):20–4. [12] Ekerhovd E, Bullarbo M. Sublingual nitroglycerin seems to be effective in the management of retained placenta. Acta Obstet Gynecol 2008;87(2):222–5. [13] Bullarbo M, Tjugum J, Ekerhovd E. Sublingual nitroglycerin for management of retained placenta. Int J Gynecol Obstet 2005;91(3):228–32. [14] World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. http://www.wma.net/en/30publications/ 10policies/b3/index.html2008. [15] Weeks AD. The retained placenta. Best Pract Res Clin Obstet Gynaecol 2008;22(6): 1103–17. [16] Herman A, Weinraub Z, Bukovsky I, Arieli S, Zabow P, Caspi E, et al. Dynamic ultrasonographic imaging of the third stage of labor: new perspectives into third stage mechanism. Am J Obstet Gynecol 1993;168(5):1496–9. [17] Degoute CS. Controlled hypotension: a guide to drug choice. Drugs 2007;67(7): 1053–76.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Intravenous nitroglycerin for controlled cord traction in the management of retained placenta Shusee Visalyaputra a,⁎, Japarath Prechapanich b, Sukanya Suwanvichai a, Suwimol Yimyam a, Ladda Permpolprasert a, Pattipa Suksopee a a b
Department of Anesthesia, Siriraj Hospital, Mahidol University, Thailand Department of Obstetrics and Gynecology, Siriraj Hospital, Mahidol University, Thailand
a r t i c l e
i n f o
Article history: Received 25 May 2010 Received in revised form 16 August 2010 Accepted 29 October 2010 Keywords: Nitroglycerin Placenta removal Postpartum Retained placenta
a b s t r a c t Objective: To determine the effect of 200 μg of intravenous nitroglycerin in the release of retained placenta by controlled cord traction. Methods: In this randomized controlled study, 40 women with a placenta retained for 30 minutes received intravenously 200 μg of nitroglycerin or a normal saline solution before umbilical cord traction was initiated. The rates of successful removal of the retained placenta in the study (n = 20) and control (n= 20) groups were compared, as were blood pressure, pulse rate, blood loss, and adverse effects. Results: The placenta was released in only 15% and 20% of the participants in the study and control group, respectively. The remainder of the participants required general anesthesia and manual removal of the retained placenta regardless of group assignation. Blood pressure fell in significantly more women in the study group, but there were no differences in estimated blood loss or minor adverse effects. Conclusion: Intravenously administered nitroglycerin did not facilitate the release of retained placenta by umbilical cord traction. However, cord traction may be performed longer than 30 minutes to attempt releasing the placenta before operative manual removal is initiated. © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction With reported incidence rates of 2.0% or 3.3%, retained placenta is not an uncommon occurrence [1,2]. Its manual removal usually necessitates general anesthesia, which provides cervicouterine relaxation as well as analgesia. In 2009, in an effort to avoid the risks of complications arising from general anesthesia, including the risk of aspiration pneumonitis from difficult intubation [3], the WHO published guidelines for the management of postpartum hemorrhage and retained placenta [4]. These guidelines recommend injecting saline-diluted oxytocin into the umbilical vein. However a large, randomized, controlled trial recently reported that the injection had no clinically significant effect on the need to remove retained placenta manually [5]. The most commonly used pharmacologic nitrovasodilator, nitroglycerin (NTG), relaxes smooth muscle cells by releasing nitric oxide, which then stimulates cyclic guanosine monophosphate production and results in smooth muscle relaxation. The myometrium is known to synthesize nitric oxide for its own relaxation [6], and although NTG has been used mostly as a vasodilator in patients with angina pectoris or undergoing a hypertensive crisis, it has also been used in cases of uterine inversion or placental retention [7–13]. A wide majority of the
⁎ Corresponding author. Department of Anesthesia, Siriraj Hospital, Prannok, Bangkoknoi, Bangkok, Thailand 10700. Tel.: + 66 2 419 7990. E-mail address: [email protected] (S. Visalyaputra).
studies of the use of NTG for the release of retained placenta have been descriptive [7–9] or retrospective [10–12]. Only one was a randomized controlled trial of 1 mg of NTG administered sublingually in 24 women with retained placenta [13]. The present randomized controlled trial was conducted at Siriraj Hospital, a tertiary care center affiliated with the medical school of Mahidol University, Bangkok, Thailand. Its objective was to determine whether 200 μg of NTG, administered intravenously in 2 doses of 100 μg to prevent severe drug-induced hypotension, is more helpful than placebo when controlled traction is applied on the cord to release a retained placenta. 2. Materials and methods Since women with a retained placenta are in an emergency situation, obtaining written consent from them would be inappropriate and inadvisable. According to Guideline 29 of the 2008 revision of the Declaration of Helsinki regarding clinical trials, physicians may proceed without written consent in an emergency situation if this has been previously approved by a competent research ethics committee (the participant's consent to remain in the study should be obtained as soon as possible, however) [14]. The Ethics Committee of Siriraj Hospital approved our protocol, which stipulated that the informed verbal consent of conscious participants would be sufficient in emergency situations. The different types of retained placenta are associated with different clinical signs. A small and contracted fundus and a tight cervical os are
0020-7292/$ – see front matter © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2010.08.021
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signs of a trapped placenta, for example, and a soft and wide fundus suggests a placenta adherens [15]. However, these signs can be difficult to recognize and exploration by ultrasound has been suggested [16]. Since ultrasound is not used at our hospital to differentiate between types of retained placenta, we decided to recruit only women who had been diagnosed as having a retained placenta. The latter was defined as a placenta not delivered within 30 minutes after fetal delivery. The eligibility criteria were a singleton pregnancy with no cardiac, pulmonary, or other form of disease requiring treatment and a placenta retained for 30 minutes or longer following the vaginal delivery of the fetus. The exclusion criteria were pre-eclampsia, a gynecologic infection, a uterine scar, placenta accreta, a gestation less than 28 weeks, hypotension (defined as a systolic blood pressure b100 mmHg and a pulse rate N100 bpm), and umbilical cord disruption. Immediately following delivery of the fetus, in accordance with the routine management of vaginal delivery at Siriraj Hospital, 10 U of oxytocin in 1000 mL of 0.45% saline solution with 5% dextrose was administered intravenously to promote uterine contraction, at rates of 200–300 mL in the first few minutes and then of 100 mL/hour. If there were no signs of placental separation after 15 or 20 minutes, 5 more units of oxytocin were infused intravenously. If these 5 supplemental units did not provoke placental delivery, a Kelly clamp was attached to the cord as a visual way to indicate whether the placenta was being released, and controlled traction was applied to the umbilical cord (with countertraction applied to the uterine fundus to prevent uterine inversion). If the placenta was still retained 30 minutes after fetal delivery, an anesthesia team was called and manual removal was performed in the operating room. Once a diagnosis of retained placenta was made, 500 mL of a crystalloid solution was injected intravenously and pulse oximetry, an electrocardiogram, and noninvasive blood pressure monitoring were initiated. The women were approached at this time if they met the eligibility criteria. If they accepted, they were enrolled in the trial. Using the Research Randomizer program (made freely available by the Social Psychology Network at http://www.Randomizer.org), 40 successive eligible women with a retained placenta were randomized to a study or control group by the block-of-4 method, and their group assignation was enclosed in a numbered envelope. Those assigned to the study group received 200 μg of NTG intravenously, 100 μg at a time, in an amount of a normal saline solution (NSS) sufficient to fill a 10-mL syringe. Those assigned to the control group received 10 mL of NSS, also in 10-mL syringes. A nurse who did not participate in the remainder of the study opened the envelopes as needed and filled the syringes with the appropriate solutions outside the operating room. Neither the investigators who gave the injections and managed the participants’ blood pressure, nor the obstetricians who performed controlled cord traction, nor the study participants were aware of the syringe content. Before NTG or NSS was administered and cord traction initiated, 50 to 100 μg of fentanyl citrate (Fentanyl; Janssen-Cilag, Bangkok, Thailand) was given to all participants for analgesia and norepinephrine bitartrate (Levophed; Hospira, IL, USA) was administered intravenously to those with hypotension. This drug, which is supplied in 4-mL vials containing 4-mg doses (for a concentration, therefore, of 1 mg [or 1000 μg/mL]), was further diluted to 4 μg/mL in a 10-mL syringe. In the treatment group, the NTG used (David Bull Laboratories, Victoria, Australia) was supplied in 5-mL vials containing 25-mg doses in a solution. To achieve a concentration of 50 μg/mL, 1 mL (i.e. 5000 μg) of the vial solution was diluted in 9 mL of NSS to fill 10-mL syringes (to get 500 μg/mL). Then, 1 mL (500 μg) of the solution thus obtained was further diluted with 9 mL of NSS in another 10-mL syringe to get 50 μg/mL. The average time for NTG to take effect is 80 seconds [9]. Therefore, 80 seconds after the first 100 μg of NTG (or 2 mL of the solution) was injected, the obstetrician began to gently pull on the cord. If the placenta was not released within 1 minute and the participant was not in a state of hypotension, a second 100-μg
bolus from the same syringe was injected and cord traction was resumed for no longer than 2 more minutes. If the placenta was not released after 3 minutes of controlled cord traction, the procedure was considered to have failed. Oxytocin or ergometrine was administered to the participants in whom the procedure succeeded. The vital signs were recorded before the first NTG bolus and thereafter at 1-minute intervals for 5 minutes, at 2-minute intervals for 20 minutes, and then every 5 minutes for 30 minutes. Blood loss was evaluated by a nurse in the labor room after fetal delivery but prior to NTG administration, and also by the obstetricians in the operating room after manual placenta removal. The participants in whom the placenta could not be released after 3 minutes of controlled cord traction underwent general anesthesia and manual removal of the placenta. In a previous randomized study with 12 women, only 1 woman (about 10%) had her placenta successfully delivered by controlled cord traction [13]. Based on an expected difference in success rate of at least 50% (60% vs. 10%), we calculated that 20 participants per group were needed for a 2-sided type 1 error of 0.01 and 80% power. Statistical analyses were performed using SPSS software, version13.5 (SPSS, Chicago, IL, USA). Values are given as mean ± SD or number and percentage. The χ2 test or the Fisher exact test, as appropriate, was used to test differences in qualitative variables between the 2 groups. Because of unequal correlations among the repeated measurements, between-group comparisons of hemodynamic values observed 1, 2, 3, 4, 5, 7, and 9 minutes after initiation of the NTG treatment were performed using a linear mixed model with random intercept and slope. The number of minutes since treatment initiation was the independent variable. This model resulted in a linear regression equation for each group. P b 0.05 was considered statistically significant.
3. Results From January 1, 2008, to June 30, 2009, 47 women were to undergo manual removal of the placenta under general anesthesia. Of these, 5 were not approached because obstetricians had already applied controlled cord traction, 2 opted for immediate anesthesia and placenta removal, and the remaining 40 were recruited. The first traction caused cord disruption in 1 participant in each group, and the event was considered a failed outcome. One patient in the study group became severely hypotensive after the first 100-μg dose of NTG, with a systolic blood pressure of 70 mmHg, owing to uterine atony and massive hemorrhage. This event was considered a failed outcome. After the patient was treated with the rapid infusion of a crystalloid solution to prevent hypovolemic shock, followed by 26 μg of norepinephrine plus 0.2 mg of methylergometrine to increase blood pressure, she received 1 unit of packed red blood cells. The fourth failed outcome occurred in the placebo group, also because of hypotension from massive hemorrhage, in a woman who received 8 μg of norepinephrine and 2 units of blood. There were no significant differences between the 2 groups in demographic characteristics, estimated blood loss, amount of intravenous fluid used, or postoperative hematocrit values (Table 1); in success rates of placental removal by controlled umbilical cord traction; or in occurrence of adverse effects (Table 2). Only 3 participants (15%) in the study group and 4 participants (20%) in the placebo group underwent the controlled cord traction procedure successfully. The type of retained placenta was diagnosed by tactile judgment during manual removal in the remaining 33 participants. There were 6 women (18%), 3 in each group, with a trapped placenta and 27 women (82%), 14 in the study group and 13 in the placebo group, with a placenta adherens. In the study group, 3 women with a placenta adherens needed a second procedure because placental parts were incompletely removed during the first. One of these participants eventually underwent uterine curettage.
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Table 1 Patient characteristics, estimated blood loss, volume of intravenous fluid and dose of fentanyl used, and postoperative hematocrit in the 2 groups.a Variable
Study group (n = 20)
Placebo group (n = 20)
P value
Age, y Weight, kg Height (cm.) No. of abortions Gestational age, wk EBL before NTG or NSS injection, mL EBL after NTG or NSS injection, mL Volume of fluid infused before NTG or NSS injection, mL Volume of fluid infused after NTG or NSS injection, mL Fentanyl used, mg Postoperative hematocrit, %
28.4 ± 5.9 68.5 ± 11.2 157.1 ± 6.3 10 38.4 ± 2.1 217.5 ± 107.5 263.9 ± 178.9 528.9 ± 221.9
28.0 ± 6.2 66.6 ± 12.1 159.7 ± 6.1 5 37.5 ± 2.5 176.3 ± 87.2 230.6 ± 225.7 524.2 ± 276.8
0.85 0.61 0.19 0.19 0.45 0.20 0.63 0.95
788.9 ± 531.2
652.8 ± 394.9
0.39
45.0 ± 26.4 31.7 ± 4.7
47.4 ± 18.4 30.1 ± 4.6
0.75 0.29
Abbreviations: EBL, estimated blood loss; NSS, normal saline solution; NTG, nitroglycerin. a Values are given as mean ± SD unless otherwise indicated.
The blood pressure values noted 1, 2, 3, 4, 5, 7, and 9 minutes after initiation of the NTG treatment differed between the groups only at 1, 2, and 3 minutes. Systolic blood pressure differed at minutes 1 and 2 (P = 0.047 and P = 0.046, respectively) (Fig. 1) and diastolic blood pressure differed at minutes 1, 2, 3, and 4 (P = 0.003, P = 0.005, P = 0.01, and P = 0.03, respectively) (Fig. 2). However, there were no differences in pulse rates between the groups in the 10 minutes following treatment initiation (Fig. 3). 4. Discussion With success rates of 15% in the study group and 20% in the control group, 200 μg of NTG administered intravenously was ineffective in facilitating the release of a retained placenta. On the other hand, a significant drop in both systolic and diastolic blood pressure first occurred in the study group. We opted for 200 μg of NTG because, with 1 exception, it is the highest dose (the lowest being 50 μg) that has been successfully used in previous studies on the release of retained placentas [7,8,10,11]. In a 1989 study, Peng et al. [9] administered 500 μg of NTG intravenously in 15 women with a trapped placenta. We thought that a dose higher than 200 μg would increase the risk of severe hypotension in women with some degree of hypovolemia. The 3 main causes of retained placenta are placenta adherens (81%), trapped placenta (13%), and partial placenta accreta (6%) [15]. Placenta adherens occurs when contractions in the retroplacental myometrium are insufficient to completely release the placenta; a completely separated placenta becomes trapped in the presence of a constriction ring in the uterus or a closed cervix prevents its expulsion; and a partial placenta accreta occurs when a small area of the placenta remains firmly attached to the myometrium [15]. In our study, 6 women (18%) with a closed cervix required manual removal of the placenta, perhaps because they had both a closed cervix and some degree of placenta adherens. However, 3 women in the study group and 4 women in the placebo
Fig. 1. Sytolic blood pressure on admission (adm), 2 and 1 minutes (2b, 1b) before nitroglycerin injection (inj), and in the 30 minutes following the injection. Systolic blood pressure differed in the 2 groups only at minutes 1 and 2 after nitroglycerin injection (P = 0.047 and P = 0.046, respectively).
group were successfully treated by controlled umbilical cord traction. According to the WHO guidelines for the management of postpartum hemorrhage and retained placenta, in the absence of hemorrhage, 30 minutes may be allowed to pass following the 30 minutes allowed for the cord traction procedure before manual removal of the placenta, as spontaneous expulsion can still occur [4]. If more time had been allowed to pass, these 7 patients may have experienced a spontaneous release of the placenta. Peng et al. [9] reported the successful extraction of retained placentas in 15 patients treated with 500 μg of NTG intravenously. However, only women with a closed cervix were included in their study. DeSimone et al. [8] reported that intravenous doses of 50 to 100 μg of NTG had facilitated the manual extraction of retained placenta in 6 women with a contraction of the uterus around the umbilical cord. Reasons for the low success rate in our study may be that our patients were women scheduled for the immediate manual removal of a retained placenta, most often adherens, and that the adherens type needs to be manually separated from the myometrium even though the uterus and cervix may be fully relaxed. Weeks [15] also reported 81% of placenta adherens in 127 patients with retained placenta. Our results are not in agreement with those of the retrospective descriptive study by Lowenwirt et al. [11], who found that 50 to 200 μg of NTG injected intravenously facilitated placental release in 33 women
Table 2 Success and failure of placenta removal and adverse events in the 2 groups.a Variable
Study group (n = 20)
Placebo group (n = 20)
P value
Successful cord traction Severe hypotensionb Headache Palpitations Dizziness
3 2 1 1 1
4 (20) 2 (10) 0 (0) 1 (5) 1 (5)
0.63 0.96 0.32 0.97 0.97
a b
(15) (10) (5) (5) (5)
Values are given as number (percentage) unless otherwise indicated. Defined as a systolic blood pressure of 80 mm Hg or less.
Fig. 2. Diastolic blood pressure on admission (adm), 2 and 1 minutes before nitroglycerin injection (inj) (2b, 1b), and in the 30 minutes following the injection. Diastolic blood pressure differed significantly in the 2 groups at minutes 1, 2, 3, and 4 after nitroglycerin injection (P = 0.003, P = 0.005, P = 0.011, and P = 0.03, respectively).
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placenta. Because the success rate of cord traction was similar in the 2 groups, controlled cord traction should be tried longer than 30 minutes before the retained placenta is manually removed. Acknowledgments This study was supported by the research development fund of Siriraj Hospital and the Faculty of Medicine of Mahidol University, Thailand. Conflict of interest The authors have no conflicts of interest. References
Fig. 3. Pulse rate on admission (adm), 2 and 1 minutes before nitroglycerin injection (inj) (2b, 1b), and in the 30 minutes following the injection. There were no significant differences in pulse rate between the 2 groups.
with retained placenta; or with those of the prospective descriptive study by Chedraui and Insuasti [7], who successfully used the same doses of NTG in 30 patients with retained placenta; or with those of the small randomized controlled study by Bullarbo et al. [13], who compared the efficiency of 1 mg of NTG taken sublingually with placebo tablets. In that study, all 12 patients in the NTG group were successful delivery of a retained placenta by controlled cord traction, whereas only 1 patient was in the placebo group. However, the causes of retained placenta were not clarified in any of these 3 studies. The difference between the study of Bullarbo et al. [13] and ours is that these investigators used 10 supplemental intravenous units of oxytocin to promote placental separation before administering NTG tablets sublingually and applying controlled cord traction. It is therefore possible that the reason for the incomplete separation of the placenta in some of our patients could not have been corrected by the sole use of NTG. Whether, in addition to the routine dose, a dose of oxytocin injected intravenously before the intravenous or sublingual administration of NTG would help increase the success rate of umbilical cord extraction in women with retained placenta needs further study. The results of the present study do not support using umbilical cord traction following the intravenous administration of NTG for the release of retained placenta. The dilating effect of intravenous NTG on smooth vascular muscle, especially venous, is well known [17] and verified in this study, as blood pressure decreased within 4 minutes of the NTG injection, but NTG did not facilitate the release of retained
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