Carbetocin vs. oxytocin at elective caesarean delivery: a double-blind, randomised, controlled, non-inferiority trial of low- and high-dose regimens.

Carbetocin or oxytocin are given routinely as first-line uterotonic drugs following delivery of the neonate during caesarean delivery to prevent postpartum haemorrhage. Low doses may be as effective as high doses with a potential reduction in adverse effects. In this double-blind, randomised, controlled, non-inferiority trial, we assigned low-risk patients undergoing elective caesarean delivery under spinal anaesthesia to one of four groups: carbetocin 20 µg; carbetocin 100 µg; oxytocin 0.5 IU bolus + infusion; and oxytocin 5 IU bolus + infusion. The study drug was given intravenously after delivery of the neonate. Uterine tone was assessed by the obstetrician 2, 5 and 10 minutes after study drug administration according to an 11-point verbal numerical rating scale (0 = atonic, 10 = excellent tone). The primary outcome measure was uterine tone 2 min after study drug administration. The pre-specified non-inferiority margin was 1.2 points on the 11-point scale. Secondary outcomes included uterine tone after 5 and 10 minutes, use of additional uterotonics, blood loss and adverse effects. Data were available for 277 patients. Carbetocin 20 µg resulting in uterine tone of (median (IQR [range])) 8 (7-8 [1-10]) was non-inferior to carbetocin 100 µg with tone 8 (7-9 [3-10]), median (95%CI) difference 0 (-0.44-0.44). Similarly, oxytocin 0.5 IU with tone 7 (6-8 [3-10]) was non-inferior to oxytocin 5 IU with tone 8 (6-8 [2-10]), median (95%CI) difference 1 (0.11-1.89). Carbetocin 20 µg was also non-inferior to oxytocin 5 IU, and oxytocin 0.5 IU was non-inferior to carbetocin 100 µg. Uterine tone after 5 and 10 minutes, use of additional uterotonics, blood loss and adverse effects were similar in all groups.

Oxytocin at elective caesarean delivery: a dose-finding study in women with obesity.

Prophylactic oxytocin administration at the third stage of labour reduces blood loss and the need for additional uterotonic drugs. Obesity is known to be associated with an increased risk of uterine atony and postpartum haemorrhage. It is unknown whether women with obesity require higher doses of oxytocin in order to achieve adequate uterine tone after delivery. The purpose of this study was to establish the bolus dose of oxytocin required to initiate effective uterine contraction in 90% of women with obesity (the ED90 ) at elective caesarean delivery. We conducted a double-blind dose-finding study using the biased coin up-down design method. Term pregnant women with a BMI ≥ 40 kg.m-2 undergoing elective caesarean delivery under regional anaesthesia were included. Those with conditions predisposing to postpartum haemorrhage were not included. Oxytocin was administered as an intravenous bolus over 1 minute upon delivery of the fetus. With the first woman receiving 0.5 IU, oxytocin doses were administered according to a sequential allocation scheme. The primary outcome measure was satisfactory uterine tone, as assessed by the operating obstetrician 2 minutes after administration of the oxytocin bolus. Secondary outcomes included the need for rescue uterotonic drugs, adverse effects and estimated blood loss. We studied 30 women with a mean (SD) BMI of 52.3 (7.6) kg.m-2 . The ED90 for oxytocin was 0.75 IU (95%CI 0.5-0.93 IU) by isotonic regression and 0.78 IU (95%CI 0.68-0.88 IU) by the Dixon and Mood method. Our results suggest that women with a BMI ≥ 40 kg.m-2 require approximately twice as much oxytocin as those with a BMI < 40 kg.m-2 , in whom an ED90 of 0.35 IU (95%CI 0.15-0.52 IU) has previously been demonstrated.

Carbetocin at elective caesarean section: a sequential allocation trial to determine the minimum effective dose in obese women.

Postpartum haemorrhage is a leading cause of maternal death during childbirth. There is an increasing incidence of atonic postpartum haemorrhage in developed countries, and maternal obesity has been proposed as a contributing factor. The dose-response relationship of carbetocin in obese women has not yet been determined. We conducted a double-blind, dose-finding study of carbetocin using a biased coin up-and-down design in women with a body mass index ≥ 40 kg.m-2 undergoing elective caesarean section. The determinant for a successful response was satisfactory uterine tone, with no intra-operative need for additional uterotonic drugs. Secondary outcomes included the use of additional uterotonic drugs postoperatively, estimated blood loss and adverse effects of carbetocin administration. Thirty women were recruited to the study. The median (IQR [range]) body mass index was 44.93 (41.5-55.2 [40-66.5]) kg.m-2 . The ED90 of carbetocin was estimated as 62.9 (95%CI 57.0-68.7) µg using the truncated Dixon and Mood method, and 68 (95%CI 52-77) µg using the isotonic regression method. The estimated blood loss was 880 (621-1178 [75-2442]) ml. The overall rates of hypotension and hypertension after delivery were 40% and 6.7%, respectively, while nausea occurred in 26.7% of women. The ED90 for carbetocin in obese women at elective caesarean section is lower than the dose of 100 µg currently recommended by the Society of Obstetricians and Gynaecologists of Canada, but is approximately four times higher than the previously demonstrated ED90 of 14.8 µg in women with body mass index < 40 kg.m-2 .

Uterotonics in elective caesarean delivery: a randomised non-inferiority study comparing carbetocin 20 µg and 100 µg.

Postpartum haemorrhage is the leading cause of maternal mortality worldwide and prophylactic uterotonic drug administration after the delivery of the infant is advised. Carbetocin is recommended as an uterotonic, but the minimum effective dose has not been verified. We compared the efficacy of two doses of intravenous carbetocin (20 µg and 100 µg) in women undergoing elective caesarean delivery. This was a randomised, double-blind, non-inferiority study in women at low risk of postpartum haemorrhage. Carbetocin was administered on delivery of the anterior shoulder of the neonate. Uterine tone was assessed by the obstetrician 2 min and 5 min after carbetocin administration according to an 11-point numerical rating scale (0 = atonic uterus and 10 = firm uterus). The primary outcome was uterine tone 2 min after carbetocin administration. The pre-specified non-inferiority margin was 1 point on the 11-point scale. Secondary outcomes included: uterine tone at 5 min; use of additional uterotonics within 24 h; blood loss; and adverse effects. Data were available for 53 women in the carbetocin-20 group and for 55 women in the carbetocin-100 group. The mean (SD) uterine tone at 2 min was 7.5 (1.9) in the carbetocin-20 group and 8.0 (1.5) in the carbetocin-100 group. The lower limit of the one-sided 95%CI for the mean difference was outside the non-inferiority margin (at -1.1; p = 0.11) meaning non-inferiority of carbetocin 20 µg compared with carbetocin 100 µg could not be confirmed. However, the secondary outcome measures of uterine tone at 5 min, blood loss and use of additional uterotonics were similar in both groups.

Refractory uterine atony: still a problem after all these years.

Postpartum hemorrhage is a leading cause of maternal morbidity and mortality, and uterine atony is the leading cause of postpartum hemorrhage. Risk factors for uterine atony include induced or augmented labor, preeclampsia, chorio-amnionitis, obesity, multiple gestation, polyhydramnios, and prolonged second stage of labor. Although a risk assessment is recommended for all parturients, many women with uterine atony do not have risk factors, making uterine atony difficult to predict. Oxytocin is the first-line drug for prevention and treatment of uterine atony. It is a routine component of the active management of the third stage of labor. An oxytocin bolus dose as low as 1 IU is sufficient to produce satisfactory uterine tone in almost all women undergoing elective cesarean delivery. However, a higher bolus dose (3 IU) or infusion rate is recommended for women undergoing intrapartum cesarean delivery. Carbetocin, available in many countries, is a synthetic oxytocin analog with a longer duration than oxytocin that allows bolus administration without an infusion. Second line uterotonic agents include ergot alkaloids (ergometrine and methylergonovine) and the prostaglandins, carboprost and misoprostol. These drugs work by a different mechanism to oxytocin and should be administered early for uterine atony refractory to oxytocin. Rigorous studies are lacking, but methylergonovine and carboprost are likely superior to misoprostol. Currently, the choice of second-line agent should be based on their adverse effect profile and patient comorbidities. Surgical and radiologic management of uterine atony includes uterine tamponade using balloon catheters and compression sutures, and percutaneous transcatheter arterial embolization.

The association of shock index and haemoglobin variation with postpartum haemorrhage after vaginal delivery: a prospective cohort pilot study.

INTRODUCTION: Shock index and continuous non-invasive haemoglobin monitoring (SpHb) have both been proposed for the timely recognition of postpartum haemorrhage (PPH). We sought to determine, in parallel, the association of each of shock index and SpHb with blood loss after vaginal delivery. METHODS: Sixty-six women were recruited to this prospective observational study. Shock index and SpHb were recorded postpartum for 120 min. The association between each of shock index and SpHb with quantitative blood loss (QBL) at 30, 60 and 120 min postpartum was determined using linear mixed models. Area-under-the-receiver-operator-characteristic (AUROC) curves were constructed to evaluate the diagnostic ability of shock index and SpHb to detect PPH (defined as QBL ≥1000 mL). RESULTS: Shock index trend was associated with QBL over the first 30 min (r=0.37, P=0.002), but not over 60 or 120 min. There was an association of SpHb trend with QBL over the first 30 min (P=0.06), but not over 60 min (r=-0.32, P=0.009) or 120 min (r=-0.26, P=0.03). Maximum shock index within 60 min correlated with QBL (r=0.54, P <0.001) and was a predictor of PPH (P=0.0012, AUROC 0.796). Maximum change in SpHb within 60 min negatively correlated with QBL (r=-0.4, P <0.001) and was a predictor of PPH (P=0.048, AUROC 0.761). CONCLUSIONS: The trend of shock index and its peak values are associated with blood loss after vaginal delivery and are early indicators of PPH. Negative trend of SpHb is a late sign of PPH and has a weaker association with blood loss than shock index.

Anesthetic management of women with heart failure during pregnancy: a retrospective cohort study.

BACKGROUND: The incidence of heart failure among pregnant women with pre-existing cardiac disease is quoted as 13%, with 10% requiring hospitalization. There is limited literature on heart failure in the pregnant population. The study objective was to describe the etiology and management of women hospitalized in our institution for heart failure during pregnancy. METHODS: A retrospective cohort study investigated women who presented with heart failure in pregnancy between 2004 and 2017. Hospital records were interrogated using International Classification of Diseases v10 codes for heart failure. Patient characteristics, investigations, treatment, obstetric and anesthetic management, and maternal-fetal outcome data were collected and summarized using descriptive statistics. RESULTS: One-hundred-and-twenty cases (in 93 122 deliveries) were identified across the 13-year period (antepartum heart failure 51%, postpartum heart failure 49%).The most common etiologies were pre-eclampsia (28%), cardiomyopathy (22%), and valvular heart disease (18%). Cesarean delivery occurred in 76% of cases (13% because of the maternal cardiac condition). Neuraxial techniques were used for most deliveries (cesarean 83%; vaginal 90%). For cesarean delivery, titrated epidural or general anesthesia was employed in 48% and 16%, respectively. Cardiac arrest occurred in two cases (1.7%) and 44% required coronary or intensive care unit admission. CONCLUSIONS: The incidence of heart failure was 0.13% (1:776 deliveries). Pre-eclampsia was the leading cause but may have been historically under-acknowledged. Anesthetic and obstetrical decisions were tailored by means of multidisciplinary input, with cesarean delivery and regional anesthesia used in the majority. The postpartum period warrants heightened attention for these patients.

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

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.

Oxytocin-ergometrine co-administration does not reduce blood loss at caesarean delivery for labour arrest.

OBJECTIVE: To determine if intravenous infusion of a combination of oxytocin and ergometrine maleate is better than oxytocin alone to decrease blood loss at caesarean delivery for labour arrest. DESIGN: Prospective, double-blinded, randomised controlled trial. SETTING: Mount Sinai Hospital, Toronto, Canada. POPULATION: Women undergoing caesarean deliveries for labour arrest. METHODS: Forty-eight women were randomised to receive infusion of either ergometrine maleate 0.25 mg + oxytocin 20 iu or oxytocin 20 iu alone, diluted in 1 l of lactated Ringer's Solution, immediately after delivery of the infant. Unsatisfactory uterine contractions after delivery were treated with additional boluses of the study solution or rescue carboprost. Blood loss was estimated based on the haematocrit values before and 48 hours after delivery. MAIN OUTCOME MEASURES: The primary outcome was the estimated blood loss, while the secondary outcomes included the use of additional uterotonics, need for blood transfusion and the incidence of adverse effects. RESULTS: The estimated blood loss was similar in the oxytocin-ergometrine and oxytocin-only groups; 1218 +/- 716 ml and 1299 +/- 774 ml, respectively (P = 0.72). Significantly fewer women required additional boluses of the study drug in the oxytocin-ergometrine group (21 and 57%; P = 0.01). Nausea (42 and 9%; P = 0.01) and vomiting (25 and 4%; P = 0.05) were significantly more prevalent in the oxytocin-ergometrine group. CONCLUSIONS: In women undergoing caesarean delivery for labour arrest, the co-administration of ergometrine with oxytocin does not reduce intraoperative blood loss, despite apparently superior uterine contraction.

Status epilepticus after electroconvulsive therapy in a pregnant patient.

Status epilepticus after electroconvulsive therapy is a rare complication, and its occurrence during pregnancy has not been reported previously. We discuss the case of a 31-year-old primigravida at 22 weeks of gestation, with a history of bipolar disorder, who underwent electroconvulsive therapy under general anesthesia. Following three treatments she developed status epilepticus, requiring large doses of benzodiazepines, thiopental, propofol and diphenylhydantoin to control the seizure activity. She remained intubated and ventilated for several days after treatment with a complicated course. As a consequence, the fetus died. We discuss the possible causes and the management of status epilepticus after electroconvulsive therapy during pregnancy and its implications for maternal and fetal outcome.

Intraoperative nausea and vomiting during cesarean section under regional anesthesia.

Nausea and vomiting during regional anesthesia for cesarean section are very common and unpleasant events. They cause significant distress to the patient and also interfere with the surgical procedure. They have multiple etiologies, which include hypotension, vagal hyperactivity, visceral pain, i.v. opioid supplementation, uterotonic agents and motion. The obstetric anesthesia literature has addressed these causative factors for nausea and vomiting individually, making it difficult for the anesthesiologists to have a comprehensive understanding of these important complications. This review highlights the anesthetic and non-anesthetic causes of intraoperative nausea and vomiting during regional anesthesia for cesarean section and the appropriate prophylactic and therapeutic management. Intraoperative nausea and vomiting can be best prevented by controlling hypotension, optimizing the use of neuraxial and i.v. opioids, improving the quality of block, minimizing surgical stimuli and judicious administration of uterotonic agents. Although prophylactic antiemetics have been advocated during cesarean sections, strict adherence to these practices can effectively lower the incidence of intraoperative nausea and vomiting without the requirement of antiemetic agents. Antiemetics, therefore, should be reserved for the prevention of intraoperative nausea and vomiting in high-risk patients and for the treatment of nausea and vomiting not responding to routine measures.

Peripartum cardiomyopathy: postpartum decompensation and use of non-invasive cardiac output monitoring.

The utility of a non-invasive cardiac output monitor (NICOM™) in guiding the peripartum management and identification of postpartum complications in a patient with severe peripartum cardiomyopathy is reported. A 31-year-old nulliparous woman at 35 weeks of gestation presented with a three-week history of worsening dyspnea and progressive functional deterioration. A transthoracic echocardiogram showed severe left ventricular systolic dysfunction with an ejection fraction <20%. Cardiac status was monitored using NICOM™ during labor and delivery. The baseline values were: cardiac output 5.3 L/min, total peripheral resistance 1549 dynes.sec/cm(5), stroke volume 42.1 mL and stroke volume variation 18%. She received early epidural analgesia during labor, titrated slowly with a loading dose of 0.0625% bupivacaine 10 mL and fentanyl 25 µg, followed by patient-controlled epidural analgesia (0.0625% bupivacaine with fentanyl 2 µg/mL, infusion at 10 mL/h, bolus dose 5 mL and lockout interval 10 min). After epidural drug administration, total peripheral resistance decreased, cardiac output increased, and satisfactory analgesia was obtained. She had an uneventful vaginal delivery with a forceps-assisted second stage after prophylactic administration of furosemide 20 mg. NICOM™ was discontinued after delivery. Fifteen hours post-delivery, the patient developed cardiogenic shock, which resolved after aggressive therapy with inotropes and furosemide. NICOM™ can be used to guide treatment during labor and delivery in patients with critical peripartum cardiomyopathy. We suggest that use of NICOM™ be extended into the postpartum period to detect signs of cardiac decompensation in such patients.

Standardised training program in spinal ultrasound for epidural insertion: protocol driven versus non-protocol driven teaching approach.

Spinal ultrasonography provides guidance for epidural insertion in obstetric patients. The primary objective of the study was to develop a training program in spinal ultrasound for anaesthetists and to determine its effect on the skill acquisition of anaesthetists with no prior spinal ultrasound experience. Eighteen anaesthetists underwent two structured workshops (one week apart), each followed by a practice session and videorecorded assessments. Participants were randomised to a protocol-driven or non-protocol driven spinal ultrasound teaching program. Two experts rated each individual's performance using a global rating scale (GRS), checklist and image quality scale. The primary outcome was the mean difference in GRS score between the two workshops, analysed using linear mixed models. Intraclass correlation coefficients were calculated to assess agreement between assessors' ratings. A total of 108 ultrasound scans were performed on five pregnant volunteers during the assessment periods. After adjusting for confounders, GRS scores increased on all three rating scales at the second workshop, this increase being 6.01 points (95% confidence interval 4.56 to 7.46, P<0.001) from a mean score of 28.4 (95% confidence interval 24.8 to 32.0). There was no significant difference in the scores between the two teaching groups (difference in GRS scores=1.36 points, 95% confidence interval -0.77 to 3.50, P=0.211). Intraclass correlation coefficients showed substantial assessor agreement for all three assessment methods (range 0.59 to 0.89). The results demonstrate that programmed spinal ultrasound training sessions involving practice with guidance and feedback from an expert, whether protocol-based or non-protocol based, lead to improved performance.

Breastfeeding success rate after vaginal delivery can be high despite the use of epidural fentanyl: an observational cohort study.

BACKGROUND: Epidural labor analgesia inclusive of high-dose fentanyl has been thought to affect breastfeeding in multiparous patients. In our experience, this effect is not as significant as quoted in the literature. This study was designed to evaluate breastfeeding success in women receiving epidural analgesia with fentanyl-containing solutions at our institution. METHODS: Term multiparous women who received epidural analgesia for labor, had previously breastfed, and who intended to breastfeed, were recruited. Baseline demographics, as well as detailed epidural, obstetric and neonatal data, were collected. Epidural analgesia was achieved with a mixture of bupivacaine and fentanyl. Subjects were telephoned both 1 and 6 weeks after delivery, and a breastfeeding questionnaire was completed. Our primary outcome was breastfeeding cessation at 6 weeks. RESULTS: One hundred and five women were recruited, with 18 exclusions. The median cumulative epidural fentanyl dose was 151.4 microg (30-570 microg). No neonates developed complications attributable to labor analgesia. Four women stopped breastfeeding because of issues related to the baby (4.6%); only one of them received a fentanyl dose >150 microg. The breastfeeding success rate was therefore >95%. The women had a median maternity leave of 12 months, and 69% received post-partum lactation support. CONCLUSIONS: The incidence of successful breastfeeding in multiparous women who undergo vaginal delivery with epidural analgesia inclusive of fentanyl is much greater at our institution than previously reported in the literature. This may be due to favorable conditions such as time off work and post-natal support.

ED95 of phenylephrine to prevent spinal-induced hypotension and/or nausea at elective cesarean delivery.

BACKGROUND: The purpose of this trial was to determine the 95% effective dose (ED95) of phenylephrine by intermittent i.v. bolus, to prevent spinal-induced hypotension and/or nausea at elective cesarean delivery. METHODS: The study was conducted in a double-blinded fashion in 50 patients undergoing elective cesarean delivery under spinal anesthesia. The dose of phenylephrine was determined using up-down sequential allocation, modified by a variation of the Narayana rule. Systolic pressure and heart rate were assessed every minute until uterine incision. The first patient was assigned a 40-microg dose, and the dose to subsequent patients varied by 10-microg increments or decrements. An adequate response was defined as absence of hypotension (systolic pressure <80% of baseline) and nausea. The study solution was given immediately after spinal administration, without prior pressure measurement, and thereafter when the systolic pressure was 120% of baseline) was observed in 14 cases, immediately after intrathecal injection and prophylactic phenylephrine administration in all cases. CONCLUSION: The ED95 of phenylephrine, administered as intermittent boluses to prevent pre-delivery spinal-induced hypotension and/or nausea at elective cesarean delivery, is at least 122 microg (lower limit of the confidence interval). The safety of this dose warrants further studies.