Carbetocin versus combination of oxytocin and ergometirne for the preventional of post-partum hemorrhage following cesarean section

INTRODUCTION

Excessive bleeding after or after delivery, known as (PPH), is a potentially dangerous condition that is one of the major reasons of maternal death and morbidity across the world. Due to irreparable shock, maternal death frequently happens within a short amount of time. As a result, avoiding PPH is crucial to improving women's health care ^{1, 2.}

The usage of an uterotonic drug, early cord clamping, and controlled cord traction are 3 parts of active controlling of the third stage of labor. Nowadays, oxytocin and ergometrine are the most often utilized pharmacologic drugs. When compared to oxytocin only, syntometrine (a mix of oxytocin and ergometrine) is related with a notably important decrease in the rate of PPH for blood losing greater than 500 mL but less than 1000 ml. ³

The unwanted side impacts of nausea, vomiting, and increased blood pressure in previously normotensive women have been widely reported as being significantly greater in syntometrine recipients. In the third stage of labor, prophylactic use of ergot alkaloids is useful in lowering blood loss and PPH. ^{3, 4}

Syntometrine was also linked to a greater rate of retained placenta when compared to oxytocin, according to some investigators. Syntometrine, furthermore, has been linked to serious side effects such coronary artery spasm and intracerebral hemorrhage. ^{5, 6}

Furthermore, syntometrine cannot be used in 10percent to 20percent of the obstetric community due to co-existing medical diseases like as pre-eclampsia and cardiac problem. Following that, the women are given oxytocin, as it is less efficient in preventing PPH due to its brief onset of action. Prostaglandins like misoprostol and carboprost, as well as other options, have been investigated. Carbetocin is an agonist-like, long-acting synthetic octapeptide counterpart of oxytocin. Carbamate's clinical and pharmacological qualities are comparable to those of oxytocin, which is found in nature. Carbetocin, like oxytocin, attaches to oxytocin receptors on uterine smooth muscle, generating cyclic uterine contractions, higher incidence of existing contractions, and increased uterine tone. ⁷

Intravenous doses of carbetocin generated tetanic uterine contractions within 2 minutes, which lasts 6 minutes followed by rhythmic contractions for another hour, according to pharmacokinetic studies. Tetanic contractions began just under 2 minutes after the intramuscular injection, continued around 11 minutes, and were accompanied by rhythmic contractions for another 2 h. There was a substantial difference in the period of activity following intramuscular carbetocin versus intravenous carbetocin. ⁸

When compared to oxytocin, carbetocin causes a greater uterine effect regarding both amplitude and frequency of contractions when given postpartum. The longer time of im carbetocin therapy compared to im oxytocin treatment may be beneficial. It appears to have less GIT and cardiovascular adverse effects than syntometrine and other ergot alkaloids. ⁸

The goal of our randomized study is to compare the superiority, efficiency and adverse effects of I.V carbetocin as a long acting oxytocic analouge versus a combination of intraoperative oxytocin & ergometrine I.V for avoidance of  (PPH) following cesarean delivery as regards efficacy and safety of each drug.

PATIENTS AND METHODS

This study is prospective randomized study that was done at Alhwamdya General Hospital. This study enlisted the participation of 100 women after taking their written consent and were selected from the outpatient clinic of obstetrics and gynecology May 2020 to February 2021.

How randomization

Before the study began, a random-number table was used to generate a randomized schedule specifying the group to which each patient would be assigned upon entry into the trial. In case of exclusion, the next patient was randomized per schedule.

Inclusion criteria: Primigravida without any risk for postpartum hemorrhage who did cesarean section under effect of regional anesthesia, and More than thirty seven weeks gestation: the gestational age was calculated using the beginning 24 hour of the last regular menstrual cycle and verified by an ultrasound scan within the first trimester.

Exclusion criteria: Multiparity, vaginal delivery, as carbetocin is only allowed for usage with regional anaesthesia in Egypt, ladies getting caesarean section under general anaesthetic were eliminated. , gestational age less than 37 weeks, and exclusion of any risk factor for postpartum hemorrhage for examples: placenta previa, pregnancy induced hypertension, marked anemia, multiple pregnancy and accidental hemorrhage.

The women in the study were separated into two groups: Group (A) got carbetocin 100g I.V after fetal head delivery, and Group (B) got a mix of intraoperative oxytocin 10 I.U & ergometrine 0.2mg after fetal head delivery.

All patients were subjected to:

 Careful and detailed history taking.

General examination.

Abdominal examination: Detect fundal level, and presence of scars of previous laparotomies.

Vaginal examination: Cervical assessment including cervical dilatation, consistency, effacement and position

Investigations: Complete blood count, Rh typing, coagulation profile: Prothrombin time, Partial Thromboplastin Time, INR, liver function tests, and renal function tests.

6-Ultrasound scan: using trans abdominal ultrasound scan to: Confirm gestational age, and detect any risk factors for postpartum hemorrhage as placenta previa.

Indications Of Cesarean Section in This Study :

- Breech presentation

Breech presentation is the primary indication for 10% of all CS; However CS rates vary with gestational age, at term 91% women with a breech presentation had a CS.        

- Dystocia

Dystocia is abnormal labor resulting from problems related to fetopelvic or cephalopelvic disproportion (CPD), failure to progress, obstructed labor, dysfunctional labor, poor progress, and second stage arrest.

- Fetal distress

Fetal distress used to be a clinical diagnosis based on the passage of meconium, violent fetal movements and changes in the FHR.

- Other indications:which divided into maternal and fetal indications:

 Maternal indications

Antepartum hemorrhage

                CS is usually necessary when the placenta covers the internal os at 36 weeks (grade 3 or 4 placenta previa). Those women are at increased risk of blood loss of greater than 1000 ml compared to CS for other indications

                Abruptio placentae are an absolute indication for section if the hemorrhage is severe and the fetus is not immediately deliverable. In this situation, section may be indicated even in the presence of fetal death.

Vasa previa

In vasa previa, unsupported fetal vessels traverse the fetal membranes in advance of the presenting part.

Delivering by elective cesarean at or about the 35th to 36th week following steroid treatment is ideal.

Fetal indications: e.g:

Multiple pregnanciesCesarean section is often utilized for twins mainly to provide the second twin with maximum safety at birth. Cesarean section is almost always utilized for triplet and quadruplet births.

In all cases, approved ethical committee taken, information sheet completed included Age, Parity, Gestational age at delivery, also the Blood pressure, Pulse, Temperature and Hemoglobin concentration hematocrite value noted before cesarean sections and 24 hours post-partum. The differences between pre- and post C.S values were calculated in each group.

The uterine tone and size were measured by palpating the front wall of the uterus with a hand lying on the fundus. A swampy uterus combined with excessive vaginal bleeding or an increase in uterine size might lead to a diagnosis of uterine atony.

The study medicine (carbetocin or oxytocin) was provided slowly (over 30– 60 seconds) intravenously by the anesthetist after the infant was delivered through CS

Blood loss was estimated by The hematocrit value was measured immediately before delivery and 24 hours after, for more objective of blood loss, Assessment was done according to the following formula (shook et al., 2003):

EBL = EBV X preop Hct – postop Hct

 prepo Hct                                               

Estimated blood loss (EBL) = estimated blood volume (EBV) X [preoperative hematocrit (preop Hct) - postoperative hematocrit (postop Hct) / preoperative hematocrit (preop Hct)].

The patient’s estimated blood volume (EBV) was calculated as following: woman’s weight (in kilograms) X 85.

The side effects of each drug as nausea, vomiting, shivering and headache or others was noted. 

All the resulting data from the two groups was collected tabulated and analyzed statistically. 

Statistical analysis:                                           

The data will be collected, coded and entered to computer. The data was analyzed with the program (SPSS) statistical package for social science version 25 under windows 10 

Statistical tests was used in this thesis :

Description of qualitative variables by frequency and percentage.

Description of quantitative variables in the form of mean and standard deviation (mean ± SD).

Chi-square (x2) test will be used for comparison of qualitative variables with each other.

Comparison between quantitative variables was carried by using :

Student t-test of two independent samples.

Significance level (p) will be expressed as following:

P value > 0.05 is insignificant

P value < 0.05 is significant.

P value < 0.001 is highly significant.

RESULTS

Table 1: Comparison of two groups in terms of the mean values of gestational age, maternal age, BMI, incidence and severity of PPH.

Comparison between two groups as regards the mean values of gestational age, maternal age and BMI were statistically non significant. There was no significance was found between 2 groups as regard mild or moderate PPH  (Table 1).

Table 2: Comparison of two groups in terms of requirement for additional uterotoinicmedications.

When we tested the need for additional uterotonic drug comparing both groups it was non significant (Table 2).

Table 3: Hb differential between pre- and 24-hour post-operative Hb levels were compared between two groups and their statistical significance.

When comparing the Hb differential between pre- and 24-hour post-operative Hb levels, the carbetocin group was shown to be significantly superior (Table 3).

Table 4: Comparison of two groups in terms of estimated blood loss, hematocrite pre and 24h postoperative and their statistical significance.                  

Comparison between two groups as regards estimated blood loss which appear statistically significance (Table 4).

Table 5: Results of Comparison between two groups as regards maternal adverse effects and their statistical significance.

Concerning maternal adverse effects in the form of elevated blood pressure there was statistical significance in which there was 28% elevation in the non carbetocin group. Again concerning nausea and vomiting they were notably important obvious in the non carbetocin group. However, when we tested for shivering, facial flushing, headache, abdominal pain and sweating statistical difference was not significant among the two groups (Table 5).

Table 6: Comparison between both groups as regard the required additional measures either for prevention or further treatment of postpartum hemorrhage.

In four patients (one in the carbetocin group and three in the oxytocin group), uterotonics failed to stop and control PPH, necessitating surgical intervention. One woman in the carbetocin group developed atonic postpartum hemorrhage, which was treated surgically with bilateral uterine artery ligation and compression sutures. 3 patients in the oxytocin group developed atonic postpartum hemorrhage, which was treated surgically with bilateral uterine artery ligation and compression sutures; one of them required hysterectomy due to intractable bleeding. (Table 6).