Aortic Compression Trial to Reduce Blood Loss at Cesarean Section — ACT  

Anemia Clinical Trial

Official title: Aortic Compression Trial - a Randomized Controlled Trial to Reduce Blood Loss at Cesarean Section (ACT)

Status Enrolling by invitation

Clinical Trial Summary

The goal of this clinical trial is to test if manual external aortic compression can prevent heavy blood loss in cesarean section. The main question[s] it aims to answer are:

1. Is external aortic compression safe?

2. Is external aortic compression effective?

Participants will receive preventive external aortic compression or no external aortic compression right after the baby is out at cesarean section. Blood loss will be measured, as well as kidney function, hemoglobin, and hematocrit before and after the operation. Experienced discomfort will be assessed the day after surgery and breastfeeding and signs of depression will be assessed using questionnaires after 2 months.

Researchers will compare women with and without external aortic compression to see if there are differences in these outcomes.

Clinical Trial Description

The Aortic Compression Trial (ACT) - A randomized controlled trial to reduce blood loss in cesarean delivery

PURPOSE AND AIMS The purpose is to reduce the prevalence of severe postpartum hemorrhage (PPH), causing maternal mortality and morbidity worldwide. The aim is to investigate if routine manual external aortic compression (EAC) in cesarean delivery (CD) is an effective and safe measure to prevent severe PPH, in a multicenter randomized controlled superiority trial.

SURVEY OF THE FIELD Severe PPH is defined as blood loss >1000 ml at childbirth (1, 2). Severe PPH is associated with 25% of maternal mortality worldwide and the leading cause of severe morbidity, such as cardiac, respiratory or renal failure and hysterectomy, notably in low-income countries (1). PPH also entails blood transfusion, anemia, prolonged postpartum recovery, and depression (1). The global prevalence of severe PPH is 6% and increasing in high-income countries (2). In Sweden, severe PPH occurs in 7% in vaginal birth, 12% in elective CD, and 17% in emergency CD with large variation between hospitals (3). Routine intravenous oxytocin is recommended to prevent PPH in CD (1). Several mechanical methods may treat excessive bleeding, but none has been assessed for prevention of PPH (2). One method for temporizing blood loss is external aortic compression (EAC), usually applied until appropriate care is available, for example during transport (1, 4-6). The aorta is compressed by placing a fist onto the aorta through the abdominal wall which cuts off the blood supply to the uterus and hence reduces uterine bleeding (2). A Cochrane review in 2020 stated that high-quality randomized trials into mechanical and surgical methods for the treatment of PPH are urgently needed (2). Swedish SBU stated in 2022 that prevention of complications in CD is a top prioritized research area (7). The effect or safety of preventive manual EAC has never been evaluated in a clinical trial.

STUDY DESIGN A multicenter randomized controlled superiority trial (RCT) using 1:1 randomization and intention-to-treat analysis. Randomization will be stratified by site using randomized permuted blocks. Core outcomes for prevention of PPH will be reported (8).

Research questions

Does routine EAC in patients with term/near term pregnancies undergoing elective CD:

1. Reduce the prevalence of severe PPH?

2. Reduce severe morbidity and/or mortality in women?

Population: Patients undergoing elective CD. Intervention: Manual external aortic compression immediately after delivery of the baby until the bleeding from the uterine incision is controlled, usually with the first suture row of uterine incision closure. Cord clamping will be timed and performed regardless of EAC.

Control: No manual external aortic compression, unless deemed vital. Outcome: Primary:

calculated blood loss >1000 ml or blood transfusion within 2 days.

Other exploratory and safety questions are if EAC affects average blood loss; postpartum hemoglobin or hematocrit levels; time in surgery; pain, breathing, nausea or overall patient experience during surgery; conversion to general anesthesia; use of extra medication during surgery for pain, uterine tone, blood pressure, or blood loss; maternal kidney function; duration of hospital stay postpartum; neonatal outcomes; maternal well-being after childbirth; healing of the uterine scar; or healthcare costs.

Variables and measures Primary outcome: Calculated blood loss >1000 ml or a red-cell transfusion within 2 days after delivery (binary). The calculated blood loss is defined as "the estimated blood volume × (preoperative hematocrit - postoperative hematocrit) ÷ preoperative hematocrit". The estimated blood volume in milliliters is calculated = admission body weight in kilograms × 85 (9). This outcome is based on a pivotal study on blood loss in CD (9), and preferred to gravimetrical methods since it accounts for the outpouring amniotic fluid during CD.

Secondary outcome: Composite outcome of maternal mortality, hysterectomy, uterine ligation or embolization treatment, surgical trauma to bladder, ureters or intestines, intensive care, organ failure, stroke, or cardiac arrest within 42 days (binary).

Exploratory outcomes: Mean total blood loss (in ml and g) up to 6 hours after delivery, mean venous B-hemoglobin and hematocrit 1-3 days after delivery, mean start-to-finish surgery duration (min), mean days in postnatal care (mother) from operation finish time to discharge home, mean time to cord clamping (min), Edinburgh Postnatal Depression Scale at 6-8 weeks postpartum (10), Breastfeeding Self-Efficacy Scale short form at 6-8 weeks postpartum (11), breastfeeding and self-rated health 6-12 weeks postpartum (Swedish Pregnancy Register, SPR), healing measured by sonographic evaluation of the hysterotomy scar at 6 months after delivery (mean anterior wall thickness, prevalence of a niche), subsequent uterine rupture, scar dehiscence, or isthmocele surgery (5-year register follow-up), and cost-effectiveness to be detailed in a separate analysis plan.

Safety outcomes: Perioperative pain, breathing discomfort, nausea, and overall experience (numeric rating scales 0-10); analgetic treatment in addition to regional anesthesia during surgery or conversion to general anesthesia (binary); Pharmacological treatment for low blood pressure (phenylephrine, ephedrine, norepinephrine, intravenous crystalloid fluids), extra uterotonic drugs, or hemostatic drugs (tranexamic acid) (9) (binary); S-creatinine and glomerular filtration rate 1-3 days after delivery adjusted for preoperative baseline values; Prevalence of Apgar score at 5 minutes <7, neonatal acidosis (cord pH <7.00), admission to neonatal care, neonatal hyperbilirubinemia or anemia (binary, Swedish Neonatal Quality Register, SNQ).

Material: Patient selection - population, sample The trial will include patients undergoing elective CD to facilitate timely informed consent. Around 10 000 elective CD are performed annually in Sweden. Patients will be screened and recruited at scheduling or admission for CD. Results will likely be transferrable to emergency CD with higher risk of PPH in which obtaining informed consent is more challenging. Using EAC as preventive method makes safety a high priority. Patients with planned hysterectomy or preoperative anemia will be excluded since their risk of PPH or blood transfusion postpartum may not be related to blood loss at CD.

Inclusion criteria: Patients with elective CD, live fetus/fetuses if multiple pregnancy, gestational week 34+0 or more.

Exclusion criteria: Preoperative B-hemoglobin <100 g/l, planned hysterectomy in the same procedure as the elective CD, other condition as deemed by attending surgeon.

Treatment will be allocated in the operating theatre using opaque sealed envelopes professionally prepared by KTA. There is no masking due to the nature of the intervention. Analyses will be allocation blinded.

Estimated sample size and power Around 12.4% of elective CD have PPH >1000 ml (3). To demonstrate a clinically relevant relative risk reduction of 30% at 80% power, n=1069 women in each treatment arm is needed, assuming significance level α=0.05, two-sided test. The sample size will be inflated by 5% to account for drop-out and heterogeneity between centers, resulting in total sample size n=2246 women. This sample size is also sufficient to detect relatively rare outcomes, such as intensive care or hysterectomy. Sample size calculations were performed by using the POWER procedure in SAS/STAT Software, version 9.4 of the SAS System for Windows (SAS Institute Inc., Cary, NC).

Statistical methods The primary efficacy analysis will be based on the intention-to-treat (ITT) population using a generalized linear mixed-effects model with log-link, Poisson distribution, treatment as fixed effect and site as random effect to estimate the relative risk of event while accounting for center effects. Using this model, the 80% power for the primary endpoint will be retained provided that recruitment is terminated with complete blocks, i.e., with balanced treatment allocation at all sites (12). Similar methods will be employed for secondary and exploratory endpoints using appropriate models and distributions depending on the type and distribution of the outcome, i.e., Poisson model to estimate the relative risk of binary events (e.g., maternal composite outcome), log-normal distribution for continuous and positively skewed outcomes (e.g., duration of surgery), negative binomial distribution for counts (e.g., days in hospital), and normal distribution for other numeric outcomes. Patient-reported outcomes and questionnaire scales will be treated as numeric in this regard. All estimates will be provided with 95% confidence intervals. If the primary endpoint is significant, the secondary endpoint maternal composite outcome will be confirmatory tested at the 5% significance level. All safety outcomes will be presented for both the ITT population and the safety population (all randomized women according to actual treatment). The statistical analysis plan will be established in detail and documented before data lock. Responsible statisticians are Henrik Imberg, PhD, and Mattias Molin at Statistiska Konsultgruppen Sweden AB.

FEASIBILITY The trial has received a planning grant (VR 2021-06579), ethical approval Sept 20, 2022 from the Swedish Ethical Review Authority (2022-04327-01) with amendment approved Dec 20, 2022 (2022-06377-02), and formal support from www.snaks.se. The trial has started at one site (Danderyd) Dec 1, 2022, and had recruited 206 patients by Jan 31, 2024 (30% of 696 elective CD) and proven acceptable both to patients and physicians. Data is collected in RedCap and from the SPR, SNQ, and Patient Register. The intervention is readily known and requires no equipment. We are supported by the infrastructure Clinical Studies Sweden/KTA, Karolinska Institutet, Statistiska Konsultgruppen AB, and the participating hospitals' research support functions. Nine hospitals in five regions have agreed to participate in the trial: Danderyd, Karolinska, Södersjukhuset, Södertälje, Norrköping, Falun, Uppsala, and Göteborg. These sites perform approximately 3500 elective CD per year (www.graviditetsregistret.se).

We have assessed safety outcomes after 156 randomized patients. EAC was applied during mean 8.7 minutes (median 9, range 1-22). There were no clinically or statistically significant differences between the groups regarding safety outcomes (P-Creatinine postoperative (µmol/l), P-GFR postoperative (ml/min), overall maternal experience, umbilical vein pH, umbilical vein pO2, Apgar 5 min <7, or admission to neonatal care.

RISK MITIGATION Feasibility and acceptability is deemed very good so far. If 25% of patients consent to participation, inclusion will be finalized in three years. If recruitment is slower, more hospitals in Sweden can be recruited to join ACT, or inclusion criteria could be expanded to emergency CD although this would risk interfering with competing research projects. Internationalization could be an option.

REFERENCES

1. WHO. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Italy: WHO Press; 2012 [cited 2021. Available from: https://apps.who.int/iris/bitstream/handle/10665/75411/9789241?sequence=1.

2. Kellie FJ, et al. Mechanical and surgical interventions for treating primary postpartum haemorrhage. Cochrane Database Syst Rev. 2020;7:CD013663.

3. Graviditetsregistret. Annual report 2021 of the Swedish Pregnancy Register. Stockholm, Sweden 2022. Available from: https://www.medscinet.com/GR/uploads/hemsida/dokumentarkiv/Graviditetsregistrets%20Årsra pport%202021_1.0.pdf.

4. LÖF. Postpartumblödning vid vaginal förlossning. Sweden: Säker Förlossningsvård, Landstingens Ömsesidiga Försäkring; 2020 [cited 2021. Available from: https://lof.se/filer/Expertgruppsdokument-Saker-Forlossning-Postpartumblodning.pdf.

5. O'Dochartaigh D, et al. Temporizing Life-Threatening Abdominal-Pelvic Hemorrhage Using Proprietary Devices, Manual Pressure, or a Single Knee: An Integrative Review of Proximal External Aortic Compression and Even "Knee BOA". J Spec Oper Med. 2020;20(2):110-4.

6. Riley DP, Burgess RW. External abdominal aortic compression: a study of a resuscitation manoeuvre for postpartum haemorrhage. Anaesth Intensive Care. 1994;22(5):571-5.

7. SBU. Behov av kunskap och utveckling inom området kejsarsnitt. Prioritering baserad på James Lind Alliance metod. Prioritering av vetenskapliga kunskapsluckor.2022 18 February 2023. Available from: https://www.sbu.se/357.

8. Meher S, et al. Core outcome sets for prevention and treatment of postpartum haemorrhage: an international Delphi consensus study. BJOG. 2019;126(1):83-93.

9. Sentilhes L, et al. Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery. N Engl J Med. 2021;384(17):1623-34.

10. Rubertsson C, et al. The Swedish validation of Edinburgh Postnatal Depression Scale (EPDS) during pregnancy. Nord J Psychiatry. 2011;65(6):414-8.

11. Gerhardsson E, et al. The Swedish Version of the Breastfeeding Self-Efficacy Scale-Short Form: Reliability and Validity Assessment. J Hum Lact. 2014;30(3):340-5.

12. Harden M, Friede T. Sample size calculation in multi-centre clinical trials. BMC Med Res Methodol. 2018;18(1):156. ;

Related Conditions & MeSH terms

• Anemia
• Cesarean Section Complications
• Hemorrhage
• Post Partum Hemorrhage
• Postpartum Hemorrhage

• NCT number: NCT05312658
• Study type: Interventional
• Source: Karolinska Institutet
• Status: Enrolling by invitation
• Phase: N/A
• Start date: December 1, 2022
• Completion date: December 2026