REBOA in Life-threatening Postpartum Hemorrhage (PPH) in Uganda (REBOA-PPH)

Phase III, Open-label, Randomized Clinical Trial to Evaluate Efficacy and Safety of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in Life-threatening Postpartum Haemorrhage in Reducing Adverse Maternal Outcome in Uganda

Makerere University, Kawempe National Referral Hospital, St. Olavs Hospital, Helse Stavanger HF, University of Liverpool, University of Padova

Background Maternal mortality rates in many low-income countries (LMICs) remain high. The most prominent cause is bleeding after birth, called postpartum hemorrhage (PPH). In a recent report from Uganda, bleeding is the cause of 42% of all maternal deaths in Uganda. Large parts of the monitoring of mothers during active management of third stage of labor is aiming to prevent and early detect PPH and take relevant actions. In spite of this and sometimes in referring mothers to tertiary hospitals, mothers will end up in a challenging condition where quick action is needed. A new method has proven successful for such instances, the Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). This is a procedure commonly used for trauma of the lower part of the body but rarely used for PPH. In this trial, it is done by an anesthesiologist where a balloon catheter is inserted via the femoral artery in the groin into the aorta and then being inflated. This will prevent blood from passing to the lower part of the body, including the uterus. It will stop the bleeding and allow for the obstetrician to take relevant action. This is a safe procedure for up to 1 hour of inflation. Objective To assess the efficacy and safety of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in life-threatening postpartum hemorrhage (PPH) in reducing adverse maternal outcome compared to standard of care in Uganda. Study design, setting and population A phase III, open label, 1:1 randomized clinical trial will be conducted at Kawempe National Referral Hospital, Kampala, Uganda, to evaluate the efficacy and safety of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in life-threatening postpartum hemorrhage (PPH) in reducing adverse maternal outcome compared to standard of care. The inclusion criteria are: a) women with life-threatening PPH and a systolic blood pressure equal to or less than 80 mmHg, b) oral consent. The exclusion criterion is prior cardiac arrest. The sample size of the trial will be 210 participants. Enrolment will follow a group sequential design approach with two interim analyses at 1/3 and 2/3 of the total sample size, and a final analysis with full sample size. Utility of the study It is crucial to explore alternative modalities that could prevent adverse maternal outcomes in life-threatening postpartum hemorrhage in Uganda and the rest of the world.

Background Maternal mortality rates in many low-income countries (LMICs) remain high. The most prominent cause is bleeding after birth, called postpartum hemorrhage (PPH). In a recent report from Uganda, bleeding is the cause of 42% of all maternal deaths in Uganda. Large parts of the monitoring of mothers during active management of third stage of labor is aiming to prevent and early detect PPH and take relevant actions. In spite of this and sometimes in referring mothers to tertiary hospitals, mothers will end up in a challenging condition where quick action is needed. A new method has proven successful for such instances, the Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). This is a procedure commonly used for trauma of the lower part of the body but rarely used for PPH. In this trial, it is done by an anesthesiologist where a balloon catheter is inserted via the femoral artery in the groin into the aorta and then being inflated. This will prevent blood from passing to the lower part of the body, including the uterus. It will stop the bleeding and allow for the obstetrician to take relevant action. This is a safe procedure for up to 1 hour of inflation. Objective To assess the efficacy and safety of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in life-threatening postpartum hemorrhage (PPH) in reducing adverse maternal outcome compared to standard of care in Uganda. General objective To assess the efficacy and safety of the use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in life-threatening postpartum hemorrhage (PPH) in reducing adverse maternal outcome compared to standard of care in Uganda. Specific objective - To assess if the proportion of either maternal death and/or emergency hysterectomy, can be decreased from 50 % in the control arm (using standard of care alone) to 30 % or less in the intervention arm (using REBOA). Secondary objectives To assess if the proportion of either maternal death and/or emergency hysterectomy is lower in the intervention arm when excluding 'inevitable' hysterectomies due to either an irreparable uterine rupture, a pathological placenta growing into the uterus (placenta accreta, increta or percreta) or a pathological uterus, such as a bicorne uterus or one with very large fibroids. To assess the safety of REBOA in a national referral hospital in a low-income country like Uganda. To assess if the proportion of maternal deaths is lower in the intervention arm compared to the control arm. To assess if the proportion of emergency hysterectomy is lower in the intervention arm compared to the control arm. To assess if the proportion of women with acute kidney injury is lower in the intervention arm compared to the control arm To assess if the number of blood transfusion units is lower in the intervention arm compared to the control arm. To assess if post-partum hemoglobin concentration is higher in in the intervention arm compared to the control arm. To assess the time to insert the REBOA. Study design, setting and population A parallel group, open-label, individually 1:1 randomized phase III clinical trial will be conducted at Kawempe National Referral Hospital, Kampala, Uganda, to evaluate the efficacy and safety of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in life-threatening postpartum hemorrhage (PPH) in reducing adverse maternal outcome compared to standard of care. The sample size of the trial will be 210 participants. Enrolment will follow a group sequential design approach with two interim analyses at 1/3 and 2/3 of the total sample size, and a final analysis with full sample size. Results from Norway indicate that REBOA could be an efficient way to prevent post-partum hemorrhage ending in an adverse outcome such as death or emergency hysterectomy. It is not clear whether these results can be reproduced in a low-income setting where PPH is more prevalent, and resources are scarce. The REBOA device could reduce the risk of adverse outcome such as death or emergency hysterectomy. It will be compared to standard of care. Utility of the study It is crucial to explore alternative modalities that could prevent adverse maternal outcomes in life-threatening postpartum hemorrhage in Uganda and the rest of the world.

The balloon catheter is inserted via the common femoral artery in the groin, accessed under ultrasound guidance due to weak femoral pulses, and the puncture is done by the Seldinger technique. The balloon is inserted along a guidewire 25-30 cm, safely below the renal arteries, to be in the right place to stop pelvic hemorrhage including life-threatening post-partum hemorrhage

The proportion of participants with a composite outcome of either maternal death (=death within 42 days post-partum) or emergency hysterectomy

The proportion of participants with a composite outcome of either maternal death (=death within 42 days post-partum) or emergency hysterectomy due to either an irreparable uterine rupture, a pathological placenta growing into the uterus (placenta accreta, increta or percreta) or a pathological uterus, such as a bicorne uterus or one with very large fibroids

Inclusion Criteria: Patients with life-threatening PPH (PPH and a systolic blood pressure equal to or less than 80 mmHg) Oral consent Exclusion Criteria: Prior cardiac arrest

Stensaeth KH, Sovik E, Haig IN, Skomedal E, Jorgensen A. Fluoroscopy-free Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) for controlling life threatening postpartum hemorrhage. PLoS One. 2017 Mar 29;12(3):e0174520. doi: 10.1371/journal.pone.0174520. eCollection 2017.