Massive Hemorrhage Following Thrombolysis for Postpartum Pulmonary Embolism With Cardiac Arrest

CASE REPORT

Massive Hemorrhage Following Thrombolysis for Postpartum Pulmonary Embolism With Cardiac Arrest Talya Shaulov, MD,1 Michèle David, MD,2 Marieve Pellerin, MD, FRCSC,1 Francine Morin, MD3 Department of Obstetrics and Gynaecology, Centre hospitalier universitaire Sainte-Justine, Montreal QC

1

Division of Hematology, Department of Pediatrics, Centre hospitalier universitaire Sainte-Justine, Montreal QC

2

Division of Obstetrics Medicine, Department of Obstetrics and Gynaecology, Centre hospitalier universitaire Sainte-Justine, Montreal QC

3

Abstract Background: Cardiac arrest following a massive pulmonary embolism in pregnancy or the puerperium is a rare and catastrophic event. Case: We describe a case of massive pulmonary embolism with cardiac arrest in a 36-year-old patient, presenting 48 hours postpartum. She was treated with thrombolytic therapy and suffered a massive hemorrhage thereafter, which was compounded by disseminated intravascular coagulation. Following an emergency hysterectomy and massive blood-product transfusion, she survived with no neurological sequelae. The medical team present had participated in two simulation sessions with similar scenarios in the weeks before the event. Conclusion: To our knowledge, this is only the fifth case reported in the literature on thrombolytic therapy in the postpartum period, and of these has the most severe hemorrhagic complication. An effective multidisciplinary approach to such a complex situation can be acquired through simulation-based training.

Résumé Contexte : L’arrêt cardiaque qui suit une embolie pulmonaire massive pendant la grossesse ou la puerpéralité constitue un événement rare et catastrophique. Cas : Nous décrivons un cas d’embolie pulmonaire massive donnant lieu à un arrêt cardiaque qui s’est manifesté 48 heures à la suite de l’accouchement chez une patiente de 36 ans. Un traitement thrombolytique a été administré à la patiente et celle-ci a par la suite connu une hémorragie massive, laquelle a été aggravée par une coagulation intravasculaire disséminée. À la suite d’une hystérectomie d’urgence et d’une transfusion massive de produits

Key Words: Pulmonary embolism, thrombolytic therapy, hemorrhage Competing Interests: None declared. Received on December 25, 2013 Accepted on February 14, 2014

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sanguins, la patiente a survécu sans séquelles neurologiques. L’équipe médicale présente avait participé à deux sessions de simulation ayant fait appel à des scénarios similaires au cours des semaines précédant l’événement. Conclusion : À notre connaissance, il s’agit seulement du cinquième cas à être signalé dans la littérature en ce qui concerne la mise en œuvre d’un traitement thrombolytique pendant la période postpartum, en plus d’être celui qui a connu la complication hémorragique la plus grave. Une approche multidisciplinaire efficace permettant de faire face à une situation d’une telle complexité peut être acquise par l’intermédiaire d’une formation fondée sur la simulation. J Obstet Gynaecol Can 2014;36(6):498–501

BACKGROUND

Acute pulmonary embolism has an associated mortality of 25% in the general population. When cardiac arrest occurs, the risk of death increases to 70%.1 Venous thromboembolism contributes to 20% of pregnancyrelated mortalities. The highest risk is in the puerperium.1 We describe here a case of postpartum PE with cardiac arrest in a 36-year-old patient. She was treated with thrombolytic therapy but developed early severe hemorrhage, which was successfully managed with a massive transfusion protocol and a multidisciplinary approach. THE CASE

The patient, a 36-year-old gravida 2, para 2, had a past history of distal deep vein thrombosis while on oral contraceptives. Her BMI was 32. Assessment for possible thrombophilia was negative for lupus anticoagulant, anticardiolipin antibodies, factor V Leiden mutation, and prothrombin gene mutation.

Massive Hemorrhage Following Thrombolysis for Postpartum Pulmonary Embolism With Cardiac Arrest

The patient was followed in our centre, a tertiary maternity and pediatric care university hospital. The centre is staffed by obstetricians, adult internists, and pediatric specialists. Women requiring acute adult care are often transferred to general adult centres if hemodynamic stability permits. During both pregnancies the patient had received prophylactic low molecular weight heparin antepartum and postpartum. In her first pregnancy, Caesarean section was performed for abnormal progression of labour, and she opted for an elective Caesarean section at 39 weeks in her second pregnancy. Daily dalteparin (5000 units subcutaneously) was switched to prophylactic unfractionated heparin at 36 weeks (5000 units subcutaneously, twice daily) which was stopped 12 hours before surgery and restarted eight hours postoperatively, in association with intermittent pneumatic compression. Intraoperatively, she had an estimated blood loss of 600 mL and received a routine dose of 100 μg of intravenous carbetocin. At 48 hours postpartum, she complained of left leg numbness followed by transient syncope and shortness of breath. Moments after an initial evaluation, she developed asystole. Cardiopulmonary resuscitation was immediately initiated. She was intubated within three minutes and standard acute cardiovascular life support protocol was followed. After 15 minutes of CPR, the patient transiently awakened, but quickly went into pulseless electrical activity. Together with a pediatric intensivist, internist, hematologist, and cardiac surgeon, it was decided to initiate thrombolysis for a presumed pulmonary embolism. Transfer to an adult centre was not considered safe or feasible at this time. She received 50 mg of recombinant tissue plasminogen activator (rt-PA, alteplase) at 30 minutes after cardiac arrest and a further 50 mg 15 minutes later. She then had transient return of spontaneous circulation. An infusion of epinephrine and norepinephrine was initiated. ROSC with a blood pressure of 83/46 was finally obtained 65 minutes after the initial cardiac arrest. She was transferred to the pediatric intensive care unit, where a bedside echocardiogram showed clots in both pulmonary arteries with a dilated and hypokinetic right ventricle. She had a hemoglobin concentration of 78 mg/L. The institutional massive hemorrhage protocol was initiated and transfusions of packed red cells started. At one hour and 40 minutes after initial arrest, CPR was restarted and continued on and off for the next hour, during which massive bleeding from the surgical site and vagina became ABBREVIATIONS CPR

cardiopulmonary resuscitation

PE

pulmonary embolism

ROSC

return of spontaneous circulation

apparent. Vaginal packing and Bakri balloon tamponade were unsuccessful. At this stage, we did not use uterotonics as the bleeding was not considered to be a result of uterine atony. A repeat echocardiogram showed a decrease in right ventricular volume and absence of clots. The patient required cardioversion for atrial fibrillation 45 minutes after restarting CPR, which was followed by sustained ROSC. She received 36 packs of cryoprecipitate, 10 g of fibrinogen concentrate, 11 units of frozen plasma, 15 units of packed red-cell, and 5 units of platelets. Hypothermia, acidosis, and hypocalcemia were corrected. Bleeding persisted with the need for vasopressors. A decision was made to proceed to hysterectomy, three hours and 15 minutes after the initial cardiac arrest. Laboratory values showed a serum lactate of 18 mmol/L, APTT > 250 seconds, INR of 2.7, and plasma fibrinogen of 0.8 g/L. Bleeding was difficult to control despite aggressive replacement therapy. We opted not to give tranexamic acid or recombinant factor VIIa (rVIIa) to avoid further thromboembolic complications. The patient was in the operating room for five hours and underwent a subtotal hysterectomy. She remained stable on an intravenous infusion of norepinephrine. She required cardioversion for a repeat episode of atrial fibrillation. She received a further 16 units of packed red-cells, 67 packs of cryoprecipitate, 12 units of frozen plasma, and 10 units of platelets. Postoperatively, the patient’s condition was stable. She was transferred to a tertiary adult centre. An inferior vena cava filter was inserted and she was extubated 72 hours after surgery. A computed tomography pulmonary angiogram showed extensive bibasilar pulmonary embolism. She had transient elevation of liver enzyme levels and lower gastrointestinal bleeding with negative lower and upper endoscopies. She required 10 days of hemodialysis for acute kidney injury. Over the subsequent week, there was a progressive decline in hemoglobin concentration. An abdominal CT scan showed progression of an intramuscular rectus hematoma with free intra-abdominal blood. Ten days later, seven litres of fresh blood were evacuated by laparotomy. She was discharged one month later on therapeutic doses of low molecular weight heparin and antibiotics. She was neurologically intact. Three months later, a pulmonary ventilation perfusion scan showed a persistent matched defect in both lower lobes. She has remained asymptomatic. DISCUSSION

Massive pulmonary embolism, an immediately lifethreatening condition, requires rapid management. JUNE JOGC JUIN 2014 l 499

Case Report

Ideally, the diagnosis should be confirmed by means of a ventilation perfusion scan or computed tomography pulmonary angiogram. However, in the presence of hemodynamic instability, a bedside echocardiogram can be highly suggestive of massive PE.2,3 In the non-gravid state, it is recommended by the American College of Chest Physicians to administer thrombolytic therapy with a short two-hour infusion time.1 Among the relative contraindications listed by the College are pregnancy and recent surgery. Thrombolytic therapy in the treatment of PE in the non-pregnant state has been widely studied, and the rate of major hemorrhage is approximately 12%.4 Reported experience with thrombolytic agents in pregnancy and the puerperium is limited to case series and case reports. In the available literature on thrombolysis for massive PE in pregnancy, no maternal deaths have been reported.3 In the postpartum period, we found only four reported cases of PE in which thrombolysis was used.2–5 Bleeding complications were described in all four of these cases, the worst of which occurred when reteplase was administered intraoperatively during an emergency Caesarean section performed for maternal hemodynamic instability.3 A “pack and wait” technique salvaged the patient’s uterus and she survived with no neurologic sequelae.3 The only other report of PE occurring in a patient delivered by Caesarean section describes intense vaginal bleeding three hours after thrombolysis with streptokinase. Conservative management of the bleeding is not detailed; however, it ceased within five hours and the patient received three bags of concentrated erythrocytes and two bags of frozen plasma.5 In a report by O’Keeffe et al.,4 a patient with a PE diagnosed at 32 weeks of pregnancy underwent thrombus fragmentation while pregnant. Catheter-directed thrombolysis with rt-PA was deferred until three days after labour induction and delivery, following which the patient developed a hematoma at the site of episiotomy requiring surgical evacuation. The fourth reported case of postpartum PE treated with thrombolysis manifested four hours after spontaneous vaginal delivery. This patient received a 30 mg bolus of tenecteplase and had blood loss of 1800 mL, which ceased with administration of oxytocin.2 Techniques such as catheter-directed thrombolysis require an adequate set-up and local experience. Our patient’s hemodynamic status did not permit such an approach. We also considered surgical embolectomy. However, it would have created too long a delay in definitive treatment and would have rendered continuous high quality CPR difficult during preparation and transport to the surgical suite. In 500 l JUNE JOGC JUIN 2014

our case, we felt that intravenous thrombolysis was the most appropriate and rapid treatment. Our patient suffered massive hemorrhage following thrombolytic therapy, far in excess of that reported in all of the English and French literature. As noted above, there have been very few reports regarding this treatment in the postpartum period. Our patient had significant fibrinogenolysis with profound hypofibrinogenemia. A likely major contributing factor was the presence of concomitant disseminated intravascular coagulation secondary to prolonged cardiac arrest with tissue hypoperfusion. Another contributing factor could have been the rapid administration of 100 mg of alteplase over 20 minutes. However, the half-life of rt-PA is short (5 minutes) and in a six-patient case series reported by Ruiz-Bailen et al.,6 rt-PA was administered during cardiac arrest in two boluses of 50 mg within a 30-minute interval in five of six patients. Only two of these patients developed hemorrhagic complications, and only one required transfusion. The hemorrhagic risk seems to be higher in cases of increased fibrinogen turnover and formation of fibrinogen degradation products. Matosevic et al.7 described an increased risk of bleeding complications when a decrease of ≥ 2 g/L in the fibrinogen levels occurred within six hours of thrombolysis. Despite some fibrin specificity, alteplase also cleaves circulating fibrinogen. Fibrinogen degradation products interfere with fibrin polymerization and can activate platelets and have antithrombin-like effects. In our patient’s case, plasma fibrinogen reached a nadir of < 0.6 g/L within 3.5 hours of the first dose. One strategy to decrease bleeding complications could be to use a more fibrin-specific fibrinolytic agent such as tenecteplase. Azarisman et al.2 reported the only case of tenecteplase used in the puerperium. As described earlier, this patient received a bolus injection four hours after a spontaneous vaginal delivery and the subsequent hemorrhage ceased with use of uterotonics. Lastly, it is important to note that our patient was on prophylactic unfractionated heparin at the time of her embolism, as recommended by the American College of Chest Physicians for patients at increased risk of venous thromboembolism following Caesarean section.1 Using indirect evidence from data in general surgery patients, there is an increase in major bleeding events with such prophylaxis.1 In our patient, it is unlikely that it played a significant role, as she had received her last dose 10 hours before her arrest. Thrombolysis and concomitant disseminated intravascular coagulation were the major contributing factors of her massive bleeding.

Massive Hemorrhage Following Thrombolysis for Postpartum Pulmonary Embolism With Cardiac Arrest

When using rt-PA in a case with increased hemorrhagic risk, the blood bank should be put on high alert to minimize delay in the procurement of blood products. A standardized massive hemorrhage protocol has been in place for the last year in our centre and was, in our opinion, instrumental in our successful outcome. We launched the protocol immediately after the administration of rt-Pa and were ready as soon as bleeding occurred. We should also stress the importance of rapid fibrinogen replacement with cryoprecipitate and/or fibrinogen concentrate if fibrinogenolysis with severe bleeding occurs during or after thrombolytic therapy. A further aspect of this case is the use of thrombolysis during CPR. Recent guidelines for CPR recommend giving thrombolytic therapy during CPR only when pulmonary embolism is presumed to be the cause of the arrest.8 During cardiac arrest, a bolus infusion of 50 mg rt-PA in ≤ 15 min is to be considered.1 A retrospective study by Er et al.8 showed that the time between the cardiac arrest and the administration of rt-PA is of high importance to achieve successful ROSC. This time was significantly shorter in patients with ROSC, and the mean CPR duration was significantly longer in patients without ROSC. Therefore, efforts should be made to confirm the diagnosis as early as possible in the course of events in order to begin treatment expeditiously. Another major factor in the successful outcome of this case was the fact that many of the team members had participated in simulation sessions at our hospital’s simulation centre (Centre de simulation Mère-Enfant) in the weeks prior to the event. This is of particular importance since we practise in a maternity and pediatric centre with limited experience in managing adult cardiac arrest. One of the simulation scenarios was that of a pregnant patient with pulmonary emboli and cardiac arrest. Another scenario involved the use of the institutional massive hemorrhage protocol. In a feedback session that took place following the real events, the participants stated that the simulation strongly and positively influenced their ability to perform on the day of the actual case. The simulation sessions involved medical staff and residents of different specialties, nurses, respiratory therapists, orderlies, and blood bank personnel. During these sessions a strong emphasis is put on crew resource management as well as medical expertise. Simulation in obstetrics has been developed in the last 10 years, and recent literature shows that it plays an active role in the acquisition of acute care technical skills as well as non-technical skills, such as communication, especially for rare events.9

CONCLUSION

In this report, we describe the fifth reported case of pulmonary embolism involving use of thrombolytic therapy in the postpartum period. Massive PE in the puerperium requires rapid investigation and treatment. The feasibility of thrombolytic therapy makes it an option in near-fatal situations, and it should be administered sooner rather than later, especially in the setting of cardiac arrest. The potential bleeding complications secondary to thrombolysis cannot be overemphasized, and the treating team should be prepared for such complications prior to their occurrence. Launching a massive hemorrhage protocol ensures rapid administration of blood products. Maintaining plasma fibrinogen in a normal or near-normal range may help limit blood loss. Finally, a successful outcome in such complex situations is dependent on effective communication and collaboration between team members, which can be enhanced by simulation-based training in rare clinical events. ACKNOWLEDGEMENTS

The woman whose story is told in this case report has provided written consent for its publication. REFERENCES 1. American College of Chest Physicians. Antithrombotic therapy and prevention of thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e419S–e7236S. 2. Azarisman SM, Liza RA, Radhiana H, Sujana SS, Maskon O, Rosli MA, Fauzi AR. Immediate postpartum cardiorespiratory collapse: a management quandary. Blood Coagul Fibrinolysis 2010;21(6):601–4. 3. Wenk M, Popping DM, Hillyard S, Albers H, Mollmann M. Intraoperative thrombolysis in a patient with cardiopulmonary arrest and undergoing caesarean delivery. Anesth Intensive Care 2011;39:671–4. 4. O’Keeffe SA, McGrath A, Ryan JM, Byrne B. Management of a massive pulmonary embolism in a pregnant patient with mechanical fragmentation followed by delayed catheter-directed thrombolysis in the early postpartum period. J Matern Fetal Neonatal Med 2008;21(8):591–4. 5. Stefanovic BS, Vasiljevic Z, Mitrovic P, Karadzic A, Ostojic M. Thrombolytic therapy for massive pulmonary embolism 12 hours after cesarean delivery despite contraindication? Am J Emerg Med 2006;24(4):502–4. 6. Ruiz-Bailen M, Aguayo-de-Hoyos E, Serrano-Corcoles MC, Diaz-Castellanos MA, Fierro-Roson LJ, Ramos-Cuadra JA, et al. Thrombolysis with recombinant tissue plasminogen activator during cardiopulmonary resuscitation in fulminant pulmonary embolism. A case series. Resuscitation 2001;51:97–101. 7. Matosevic B, Knoflach M, Werner P, Pechlaner R, Zangerle A, Ruecker M, et al. Fibrinogen degradation coagulopathy and bleeding complications after stroke thrombolysis. Neurology 2013; 80(13):1216–24. 8. Er F, Nia AM, Gassanov N, Caglayan E, Erdmann E, Hoppe UC. Impact of rescue-thrombolysis during cardiopulmonary resuscitation in patients with pulmonary embolism. PLos One 2009;4(12):e8323. 9. Jastrow N, Irion O, Savoldelli G, Picchiottino P. Simulation in obstetrics. Revue Médicale Suisse 2013;9(403):1938–40.

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