Intracerebral hemorrhage (ICH) is a dreaded complication of thrombolytic therapy. Published guidelines related to use of antithrombotic and thrombolytic therapy for ischemic stroke1 report an incidence of symptomatic ICH after thrombolytic therapy in acute ischemic stroke of 7.3% compared with 5.9% in stroke trials. Additional guidelines recommend against thrombolysis for the treatment of stroke2 or pulmonary embolism3 after recent intracranial surgery.
We describe successful thrombolytic treatment of massive bilateral pulmonary embolism occurring several hours after intracranial aneurysm clipping for a ruptured intracranial aneurysm. The local scientific and ethics committee of Comite d’Organisation et de Gestion de l’Anesthesie-Reanimation du Centre Hospitalier Universitaire de Montpellier approved the case report. We obtained patient permission to publish this case report.
A 71-year-old conscious and oriented man was admitted to the Montpellier University Hospital’s Stroke Center after 5 days of severe headache. The cerebral computed tomography (CT) scan revealed a right frontotemporal subarachnoid hemorrhage and a cerebral aneurysm of the right middle cerebral artery. Embolization of the aneurysm was scheduled 1 day later, but before it could be performed, the patient presented left hemiplegia with a Glasgow coma score of 7 (eyes, 2; verbal, 2; motor, 3). After tracheal intubation, repeat CT scan revealed a large ICH (Fisher grade 4) and he underwent emergent aneurysm clipping and insertion of external ventricular drain.
Four hours after admission to the intensive care unit (ICU), and while sedated with midazolam and fentanyl, he became hypoxemic and hemodynamically unstable. Cardiac ultrasound showed a dilated right ventricle, and lung CT scan with injection of contrast confirmed a massive pulmonary embolism. The coagulation data were normal with a prothrombin time (PT) at 12.3 seconds, activated partial thromboplastin time (APTT) at 24 seconds (ratio = 0.9), fibrinogen at 4.2 g/L, and 2,32,000/mm3 blood platelets. A cerebral CT scan was also performed (Fig. 1A). After discussion with the thoracic surgeon, surgical thrombectomy was not recommended. His hemodynamic state worsened quickly until cardiac arrest (pulseless electrical activity) occurred. Immediate resuscitation was instituted using 2 mg epinephrine and 1 minute of external cardiac compression (0 minutes of no flow and 1 minute of low flow) restored his arterial blood pressure to 110/60 mm Hg. Rescue fibrinolysis (alteplase-recombinant tissue plasminogen activator [rTPA]) was performed using an IV bolus of 10 mg followed by 40 mg in 30 minutes (patient weight: 80 kg, i.e., 0.6 mL/kg), through the right subclavian central venous access. Additional therapy using nonfractioned heparin and intermittent pneumatic compression was then started as a backup. In the evening, his PT was at 12.8 seconds and his APTT at 28.9 seconds (ratio = 1), with a fibrinogen at 4.4 g/L. The day after, under heparin therapy, the APTT was at 90.8 seconds (ratio = 2.7) and PT at 13.8 seconds. His hemodynamic variables were monitored by an echocardiography pulmonary artery catheter. Two hours after resuscitation, his cardiac output was 2 L/min. The urine output without diuretic therapy and the lactates (2 mmol/L) were normal. We used norepinephrine to maintain mean arterial blood pressure >65 mm Hg. Two days later, his cardiac output was 3.5 L/min with a gradient between the right ventricle and right atrium of 38 mm Hg, and a control CT scan showed worsening ICH and intraventricular bleeding (Fig. 1B). During his stay, the APTT was maintained between 70 and 90 to achieve a ratio between 2 and 3. The PT remains stable between 13.7 and 12.9 seconds. Regular CT scans were performed to monitor the intracerebral bleeding, and intracranial pressure was assessed every hour using an intraventricular catheter. His intracranial pressure remained low, and no cerebrospinal fluid was removed.
After 2 weeks of mechanical ventilation due to a persistent lung infection, the sedation was stopped and the patient regained consciousness 1 day later. His cardiac output was estimated at 5 L/min without pulmonary arterial hypertension. At day 28, his trachea was successfully extubated and cerebral tomography showed the disappearance of the intraventricular hemorrhage (Fig. 1C). At day 33, he was discharged from the ICU. He had a slight motor deficit in the left arm, was perfectly conscious, oriented, and did not require oxygen. One month later, he was discharged from the hospital and sent home, his blood anticoagulated with a vitamin K antagonist.
Massive pulmonary embolism leading to cardiac arrest a few hours after clipping of cerebral aneurysm is uncommon. We present a case of such a patient successfully treated by rescue fibrinolysis (alteplase-rTPA). Indeed, 1 month after the fibrinolysis, the patient was discharged from the ICU with his neurological state restored and good cardiac and pulmonary functions.
A review related the use of alteplase for stroke beyond the guidelines4 and described 5 patients with an unruptured aneurysm who received IV alteplase for stroke.5 Two of them had a fatal ICH. During liver transplantation, Boone et al.6 reported the successful use of low-dose rTPA (0.5–4 mg) administration in 4 patients for the treatment of intracardiac thrombosis and pulmonary embolism.
In our case, recent clipping of a ruptured aneurysm was an absolute contraindication to thrombolysis.3 However, in patients with massive and hemodynamically unstable pulmonary embolism, thrombolytic therapy has shown to rapidly improve their hemodynamics.3,7 Thus, in this case recognizing the risk of administering thrombolytic therapy, and faced with an immediate life-threatening situation, we chose to administer alteplase as a compassionate rescue therapy. The dose of alteplase was 0.6 mL/kg, as advised in case of extremely severe pulmonary embolism.7
Alternative approaches other than we used and as suggested by the guidelines might have been selected.2,3 First, indeed, surgical mechanical thrombectomy could have been performed,8 but the surgical advice we received suggested otherwise. Second, catheter-directed thrombolytic therapy could have been administered directly into the right heart or pulmonary artery as previously described.9–12 This might have reduced the overall dose of rTPA, potentially reducing bleeding complications. This type of therapy was not discussed with the radiologists. Indeed, these alternatives were difficult to manage in our case because of the extreme emergency, wherein resuscitation from cardiac arrest, hemodynamic instability, and immediate difficulty transporting the patient to the thoracic center were all considerations.
Hypothermia, which has been shown to reduce neurologic injury after pulseless electrical activity,13–15 was not performed because the patient was resuscitated after cardiac arrest in <1 minute. However, therapeutic hypothermia has been shown to be of particular benefit in patients with a short duration of cardiac arrest (<30 minutes).16 Therefore, perhaps it should have been performed in this case.
Finally, despite a low cardiac output after the cardiac arrest, we used vasopressors (norepinephrine) and not inotropic drugs such as dobutamine or epinephrine. However, the respective indications of vasopressors and inotropes are still being debated.17
In conclusion, this case report emphasizes that when the prognosis for survival is extremely poor, as was the case in our patient, physicians should consider “heroic therapy” as reflected by our use of rescue thrombolysis therapy in case of life-threatening pulmonary embolism if safer approaches such as surgical thrombectomy or catheter-directed thrombolytic therapy are not available.
1. Lansberg MG, O’Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE, Sonnenberg FA, Schulman S, Vandvik PO, Spencer FA, Alonso-Coello P, Guyatt GH, Akl EAAmerican College of Chest Physicians. . Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e601S–36S
2. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EFAmerican Heart Association; American Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology and Intervention Council; Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. . Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655–711
3. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SRAmerican College of Chest Physicians. . Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S–94S
4. De Keyser J, Gdovinová Z, Uyttenboogaart M, Vroomen PC, Luijckx GJ. Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke. 2007;38:2612–8
5. Kane I, Sandercock P, Thomas B. Can patients with unruptured intracranial aneurysms be treated with thrombolysis? Cerebrovasc Dis. 2005;20:51–2
6. Boone JD, Sherwani SS, Herborn JC, Patel KM, De Wolf AM. The successful use of low-dose recombinant tissue plasminogen activator for treatment of intracardiac/pulmonary thrombosis during liver transplantation. Anesth Analg. 2011;112:319–21
7. Masotti L, Mannucci A, Antonelli F, Maurini V, Testa R, Marchetti S, Landini G, Cappelli R. The Risk-based Treatment of Acute Pulmonary Embolism. J Clin Med Res. 2009;1:1–7
8. Leacche M, Unic D, Goldhaber SZ, Rawn JD, Aranki SF, Couper GS, Mihaljevic T, Rizzo RJ, Cohn LH, Aklog L, Byrne JG. Modern surgical treatment of massive pulmonary embolism: results in 47 consecutive patients after rapid diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg. 2005;129:1018–23
9. Nassiri N, Jain A, McPhee D, Mina B, Rosen RJ, Giangola G, Carroccio A, Green RM. Massive and submassive pulmonary embolism: experience with an algorithm for catheter-directed mechanical thrombectomy. Ann Vasc Surg. 2012;26:18–24
10. Ferrigno L, Bloch R, Threlkeld J, Demlow T, Kansal R, Karmy-Jones R. Management of pulmonary embolism with rheolytic thrombectomy. Can Respir J. 2011;18:e52–8
11. Kuo WT, Gould MK, Louie JD, Rosenberg JK, Sze DY, Hofmann LV. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol. 2009;20:1431–40
12. Eid-Lidt G, Gaspar J, Sandoval J, de los Santos FD, Pulido T, González Pacheco H, Martínez-Sánchez C. Combined clot fragmentation and aspiration in patients with acute pulmonary embolism. Chest. 2008;134:54–60
13. Roberts BW, Kilgannon JH, Mitchell JA, Mittal N, Aji J, Kirchhoff ME, Zanotti S, Parrillo JE, Chansky ME, Trzeciak S. Emergency Department inter-hospital transfer for post-cardiac arrest care: Initial experience with implementation of a regional cardiac resuscitation center in the United States. Resuscitation. 2013;84:596–601
14. Sanders AB. Therapeutic hypothermia after cardiac arrest. Curr Opin Crit Care. 2006;12:213–7
15. Lundbye JB, Rai M, Ramu B, Hosseini-Khalili A, Li D, Slim HB, Bhavnani SP, Nair SU, Kluger J. Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms. Resuscitation. 2012;83:202–7
16. Oddo M, Schaller MD, Feihl F, Ribordy V, Liaudet L. From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med. 2006;34:1865–73
17. Bracht H, Calzia E, Georgieff M, Singer J, Radermacher P, Russell JA. Inotropes and vasopressors: more than haemodynamics! Br J Pharmacol. 2012;165:2009–11