Life-threatening complications with tPA – what emergency physicians should know

Authors: Andrew Pugh, MD (Emergency Medicine Resident, University of Utah Hospitals, Salt Lake City, Utah, @DrAEPugh) and Rob Stephen MD (Emergency Medicine, University of Utah School of Medicine, Salt Lake City, Utah) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case 1

A 75-year-old male arrives at your facility via air ambulance after a 20-minute transport time, having presented to an outside community hospital with right sided hemiplegia and aphasia. Tissue plasminogen activator (tPA) administration was started at the outside facility for presumed stroke, with the infusion continued on route. On arrival, you notice unilateral right sided lip and anterior tongue swelling. The flight crew verify this was not present prior to transport.

Case 2

An 85-year-old female is given tPA after presenting to your emergency department with right sided facial droop, aphasia and right arm weakness. After 20 minutes, you notice a significant deterioration in her level of consciousness, her Glasgow coma score (GCS) declining from 15 to 11. You suspect intra-cranial hemorrhage, discontinue the tPA infusion and consider your next therapeutic options.


Background

Intravenous tissue plasminogen activator (tPA) is the fibrinolytic agent of choice for treatment of patients with acute ischemic stroke1. However, there are a number of potentially deadly complications. Bleeding, most commonly symptomatic intracranial hemorrhage (ICH), is the most common and feared life-threatening complication of administering tPA2. Another increasingly recognized complication is angioedema, which has potential to cause acute airway compromise if not recognized early3. This post will evaluate these two complications.


Angioedema

Angioedema is estimated to occur in 1.3 – 5.1% of stroke patients receiving tPA, although the risk is much higher for those patients on concomitant ACE inhibitor medications (Relative Risk [RR] 13.6) and, interestingly, in those patients with early signs of ischemia of the insular and frontal cortex on initial CT brain (RR 9.1)4,5.

Pathophysiology

The fibrinolytic effect of tPA is a product of its ability to catalyze the formation of plasmin from plasminogen6. Although the pathophysiology of tPA induced angioedema is poorly understood, it is thought to involve complement and plasmin mediated bradykinin release7. Bradykinin is a vasodilator and increases vascular permeability, allowing fluid to move into interstitial tissues. Other bradykinin mediated reactions include those seen in patients taking ACE inhibitors (the most common cause of medication induced angioedema), and in those patients with C1-esterase deficiency8. Interestingly, the swelling in tPA induced angioedema is often unilateral and opposite that of the ischemic cerebral hemisphere. This is thought to be secondary to autonomic dysfunction of the newly hemiparetic side5.

Presentation

The presentation in 95% of cases is that of unilateral, anterior orolingual angioedema7,9. The majority of cases present during or shortly after the tPA infusion is started, one study demonstrating a mean time to onset of 70 minutes from infusion initiation4,10. The majority of cases are mild and self-limiting, however, there is a risk that a few will progress to life threatening levels of edema and airway compromise (<5% of cases)11,12.

Treatment

Given that most cases are mild, often no further treatment is required other than stopping the tPA infusion and subsequent observation12. The decision to intubate can be difficult; pay particular attention to stridor, inability to handle secretions, progression of edema, and the anatomical location of the swelling itself13. Isolated anterior swelling is much more reassuring than swelling involving the posterior tongue. Intubation should be performed by the most experienced provider. Consider an awake intubation and have a clear airway rescue plan and equipment prepared. Fortunately, the need for emergent cricothyrotomy is rare12.

Medical therapy may be trialed in an attempt to stave off intubation and accelerate resolution8. Many patients receive antihistamines, corticosteroids, and epinephrine, however these agents, which are efficacious in histamine mediated reactions, are unlikely to be effective in this scenario14. Fresh frozen plasma (FFP), C1-inhibitor concentrate, icatibant, ecallintide, and even TXA are potential medical therapies with mixed evidence for the efficacy in bradykinin mediated edema, but no direct evidence for their use in tPA induced angioedema8.


But what about bleeding?

The most feared complication with intravenous tPA for stroke is symptomatic intracranial hemorrhage; the varied definitions throughout trials that have examined thrombolytic therapy account for the widely reported incidence rate of 2-7%2,15. In a systematic review and meta- analysis of 55 studies, older age, greater stroke severity, higher baseline glucose, hypertension, congestive heart failure, renal impairment, and visible acute infarction on brain imaging were all associated with increased risk16.

Systemic bleeding is less common but can be life threatening.

Presentation

Symptomatic intracranial hemorrhage should be considered in any patient in whom there is rapid neurological deterioration after tPA administration (usually within the first 24 hours)15. Neurological deterioration also has different definitions in clinical trials, but the most important and consistent features to be aware of include a ≥4-point increase in the NIHSS score and decline in GCS17–19.

Treatment

According to the American Heart Association (AHA), the principles of treating post thrombolytic symptomatic intracranial hemorrhage in the setting of ischemic stroke are similar to those used in treating spontaneous intracerebral hemorrhage and include cardiovascular and respiratory support when needed, blood pressure management, and monitoring for further neurological deterioration2.

Evidence on the best treatment strategy is limited. Most guidelines recommend fibrinogen supplementation in the form of cryoprecipitate – an initial dose of 10 packs is reasonable, with a focus on maintaining the fibrinogen level > 150 mg/dL2,20. Mechanistically, an antifibrinolytic agent such as tranexamic acid (TXA) makes sense and is usually readily available20,21. AHA guidelines reference the paucity of evidence behind platelet, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) administration, describing their use as controversial – however, in patients with thrombocytopenia (platelets < 100 000), platelets might be reasonable, and in patients with prior warfarin use, FFP or PCC should be considered in conjunction with vitamin K2. Be aware that neurosurgical treatment may be considered in select patients with symptomatic hemorrhage for whom surgery may improve outcome despite the ischemic injury – for example, in cerebellar hemorrhage with brainstem compression22. Although few patients will be amenable to neurosurgical intervention, consider neurosurgical consultation. Unfortunately, the natural history of patients with symptomatic intracranial hemorrhage is poor, with mortality approaching 50%.


Case Conclusions

Case 1

The tPA infusion is discontinued and he is subsequently admitted to the neurocritical care unit for close observation. His angioedema completely resolves over the next 72 hours without the need for endotracheal intubation.

Case 2

The tPA infusion is discontinued, and repeat CT head demonstrates a large intracranial hemorrhage. You administer cryoprecipitate and TXA immediately. Unfortunately, her GCS continues to decline, and after discussion with her immediate family and next of kin, the decision is made to focus on comfort care and allow a natural death.


Take home messages

  • Two major life-threatening complications of administration of tPA for ischemic stroke include angioedema and symptomatic intracranial hemorrhage.
  • Angioedema is usually benign and self-limited, however one must be vigilant to signs of developing airway compromise and be ready to intubate.
  • Consider symptomatic intracranial hemorrhage in any patient with neurological deterioration following tPA administration; stop the tPA infusion and get a head CT.
  • Cryoprecipitate and TXA are important first line therapies for ICH; consider platelets, FFP and / or PCC in certain populations.

References/Further Reading:

  1. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. doi:10.1056/NEJM199512143332401
  2. Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2017;48(12). doi:10.1161/STR.0000000000000152
  3. Rathbun KM. Angioedema after thrombolysis with tissue plasminogen activator: an airway emergency. Oxf Med Case Reports. 2019;2019(1):omy112. doi:10.1093/omcr/omy112
  4. Hill MD, Lye T, Moss H, et al. Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke. Neurology. 2003;60(9):1525-1527. doi:10.1212/01.wnl.0000058840.66596.1a
  5. Fugate JE, Kalimullah EA, Wijdicks EFM. Angioedema after tPA: what neurointensivists should know. Neurocrit Care. 2012;16(3):440-443. doi:10.1007/s12028-012-9678-0
  6. Molinaro G, Gervais N, Adam A. Biochemical basis of angioedema associated with recombinant tissue plasminogen activator treatment: an in vitro experimental approach. Stroke. 2002;33(6):1712-1716. doi:10.1161/01.str.0000017284.77838.87
  7. Castaneda C, Beri S, Karim S. tPA-Induced Angioedema in a Patient Taking Angiotensin Converting Enzyme Inhibitors: A Case Report and Review of the Literature. Chest. 2017;152(4):A352. doi:10.1016/j.chest.2017.08.378
  8. Josh Farkas. Internet Book of Critical Care (IBCC): Angioedema.; 2019. https://emcrit.org/ibcc/angioedema/
  9. Maertins M, Wold R, Swider M. Angioedema after administration of tPA for ischemic stroke: case report. Air Med J. 2011;30(5):276-278. doi:10.1016/j.amj.2010.12.011
  10. Myslimi F, Caparros F, Dequatre-Ponchelle N, et al. Orolingual Angioedema During or After Thrombolysis for Cerebral Ischemia. Stroke. 2016;47(7):1825-1830. doi:10.1161/STROKEAHA.116.013334
  11. Werner R, Keller M, Woehrle JC. Facial Angioedema and Stroke. Cerebrovasc Dis. 2014;38(2):101-106. doi:10.1159/000365205
  12. Matt Astin. tPA-Associated Angioedema; REBEL EM blog. Published April 3, 2014. https://rebelem.com/tpa-associated-angioedema/.
  13. Grant NN, Deeb ZE, Chia SH. Clinical experience with angiotensin-converting enzyme inhibitor-induced angioedema. Otolaryngol Head Neck Surg. 2007;137(6):931-935. doi:10.1016/j.otohns.2007.08.012
  14. Pahs L, Droege C, Kneale H, Pancioli A. A Novel Approach to the Treatment of Orolingual Angioedema After Tissue Plasminogen Activator Administration. Ann Emerg Med. 2016;68(3):345-348. doi:10.1016/j.annemergmed.2016.02.019
  15. Seet RCS, Rabinstein AA. Symptomatic Intracranial Hemorrhage following Intravenous Thrombolysis for Acute Ischemic Stroke: A Critical Review of Case Definitions. Cerebrovasc Dis. 2012;34(2):106-114. doi:10.1159/000339675
  16. Whiteley WN, Slot KB, Fernandes P, Sandercock P, Wardlaw J. Risk Factors for Intracranial Hemorrhage in Acute Ischemic Stroke Patients Treated With Recombinant Tissue Plasminogen Activator: A Systematic Review and Meta-Analysis of 55 Studies. Stroke. 2012;43(11):2904-2909. doi:10.1161/STROKEAHA.112.665331
  17. von Kummer R, Broderick JP, Campbell BCV, et al. The Heidelberg Bleeding Classification: Classification of Bleeding Events After Ischemic Stroke and Reperfusion Therapy. Stroke. 2015;46(10):2981-2986. doi:10.1161/STROKEAHA.115.010049
  18. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29(1):4-11. doi:10.1161/01.str.29.1.4
  19. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352(9136):1245-1251. doi:10.1016/s0140-6736(98)08020-9
  20. Scott Weingart, MD and Anand Swaminathan, MD FAAEM. EM:RAP Critical Care Mailbag: Alteplase Reversal. https://www.emrap.org/episode/emrap2020april/criticalcare
  21. Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of natural history and treatment. JAMA Neurol. 2014;71(9):1181-1185. doi:10.1001/jamaneurol.2014.1210
  22. Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032-2060. doi:10.1161/STR.0000000000000069

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