Journal Pre-proof Subdural Catheter Injection of Tissue Plasminogen Activator for Residual Hematoma Post Drainage of Acute-On-Chronic Subdural Hematoma: A Novel Case Report of Two Patients Jordan Lam, MBBS, Darrin J. Lee, MD PhD, Azeem Oladunjoye, MD PII: S1878-8750(19)32622-1 DOI: https://doi.org/10.1016/j.wneu.2019.10.007 Reference: WNEU 13478 To appear in: World Neurosurgery Received Date: 1 September 2019 Revised Date: 30 September 2019 Accepted Date: 1 October 2019 Please cite this article as: Lam J, Lee DJ, Oladunjoye A, Subdural Catheter Injection of Tissue Plasminogen Activator for Residual Hematoma Post Drainage of Acute-On-Chronic Subdural Hematoma: A Novel Case Report of Two Patients, World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.10.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. 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Title: Subdural Catheter Injection of Tissue Plasminogen Activator for Residual Hematoma Post Drainage of Acute-On-Chronic Subdural Hematoma: A Novel Case Report of Two Patients Authors: Jordan Lam MBBS1, Darrin J Lee MD PhD1, Azeem Oladunjoye MD2 Affiliations: 1Department of Neurosurgery, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, Room B51 McKibben Hall, Los Angeles, CA 90033, United States of America 2 Department of Neurosurgery, San Joaquin General Hospital, 500 West Hospital Road, French Camp, CA 95231, United States of America Details of previous presentation(s): none Funding: none Acknowledgments: none Corresponding author: Jordan Lam, Department of Neurosurgery, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, Room B51 McKibben Hall, Los Angeles, CA 90033, United States of America. Jordan.lam@med.usc.edu Keywords: Acute Subdural Hematoma; Chronic Subdural Hematoma; Catheter Injection; Recombinant Tissue Plasminogen Activator; tPA; Thrombolytic Therapy Short Title: Subdural tPA for Residual SDH Post-Drainage Abstract Background: Residual hematoma following operative management of acute subdural hematoma contributes to reoperation and is cited as a reason for deferment of less invasive drainage strategies. Although local antithrombolytic therapy has been studied in intracerebral hemorrhage and chronic subdural hematoma, to date there are no reports of recombinant tissue plasminogen activator for residual hematoma post drainage for acute subdural hematoma. Clinical Presentation: Two patients presented with altered mental status secondary to acute-on-chronic subdural hematomas and underwent emergent craniotomies. The first, a 78-year-old man, had poor subdural drain output and deteriorated with seizures and evidence of a new acute subdural hematoma formation. Recombinant tissue plasminogen activator was injected through the subdural catheter on postoperative day three. The second patient, a 64-year old male, received recombinant tissue plasminogen activator postoperatively. Subsequently, both experienced good subdural drainage, clinical and radiological improvement and successful discharge to a skilled nursing facility. Conclusions: Subdural thrombolytic therapy has can improve hematoma evacuation. A potential implication of this is facilitation of minimally invasive options such as twist-drill craniotomy, previously deferred due to inadequate evacuation. However, there is a paucity of evidence and more research is needed to substantiate the safety and efficacy, refine this technique and guide patient selection. 1 2 3 4 5 Subdural Catheter Injection of Tissue Plasminogen Activator for Residual Hematoma Post Drainage of Acute-OnChronic Subdural Hematoma: A Novel Case Report of Two Patients 6 Abstract 7 Background: Residual hematoma following operative management of acute subdural hematoma 8 contributes to reoperation and is cited as a reason for deferment of less invasive drainage strategies. 9 Although local antithrombolytic therapy has been studied in intracerebral hemorrhage and chronic 10 subdural hematoma, to date there are no reports of recombinant tissue plasminogen activator for residual 11 hematoma post drainage for acute subdural hematoma. 12 Clinical Presentation: Two patients presented with altered mental status secondary to acute-on-chronic 13 subdural hematomas and underwent emergent craniotomies. The first, a 78-year-old man, had poor 14 subdural drain output and deteriorated with seizures and evidence of a new acute subdural hematoma 15 formation. Recombinant tissue plasminogen activator was injected through the subdural catheter on 16 postoperative day three. The second patient, a 64-year old male, received recombinant tissue plasminogen 17 activator postoperatively. Subsequently, both experienced good subdural drainage, clinical and 18 radiological improvement and successful discharge to a skilled nursing facility. 19 Conclusions: Subdural thrombolytic therapy has can improve hematoma evacuation. A potential 20 implication of this is facilitation of minimally invasive options such as twist-drill craniotomy, previously 21 deferred due to inadequate evacuation. However, there is a paucity of evidence and more research is 22 needed to substantiate the safety and efficacy, refine this technique and guide patient selection. 23 Background 24 The relevance of acute subdural hematoma (aSDH), with a mortality rate of 52-57% and comprising up 25 to 30% of severe head injuries, is ever increasing due to an ageing population that remains active with 26 increasing comorbidities and anticoagulant use.11,14,18,19 Despite aggressive management, reoperation rates 27 remain high principally due to recurrence or residual hematoma.4,6 28 The use of subdural injection of thrombolytic agents in chronic SDH (cSDH) has been reported to 29 successfully improve drainage in patients after inadequate evacuation of hematoma.3,7,8 However, this has 30 only been reported in one study in the context of aSDH in which three patients underwent subdural 31 urokinase injection following inadequate intraopertative evacuation of hematoma.12 32 In this paper, we report the first use of subdural recombinant tissue plasminogen activator (tPA) in two 33 patients with acute-on-chronic SDH (acSDH). 34 Case Descriptions 35 Case 1 36 A 78-year-old male presented with altered mental status, GCS 4-8, before being sedated and intubated. 37 On arrival, examination was E1 M1 VT and INR was 2.2 secondary to rivaroxaban. CT showed acSDH of 38 2.5cm maximal thickness and 1.4cm of midline shift with mass effect. The patient was administered 2070 39 units of prothrombin complex concentrate and emergently taken to the operating room for right-sided 40 craniotomy for subdural hematoma evacuation. The dura was tense and upon durotomy, there was 41 effusion of motor-oil colored subdural clot under pressure, with acute blood evacuated circumferentially 42 in the subdural space. A subdural drain was placed and the dura was tacked to the bone, reapproximated 43 and covered with DuraGen. Postoperatively, INR was 1.2 and the patient was started on Keppra. 44 Immediately postoperative CT showed improvement of mass effect and midline shift but with residual 45 hematoma of maximal thickness of 1.2cm and 0.8cm midline shift. On postoperative day one, the patient 46 was following commands, E4 M6 VT, subdural catheter drained 4mL. On postoperative days two to 47 three, the patient experienced seizures and the examination deteriorated at E1 M1 VT, the subdural 48 catheter drained 6-21mL and CT showed residual hematoma, now with an expanding acute components. 49 The patient received 0.5mg of tPA through the subdural catheter to promote breakdown of the residual 50 acute subdural. On postoperative day four, the patient’s examination improved to E2 M5 VT, subdural 51 drainage increased to 237mL and CT showed interval evacuation of much of the residual subdural with 52 maximal thickness 0.5cm and midline shift of 0.1cm. Examination improved to E4 M6 VT and drain 53 output was 74mL, 142mL and 53mL on postoperative days six to eight before removal on day eight, 54 extubation on day nine and subcutaneous heparin restarted on day ten, when the patient was discharged in 55 stable condition to a skilled nursing facility. 56 Case 2 57 A 64-year-old male presented with altered mental status secondary to a ground-level fall, GCS 13 but 58 deteriorated and was sedated and intubated. On arrival, examination was E1 M1 VT with 5mm sluggish 59 pupils. CT showed acute bilateral SDH of 1.9cm on the right and 1.5cm on the left, 1.4cm of mass effect 60 but no midline shift. The patient was emergently taken to the operating room for bilateral craniotomies. 61 The dura was tense and the operation proceeded as the first case. 62 Immediately postoperatively the next morning, the patient was following commands, E4 M6 VT. CT 63 showed improvement of mass effect and midline shift but with residual hematoma of maximal thickness 64 of 1.2cm on the left and 0.8cm on the right. Due to the large amount of residual hematoma and high 65 possibility of drain blockage, the decision was made to administer 0.5mg of tPA through bilateral 66 subdural catheters. On postoperative day two, examination was stable, subdural drainage was 143mL on 67 the right and 103mL on the left and CT showed continued decrease of subdural hematomas bilaterally, 0.2 68 on the right and 0.4cm on the left. On postoperative day three, subdural drainage was 34mL on the right 69 and 50mL on the left and both were removed. The patient was discharged on postoperative day seven to a 70 skilled nursing facility in stable condition with plan to start subcutaneous heparin on postoperative day 71 14. 72 Discussion 73 Although the indications for operative intervention in aSDH are well defined, there is poor consensus on 74 the optimal management. With little evidence supporting one procedure over another, operative strategy 75 depends on individual patient factors along with surgeon preference.1 One important operative 76 consideration is extent of hematoma evacuation, with residual hematoma leading to cSDH or requiring 77 reoperation. Reoperation rates of 9.1% after SDH evacuation and 27.9% after aSDH evacuation have 78 been reported with recurrent or residual hematoma comprising the largest proportion of these, at 38% of 79 reoperations.4,6 On the other hand, avoidance of residual hematoma must be balanced with other 80 considerations, including risk from surgery in the context of patient age, comorbidities and antithrombotic 81 or anticoagulant use. Illustrating this point, a meta-analysis of decompressive craniectomy versus 82 craniotomy for aSDH demonstrated lower rates of residual hematoma but higher morbidity and mortality 83 after decompressive craniectomy.17 This has especially important implications for elderly and/or 84 comorbid patients, whose candidacy for more invasive strategies may be less appropriate. While twist- 85 drill craniotomy is often used for cSDH, its use in aSDH has only been reported by one group due to 86 difficulties in draining an acute clot through a closed drainage system. 87 Huang and colleagues reported outcomes after twist-drill craniotomy for aSDH in a case series of seven 88 patients (age range 65-81) in which a large craniotomy was deferred due to age, comorbidities or family 89 refusal.12 Four patients showed 79-90% hematoma evacuation on postoperative CT, requiring 1-2 days of 90 drainage. In the remaining three patients, less than 20mL of hematoma was intraoperatively evacuated, 91 and as per protocol, 5,000-10,000 IU of urokinase in 2mL of saline was injected through a subdural 92 catheter, clamped for 2-4 hours. These patients subsequently showed a 70-91% hematoma evacuation on 93 CT and required 2-5 days of drainage. Favorable outcomes with no cases of rehemorrhage or ipsilateral 94 cSDH were reported at six months. This study provided a successful and intriguing first example of both 95 twist-drill craniotomy and subdural injection of urokinase to treat aSDH less invasively, thereby limiting 96 the elevated operative risk of larger craniotomies or craniectomies. Further, minimally-invasive 97 stereotactic craniotomy in conjunction with thrombolytics have been used for operative clot evacuation in 98 intracerebral hemorrhage (ICH), with the (Minimally Invasive Surgery Plus Alteplase for Intracerebral 99 Hemorrhage Evacuation) MISTIE trials substantiating the safety and efficacy for the procedure.10,15,16 100 In contrast to urokinase used in the three patients treated by Huang and colleagues, tPA was used in our 101 patient.10 tPA offers a theoretical advantage of higher specificity to fibrin compared to urokinase and 102 some in vitro studies have shown faster rates of thrombolysis compared to urokinase.2,9 In clinical studies 103 however, both agents show similar fibrinogenolysis, outcomes and complications, including a 104 retrospective comparison of tPA versus urokinase for thrombolytic evacuation of spontaneous ICHe.5,13 105 In our first patient, tPA was administered on postoperative day three. Our decision was not based on 106 predefined measurements at a single timepoint, rather a dynamic, multifactorial decision based on the 107 patients deteriorating examination, poor subdural drain output and evidence of both residual and acute 108 component of hematoma on CT imaging. In contrast, tPA was administered to the second patient 109 immediately postoperatively, the decision based on the large residual on postoperative CT, similar to 110 Huang and colleagues, who administered thrombolytic therapy immediately postoperatively based on 111 intraoperative evacuation volume.10 It was felt that subdural thrombolytic therapy would reduce the risk 112 of subdural drain blockage from the clot. 113 The advantage of subdural thrombolytic therapy to increase hematoma evacuation following operative 114 aSDH is minimization of the residual hematoma, which may reduce reoperation rates.4 This has important 115 implications for operative strategy: surgeons who may have performed a more invasive procedure for 116 maximal clot evacuation may opt for a less invasive procedure with the option for thrombolytic therapy to 117 increase drainage postoperatively with associated lower operative risk.17 Further, improved hematoma 118 drainage from thrombolytic therapy may facilitate the consideration of procedures previously deferred 119 due to inadequate drainage, such as twist-drill craniotomy.12 Thus, aSDH patients unsuitable for larger 120 procedures such as craniotomy or decompressive craniectomy, due to comorbidities, medications or 121 refusal, may benefit from less invasive procedures such as twist-drill craniotomy in combination with 122 thrombolytic therapy. Local thrombolytics therapy to facilitate less invasive operative strategies has also 123 been demonstrated in intracranial hemorrhage and to a lesser extent cSDH and is in keeping with a 124 universal trend of minimally invasive surgery to reduce operative morbidity and mortality.3,7,8 125 As the only two patients treated with subdural tPA and among only five treated between with any 126 subdural antithrombotic therapy for SDH with an acute component, the safety and efficacy of this 127 technique remains to be proven. Moreover, the impact of a variety of factors is unknown, including 128 patient factors, dose and timing of injection. Certainly, more research is needed to study outcomes, refine 129 this technique and guide patient selection. 130 Conclusions 131 We report the first two cases of subdural injection of tPA following drainage of acSDH, with subsequent 132 clinical and radiological improvement and favorable outcome. 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Serial noncontrast CT head imaging of case 2 200 201 a – preoperative, showing acute-on-chronic bilateral SDH of 1.9cm on the right and 1.5cm on the left, 1.4cm of mass effect but no midline shift. 202 203 b – immediately postoperative, pre-tPA, showing improvement of mass effect and midline shift but with residual hematoma of maximal thickness of 1.2cm on the left and 0.8cm on the right. 204 205 c – postoperative day two, post-tPA, showing continued decrease of subdural hematomas bilaterally, 0.2 on the right and 0.4cm on the left. 206 207 208 aSDH acute subdural hematoma acSDH: acute-on-chronic subdural hematoma cSDH: chronic subdural hematoma GCS: Glasgow coma scale INR: international normalized ratio tPA: tissue plasminogen activator