key: cord-0876120-025ioy3r
authors: Usman, AA; Han, J; Acker, A; Olia, S; Bermudez, C; Cucchiara, B; Mikkelsen, ME; Wald, J; Mackay, E; Szeto, W; Vernick, WJ; Gutsche, JT
title: A Case Series of Devastating Intracranial Hemorrhage during Venovenous Extracorporeal Membrane Oxygenation for COVID-19
date: 2020-07-28
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2020.07.063
sha: 72a89caae6430febc65e1daa336c7eee25d30820
doc_id: 876120
cord_uid: 025ioy3r

OBJECTIVE Anticoagulation may be a challenge in coronavirus disease 2019 (COVID-19) extracorporeal membrane oxygenation due to endothelial injury and dysregulation of coagulation, which may increase the risk of thrombotic and bleeding complications. This report was created to describe the authors' single institutional experience, with emphasis on the high rate of intracranial hemorrhage for the first 10 patients with COVID-19 placed on venovenous extracorporeal membrane oxygenation (VV ECMO). DESIGN Case series, retrospective analysis. SETTING Single institution. PARTICIPANTS Ten patients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patient characteristics, mortality, stroke rate, and length of stay data were collected in all patients. In addition, laboratory values of D-dimer and C-reactive protein and standard measurements of prothrombin and activated partial thromboplastin time were collected on all patients. Ten patients, each confirmed with COVID-19 via reverse transcription-polymerase chain reaction, were supported on VV ECMO for acute respiratory distress syndrome (ARDS) for a mean duration of 9.4 ± 7 days. Four of 10 patients had hemorrhagic strokes, 3 of which resulted in death. At 30 days after initiation of VV ECMO, a total of 7 survivors included 6 patients discharged from the hospital and 1 patient who remained in the intensive care unit. CONCLUSIONS In this small study of 10 patients, intracranial hemorrhage was a common complication, resulting in a high rate of death. The authors urge caution in the anticoagulation management of VV ECMO for patients with severe ARDS and COVID-19 patients. Close monitoring of all hematologic parameters is recommended during ECMO support while awaiting larger, multicenter studies to examine the best practice.

Infection with severe acute respiratory coronavirus (SARS-CoV2) was designated a worldwide pandemic in March of 2020. Corona Virus Disease 2019 , the illness caused by SARS-CoV2, has rallied the world behind efforts to investigate and report the optimal clinical management and treatment for this disease. Despite maximal medical therapy, COVID-19 can progress to severe, refractory acute respiratory distress syndrome (ARDS) prompting clinicians to consider utilization of extracorporeal membrane oxygenation (ECMO) in appropriate cases, although early reports appeared to have high rates of mortality. 1 In general, patients with severe ARDS supported with VV ECMO are anticoagulated to reduce the risk of circuit clot or associated venous thromboembolism. Patients with COVID-19 demonstrate complex pathophysiology with multi-organ involvement; in particular, changes in patients' coagulation profiles stemming from the combination of inflammation and vascular endothelium activation. 2, 3 In addition, arterial and venous thrombosis appears to a potential source of the organ dysfunction seen in COVID-19 patients. 4, 5 The risks and benefits of anticoagulation and the complex interplay between COVID-19 infection, inflammation, and hypercoagulability in this population remains unstudied in the setting of VV ECMO.

This case series describes our single institutional neurological outcomes for the first ten patients placed on VV ECMO for COVID-19, of whom three had severe intraparenchymal hemorrhagic strokes resulting in death, one patient had a small subarachnoid hemorrhage and one patient had severe gastrointestinal bleeding. This case series describes a hemorrhagic stroke rate that far exceeds that expected for VV ECMO treatment in severe ARDS.

This study was approved by the institutional review board at the University of Pennsylvania. Our ECMO team consists of a multi-disciplinary group that have managed a robust VV-ECMO lung rescue program including the ability to perform mobile ECMO. 6, 7 A decision was made to continue utilizing VV-ECMO during the COVID-19 pandemic with rigorous, multidisciplinary patient selection. Due to limited access to ECMO circuits and concern about an overwhelming number of consults for ECMO, we restricted our previously published criteria 8 to the following: All patients in this study were cannulated at our institution or at an outside hospital by our mobile ECMO team, and were subsequently admitted to specialized units staffed by critical care specialists and highly skilled ICU nurses trained in ECMO management.

ECMO circuits were standardized per our institutional practice. Cardiohelp and Rotaflow (Maquet Getinge Group, Germany) devices were used for all patients, with standard cannulation using a femoral venous inflow cannula and a right internal jugular outflow cannula. Patients' pump settings and lab values were obtained at close intervals for pre-and post-oxygenator monitoring. Standard safety check lists included safety hand crank, wall, as well as tank oxygen supply were permanently placed at the bedside.

Our standardized protocol for anticoagulation of patients on VV-ECMO utilizes a heparin infusion targeting an aPTT of 40-50 seconds and 50-60 seconds if oxygenator failure or evidence of clotting occur. Reference range for normal aPTT at our institution is 21.8 -32.5 seconds. One patient was anticoagulated with a bivalirudin infusion due to problems with recurrent clotting of their continuous renal replacement therapy circuit while on a heparin infusion prior to ECMO support. All patients at the time of cannulation received a standard 50 unit/kilogram intravenous unfractionated heparin bolus. Heparin infusion was started after cannulation and adjusted per our institutional provider-driven protocol, with aPTT measured every six hours initially and every twelve hours once target range was achieved. Additional standard lab values were collected at daily intervals including d-dimer, ferritin, fibrinogen, PTT, PT, INR, and platelet counts.

Between 3/21/2020 to 4/25/2020, patients meeting inclusion criteria with severe refractory ARDS due to COVID-19 who failed a trial of proning therapy with a muscle relaxant infusion were placed on VV ECMO. Patients were considered if their PaO2/FIO2 was < 80 on 100% oxygen with appropriate positive end expiratory pressure. 9, 10 Retrospective chart review was performed on all patients with COVID-19 requiring VV ECMO. All data was reviewed by two independent reviewers AAU and JH. Data was placed in Excel 2019 (Microsoft). Data was summarized with means, standard deviations, and proportions within each cohort. Each cohort was analyzed and compared using a χ2 test or Fisher's Exact test for categorical variables and Kruskal-Wallis tests for continuous variables. All analyses were performed using Stata 14 (StataCorp, College Station, TX), and a p<0.05 was defined as statistically significant. Data for patient specific averages are reported as mean +/-25 th /75 th quartile ranges. Data for laboratory data is reported as mean +/-standard deviation.

The primary outcome was incidence of any type of stroke for the duration of VV ECMO. A diagnosis of stroke was suspected based on bedside findings of focal neurologic deficits, notably an abnormal pupillary exam in cases treated with heavy sedation and neuromuscular blockade agents. A stroke alert with a formal emergency neurology consultation and a CT scan was obtained in all cases of suspected stroke. Intracranial bleeding was categorized as subarachnoid hemorrhage (SAH), Intraparenchymal hemorrhage (IPH), or Intraventricular extension of IPH. Ischemic stroke was defined by large vessel occlusion and evidence of ischemia or infarction on CT scan. Secondary outcomes evaluated include total days of ECMO support, time to decannulation, time to tracheostomy and 30-day survival. We also evaluated patients for 30-day neurological status post admission, number of circuit exchanges required for oxygenator clot, CVVH circuit exchange events due to clot, and evidence of pulmonary embolism. Lab values were also recorded and analyzed daily and at the time of stroke evaluation.

Ten patients, each confirmed COVID-19 cases via RT-PCR, were cannulated for VV ECMO for were temporally related to the 24-hour period preceding the stroke diagnosis. The fibrinogen level on average was higher in the stroke patients versus the non-stroke patients 513.7 +/-69.6 versus 344.4 +/-46.03 (p < 0.001). There was a total of 10 circuit exchanges during the total of 167 ECMO days in the 10 patients. 8 out of 10 circuit exchanges occurred in the patients with stroke. All 8 circuit exchanges occurred due to rapidly declining oxygenator function due to clot with a PaO2/Fio2 <200 on 100% oxygen. One circuit exchange occurred in the non-stroke group due to oxygenator clot and the last circuit exchange occurred in order to make a mobile transport console available for clinical use. All 6 patients without stroke were neurologically intact and participating in physical therapy at the time of discharge.

To our knowledge, this report is the first of its kind to focus on the rate of intracranial hemorrhage for COVID-19 patients on VV ECMO. COVID-19 is a new disease and it is important to report early institutional experiences which may impact patient management at other ECMO hospitals. To better understand how unusual this rate of ICH is in VV ECMO, we reviewed the literature. Nasr et al., analyzed data from the nationwide inpatient sample from 2001 -2011, including 8,398 adults who received VV or VA ECMO. 11 The authors found that 10.9% suffered neurologic complications but only 3.6% had ICH. This sample, although large, included VA and VV ECMO which have different anticoagulation requirements and risk profiles.

In addition, this study did not report if the ICH occurred while patients were on ECMO or after decannulation, but only noted that ICH occurred prior to hospital discharge. Lorusso and colleagues, analyzed data from the Extracorporeal Life Support Organization to assess the incidence of neurologic outcomes in patients supported with VV-ECMO. In an analysis of 4,988 patients supported with VV ECMO for non-COVID-19 related respiratory failure, ICH was diagnosed in 181 (3.6%) patients with a mortality of 79.6%. 12 The Cesar Trial found neurologic injury was observed in 4% of patients, however the type of neurologic injury was not differentiated into subtypes. 13 In the EOLIA trial, of the 124 patients randomized to ECMO support, 3 patients suffered from hemorrhagic stroke. 14 Our center has extensive experience offering ECMO to patients with severe ARDS including a mobile program which has been able to continue implementing ECMO cannulation in regional hospitals in a limited fashion during this pandemic. To date, at our institution, we have had less than 1% intraparenchymal hemorrhage during non-COVID lung rescue VV ECMO in 266 patients since 2015.

This unprecedented intracranial hemorrhage rate in COVID related ARDS requiring VV ECMO has prompted an evaluation of our anticoagulation practice by experts in hematology and neurology. In an abundance of caution, we are now using VTE prophylaxis dose 5000-7500 units of subcutaneous heparin three times a day and 81 mg of aspirin daily for COVID-19 patients on VV ECMO. Using VTE prophylaxis alone has been utilized by others. Krueger et al.

in 2017 described their experience with sixty-one patients with subcutaneous enoxaparin alone. 15 The authors found thrombotic complications in four patients, three of them in the centrifugal pump after a runtime of more than 5 days. No Intracranial hemorrhages were reported in this single center retrospective analysis. We opted for this approach after extensive discussion with hematology and neurology experts keeping in mind the fatal nature of the IPH we experienced. Although we temporarily ceased using heparin infusions in COVID-19 ECMO patients, we have not yet experienced an increase in fatal thrombotic complications or reduced circuit durability.

The three initial reports from Wuhan, China reported the use of ECMO in 4/36, 6/52, and 5/173 critically ill COVID-19 patients. 3, 16, 17 The neurological outcomes for ECMO patients in these studies were not reported. Recently, Jacobs et al. describes the outcomes of 32 ECMO patients in 9 hospitals. 18 Fifteen patients were decannulated and ten of these patients had died. One patient death was attributed to intracranial hemorrhage and two to DIC. The Extracorporeal Life Support Organization has created a live COVID ECMO dashboard and to date, May 23, 2020, the report records 591 completed ECLS runs with a total of 1 stroke (<1%) and 35 intracranial hemorrhage (5%). 19 The granular neurological and hematological outcomes data for COVID-19 from the currently published literature is limited and it remains unclear if centers are experiencing similar rates of intracranial hemorrhage or bleeding complications such as DIC.

Evidence is mounting that a subset of COVID-19 ICU patients can progress to a disseminated intravascular coagulopathy (DIC). 20, 21 Elevated D-Dimer and fibrin/fibrinogen-degradation products have been identified as an early marker for disturbances in the coagulation pathway, whereas abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are relatively uncommon in initial presentations. 4 It is also possible that aPTT may inadequately measure anticoagulation levels in patients with COVID-19, but it is unclear why this would only manifest as increased bleeding in VV-ECMO patients. For future patients, we will consider using heparin assay results in conjunction with aPTT to guide anticoagulation. Prior to 2015, our institution regularly used activated clotting time to guide anticoagulation with heparin infusion.

Anecdotally, our patients suffered from much higher rates of bleeding complications in that era.

VV-ECMO bleeding is typically associated with platelet dysfunction. 22 , 23 Based on our results, patients who suffered from stroke had more ECMO circuit exchanges. This may simply be a marker for a prothrombotic state or risk for microvascular thrombosis that resulted in parenchymal cerebral hemorrhage.

COVID-19 appears to be an independent risk factor for coagulopathy and thrombosis, however the mechanism and pathophysiology is currently under active investigation. There have been reports of high rate of thrombotic complications including VTE and stroke. However, the neurological and hematological outcomes of COVID-19 are still emerging, even with pathology report data appear to indicate that thrombosis is the more common problem. 24 It is essential to tease out the degree of contribution to coagulopathy from COVID-19 in multiorgan system illness. ARDS, paralysis, and critical illness itself has been demonstrated to be a risk factor for thrombosis. It is unclear why the rate of ICH in our COVID-19 population was so high, but it may be related to vascular inflammation associated with COVID-19. 25 There is continued evidence that COVID-19 results in a cytokine storm and inflammatory cascade that may be exacerbated by extracorporeal circuitry and may be attenuated by anti-inflammatory agents (i.e., corticosteroids). 26 In addition, biomarkers associated with thrombosis, such as d-dimer, and actual thrombotic event rates have been consistently elevated in COVID-19. 25, 27 Further study, designed to test the balance of required anticoagulation in COVID-19 patients on ECMO are warranted.

There are several limitations to the study which include the low number of patients studied. This report hopes to emphasize early reporting of sentinel unexpected events; however, results may be difficult to interpret due to low numbers. Additionally, this represents a single institutional outcome. ECMO selection criteria vary from center to center, in addition ECMO capabilities fluctuate based on the level of the COVID-19 surge capacity of a hospital system. Furthermore, anticoagulation policies may vary across institutions. Finally, conventional coagulation studies such as aPTT testing may have limited predictive value for actual coagulation status in COVID-19 and perhaps institutions should consider routine viscoelastic testing for this special patient population.

Our report demonstrates the other hematologic spectrum of COVID-19, in particular in the setting of anticoagulation and extracorporeal devices. This report highlights that this disease we now are grappling with is not just a prothrombotic disease; rather, a disease that causes severe imbalance in bleeding and thrombosis risk; in particular with extracorporeal circulation. Based on our results we urge close evaluation of anti-coagulation strategies during the use of VV ECMO in COVID-19. Furthermore, we suggest all ECMO programs internally evaluate their anticoagulation protocols. Close neurological monitoring is recommended based on this limited case series. Rapid reporting of complications remains essential as clinicians around the world apply various potentially lethal treatment modalities to this pandemic illness. 

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.