key: cord-0881808-ziizp649 authors: Kelly, A.; Head, L.; Garcia, M.; Hayes, T.; Charlesworth, M. title: Anticoagulation strategies and determining the rate of fatal intra-cerebral haemorrhage associated with VV-ECMO in patients with COVID-19 date: 2020-10-24 journal: J Cardiothorac Vasc Anesth DOI: 10.1053/j.jvca.2020.10.039 sha: 313fd6a5c033a33885fd17eb075e21df15def285 doc_id: 881808 cord_uid: ziizp649 nan In their case series reporting experience from a single centre of the first 10 patients with COVID-19 to receive venovenous extracorporeal membrane oxygenation (VV-ECMO), Usman et al. [1] describe significant clinical challenges managing anticoagulation. Four (40%) suffered intracerebral haemorrhage (ICH), three (30%) of which led to death. They advise caution in the anticoagulation of COVID-19 patients undergoing VV-ECMO, and that heparin is monitored actively and frequently. Whilst we agree that COVID-19 presents new challenges for centres providing VV-ECMO, we wish to comment on some of the limitations 2 of their study in the context of our own experiences. This will hopefully set out some of our own experiential learning as well as aid in the interpretation of their case series and its applicability to future practice. First, the number of patients included means our ability to draw any conclusions about the rate of ICH in similar, larger populations from these data is extremely limited. Although the authors acknowledge this, we wish to provide further mathematical rationale. It is possible to determine the 95% confidence interval of the proportion of those who died (30%) as 12-74%. This is a simple mathematically transformation of a nominator/denominator combination and is simply a way of incorporating sample size into any calculated proportion. A small sample size results in a wide confidence interval. It can be shown by simulating these calculations for different sample sizes that the confidence interval of any proportion is extremely sensitive to n when n is below 50, irrespective of the event rate [2] . As such, these data are useful, but the true rate of fatal ICH in patients with COVID-19 undergoing VV-ECMO may be much higher or even lower than that shown by Usman et al. Second, the authors describe the use of activated partial thromboplastin time (APTT) as the sole measure of effectiveness of anticoagulation with heparin but do not mention using any other laboratory measure. There is considerable evidence of discordance between antifactor Xa levels (which arguably better reflects heparin effect) and APTT [3] , and the use of anti-factor Xa levels alongside APTT or as a lone measure may allow for more nuanced tailoring of anticoagulation strategies, especially in the context of COVID-19 [4] . For patients with COVID-19, a prolonged APTT may indicate a specific or non-specific clotting factor deficiency, and the presence of lupus anticoagulant, which is an indirect deficiency and not associated with bleeding, may affect in-vitro tests of anticoagulation. The presence of lupus anticoagulant and a discordance between APTT and anti-factor Xa levels for patients 3 receiving intravenous unfractionated heparin was a common finding at our centre for patients with COVID-19 on VV-ECMO. At the beginning of the pandemic and before we understood the limitations of APTT monitoring in COVID-19, we were more aggressive with anticoagulation due to concerns about severe thromboembolic disease, with a starting dose of 1000 units.hr -1 unfractionated intravenous heparin titrated upwards incrementally according to the APTT. A few early cases developed fatal ICHs, which lead to a more conservative strategy of 250 units.hr -1 titrated incrementally to a maximum of 1000 units.hr -1 with twice daily anti-factor Xa levels for titration. All heparin dosing prescriptions and changes were made on a case-by-case basis and according to the overall clinical picture, usually following discussion amongst two or more consultants. We had one heparin-free run of 60 days due to airway bleeding, and experienced no associated circuit problems with this case and other heparin-free/sparse runs. Third, regarding the wider disease process, the authors describe issues with extracorporeal thrombosis and specifically, oxygenator failure. Since the start of the COVID-19 pandemic and with 37 patients treated, we have not seen an oxygenator or pump failure due to thrombosis, and certainly not to the extent described by Usman et al. However, we have found venovenous haemofiltration to be an issue, with the circuits clotting off at a higher rate than we would normally expect. This runs alongside another issue not addressed by the authors -what to do in patients presenting with thromboembolic disease, such as pulmonary embolism (present in up to 30% of patients), more so when there is radiological evidence of ICH [5] . If pulmonary embolic disease is a contributor to respiratory failure prior to ECMO, decisions about anticoagulation strategies have no easy answers. Such pathology might be seen on a whole-body CT scan and we decided, early in the pandemic, to undertake interval CT scans following admission and throughout the ECMO run. Although not without 4 risk, this was an extremely beneficial strategy to enable individual decisions to be made about anticoagulation, and we saw our ICH rate reduce as a result. Finally, in our own experience as a regional ECMO centre for the North West of England, we had 37 patients (again, with n < 50 it is difficult to generalise our experiences) with COVID-19 undergo VV-ECMO. Of these, 14 (37.8%) were discharged home and 23 (62.2%) have died. Eight (21.7%) had ICHs, of which five (13.5%) were fatal. We did not see any cases of heparin induced thrombocytopenia (HIT) in patients with COVID-19, which is usually a common occurrence (~5%) during non-COVID-19 VV-ECMO. The reasons for this are not yet known, but when HIT was suspected clinically due to, for example, a relative or absolute decrease in platelet count, we retained a high degree of suspicion and tested for it. We did not experience problems with circuitry and/or oxygenators, in contrast to the authors who described 10 circuits changes in their 10 patients, nine of which were due to oxygenator clots. Perhaps the type of equipment is important, and the magnetic levitating centrifugal pump systems we use may be associated with less thrombogenesis [6] . We have also accumulated much clinical experience with the dynamic nature of cerebral compromise associated with VV-ECMO in patients with COVID-19. We have seen subarachnoid haemorrhage, isolated intracranial haemorrhages and posterior reversible encephalopathy syndrome, sometimes in the same patient. There should always be hope for patients who develop ICH, as one case of a large ICH almost completely resolved by the end of the run, following which hospital discharge ensued. Overall, Usman et al. should be congratulated for their detailed analysis during a difficult time at the start of the pandemic, but there is now an urgent need for the analysis and publication of larger registry datasets to reveal the true incidence of problems associated with anticoagulation, together with a consensus approach on how best to tailor 5 anticoagulation strategies for individual patients. Our understanding of the neurological and haematological sequalae of VV-ECMO in patients with COVID-19 is at a very early stage and we hope we can continue to add to this understanding by learning from each other through collaboration and data sharing amongst centres. No conflicts of interest declared A Case Series of Devastating Intracranial Hemorrhage During Venovenous Extracorporeal Membrane Oxygenation for COVID-19 If it hasn't failed, does it work? On 'the worst we can expect' from observational trial results, with reference to airway management devices Activated partial thromboplastin time and anti-xa measurements in heparin monitoring: biochemical basis for discordance Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19 Understanding the COVID-19 coagulopathy spectrum Thrombotic circuit complications during venovenous extracorporeal membrane oxygenation in COVID-19 No funding or conflicts of interest to declare.