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Ignacio: Good morning and welcome to our series of interviews from the International Society of Nephrology with experts and authors of articles relevant to nephrology and COVID 19. My name is Ignacio Portales and I’m a second year nephrology fellow at the Brigham and Mass General Joint Program. Today, we are happy to have with us Dr. Allegretti. Dr. Allegretti is the director of the Nephrology ICU at Mass General and an assistant professor of medicine at Harvard Medical School. He is also the author of an original article concerning the strategies to reduce clotting in patients with COVID 19 undergoing dialysis, which was just published last year. Rosovsky, Rachel P. et al. “Filter Clotting with Continuous Renal Replacement Therapy in COVID-19.” Blood vol. 136 (2020): 22–23. doi:10.1182/blood-2020-142106.

Andrew A: Thanks for having me.

Ignacio: During the first wave of the COVID 19 pandemic, the intensive care units across the affected cities, including Boston, were at or beyond capacity with patients with COVID 19. Almost one of every five patients of this very sick population required renal replacement therapy. What were the adjustments done at your institution to handle this increase in population requiring renal replacement therapy?

Andrew A: Great question. I think when you think about the beginning of the surge, which in some ways feels like a long time ago, there are really two different levels. One was on the patient care level and one was sort of on a bigger picture supply chain and resource allocation level. Many things took us by surprise and revealed difficulties and just general care provisions in terms of PPE, staffing, ICU capacity and among them were dialysis and in particular continuous renal replacement ICU dialysis and patients who are critically ill, who represented the most dire of the of the presentations and that initial surge. So on the supply chain level, we really had to figure out where we’re going to have enough replacement fluid in dialysis and machines and staffing. Things that at American medicine, for example, we often take for granted because they’ve just always been there. It was very much not the case. So understanding that aspect was new. And then on the patient care level, we really focused on trying to understand how these patients were different, how to provide the best renal replacement therapy, how to minimize filter clotting and loss of resources and poor outcomes from a dialysis standpoint. As nephrologist, we really try not to make kidney function and dialysis delivery a limiting step in providing care for patients who are critically ill in the ICU of other things. But in this case, that was a real challenge. So we addressed that, and one of the main things we saw early was just how frequently these patients were clotting their filters and how we would take steps to mitigate that.

Ignacio: You were already mentioning something about the clotting, which we will talk a little bit more. But in general, what did the COVID 19 change in terms of how we how we prescribe renal replacement therapy in the ICU?

Andrew A: Aside from the frequency at which we were prescribing it, the incidence of severe AKI and COVID 19 ARDS was extremely high. First we did a lot of trial and error. In the beginning when there was no data and we were trying to figure out how best to deliver renal replacement therapy. We were almost exclusively running continuous renal replacement therapy, specifically CVVH and the ICUs. That was our modality of choice. We found very quickly that citrate based replacement fluid strategies, which had previously and per the evidence done pretty well at minimizing filter clotting was really not effective. So we try to increase replacement fluid rates in a pre-filter model. We tried to increase blood flow rates, sacrificing a little bit of clearance for potentially decreased rates of clotting and ran a lot more systemic heparin. All of those strategies were sort of initial, specifically systemic heparin at a rate higher than we had previously required for this population.

Ignacio: This clotting problem during dialysis is not really a new problem. It has been historically an issue with dialysis, but I don’t think any of us were so aware of it until this pandemic. You recently wrote this article addressing this problem of flooding in COVID 19, and you measure the median time of survival of these circuits and compare it across different anticoagulation strategies. What were the main findings of your article?

Andrew A: Sure. Filter typically last in a septic patient anywhere between 20 and 40 hours. But we were finding that our patients were lasting, in some cases, four to six hours, it was quite low. And so we started talking to our hematologist and our critical care colleagues. Many of these patients had other indications for anticoagulation anyway. So we introduced what we thought was going to be a reasonable stepwise approach to anticoagulation where we would start with normal strategies, normal renal replacement prescriptions and then on the first filter loss, we instituted a low dose heparin. And if you continued to clot through that, we escalate it to a systemic dose. And then finally, if that was remained unsuccessful, we escalated further still to maybe a direct thrombin inhibitor. I would say the one biggest change that we made and probably the most important one was rather than measure anticoagulation efficacy using PTT monitoring for a systemic unfractionated heparin, we chose and had the availability to measure anti factor X levels. Most of these patients came in with elevated PTT levels at baseline, such that they were already in the therapeutic range just from their systemic inflammation, their DIC, and the elevated PTT didn’t reflect necessarily their anticoagulation status, but just their critical illness. Anti Factor 10 levels weren’t affected by that, and we found that measuring that level, if it’s available at the institution that you’re at, was far more accurate.

Ignacio: That’s pretty interesting, and it seems like some of the main difference between the pre-COVID and now this COVID during the COVID pandemic was the measurement of these anti-X levels, and a lot more use of systemic heparin. What are some other findings that you had by treating these patients that were not necessarily reflected in this article and you think they are important to share?

Andrew A: Early on in the pandemic, we saw a couple of different phenotypes very frequently. We found like there was this patients with “dry ARDS”, where the imaging findings didn’t look like your typical septic patient with pulmonary edema, renal failure patient who is in anuric. There were some patients like that, for sure, but there are also these patients that just weren’t able to open their airways, but didn’t seem that volume overloaded based on clinical exam and imaging. So understanding a little bit of the physiology in the different patient phenotypes was really important. You obviously want to dry out these patients in the sense that if you have ARDS, any extra fluid that’s causing pulmonary edema is going to impair oxygenation. We certainly proned a lot more patients than we would have had previously. But proning, a patient, provides a lot of challenges to renal replacement therapy, even if you have a good, clean internal jugular renal replacement line. Those are some of the sort of in the moment points of just seeing these patients and being in the rooms with them that we sort of had to deal with that wasn’t necessarily in the paper, but just really reformatting our whole treatment approach.

Ignacio: Now as we as we see more vaccinations come in and we are hoping that that the cases of severe COVID 19 around the world hopefully will decrease. Do you think that some of the lessons learned in particularly regarding anticoagulation strategies in patients with COVID 19 will apply to some of the non-COVID-19 population?

Andrew A: I think that while there were definitely some things that were special about this disease in terms of unique management points and some of the treatment strategies dexamethasone, remdesivir have sort of borne out of that. There are many lessons that I think we can take from this. One of them is measuring the anti factor 10 levels in a critically ill patient. I think it’s totally reasonable and in fact, maybe even better to use that as your marker for anticoagulation efficacy rather than a PTT level that may be elevated at baseline in any critically ill patient. We altered our dialysis prescriptions. We had to train a whole nursing staff who’s never or infrequently has done a certain modality working with the different ICUs and communication. Being a good communicator is such an integral part to being a critical care nephrologist and working as a consultant in the ICU. The nurses were on the front lines here.

Ignacio: Well, thank you, Dr. Allegretti, I think this was a very insightful talk in both terms of the patient perspective and also just how things changed in the ICU environment. And thanks again for being with us, and we look forward to reading your next research on an intensive care unit on nephrology. Thanks all for listening.

Andrew A: Yeah. Thank you for the invitation and thank you for all for providing the care in this difficult time.