The Latest in Critical Care, 11/6/23 (Issue #19)

Convalescent plasma for severe Covid-19; Cryoprecipitate for massive hemorrhage (CRYOSTAT-2); Aortic balloon occlusion for trauma (UK-REBOA)

Convalescent plasma for ARDS due to Covid-19

Convalescent plasma, donated by patients after recovering from Covid-19 and distributed by the Red Cross, represented one of the many ethical and policy controversies generated by the pandemic. The therapy was approved for emergency use in 2020 by FDA after an observational study of 10 patients showed likely benefit (yes, 10, which should remind us of our collective desperation). The critical care world split into clinicians who “liked” plasma and those who held back on its use due to the lack of robust evidence.

Numerous randomized trials were performed, and were largely negative. Small positive studies were widely considered outliers, or biased. Convalescent plasma, it was concluded, didn’t help patients with severe Covid-19 as a general group. Intuitively, plasma seemed even less likely to help the very sickest of the sick— those mechanically ventilated with ARDS from Covid-19, whose mortality rate was well over 50% at many centers.

Only it turns out, it did help. Or could, anyway.

Among 475 patients with ARDS due to Covid-19, randomized within 5 days of ventilation to receive convalescent plasma or usual care (i.e., open label) at 17 sites in Belgium in 2020-2022, 35% of those receiving plasma died at 28 days, vs. 45% of the usual care patients — a number needed to treat of 10 to save one life.

The benefits were concentrated in those who received plasma in the first two days of mechanical ventilation (33% mortality vs. 47%, a NNT of 8), with no benefit observed when plasma was given after 48 hours (42% vs 40% mortality). The sicker the patients (i.e. the higher the SOFA score), the greater the observed benefit of convalescent plasma, if they received it early.

There were no adverse events directly attributable to convalescent plasma (although the high rate of adverse events attributed to Covid-19, obscured the picture).

This trial stopped slightly short of enrollment, when the less-virulent Omicron strain stopped causing ARDS.

Convalescent plasma was also previously shown to be effective at preventing severe disease in outpatients, when given in the first nine days of infection (to mostly unvaccinated U.S. patients infected with the Wuhan/Delta variants in 2020-2021).

I recall very well my (unjustified) negative view on convalescent plasma in 2020 and 2021 — it was probably minimally effective, and I would never spontaneously offer it. A large part of that reluctance, I believe, stemmed from being in the position of deciding who would receive it, guided only by my intuition: this felt abhorrent. There was a severe shortage—but it wasn’t clear for whom the limited supplies should be reserved. I defaulted to a stance where if a family requested plasma I would prescribe it, because I couldn’t say it didn’t work and there was no institutional policy controlling its use. This made no real sense and wasn’t fair, basically favoring the families with the best internet search skills (who were usually also requesting hydroxychloroquine and ivermectin). But lacking specific guidance, which would itself have been arbitrary at that time, I’m not sure what method of rationing would have been better.

Along with the aforementioned outpatient study, these results seem to confirm the utility of convalescent plasma in some severe viral illnesses. This could inform responses in future infectious disease outbreaks; one key seems to be to ensure high titers of neutralizing antibody (at least 1:320 in this study) are present in donor plasma.

How’s this for a fantasy for the next pandemic: armed with these findings, the Red Cross organizes a massive global plasma collection campaign from the outset. Tens of millions of recovered people respond by donating. A statistics-based “lives saved by plasma” clock goes up in Times Square. Fear, hatred and division still rage, but are defied by a growing tide of national purpose and individual altruism. Hey, a guy can dream. Read in NEJM

Cryoprecipitate for massive hemorrhage from trauma (CRYOSTAT-2)

Trauma is the most common cause of death for people under age 45 (with 4 million deaths/year globally), and hemorrhage causes many of those deaths. Uncertainty has persisted about the ideal blood transfusion strategy to resuscitate and support trauma victims as they are prepared to undergo surgical and other mechanical interventions to achieve hemostasis.

Massive transfusion (more than 10 units of packed red blood cells transfused in 24 hours or less) generates a coagulopathy due to depletion/dilution of clotting factors (absent from packed red cells). Although no strategy is proven superior, many centers now transfuse one unit each of fresh frozen plasma and platelets with each unit of packed RBC. Other centers transfuse whole blood (containing all these components).

Because low fibrinogen levels are associated with death from trauma, a strategy of transfusing high-dose cryoprecipitate was tested in the CRYOSTAT-2 trial. Along with standard care (massive transfusion), 1604 trauma patients at multiple centers in the US and UK were randomized to also receive 3 pools (~6 g) of fibrinogen, or not, within 90 minutes.

There was no difference in mortality (25% vs 26%) at 28 days, nor in 6-hour mortality, 12-hour mortality, 6-month mortality or 12-month mortality.

Based on this data, transfused cryoprecipitate does not seem to a merit addition as a component of massive transfusion protocols for trauma.

Thromboelastometry (e.g., TEG or ROTEM) is becoming a more widely used tool to help guide the administration of blood products in hemorrhage from trauma, although its effects on meaningful clinical outcomes remain uncertain. Read in JAMA

Aortic balloon occlusion for traumatic hemorrhage (UK-REBOA trial)

In massive hemorrhage due to trauma, a balloon can be inserted through the common femoral artery, advanced into the aorta, and temporarily occluded. This can interrupt massive blood loss and buy time for potentially life-saving damage control surgery. The intervention is called resuscitative endovascular balloon occlusion of the aorta (REBOA).

Limited data were available regarding its efficacy. It appeared to have benefits, but only at experienced centers.

In the UK-REBOA trial, 90 patients with massive hemorrhage due to torso trauma were randomized to REBOA plus standard care or standard care alone. Sixteen major UK trauma centers participated, some with more experience than others. The intervention took place in the emergency department, with device placement by ED physicians.

Only 19 patients in the intervention arm (of 46) underwent balloon insertion. The others either improved without it (n=17), deteriorated (n=2) or experienced technical failures (n=8). The balloon generally required 30 minutes to insert.

Patients randomized to REBOA experienced worse outcomes (3-hour mortality, 6-hour mortality, 24-hour mortality) and their hemorrhages took longer to control.

It was hypothesized that performing REBOA in the emergency department (as opposed to operating rooms or interventional suites) may have led to delays in definitive surgical procedures to control hemorrhage.

The trial is impressive for having been conducted at all. Overcoming the barriers of obtaining consent, performing randomization, etc., in the massively time-compressed environment of trauma resuscitation is an enormous achievement.

Because of the operational and technical factors specific to this trial, and its relatively small size, the results shouldn’t be taken as the last word that REBOA is ineffective. If REBOA is ever shown to be beneficial, the data might come from those few centers with the most accumulated experience with the technique. Besides individual operators’ technical skills, intangible factors like culture, interdisciplinary cooperation (between surgery and ED staffs) and administrative support are the secret ingredients for effective deployment of any new, technically complex invasive device with a narrow therapeutic window for effective use. Read in JAMA