Tag Archives: resuscitation

Resuscitation

Artificial Platelets Under Development!

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Uncontrolled bleeding is the bane of trauma professionals everywhere. Early in a resuscitation, we focus on identifying potential sources. We’ve developed numerous techniques for plugging them up. And we have processes in place to replace the blood that’s been lost.

Unfortunately, blood products are a perishable item. Packed red blood cells have a typical shelf-life of 42 days. Whole blood lasts only 21-35 days. Plasma is only suitable for up to five days once thawed. However, it can be frozen and used only when needed.

Platelets are another short-lifespan product, typically lasting only five days. This is a major reason for the relative lack of availability, especially at smaller hospitals. Unfortunately, freezing them or attempting cold storage renders them less active. For this reason, the platelet shortage persists.

As you know, platelets are fragments of cells produced by the bone marrow that have a major function in hemostasis. They bind to injured surfaces of disrupted blood vessels. Seconds later, they become activated and begin to clump with other platelets. They also release factors that result in fibrin deposition, creating a clot that helps stop bleeding.

Researchers have been trying to develop artificial blood substitutes for decades. I remember reading about rat experiments using these products in the 1980s. Unfortunately, they remain experimental to this day.

I found a recent article describing recent work on artificial platelets that piqued my interest. It was published by the biomedical engineering groups at North Carolina State University and UNC Chapel Hill. They used nanoparticles made of an ultrasoft microgel that were similar in size and shape to natural platelets. Fibrin-binding antibody fragments were embedded on the surface. These were selected to target only activated fibrin and not circulating fibrinogen.

Source: Science Translational Medicine

The groups devised a rat and pig trauma model by creating a liver laceration and then infusing varying doses of the artificial platelets (AP). Postmortem analysis of the wounds showed:

  • The APs did home in on the injured sites and were found in the injured areas
  • There was increased fibrin deposition at the wound site when compared to saline controls
  • Less bleeding was seen in the animals that received the APs vs saline
  • No significant deposition of APs was found in other tissues
  • The APs were excreted in the urine of the animals

Bottom line: This is very exciting, if preliminary, work. These artificial platelets are relatively easy to produce and can be frozen or stored at room temperature for extended periods. They appear harmless to the animals and decrease bleeding from the liver injury.

I am still somewhat cautious in my assessment. This same excitement was present 40 years ago in the early years of artificial hemoglobin solutions. And look where we are now. But, fingers crossed, there may be a solution to our chronic platelet shortage at some point in the future.

Reference: Ultrasoft platelet-like particles stop bleeding in rodent and porcine models of trauma. Sci Transl Med. 2024 Apr 10;16(742):eadi4490. doi: 10.1126/scitranslmed.adi4490. Epub 2024 Apr 10. PMID: 38598613.

Technology

First, There Was REBOA, And Now… GROA?!

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REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) is a “newer” resuscitative technique that has actually been around since the Korean War. It was first used to treat two injured soldiers, and although they ultimately died, it spurred research into the technique and its applications.

Balloon occlusion techniques were then adopted by vascular surgeons and were found to be useful as an adjunct in managing ruptured abdominal aneurysms. A slow trickle of studies on human use in trauma began to surface. But when autopsy studies carried out during the Gulf War showed that uncontrolled torso hemorrhage was a major cause of death, research in the technique exploded.

First, there were a rash of pig studies evaluating the feasibility of using a percutaneously placed occlusion device in the early 2010s. This transitioned to human studies around 2014, and after that we were off to the races. Over 100 papers on REBOA are now published each year.

REBOA has been shown to have some advantage in patients with abdominal or pelvic sources of bleeding. The catheter is inserted in the groin and the balloon inflated in one of two zones, depending on the location of the hemorrhage (see diagram below). For abdominal bleeding, it is inserted just above the diaphragm in Zone I. For pelvic bleeding, it is inserted below the takeoff of the visceral arteries and above the aortic bifurcation, in Zone III.

In the US, REBOA catheters are only inserted upon arrival to the hospital. There are a few random reports of field placement where a physician is part of the prehospital team. By definition, this technique is generally not available in austere environments, only upon arrival in the emergency department.

Researchers at the University of Michigan began looking for an alternative technique that could be applied in the field by non-physicians. They noted the close anatomic relationship of the distal esophagus, proximal stomach, aorta, and thoracic vertebrae, and designed a device to compress the aorta against the spine in this area.

They developed a prototype device which they named GROA (gastro-esophageal resuscitative occlusion of the aorta). It consists of a gastro-esophageal tube with an ovoid balloon, an air pump with pressure measurement device, and an external compression device. Here is a picture of the device:

And here’s a diagram of what it looks like when inserted:

The tube is inserted and the balloon inflated. The external compression device is then placed around the patient, with the top plate located over the epigastrium and the bottom plate under the patient. It is designed to apply anterior pressure over the balloon, but to avoid circumferential constriction of the abdomen.

Bottom line: This device is an interesting development in the balloon occlusion space. As with early studies of REBOA, GROA is currently being investigated using a pig model. If it appears to be beneficial, it will still be several years before it makes the jump to human subjects. If effective, this concept would allow prehospital providers to apply some degree of hemorrhage control when it originates in the abdominal cavity.

There are currently exactly three papers on this new technique, and I have included the references below if you are interested in reading them. I’m sure there are many more to come and it may eventually be competing with REBOA for journal space.

There is one consideration to be aware of when reading these papers that is similar to much of the research on REBOA. Two of the authors have a financial interest in the company that licenses the GROA technology. And in the most recent study, another one of the authors is an advisory board member for one of the manufacturers of REBOA catheters. For these reasons, it is less likely that they will publish papers that are not favorable to the product. So read critically!

References:

  • Gastroesophageal resuscitative occlusion of the aorta: Physiologic tolerance in a swine model of hemorrhagic shock, Journal of Trauma and Acute Care Surgery: December 2020 – Volume 89 – Issue 6 – p 1114-1123 doi: 10.1097/TA.0000000000002867
  • Gastroesophageal resuscitative occlusion of the aorta prolongs survival in a lethal liver laceration model, Journal of Trauma and Acute Care Surgery: May 2022 – Volume 92 – Issue 5 – p 880-889 doi: 10.1097/TA.0000000000003444
  • Tandem use of Gastroesophageal Resuscitative Occlusion of the Aorta followed by REBOA in a Lethal Liver Laceration Model, Journal of Trauma and Acute Care Surgery: June 10, 2022 –  doi: 10.1097/TA.0000000000003719
Resuscitation

Best Of EAST #1: When Is MTP Blood Use Too Much?

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The 35th Annual Scientific Assembly of the Eastern Association for the Surgery of Trauma (EAST) begins in only a month! I will be there, sitting in the front row listening to all the great presentations. As usual, I have selected some of the abstracts that I find most interesting and will be sharing my thoughts on them with you over the coming weeks.

Let’s start out with a paper about the massive transfusion protocol (MTP). Blood has always been a scarce resource. And now, thanks to COVID, it is becoming even more so. Every trauma professional reading this has likely been involved in a trauma resuscitation that has used dozens of units of blood and other products. Unfortunately, most of the patients who require this much do not survive.

How does one balance the rapid use of many, many units of blood products with the (un)likelihood of survival and the impact of having less blood for other patients in your hospital or future incoming trauma patients? In other words, when does the use of additional blood become futile? Until now, there have been no real answers to these questions.

The trauma group at George Washington University did a deep dive into the TQIP database seeking some guidance on this topic. They reviewed five years of data, targeting patients who received at least one unit of blood within four hours of arrival. Four-hour and 24-hour mortality was analyzed to determine the point at which additional blood products did not improve survival.

The authors looked at the data two ways. They analyzed the results for all comers, as well as for patients who received balanced resuscitation. Balanced was defined as a red cell to plasma ratio in the range of 1:1 to 2:1. Results were controlled as best as possible for age, sex, race, highest AIS in each body region, comorbidities, advanced directives, and the type of surgery performed to control bleeding.

Here are the factoids:

  • Nearly 100,000 patient records were analyzed, and about 30,000 patients were found to have balanced resuscitation
  • In the all-comers group, mortality plateaued after 41 units at 4 hours and 53 units at 24 hours
  • In the balanced resuscitation patients, mortality plateaued at 40 units (4 hours) and 41 units (24 hours)

The authors concluded that this data should be used as markers for resuscitative timeouts to assess the plan of care.

My comments: This paper is very focused and provides some apparently straightforward results. However, it required some sophisticated statistical analysis to sift through the many variables that need to be controlled to obtain meaningful results. From reading the abstract, it appears that they did a good job of this.

I believe the lower number of units needed by 24 hours in the balanced resuscitation group demonstrates the benefit of getting the MTP ratios right. Non-balanced resuscitation is less efficient / effective and requires the use of more products to hit the mortality plateau.

This paper supports my opinion that a resuscitation timeout is a useful tool in helping us protect our valuable blood product resources and ensuring availability for as many patients in need as possible. What would this look like? Here are my thoughts:

  • Assign one person to monitor the MTP process in real-time. This obviously cannot be the surgeon or a member of the anesthesia team. Or even the operating room crew, as everyone will be very busy. The best practice I’ve seen is to have a dedicated trauma nurse or APP in the ED/OR recording the process on a specialized form and directing which units to give to keep the resuscitation balanced.
  • Call a timeout when the magic threshold is reached. This paper suggests that 40 is a good number.
  • Require that another trauma surgeon come into the room and review the patient condition, operative findings, and progress thus far. The two surgeons should then come to a consensus regarding utility vs futility of further surgery. Based on that decision, the operative procedure either continues or stops.
  • If the operation is to continue, then more timeouts should occur after a defined number of additional products are given.

Here are my questions for the authors / presenter:

  • The statistical analysis required is fairly advanced. Please explain in simple language why the specific regression analysis with bootstrapping was selected.
  • How do you envision applying the thresholds discovered in your paper?

This is an exciting paper and provides important information about the MTP process. I’m looking forward to hearing it in person!

Reference: CRESTING MORTALITY: DEFINING A PLATEAU IN ONGOING MASSIVE TRANSFUSION, EAST 25th ASA, oral abstract #14.

Resuscitation

Are You A TXA Believer, Or TXA Hesitant?

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I’ve visited several hundred trauma centers over the past 25 years, and recently I’ve begun to appreciate that there are two camps when it comes to the use of tranexamic acid: the TXA believers and the TXA hesitant.

There have been a number of large studies that seem to suggest a benefit with respect to survival from major hemorrhage, particularly if given soon after injury (CRASH-2, MATTERs). This drug is dirt cheap and has been around a long time, so it has a clearly defined risk profile.

However, many of those hesitant to use it point to the possibility of thromboembolic events that have been sporadically reported. Several years ago, I did my own literature review and found that the number of thrombotic events from TXA was nearly identical to that of transfusing plasma.

JAMA Surgery just published a large systematic review, meta-analysis, and meta-regression that sought to examine the association between thromboembolic events (TE) in patients of any age and involving all medical disciplines, not just trauma.

The anesthesia group at the University Hospital Frankfurt in Germany did a systematic search of the Cochrane Central Register of Controlled Trials, as well as MEDLINE, for randomized controlled trials involving TXA. They covered all published studies through December 2020.

The authors adhered to standard guidelines for con-ducting reviews and meta-analysis (PRISMA). They specifically searched for outcomes involving TEs, such as venous thromboembolism, myocardial infarction or ischemia, limb ischemia, mesenteric thrombosis, and hepatic artery thrombosis. They also tallied the overall mortality, bleeding mortality, and non-bleeding mortality.

Here are the factoids:

• A total of 216 eligible trials were identified that included over 125,000 patients

• Total TEs in the TXA group were 1,020 (2.1%) vs 900 (2.0%) in the control group

• Studies at lowest risk for selection bias showed similar results

Bottom line: The authors concluded that IV TXA, irrespective of the dose, does not increase the risk of thromboembolic events. Period.

Hopefully, this is the final study needed to convince the TXA hesitant that it is safe to administer. They may still argue the efficacy, but at less than $100 per vial it is becoming impossible to ignore.

Reference: Association of Intravenous Tranexamic Acid
With Thromboembolic Events and Mortality A Systematic Review, Meta-analysis, and Meta-regression. JAMA Surgery 156(6):3210884, 2021.

Resuscitation

Best Of AAST 2021: Are We Getting Better At Balanced Resuscitation?

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The way we resuscitate major trauma patients has been changing over the past decade. Even the 10th edition of the ATLS course has recognized that so-called balanced resuscitation is important. This concept limits the use of crystalloid and relies more heavily on blood component administration in ratios that more closely approximate whole blood.  Balanced resuscitation typically translates as the use of less than two liters of crystalloid, and blood product transfusion ratios of 1:1 to 2:1 (PRBC to plasma).

We have also recognized the critical importance of rapid control of major hemorrhage, which is best accomplished in an operating room.  The group at the University of Arizona massaged the TQIP database to see if these changes are having a significant impact on our patients.

They looked at five years worth of data, specifically reviewing information on adult patients with both transfusion and laparotomy occurring within four hours of arrival. The authors performed regression analyses to identify trends over the study period.

Here are the factoids:

  • Nearly 10,000 patients met study criteria with a mean age of 44 and ISS 34
  • Patients were in shock, with mean SBP 78 and median number of transfusions of 9 PRBC and 6 plasma
  • Time to laparotomy decreased from 1.87 hours to 1.37 hours over the five year period
  • 24-hour mortality decreased from 23% to 19% during the study
  • Blood product ratio decreased from 1.93:1 to 1.73:1
  • The authors state that the blood product ratio was independently associated with 24 hour mortality (odds ratio of 1.09) and in-hospital mortality (1.10) (??)

The authors conclude that resuscitation is becoming more balanced and time to surgery shorter, with a significant improvement in mortality.

Bottom line: Well, this is an interested study of associations. It uses a large database, which of course limits some of the information available. There are obvious trends toward faster time to OR (by 30 minutes) and a 4% improvement in survival. But the transfusion ratio really looks to be about the same. 

Let’s do the math, assuming that an average of 10 units of PRBC were given. A ratio of 1.93 would mean that 5.2 units of plasma were give (1425 cc, assuming 275 cc per unit). The ratio of 1.73 noted in 2017 would then be 5.8 units, or 1590 cc. This is an increase in FFP transfusion of 165 cc.

The authors stated that the improvement in transfusion ratios was statistically associated with the improvement in survival. I think this is one of those situations where there is a big difference between statistical significance and clinical significance. Do you really think that giving just 165 additional ccs of plasma could have that much overall effect on survival?

My suspicion is that there is a true association between the more rapid time to OR (and presumably surgical control) and survival. It’s just that the numbers were not clean enough to meet statistical rigor.

This is an interesting abstract, and shows that we are slowly getting better at controlling bleeding. But I think the most important takeaway is that we are not as good at balanced resuscitation as we think we are. We seem to be hovering at the 2:1 ratio, and only very slowly moving toward 1:1.

Questions for the authors / presenter:

  • Were you able to see a correlation between time to OR and survival?
  • Please comment on the association between transfusion ratios and survival, especially given the very small change over time.
  • Please clarify the in-hospital mortality and 24-hour mortality variables. In-hospital mortality suddenly pops up at the end of the results, but was never mentioned before.

Reference: AFTER 9,000 LAPAROTOMIES FOR BLUNT TRAUMA, RESUSCITATION IS BECOMING MORE BALANCED AND TIME TO INTERVENTION SHORTER: HOW LOW CAN WE GO? AAST 2021, Oral abstract #3.