Best Of EAST #6: How Long Does Risk For VTE Last After Spine Fracture?

Most trauma centers use an existing venous thromboembolism (VTE) guideline or have developed their own injury-specific one. These include risk factors, contraindications, specific agent, and dosing recommendations. But one thing most do not include is duration of prophylaxis!

The length of time a patient is at risk for VTE is not well delineated yet. The group at the University of Arizona decided to tackle this program using the National Readmission Database. This dataset is a comprehensive resource for critically analyzing patients who are discharged and readmitted, even for multiple occurrences. It covers 30 states and almost two thirds of the population.

The authors focused on VTE occurring during the first six months after injury. Patients who died on the initial admission, were taking anticoagulants, had spinal surgery, or sustained a spinal cord injury were excluded. Over 41,000 records from the year 2017 met these criteria.

Here are the factoids:

  • The average age was 61, which shows the skew toward the elderly with these injuries
  • Spine areas injured were cervical in 20%, thoracic in 19%, lumbar in 29%, sacrococcygeal in 11%, and multiple levels in 21%.
  • During the initial admission, 1.5% developed VTE: 0.9% were DVT and 0.7% were PE
  • Within 1 month of discharge, 0.6% of patients were readmitted for VTE: 0.4% DVT and 0.3% PE
  • In the first 6 months, 1.2% had been readmitted: 0.9% DVT and 0.6% PE
  • Mortality in the first 6 months was 6.7%
  • Factors associated with readmission for VTE included older age, discharge to a skilled nursing facility, rehab center, or care facility

The authors concluded that VTE risk remains high up to 6 months after conservatively managed spinal fractures. They recommend further study to determine the ideal prophylactic agent and duration.

Bottom line: This is a creative way of examining a difficult problem. We know that VTE risk does not stop when our patient is discharged. This is one of the few ways to get a sense of readmissions, even if it is not to the same hospital. And remember, this is an underestimate because it’s possible for a patient living near a state border to be re-hospitalized in a state not in this database.

This study might prompt us to prescribe up to six months of prophylaxis, particularly in seniors who are discharged to other care facilities.

Here are my questions for the author and presenter:

  • Is there any way to extrapolate your data to the entire population of the US, or to compensate for the “readmission over state lines” problem?
  • Is the odds ratio of 1.01 for risk of VTE in the elderly age group significant in any way? It seems like a very low number that would be easily overwhelmed by the “noise” in this data set.
  • Is the mortality number for all causes, or just VTE?

This is an intriguing study, and one that should influence the VTE guidelines in place at many trauma centers!


Best Of EAST #5: Ultrasound vs Chest X-Ray After Chest Tube Removal

The chest is one of the most commonly injured body regions. Patients are frequently found to have either air or blood in the chest, and many require a chest tube (tube thoracostomy) for these conditions. There is an art to chest tube removal, and even in 2021, the best practice has not been fully worked out.

Some believe that pulling the tube during a breath hold is best. Others do this during full expiration. Most centers confirm an uneventful tube removal with a plain chest x-ray. But the time interval after removal varies considerably.

The trauma group at the University of Tennessee – Chattanooga examined the use of chest ultrasound as the confirmatory test for residual pneumothorax after removing a chest tube. They developed an institutional practice guideline requiring a trans-thoracic ultrasound performed by a first-year resident two hours after tube removal. The interns all completed a 30-minute standard ultrasound course for training prior to beginning the study.

Two hours after tube removal, an intern performed the ultrasound (US) and interpreted it. A chest x-ray (CXR) was then ordered and the results compared.

Here are the factoids:

  • A retrospective review of 46 patients was performed, but the inclusion criteria were not listed in the abstract
  • Eleven of the 46 (24%) had a residual pneumothorax on CXR, and the US detected it in 12 (26%)
  • Three patients had PTX on CXR, but not US
  • Four patients had PTX on US, but not CXR
  • None of the PTX were clinically significant, and none required tube reinsertion
  • Cost of care savings was projected to be $4,000 if chest x-ray was not needed

The authors concluded that bedside ultrasound was an acceptable alternative to chest x-ray, with decreased radiation exposure and cost.

Bottom line: This is an intriguing abstract. It shows us that there might be an alternative to the standard chest x-ray confirmation after chest tube removal. It’s a very small study, so non-inferiority can’t truly be established yet. The studies are complementary since each study misses a few pneumothoraces that the other picks up.

At this point, I wouldn’t recommend switching entirely to ultrasound until we have a larger series. But I bet we will be able to in the future. Ultimately, this could reduce radiation exposure (tiny anyway for a chest x-ray) and save a small amount of money. But it will reduce x-ray department resource usage, which may be very helpful for the hospital.

Here are my questions for the authors and presenter:

  • How did you select your patients? What were the selection criteria? How long did it take to accrue 46 patients? It’s important that all patients with a chest tube had the criteria applied, otherwise there is an opportunity for bias. We want to make sure that you didn’t inadvertently enroll only the patients for whom ultrasound works well.
  • How much of a burden was placed on the interns who did the exam? Was the ultrasound unit nearby? Or did they have to spend 30 valuable minutes rolling it to the floor and doing the study? Radiology department resource use needs to be balanced with intern resource utilization.
  • Why did you have such a high rate of residual pneumothorax after the tubes were pulled (about 25%). This seems a bit higher than what the literature reports.
  • What does your protocol require when a residual pneumothorax is found? Do you have to perform another study after an additional time interval to prove that it is not getting larger? Serial ultrasound exams? Another chest x-ray? Please show us your entire guideline.

I really enjoyed this paper. I’m looking forward to hearing the nitty gritty details during the presentation.


Best Of EAST #4: 4-Factor PCC vs Andexanet Alfa For Factor Xa Inhibitor Reversal

Falls are by far the most common mechanism of injuries in US trauma centers these days. They typically occur in elderly patients, and a growing number are on some type of oral anticoagulant for their medical conditions. And the number of these patients who are taking a DOAC (direct thrombin inhibitor or factor Xa antagonist) is rising quickly.

Unfortunately, most of the DOACs do not have good reversal agents, and they are very, very expensive. Specifically, Andexanet Alfa, the antidote for rivaroxaban and apixaban used to cost in excess of $50,000 per dose. This has come down over time to “only” $22,000 per dose. Unfortunately, the half-life is much shorter than the agent it is neutralizing, frequently requiring two doses. And the kicker is that there are no studies definitively showing that Andexanet Alfa improves mortality when used for CNS hemorrhage.

Prothrombin complex concentrate (PCC) has been used for reversal of these agents as well. Its efficacy is also not well known. The group at George Washington University is presenting an abstract comparing it against Andexanet Alfa (AA) for reversal of either of the Factor Xa inhibitors (rivaroxaban, apixaban). They performed a multicenter study involving 10 trauma centers. The endpoints studied were number of transfusions, mortality, and ICU length of stay.

Here are the factoids:

  • From a total of 263 patients, 77 received AA and 186 received PCC
  • Only 4% of patients received a second dose of AA despite its short half-life
  • There was no significant difference in the number of PRBCs transfused
  • The authors stated that the mortality was significantly lower with PCC but the p value in the data table provided was = 0.05
  • They also stated that the ICU LOS was significantly lower with PCC (1.2 vs 1.5 days, p = 0.04)

The authors concluded that PCC is non-inferior to AA for reversal in bleeding trauma patients. They recommended a randomized study be done.

Bottom line: The first thing for you to know is that I have never been impressed with the data on Andexanet Alfa. Which means I have to be very careful and aware of my own cognitive bias. In practice, this means I can’t just look at the study title or abstract and be happy that it meets my confirmation bias. I have to make a conscious effort to critically read the paper or abstract and see if it really does mean what I want it to mean, or if I need to change my opinion.

This abstract doesn’t really satisfy my confirmation bias. The title states that PCC is not inferior to AA. I would certainly like to believe that. But in order to safely say that, it is vitally important that a power analysis is performed to ensure that enough patients are present in both treatment groups to confidently state that there was no difference. If the number of patients is too small, significance can’t be detected and non-inferiority cannot be confirmed.

The body of the abstract claims that mortality was significantly lower in the PCC group, although the table states that the p value was 0.05, which technically is not significant. The difference in mortality numbers is impressive (PCC mortality 20% vs 32% for AA) so why the significance issue?

And one note about significance. Be careful not to conflate statistical significance with real-life significance. ICU length of stay in this study was statistically significantly shorter in the PCC group (1.2 vs 1.5 days) but I doubt that a difference of 7 hours in the ICU is clinically relevant.

Here are my questions for the authors and presenter:

  • Did you have enough patients in the study to assure that the PCC treatment was actually non-inferior? Please show us your power analysis.
  • What were the inclusion criteria for the study? This will help us understand the patient group better. Were these primarily head bleeds, actual external or intra-cavity hemorrhage?
  • Please clarify the significance claim for mortality. The raw percentages are impressively different, but the P value is not significant.
  • Could the low rate of administering a second dose of AA have influenced the outcomes? As mentioned above, the half-life of the antidote is much shorter than that of the DOAC. Perhaps giving a second dose is actually needed and could have moved the results in favor of AA.

This is a thought-provoking abstract for me. Let’s see if you can either confirm or refute my opinion on AA!


Best Of EAST #3: More Blood Product Stuff! Cryo vs Fibrinogen Concentrate

I’ve got more blood transfusion stuff for you today! This one isn’t exactly MTP, but it does deal with patients suffering from blood loss. Major trauma patients requiring transfusion are losing all of their clotting factors in addition to red cells and platelets. Some factors can be replaced by giving plasma. However, clotting factor I (fibrinogen) is not one of them. For that reason, most MTPs include administration of cryoprecipitate to replace it at key points in the algorithm.

However, fibrinogen replacement actually is available in two forms, cryoprecipitate (cryo) and fibrinogen concentrate (FC). These two forms have very different properties and costs. The authors from the University of Arizona Tucson massaged two years worth of data from the TQIP database. They included all trauma patients who received either cryo or FC, except for those with known clotting issues from bleeding disorders, liver disease, or anticoagulants they were taking. They analyzed differences in mortality, complications, transfusion requirements, and length of stay.

Here are the factoids:

  • A total of 85 patients received FC and 170 received cryo (?)
  • Blood product usage (red cells, plasma, and platelets) was less in the fibrinogen concentrate group (see table)
  • ICU and hospital lengths of stay were less in the FC group (see table)
  • There was no difference in complications between the two groups

The authors concluded that use of fibrinogen concentrate was associated with improvement in the outcomes they measured. They recommended that further studies be done to evaluate use of FC.

Bottom line: This study suggests that use of fibrinogen concentrate may be better than cryoprecipitate. But there are a lot of things to think about before jumping to conclusions. First, remember that this is an association paper. It cannot detect cause and effect. Blood component usage and LOS were indeed less in the FC group. But how many hundreds of other variables factor into those outcomes: specific injury pattern, ISS, body temperature, resuscitation balance, time to OR, and product availability are just a few. These and a host of others cannot be controlled easily in a study using TQIP data alone.

Next, look at the number of units of blood products given as listed in the table above. These are the average number of units given within 24 hours! These are relatively low numbers, and below what most would consider a “massive transfusion” threshold. Most of the time, we wouldn’t even think to measure fibrinogen in patients with such low blood replacement needs. Perhaps we should?

And finally, I have questions about the low number of subjects in the study. There are only 255 patients analyzed, and propensity score matching was used. This implies that overall numbers were low and that several covariates had to be considered. It seems like more subjects should have been available in the tens of thousands of patients submitted in two years to TQIP

Here are my questions for the authors and presenters:

  • Please review your statistical analysis with the audience. Why is the number of subjects so low? What did you control for in your propensity score matching and how did this impact your n?
  • Comment on the low numbers of blood products given. Do you think that patients who have such a relatively low transfusion requirement even needed a fibrinogen supplement?
  • Did you consider performing this analysis on patients who underwent massive transfusion? The effect might have been more pronounced in that group.
  • Since fibrinogen concentrate costs about 3x what cryo does, how would this factor into the math involved in deciding to use FC?

This study raises a lot of interesting questions. I hope the authors incorporate the answers into their presentation!


Best Of EAST #2: Pay Attention To Platelet Ratios In Your MTP!

More MTP stuff! Every trauma center has a massive transfusion protocol, and current literature encourages them to try to achieve an “optimal” transfusion ratio. The literature has converged on a red cell to plasma ratio of somewhere between 1:1 and 2:1. Less has been written about platelet ratios, and trauma centers often don’t pay as much attention to this ratio when reviewing MTPs.

But is it important? The trauma group at the Massachusetts General Hospital examined the impact of platelet ratios on mortality in patients undergoing MTP. This was another TQIP data analysis, performed over a nine year period.

The authors defined massive transfusion as ten or more units of PRBC in the first 24 hours, or any number of units of red cells, plasma, or platelets given within the first four hours. They also defined “balanced” as a ratio of RBC to FFP and RBC to platelets <2. Multivariate regression analysis was performed to gauge the impact of ratios and achievement of a balanced resuscitation on 24-hour mortality.

Here are the factoids:

  • A total of 7,520 patients in the dataset underwent MTP
  • Nearly 83% achieved RBC to FFP balance, but only 6% had RBC to platelet balance (!)
  • Patients with both balanced FFP and platelets had the lowest mortality at 24 hours
  • Mortality increased by 2x with unbalanced plasma, a little more than 2x with unbalanced platelets, and 3x if both were out of balance (see figure)

The authors concluded that the platelet component of the MTP was frequently out of balance, and that it is associated with mortality to a greater degree than with unbalanced plasma.

Bottom line: This paper confirms my observations that trauma centers pay a lot more attention to the red cell to plasma ratio and don’t get as excited when the platelets are out of line. Part of this is probably due to confusion over how to count platelet packs. Typically they are delivered in packs called “pheresis” or “apheresis.” Each is the equivalent of about 6 units of platelets (check with your blood bank for more exact numbers). This means that a ratio of 6 RBC to 5 plasma to 1 platelets would be considered balanced. But a ratio of 28:28:2 would not.

According to this abstract, the use of sufficient platelets is important. This makes sense. However, the exact mechanism cannot be determined from this type of study. It could be a direct effect of not having enough platelets to form good clot. Or it could be something completely outside the clotting mechanism, just an association with something in the care processes that occurs as these patients undergo resuscitation. 

The why doesn’t matter so much, though. This abstract presents compelling data that suggests that we really need to pay attention to the platelet ratios given during the MTP. They should be analyzed just as closely as plasma ratios during PI review, and changes to the MTP process implemented to normalize this important ratio.

Here are my questions for the authors and presenter:

  • There is a statement in the methods section that is not clear. “only patients with steady RBC/PLT and RBC/FFP ratios between 4-and 24-hr were analyzed.” What is your definition of “steady?”
  • Did you see any mortality patterns in the data you analyzed that might suggest why lower platelet volumes were more deadly?

This was a nicely done abstract, and I look forward to the live presentation and the finished manuscript!