1. When do you use tranexamic acid in trauma?

Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine. It was discovered in the 1950s and has traditionally been employed in surgery to minimize blood loss. TXA works by inhibiting lysine binding sites on plasminogen, thereby preventing its conversion to plasmin and reducing fibrinolysis and clot breakdown.

Trauma is consistently in the top ten leading causes of death worldwide (WHO, 2013). TXA has been studied to see if it can be used to improve morbidity and mortality. The major randomized controlled trial (RCT) is the CRASH-2 trial, which randomly assigned over 20,000 adult trauma patients in 40 countries with, or at risk of, significant bleeding, to either TXA or placebo (Shakur, 2010). The TXA protocol entailed given a loading dose of 1g over 10 minutes then an infusion of 1g over eight hours. The primary outcome was death in hospital within four weeks of injury, and the results were favorable for TXA. All-cause mortality was significantly reduced by 1.5% (14.5% TXA vs. 16.0% placebo (RR 0.91, 95% CI 0.85-0.97; p=0.0035)). Risk of death due to bleeding, which was a secondary outcome, was also significantly reduced by 0.8% when using TXA (RR 0.85, p=0.0077). The trial was large enough for subgroup analyses, which found the group that benefited most from TXA received it less than three hours from injury (RR 0.87, 99% CI 0.75-1.00). The study also showed there was no significant difference in deaths from vascular occlusion (MI, CVA, PE), multiorgan failure, or head injury between TXA and placebo. The strength of this trial lies in the large sample from multiple settings and countries, the double blinded randomization, similar baseline factors in both groups, and minimal loss to follow up. One of the weaknesses mentioned by the authors is that the diagnosis of traumatic hemorrhage can be difficult and some included patients might not have been bleeding at the time of randomization, which could reduce the power of the trial. However using a broad clinical inclusion criteria (hypotension, tachycardia, physician judgment) and not depending on lab results or imaging also makes this study more applicable and generalizable. In addition, the study found no difference in RBC transfusion in both groups. The lack of difference may be secondary to transfusion decisions made prior to completion of TXA administration; since there were more survivors in the TXA group, they also had greater opportunity to receive RBCs.

The CRASH-2 data was subsequently reanalyzed in other studies. One such study looked at four predefined risk of mortality groups (<6%, 6-20%, 21-50%, >50%) and showed that TXA was beneficial in terms of all-cause mortality and deaths from bleeding regardless of baseline risk of death. The implication is that TXA should be considered in all comers with traumatic hemorrhage within three hours of injury (Roberts, 2012). Subsequent studies found the greatest benefit of TXA if given in the first hour. If it is given more than three hours after injury, an increase in deaths from bleeding was observed (Roberts, 2011).

In 2012 the MATTERs study, a retrospective, observational study of combat injuries in Afghanistan, was published (Morrison, 2012). The study looked at the non-randomized use of TXA in hemorrhagic trauma patients that received at least one unit of RBCs. They found decreased mortality in the patients who were given TXA (17.4% vs. 23.9%) and a more marked mortality reduction in the group receiving massive transfusion (14.4% vs. 28.1%). This study has a number of limitations including external validity (most of us aren’t treating high velocity rifle injuries from combat) and the lack of randomization and blinding.

Although TXA is not yet standard of care in traumatic hemorrhage, it appears to be safe in terms of thrombotic complications, and if given within three hours of injury, also beneficial in decreasing bleeding and mortality. The use of TXA in traumatic hemorrhage should be considered in future pre-hospital and ED trauma resuscitation protocols.

2. When you can’t get peripheral access in a trauma patient, do you prefer a subclavian, femoral or intraosseous (IO)?

Establishing IV access is a vital early step in the ATLS algorithm. The sickest patients need access the fastest, yet are often the most difficult. Whether due to intravascular depletion causing venous constriction or severe trauma limiting access to the extremities, emergency physicians should always be ready to obtain central venous access. Most trauma patients arrive in a c-collar via EMS making internal jugular access impractical and unsafe. The remaining options are subclavian, femoral or IO.

A recent prospective, observational study investigated first attempt success rates and procedure times of IO access vs. central venous catheterization (CVC) in adult resuscitation patients with inaccessible peripheral veins (Leidel, 2012). In a fairly small sample of 40 consecutive patients (73% trauma), each received IO access (55% humeral site) and a CVC (83% subclavian) simultaneously. There was a significantly higher first attempt success rate for IO [85% vs. 60% for landmark-based CVC (p=0.024)], and faster median procedure time [IO 2.0 min vs. CVC 8.0 min (p<0.001)]. The authors stated that relevant complications (infection, extravasation, compartment syndrome, cannula dislodgement, bleeding, arterial puncture, hemo/pneumothorax, venous thrombosis or vascular access related infection) were not observed. Although there are no RCTs comparing in-hospital IO vs. CVC, there are several case series and observational studies supporting higher first attempt success rates and faster access times for IOs (Valdes, 1977; Iserson, 1989; Iwama, 1996; Cooper, 2007; Ngo, 2009; Paxton, 2009; Ong, 2009). A 1996 study (Iwama, 1996) also showed similar IO (clavicular) flow rates compared to CVC (subclavian). There is also an RCT studying out-of-hospital cardiac arrests, which found tibial IO access to have the highest first-attempt success rate and the fastest time to vascular access compared to peripheral IV and humeral IO access (Reades, 2011).

When it comes to central venous access, the complication that is studied most often is catheter-related bloodstream infections (CRBI). In 2011, the CDC released a class 1A recommendation to avoid using the femoral vein for central access in adult patients (O’Grady, 2011), a view also shared by the Infectious Diseases Society of America (Marschall, 2008). Typically, a class 1A recommendation is based on multiple high quality studies. This recommendation, however, was based on a single study in Critical Care Medicine (Lorente, 2005). This was a prospective, observational study that found significant differences in CRBI between femoral (8.34%), IJ (2.99%) and subclavian (0.97%) lines. In a 2012 meta-analysis encompassing two RCTs and eight cohort studies, including over 3000 subclavians lines, 10,000 IJ lines, and 3100 femoral lines, the data against femoral access became less clear (Marik, 2012). After the authors excluded two studies that were statistical outliers (Lorente, 2005; Nagashima, 2006), they found no significant difference in the risk of CRBI between femoral and IJ routes (RR 1.35; 95% CI 0.84-2.19, p=0.2, I²=0%) or femoral and subclavian routes (RR 1.02; 95% CI 0.64-1.65, p=0.92, I²=0%). The meta-analysis also found no statistical difference in DVT complications between femoral access and the other routes combined (Marik, 2012), although a previous RCT showed increased DVT rate in the femoral site compared to subclavian alone (Merrer, 2001). The authors comment that infection rates have decreased across the board over the last 10-15 years likely due to the increased focus on sterile placement of lines. They recommend that physicians choose the site that they are most comfortable with and that is appropriate for the patient. Whether the results from this meta-analysis are applicable to the crashing trauma patient without venous access is debatable.

There are no RCTs to make a head to head comparison of these three access points in the trauma setting. At this point, a rational approach in resuscitating a sick trauma patient is to go for the quickest and easiest route, which appears to be IO, especially in EDs staffed by only one physician. There are no limitations to the medications or blood products that can be infused through an IO. At the same time, if additional personnel are available, central access, whether femoral, subclavian, or IJ can be obtained simultaneously. Practically speaking, this increases the chances of getting access quickly, and more access points may be beneficial for giving high volume and speedy fluid/blood infusions. The ultimate goal is to stabilize the patient; infection risk is not the primary concern and the lines can and should be changed in a more sterile environment.

3. Which trauma patients do you give PCC to over FFP?

It is commonly accepted that hypothermia, acidosis, and coagulopathy form a lethal triad in worsening traumatic hemorrhage. Fresh frozen plasma (FFP) is widely used to correct coagulopathies in traumatic bleeding and is an integral part of any massive transfusion protocol. With the availability of prothrombin complex concentrate (PCC) in most trauma centers, studies have arisen to determine its place in coagulopathy reversal. PCC contains coagulation factors II, VII, IX, and X. Products available in the U.S. are Kcentra™ (aka Beriplex™, Prothrombin Complex Concentrate), Profilnine SD™ (Coagulation Factor IX complex), and Bebulin VH™ (Factor IX Complex). The former contains all four factors, while the latter two contain mostly factor IX, but also factors II and X, and very low levels of factor VII. The advantage of PCC is that it can be quickly reconstituted and administered in a low volume IV bolus. FFP involves type-specific matching, thawing, longer administration times, and a larger overall volume of delivery.

Studies investigating the role of PCC in trauma have focused on reversal of elevated INR both in patients on warfarin and those not on anticoagulants. Kalina, et al. put forth a protocol at Christiana Care Hospital in Delaware to give PCC to trauma patients with an INR >1.5, history of warfarin use, and head CT showing intracranial hemorrhage (Kalina, 2008). Clinicians had the option to use the PCC protocol (54.3%) or FFP with vitamin K (35.4%). Protocol patients had improved times to INR normalization (331.3 vs. 737.8 minutes, p=0.048), number of patients with reversal of coagulopathy (73.2% vs. 50.9%, p=0.026), and time to operative intervention (222.6 vs. 351.3 mins, p=0.045). There was no difference in ICU days, hospital days, or mortality. INR reversal, however, is not a patient oriented outcome. The ability of PCC to rapidly correct the INR does not equate to an improvement in patient care. This is reflected in the lack of difference in mortality. In another study, Safaoui, et al. did a retrospective chart review of patients who presented to the ED with possible brain injury and a history of warfarin use and received FIX complex (three factor PCC) (Safaoui, 2009). Of the 28 patients who met inclusion criteria, a PCC dose of 2000 units reduced admission INR on average from 5.1 to 1.9 (p=0.008), with a mean time to correction of 116 minutes. Eleven patients who had a repeat INR drawn within 30 minutes following PCC had a mean time to INR correction of 13.5 minutes. Limitations of this study include a lack of defined target INR, heterogeneity among times to obtain INR, variation in PCC dosing, as well as variation in obtaining timely INR redraws post-treatment.

There are also a number of small, retrospective studies looking at the use of PCC in general trauma patients who are on warfarin. In 2011, a chart review of 31 patients on warfarin with trauma (13 receiving 3 factor PCC (Profilnine SD™) and 18 receiving FFP) showed a faster reversal of INR with the PCC (16:59 hours vs. 30:03 hours) (Chapman, 2011). However, there was a difference in mortality (actually, the only patient deaths were in the PCC group).

A recent prospective cohort study out of Austria looked at using fibrinogen concentrate (CF) and/or PCC alone compared with those additionally receiving FFP in 144 patients with major blunt trauma (Injury Severity Score (ISS) ≥15) (Innerhofer, 2013). Patients treated with CF alone showed sufficient hemostasis and required fewer RBCs and platelets than those also receiving FFP. They also found significantly lower rates of complications such as multiorgan failure and sepsis in the CF alone group. The limitations of this study are that it used fibrinogen concentrate (in addition to PCC) and measured hemostasis with rotational thrombelastometry, which may not be practical or obtainable in everyday ED settings. In addition, the study did not compare PCC directly to FFP.

There has not been a large meta-analysis comparing PCC to FFP and such a study may be difficult secondary to the heterogeneity in the existing studies. Differences in variables such as drug dosing, coagulation factor differences, baseline patient coagulopathy, and outcome measurements make it difficult to formulate overarching conclusive statements about PCC use. At this point, it is reasonable to treat patients with traumatic ICH on warfarin with PCC, as rapid reversal is necessary to prevent mass effect and herniation. There are no RCTs at this time to conclusively recommend the use of PCC in trauma simply for an elevated INR. Recently, data collection has been completed for a study entitled, “A Randomized, Open Label, Efficacy and Safety Study of OCTAPLEX and Fresh Frozen Plasma (FFP) in Patients Under Vitamin K Antagonist Therapy With the Need for Urgent Surgery or Invasive Procedures” (OCTAPLEX, 2013). This study is pitting Octaplex, a 4-factor PCC, head-to-head against FFP. It will be interesting to see what dose of each drug the investigators use, as PCC can be thought of as a very concentrated version of FFP, making it easier and faster to administer. The limitation, however, is that because PCC is a new drug, it is considerably more expensive than FFP.

4. In blunt abdominal/flank trauma, do you send a urinalysis or simply look for gross hematuria?

Urinalysis (UA) is traditionally performed in blunt trauma as a screening test to diagnose urogenital injuries. The most commonly injured genitourinary (GU) structure is the kidney, and the proportion of trauma patients with renal injuries ranges between 1.4-3.3% (Santucci, 2004). A retrospective observational cohort study of 1815 patients was recently undertaken to investigate whether the routine performance of UA in patients with blunt trauma is still valuable (Olthof, 2013). The main outcome measures were the presence of GU (bladder, kidney, ureter or urethral) injury, and whether the findings on urine specimen and/or imaging led to clinical consequences (additional imaging, intervention, admission for observation, or out-patient follow-up). Microscopic hematuria was defined as greater than three erythrocytes per high powered field. Macroscopic hematuria was defined as blood visible to the naked eye.

The presence of macroscopic/gross hematuria (n=16) led to clinical consequences in 73% of patients, regardless of findings on imaging. Bypassing UA and going straight to imaging resulted in clinical consequences in 1.5% (4/268) of patients, whereas performing both a UA and imaging only resulted in a 2% (22/1031) rate of clinical consequences. The authors state that the 0.5% difference in clinical consequence mostly consisted of additional imaging and outpatient follow up, indicating little added value to the initial screening UA. Limitations of this study include the retrospective design, as it was not possible to determine whether the physician performed imaging based on the UA results or independent of it. In addition, the definition of macroscopic/gross hematuria was subject to the physician’s interpretation and could be influenced by certain foods, medications, or menstruation.

An older study, from 1989, prospectively looked at 1146 consecutive patients with either blunt (1007) or penetrating (139) renal trauma (Mee, 1989). Of the 812 patients with blunt trauma and microscopic hematuria without shock (SBP >90), there were no significant injuries (significant = grade 2-5 renal injury). A related study from the same group, but using more data, found that in 1588 blunt trauma patients with microscopic hematuria and no shock, 3 out of 584 (0.5%) who had imaging had significant injuries (Miller, 1995). Of the 1004 that did not get imaging, 51% were followed up and had no significant complications. These studies support the premise that microscopic hematuria rarely picks up significant renal injuries. Of note, in the 436 patients who had gross hematuria, or microscopic hematuria plus shock, 78 significant renal injuries were identified (Miller, 1995).

In the setting of blunt trauma and hemodynamic stability, it appears reasonable to avoid screening UAs and only look for gross hematuria. The practical benefit is that one can make a disposition decision without having to wait for microscopic UA results. In addition, making decisions based on a UA can be falsely reassuring, as bleeding in the kidney parenchyma may not cause hematuria.