Guidelines for External Hemorrhage Control

Hot off the press from Prehospital Emergency Care is the newly released Guidelines for External Hemorrhage Control provided by the ACS Committee on Trauma. This is a pretty nice summation of the available evidence and, as such, it is recommended that you grab yourself a copy and read through the full-text yourself. Having said that, here is a summary of what was stated within this paper...

The authors of this paper ("reps from the military's Tactical Casualty Combat Committee, PHTLS, civilian state EMS directors, trauma surgeons, emergency physicians, a pediatric surgeon, an EMS researcher, a GRADE methodologist, and a paramedic" - from USA & Canada) systematically reviewed the literature regarding the use of tourniquets and hemostatic agents for the management of life-threatening extremity and junctional hemorrhage. After sifting through the evidence, the authors then applied GRADE methodology to formulate and answer relevant clinical questions regarding these products as well as to summarize the quality of the evidence.

Here's what they came up with:

Tourniquets

1. We recommend the use of tourniquets in the prehospital setting for the control of significant extremity hemorrhage if direct pressure is ineffective or impractical. [Strength: Strong; Quality: Moderate]
2. We suggest using commercially produced windlass, pneumatic, or ratcheting devices that have been demonstrated to occlude arterial flow. [Strength: Weak; Quality: Low]
3. We suggest against the use of narrow, elastic, or bungee-type devices. [Strength: Weak; Quality: Low]
4. We suggest that improvised tourniquets be applied only if no commercial device is available. [Strength: Weak; Quality: Low]
5. We suggest against releasing a tourniquet that has been properly applied in the prehospital setting until the patient has reached definitive care. [Strength: Weak; Quality: Low]

Junctional Hemorrhage Devices

"We believe this is an important area for further study, but did not find sufficient evidence to make a recommendation at this time."

Topical Hemostatic Agents

1. We suggest the use of topical hemostatic agents, in combination with direct pressure, for the control of significant hemorrhage in the prehospital setting in anatomic areas where tourniquets cannot be applied and where sustained direct pressure alone is ineffective or impractical. [Strength: Weak; Quality: Low]
2. We suggest that topical hemostatic agents be delivered in a gauze format that supports wound packing. [Strength: Weak; Quality: Low]
3. Only products determined effective and safe in a standardized laboratory injury model should be used. [Strength: Weak; Quality: Low]

Additional Recommendations

• We advise that tourniquets and topical hemostatic agents be used under clinical practice guidelines and following product specific training.
• We advise that hemostatic agent training for prehospital personnel include proper wound packing and pressure application techniques.
• We advise that tourniquets and topical hemostatic agents use be expanded to include all prehospital personnel, including emergency medical responders.

Bibliography:

Bulger et al."An Evidence-Based Prehospital Guideline for External Hemorrhage Control: American College of Surgeons Committee on Trauma" Prehospital Emergency Care 2014, 18(2):163–73.

TXA Fully Reverses Fibrinolysis in Swine Model of Simulated Hyperfibrinolysis & Acidosis.

The Paper: Debarros et al. "Tranexamic acid corrects fibrinolysis in the presence of acidemia in a swine model of severe ischemic reperfusion." J Trauma Acute Care Surg 2014; 76(3): 625-33.

Study Design: Prospective controlled in vivo swine model.

PICO:

• Population: 10 healthy yorkshire swine under general anesthesia with controlled hemorrhage, simulated hyperfibrinolysis, and acidosis (discussed in more detail below).
• Intervention: 1000mg IV TXA (n=5).
• Control: No TXA (n=5).
• Outcome: Resolution of fibrinolysis as measured by ROTEM Maximum Lysis (ML) directly after TXA administration.

What they did:
The pigs were intubated and placed on invasive monitors (PA + arterial) under general anesthesia. Blood samples were then drawn at baseline and repeated at 30 minutes, 1 hour, and 4 hours post-resuscitation. To achieve simulated hemorrhage ischemic-reperfusion injury, all pigs were bled 35% of their total circulating volume (26ml/kg) through their inferior vena cava via a midline laparotomy. Immediately after, the aorta was cross-clamped and pigs were left for 50 minutes to create a "severe truncal ischemia". Resuscitation phase began after a 5 minute controlled release of the aortic clamp. 30 minutes into the resuscitation, all pigs were given 100mg tPA. At 35 minutes, the intervention group was given 1000mg TXA. Crystalloid was given to all animals who's MAP < 40 and PCWP < 150% baseline. Epinephrine was given if MAP < 40 mmHg and PCWP > 150% of baseline.

Results:

• All pigs survived.
• At the time of TXA administration, average pH was 7.2.
• In intervention group, Maximum Lysis returned to baseline 10 minutes after administration of TXA (92% vs 9%, p<0.001).

% Maximum Lysis (Times)	TXA	No TXA
Baseline	9.2%	8.6%
30 Minutes (just after tPA)	99.4%	100%
45 Minutes (just after TXA)	9%	91.6%
4 Hours	2.8%	1.8%

Limitations:

• Swine model does not directly represent human model of coagulation. Authors acknowledge that swine coagulation profile is much more robust and, because of this, both groups returned to baseline at the end of resuscitation at 4 hours.
• Serum lactate was significantly higher in the TXA group (3.5mmol/L vs 7.0mmol/L) → authors state this may be due to a higher epinephrine requirement in intervention group (unable to know for sure as it was not powered to answer that question).
• Simulated model of "trauma-induced coagulopathy" is not consistent with actual traumatic coagulopathy.

What can we take home from this study?

• While this certainly is not practice changing by any means, it does seem to show effectiveness of TXA in an acidic environment. 

Reblog (Trauma Pro Blog): EAST 2014: Device Alert! Instant Hgb Monitor

Dr. McGonigal, of The Trauma Professional's Blog, posted briefly this morning on the results of a hugely interesting abstract from EAST 2014. Check it out here.

http://regionstraumapro.com/post/72871485249

Powdered Plasma Performed Particularly Perfect in Perishing Piggies!

This week I came across a study in JAMA Surgery (formerly Archives of Surgery) that was published wayyyy back in 2009. This paper looked at the effectiveness of lyophilized plasma (LP) used to resuscitate severely injured, shocked swine and, well, I found it to be pretty remarkable.

What they did:

Prior to the start of the study:

• The investigators exsanguinated healthy juvenile swine carefully into citrated blood donation bags. 
• The whole blood was then centrifuged and plasma was collected. At this point, the plasma was analyzed for levels of fibrinogen, protein C, antithrombin III, PT, PTT, and factors II, V, VII, VIII, IX, X, XI, and XII.
• 1/2 of the collected plasma was stored and shipped at -20°C to a lyophilization laboratory; the other half was frozen and stored as Fresh Frozen Plasma (FFP).
• After lyophilization, the powdered plasma was returned and then stored at room temperature for 1 month.
• The powdered plasma was re-analyzed for the aforementioned parameters just prior to administration on the day of the study.

On the day of the study:

• 32 healthy yorkshire swine were split into 4 groups (n=8/group).
1. FFP only resuscitation
2. LP only resuscitation
3. FFP + PRBC with 1:1 ratio resuscitation
4. LP + PRBC with 1:1 ratio resuscitation
• The swine were first given identical femur and overlying soft-tissue injuries using a captive bolt gun.
• Next, a laparotomy was performed and the pigs were cooled to 33°C using chilled intraperitoneal isotonic saline while simultaneously removing 60% of their estimated blood volume via a central line.
• The swine were then left in this state for 30 minutes to simulate prolonged shock complicated with hypothermia.
• Next, the swine were infused with normal saline at 3x the controlled hemorrhage volume to induce acidosis and dilutional coagulopathy.
• Finally, all animals received a grade V liver injury followed by 30 seconds of uncontrolled hemorrhage. 
• The intervention period began with the packing of the liver with pre-weighed laparotomy sponges → each animal received resuscitation according to the study protocol. Volume infused to each pig was equal to the volume lost during controlled hemorrhage.

What they found:

Clotting profile of LP compared to FRESH, NEVER-FROZEN plasma:

• Factor V: 84% activity
• Factor VIII: 84% activity
• Factor IX: 100% activity
• Antithrombin III: 93% activity
• INR: prolonged by 9%
• PTT: prolonged by 13%

Performance between the groups:

• All pigs survived.
• Blood loss lowest in LP+PRBC (p=.03) → all other groups showed similar loss.
• MAP significantly lower in FFP group than other groups at various points (p= <0.05).
• Lactate similarly showed a stepwise decline in all groups.
• PT similar between all groups at all 4 time points.
• PTT significantly lower in LP group compared to the LP+PRBC & FFP+PRBC groups (p= <0.05).

What they concluded:

This study shows that the lyophilization process results in a modest reduction in clotting factor activity in vitro. Interestingly, there was no evidence of this reduction in the in vivo animal study. The study also shows that LP is as safe and effective as FFP for resuscitation after severe multisystem injury.

Final thoughts:

In my opinion, this study was extremely well done. The investigators utilized a model that represents the patients we see in the field - injured, cold, acidemic, and coagulopathic. 

Obviously, with any lab-based animal study, there will be flaws by design. The small sample size makes the waters a bit murkier as well. Because of these flaws, we're left with some unanswered questions:

1. Does swine plasma exactly reflect the physiology of human plasma? 
2. Would storing the LP on the shelf for longer than 1 month alter the efficacy? 
3. Would the LP use result in more episodes of meaningful VTE complications if the investigators kept the pigs alive?
4. Did reconstitution of the LP with a vitamin-C containing solution synergize efficacy?

However, what was made clear is LP appears to be at least as effective as FFP in trauma resuscitation (albeit, with small sample size). This study should be used as a springboard for further investigation and human trials should be aggressively sought. 

In closing, as our friend Peter Griffin would say....

I'd love to hear your thoughts, ladies and gents! 

Emergency Transfusion Score (ETS)

During the initial phases of trauma resuscitation, one of the most complex tasks for the Resuscitationist is making the decision to activate the Massive Transfusion Protocol. While clinician gestalt is highly sensitive, the specificity is variable leading to large rates of either over or undertriage. While some argue, "it's better to be safe than sorry", buying into a liberal transfusion approach (overtriage) is dangerous not only to the patient (TRALI, TACO, anaphylactoid reactions), but also to the institution ($$$). Thus, over the last decade, a multitude of prediction tools were developed. One score I just became familiar with is the Emergency Transfusion Score (ETS).

What is it?

• The ETS contains 9 predictive values (all of differing weights ['coefficients']) based on regression analysis of retrospectively collected data from 1,103 patients admitted to a single institution over a 4-year period. [1]
• ETS was later validated again by Kuhne et al with prospectively collected data from 481 patients on admission to a single-institution over a 17-month period. [2]
• Data from the latter validation concluded that an ETS ≥ 3 is a positive test and the massive transfusion protocol should therefore be initiated. 

What are the variables?

Variable		Coefficient	p Value
Age (years)			< 0.001
	20 - 60	0.5
	> 60	1.5
Admission from scene of accident		1	< 0.004
Injury mechanism
	Traffic Accident	1	< 0.002
	Fall > 3m	1
Systolic Blood Pressure
	0-90 mmHg	2.5	< 0.001
	90-120 mmHg	1.5
Pelvic Ring Disruption		1.5	< 0.001
Abdominal Free Fluid (FAST)		2	< 0.001

How did ETS perform? [2]

	ETS ≥ 2	ETS ≥ 3	ETS ≥ 4
Sensitivity	100%	97.5%	84.2%
Specificity	44.2%	68%	92.5%
PPV	11.5%	22.2%	31.4%
NPV	100%	99.7%	98.4
LR+	1.79	3.16	11.23
LR-	0	0.04	0.17

Conclusion

The ETS has been proven on 2 occasions to be moderately accurate in the prediction in the need (or lack of need) for massive transfusion. Kuhne et al [2] claimed that their institution was able to save a substantial amount of blood (176 MT+ vs 481 MT+) and money ($97,600 USD saved) compared to their traditional "clinician gestalt" approach. Obviously, it seems like their "standard" approach is wildly liberal so it would be wise to interpret these savings carefully in your institution.

Having said that, 3 caveats with ETS are:

1. Remembering the coefficient variable at the bedside without some form of a checklist would be daunting.
2. ETS has not been validated to be used in patients with penetrating trauma.
3. The ETS and the ABC Score perform similarly, however the ABC score is much easier to perform/remember. 

At the end of the day, I'm still partial to the ABC score.

Bibliography:

1. Ruchholtz et al."The Emergency Room Transfusion Score (ETS): Prediction of Blood Transfusion Requirement in Initial Resuscitation after Severe Trauma" Transfusion Medicine 2006, 16(1):49–56
2. Kuhne et al."Emergency Transfusion Score (ETS): A Useful Instrument for Prediction of Blood Transfusion Requirement in Severely Injured Patients" World J Surg 2008, 32(6):1183–8

CRYOSTAT Results Are Near!

This morning, Dr. Karim Brohi tweeted this:

CRYOSTAT. OMG!
— Karim Brohi (@karimbrohi) December 9, 2013

RT @flightmed1: @karimbrohi Are results in? [Preliminary results. We'll be presenting some at the #LTC2013 research day on Thursday] [OMG!]
— Karim Brohi (@karimbrohi) December 9, 2013

Results are close, folks! Stay tuned!!

For more info on CRYOSTAT, visit http://hurtregistry.org/coagulation-factor-concentrates/cryoprecipitate/

RCT on TXA for TBI: Swing & A Miss

This month in BMC Emergency Medicine, an RCT was published looking at the effects of tranexamic acid (TXA) in patients with moderate to severe TBI. Don't get too excited about this one.

What they did:

• Single-center, randomized, double-blind, placebo controlled trial in Thailand between October 2008 to August 2009
• Inclusion:
• Age > 16 AND
• Moderate to severe TBI (post-resus GCS 4-12) AND
• CT scan of the head within 8 hours of injury AND
• No indication for surgery
• Exclusion:
• Pregnant females
• Evidences of coagulopathy
• Platelet count < 100,000
• PT/INR > 1.5 times normal 
• aPTT > 10 seconds normal
• Known to be receiving a medicine that effects hemostasis
• Serum creatinine > 2 mg/dL
• Intervention:
• TXA given at a loading dose of 1 gram over 30 minutes followed by 1 gram over 8 hours.
• Primary outcome:
• Progressive intracranial hemorrhage
• Secondary outcomes:
• Death
• Functional status at discharge (using Glasgow Outcome Scale)
• Blood transfusion
• Neurosurgical operation
• Any in-hospital thrombotic events

What they found:

• No differences in
• Rate of progressive ICH → TXA 18% vs control 27% (RR 0.65; 95% CI 0.40-1.05)
• Death → TXA 10% vs control 14% (RR 0.69; 95% CI 0.35-1.39)
• Unfavorable GOS outcome → TXA 18% vs control 23% (RR 0.76; 95% CI 0.46-1.27)
• Rate of thromboembolic events → TXA 0/120 vs control 3/118

What can we take home from this trial?

• Unfortunately, not much. This trial has a significant amount of flaws that do not allow us to draw any hard conclusions. Some flaws that I didn't particularly like are:
1. Patients with coagulopathy were EXCLUDED.
• If we know that severe TBI increases incidence of coagulopathy, DIC, etc, then why are we removing them from this trial? The authors state:

"Coagulopathy was a risk factor for developing PIH and mortality in previous studies or recent reports. Hence it was [a] confounding factor to be controlled by exclusion.

•  I would argue that this would not be confounding if the subgroups were equally matched in randomization. We are creating a HUGE selection bias by excluding these patients.
2. Primary outcome was progressive ICH.
• Can we please get away from focusing on surrogate endpoints? This is not a patient-centered endpoint and, furthermore, it would be useless to think a drug/intervention was effective if it reduced a surrogate endpoint but increased death.
3. All patients with head injuries were included -- multiple trauma, isolated, etc. 
• Including patients with multiple trauma of varying degree makes it extremely hard to draw conclusions on treatment effect due to confounding factors from other variable injuries. The *perfect* trial would be one that only includes isolated head injuries.
4. Randomization of this trial was competed over 4 years ago and it's just being published now? 
• Seems fishy.
• What we can take home is that administration of TXA probably does not increase incidence of thromboembolic events in this very select group of patients with TBI.

Bibliography:

• Yutthakasemsunt et al."Tranexamic Acid for Patients with Traumatic Brain Injury: A Randomized, Double-Blinded, Placebo-Controlled Trial" BMC Emergency Medicine 2013, 13(1):20