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

Spinal Immobilization: Friend or Foe? Tales from the EMJ Prehospital Spinal Immobilization Consensus Statement

Due to the tremendous popularity of my previous post highlighting the EMJ pelvic fracture consensus statement, I decided to add in highlights from this one too. This paper, written by Connor et al, highlights the 7 conclusions from the consensus meeting held by the Faculty of Pre-hospital Care, Royal College of Surgeons of Edinburgh in March 2012. Again, I think these authors hit this one out of the park; I agree 100% with their conclusions. Without further ado, here's what they concluded:

1) The long spinal board is an extrication device solely. Manual in-line stabilization is a suitable alternative to a cervical collar.

• The authors speak here about the scant evidence for the use of a spine board. The authors then go on to mention: 

current guidance is founded upon expert opinion rather than definitive evidence and current protocols have a strong historical rather than scientific precedent.

• They then go on to talk about how spinal immobilization on a long spine board is not without risk.

 [Spinal immobilization] is uncomfortable; takes time and delays initiation of specialist treatment in time-critical patients; raises intracranial pressure; increases aspiration risk and the risk of decubitus ulceration; and also potentially reduces airway opening and respiratory efficacy.

• As an aside - it seems like the unanimous favorite for the type of spinal immobilization by the authors is either the scoop stretcher, or the vacuum mattress. 

 2) An immobilization algorithm may be adopted although the content of this remains undefined.

• They mention that although scoring systems like "NEXUS" or the Canadian C-Spine Rule are highly sensitive for spinal injury, they are not at all specific. Both of these criterion were designed to be decision aides for imaging, not to determine whether or not the patient requires a spine board. For the purpose of imaging, the ultra-high sensitivity for any injury is a must. Because of this, we can accept the low specificity. For the purpose of backboarding a patient, we would require a test to be highly sensitive for a severe/unstable injury while also being moderately specific to avoid over-utilization of spine boards (this paper states currently approx 1/100 backboarded patients have have any SCI). For these reasons, this paper recommends better decision aides be sought.

3) There may be potential to vary the immobilization algorithm based on conscious level of the patient.

• They state that in the conscious, cooperative patient with potential life-threatening injuries, it would be reasonable to delay immobilization until first completing the primary survey.

4) Penetrating trauma with no neurological signs does not require immobilization.

• This is fairly well described in the current literature. Not much to say here.

5) 'Standing take down' practice should be avoided.

• The authors here basically just agreed that it is silly to backboard a patient who is already standing up and walking using the "standing take down" method that I'm sure you all absolutely love.

6) In the conscious patient with no overt alcohol or drugs on board and with no major distracting injuries, the patient, unless physically trapped, should be invited to self-extricate and lie on the trolley cot. Likewise, for the non-trapped patient who has self-extricated, they can be walked to the vehicle and then laid supine, examined, and then if necessary immobilized.

• The recommendation here is quite descriptive. Not much to say here other than I agree.

7) Further research into effective, practical, and safe immobilization practice, and dissemination of this, is required.

• Yep.

So there you have it! Very controversial stuff here! I applaud the authors on their recommendations. Leave your thoughts in the comments. I'd love to hear them!

Bibliography:

• Connor D, Greaves I, Porter K, et al. "Pre-hospital spinal immobilisation: an initial consensus statement" Emerg Med J 2013; 30:1067-1079

New Consensus Statement Released for Prehospital Management of Pelvic Fractures

Good evening, folks!

Earlier this month, EMJ published a consensus statement containing 9 recommendations on the prehospital management of pelvic injuries. The consensus meeting was held in March, 2012. I am very pleased with the recommendations this paper provides, so I'll take a moment to quickly summarize what they came up with. I highly recommend obtaining the full-text and having a look for yourself.

The 9 recommendations are as follows:

1) A pelvic binder is a treatment intervention rather than a packaging intervention and should be applied early.

• The authors then state, "If the patient is hemodynamically compromised with a significant mechanism suggestive of a pelvic injury, a pelvic binder should be applied." 

2) A select group of patients may not need a binder.

• The authors state that pelvic trauma may be excluded from a select group of patients - namely, those with hemodynamic stability (undefined) and a "normal" GCS (GCS > 13).
• Within this recommendation, the authors go on to agree that "springing the pelvis" is a very poor indicator of pelvic injury - the sensitivity and specificity being 59% and 71% respectively.

3) No one pelvic binder device can currently be recommended over another.

• The evidence supporting one device over another is almost exclusively anecdotal, so no recommendations can be made here. 
• However, the authors recommend that the ideal device should:
1. Be easy to apply
2. Not cause further harm.
3. Allow radiological and surgical intervention without the need for removal.
• The authors state, "the two devices with the strongest evidence base are the SAM pelvic sling and the T-POD devices".

4) Adequate training must be provided to avoid misplacement of devices.

•  The authors state that, although there is some evidence out there of devices being incorrectly placed, this is likely due to improper training rather than design fault.

5) Associated femoral fractures should also be reduced.

• Hallelujah! Can we finally put the myth to rest that femur fractures with associated pelvic injuries can not be reduced? 
• Side note: the authors advise against using devices that exert pressure using traction against the pelvis in the midline (e.g. the sager device). 

6) Patients should not be log rolled or transported on a spinal board.

• Maybe it's the controversial side in me that likes this recommendation so much, but regardless of the reason, the authors state "Logrolling only has a place in turning a patient onto their back to allow access to their airway. There is no place for routine logrolling in blunt trauma victims."
• The authors then go on to say, "No patient should be log rolled onto or off a spinal board with a pelvic injury." 

7) The use of pelvic binders is associated with the risk of low pressure skin necrosis.

• Not much to say on this one. It is self-evident and reasonably described in the literature.

8) The pelvic binder should be placed next to skin.

• In this discussion, the authors expose that there is zero evidence that placement over clothes provides the same degree of stabilization or risk of pressure damage. They state that it should also be placed directly over skin to avoid the need to remove the splint on arrival to the hospital to remove clothes at that time. Completely agree here.

9) A pelvic binder should be applied prior to extrication.

• The authors openly state that there is no hard evidence to support this guideline. The recommend this simply due to the fact that handling the patient prior to splinting has been described to disrupt clots that have already formed. This is reasonable. 

So there you have it! What do you all think of all this? Leave your thoughts in the comments!

Bibliography:

• Scott I, Porter K, Laird C, et al."The Prehospital Management of Pelvic Fractures : Initial Consensus Statement" Emerg Med J 2013; 30:1070-1072

Tranexamic Acid Primer

Tranexamic Acid (TXA)

What is it?

• TXA is an antifibrinolytic drug → TXA is synthetic analog of lysine that competitively binds to the lysine sites on plasminogen that prevents conversion of plasminogen to plasmin. This action prevents fibrinolysis (the breakdown of fibrin) and promotes clot stability.
• Easy way to look at it → TXA is (in essence) the polar opposite of tPA.

Why should we worry about this in trauma?

• Hyperfibrinolysis is present in 7-20% of all adult trauma patients and is associated with increased mortality; some studies cite it is present in up to 57% of all trauma patients. [1,2]
• If present, hyperfibrinolysis occurs early (<1 hour) and is associated with increased massive transfusion requirements, coagulopathy, and hemorrhage-related death. [3]
• Mortality rate has been reported to be approximately 88% in trauma patients with hyperfibrinolysis on admission detected by TEG/TEM. [3]

Does it work/What are the risks?

CRASH-2 Trial: [4]

• Prospective, double-blind, multinational, randomized, placebo-controlled trial.
• 274 hospitals. 40 countries. 
• 20,211 adult trauma patients (10,060 treatment arm - 10,067 placebo arm) with or at risk of significant bleeding ("all-comers")
• SIGNIFICANT reduction in all-cause mortality if given within 3 hours of injury (RR= 0.91; 95% CI 0.85 to 0.97; P=.004)
• NO INCREASE in fatal vascular occlusive events or in deaths caused by multiple organ failure, head injury, etc.

MATTERS Trial: [5]

• Retrospective, observational, single-center, "before & after" cohort study from Jan 2009 to Dec 2010.
• 896 military combat trauma patients who received at least 1 unit of PRBCs after admission.
• TXA was incorporated into the center's "major hemorrhage protocol" in 2010 - results were compared between the 2 groups. 
• Patients who received > 10 units RBCs within 24 hours were also subdivided into a "Massive Transfusion" cohort.
• SIGNIFICANT reduction in-hospital mortality in TXA group → absolute reduction in-hospital mortality in TXA group was 6.5% and in the TXA "massive transfusion" group was 13.7% → Relative reduction of 49%.
• The authors quote:

"In a separate analysis, none of the clinical parameters had an association with DVT or PTE in either the overall or MT cohort. As such, no parameters, including administration of TXA, were associated with DVT or PTE"

Conclusion

• Early administration of TXA in the severe trauma patient in the prehospital setting is a NO-BRAINER.

1) Kutcher et al. J Trauma 2012; 73:87-93

2) Raza et al. J Thromb Haemost 2013; 11(2):307-14

3) Schochl et al. J Trauma 2009; 67(1):125-31

4) CRASH-2 Collaborators. Lancet 2010; 376:23-32

5) Morrison et al. Arch Surg 2012; 147(2):113–9