Hemorrhagic Shock John B. Holcomb, MD, FACS Commander, US Army Institute of Surgical Research Trauma...

Hemorrhagic ShockJohn B. Holcomb, MD, FACS Commander, US Army Institute ofSurgical ResearchTrauma Consultant for the Surgeon GeneralFort Sam Houston, Texas

2

Fluid Resuscitation Following Injury: Rationale for the Use of Balanced Salt Solutions

Rationale• Early use of type-specific whole blood remains the primary

treatment for shock due to blood loss• Lactated Ringer’s (LR) is used to replace interstitial fluid and to

support the intravascular volume until type-specific cross-matched blood is available

• LR is run at a very rapid rate—1000 to 2000 mL over 45 minutes—until whole blood is available

Subsequent Steps• Observe if the patient is a responder or nonresponder• Base further whole blood transfusion on the patient’s response

Seems very reasonable and sounds very similar to our recommendations

Carrico CJ, et al. Crit Care Med. 1976;4:46-54.

333

Discussion Platform

• >80% of combat-related deaths occur within 6 hours of wounding

• >80% of potentially preventable combat deaths are attributable to uncontrolled bleeding Majority of deaths involve truncal (noncompressible)

areas not conducive to tourniquets

• Management strategy includes novel pharmaceuticals, dressings, biological agents, tourniquets, and directed energy to stop internal bleeding that cannot be controlled by external compression methods

• Standard IV fluids can cause damage to the endothelium and coagulation system

Hemorrhagic shock is a challenge to clinicians in both the civilian and combat casualty care setting

444

A Definition of Hemorrhagic Shock

A clinical syndrome resulting from:• Decreased O2 perfusion of vital organs• Loss of blood volume

Characterized by:• Hypotension• Tachycardia• Pale, cold, and clammy skin• Oliguria• Decreased O2 delivery or utilization

555

Combat-Related Trauma

• In Operation Iraqi Freedom and Operation Enduring Freedom,

>90% of casualties experience penetrating wounds Largely from fragment dispersal of improvised

explosive devises (IEDs)

• The Joint Theater Trauma Registry compared wounding patterns in these conflicts (Oct. 2001 to Jan. 2005) with available data from WWII, Korea, and Vietnam Proportion of head and neck wounds higher Proportion of thoracic wounds lower Proportion sustained from explosions 78%, the

highest seen in any large-scale conflict – Usually 50%-60%

Owens BD, et al. J Trauma. 2008;64:295-299.

666

Markers for Hemorrhagic Shock

• HCT <32%

• SBP <110 mm Hg

• HR> 105 bpm

• Acidosis: pH <7.25

• BD <6 mmol/L

• INR> 1.5

• Temp <34°C

HCT=hematocrit; SBP=systolic blood pressure; HR=heart rate; BD=base deficit; INR=International Normalization Ratio.

Tieu BH, et al. World J Surgery. 2007;31:1055-1064. McLaughlin D, et al. J Trauma. 2008;64(suppl):57-63.

777

Classes of Hemorrhagic Shock

Class I Hemorrhage (loss of <15%)• Little tachycardia• Usually no significant change in BP, pulse pressure,

respiratory rate

Class II Hemorrhage (loss of 15%-30%)• HR >100 bpm, tachypnea, decreased pulse pressure

Class III Hemorrhage (loss of 30%-40%)• Marked tachycardia and tachypnea, decreased SBP, oliguria

Class IV Hemorrhage (loss of >40%)• Marked tachycardia and decreased SBP, narrowed pulse

pressure, markedly decreased or no urinary output• Immediately life-threatening

Gutierrez G, et al. Crit Care. 2004;8:373-381.

8Adapted from Cosgriff N, et al. J Trauma. 1997;42:857-861; discussion 861-862.

Major Torso Trauma

ProgressiveCoagulopathy

CoreHypothermia

MetabolicAcidosis

ActiveHemorrhage

IatrogenicFactors

CellularShock

TissueInjury

ContactActivation

Clotting FactorDeficiencies

MassiveTransfusion

Pre-existingDiseases

The “Bloody Vicious Cycle”

Coagulopathy Develops Over Time—1997

99

The Lethal Triad After 2003

Acidosis Hypothermia

Coagulopathy

Death

Brohi K, et al. J Trauma. 2003;54:1127-1130.MacLeod J, et al. J Trauma. 2003;55:39-44.

1010

Trauma

Shock

COAGULOPATHY

Genetics

Hemorrhage

Fibrinolysis

Inflammation

AcidemiaDilution Medications

CoTS

Resuscitation

Blood loss

Factor Consumption

HypothermiaHypothermia

Other Diseases

Data from International Group of Coagulation Investigators, 2008.

The Cycle of Coagulopathy

1111

Acute Traumatic Coagulopathy in Combat Casualty Care

• Retrospective cohort study of 391 patients who received a transfusion

• Patient outcomes of Injury Severity Score (ISS) and mortality were assessed upon arrival to the ED– Physiologic associations of long bone fractures,

central nervous system injuries, BD, and temperature

• The prevalence of acute coagulopathy in this cohort was 38% and increased with ISS

Niles S, et al. J Trauma. 2008. In press.Brohi K, et al. J Trauma. 2003;54:1127-1130. MacLeod J, et al. J Trauma. 2003;55:39-44.

12

0

10

20

30

40

50

60

INR <1.5 INR 1.5-2.0 INR 2.0

Mo

rtal

ity

(%)

12

Mortality by Level of Coagulopathy

N=391 transfused casualties

Niles S, et al. J Trauma. 2008. In press.

1313

Mortality by Coagulopathy and ISS

0

10

20

30

40

50

60

0-14 15-24 ?25 Total

Injury Severity Score

Mo

rtal

ity

(%)

Normal INR 1.5

P=.06P=.13

P.001

P.001

Niles S, et al. J Trauma. 2008. In press.

141414

Clinical Perspective

• Trauma patients who are the most severely injured (≈10%) also represent the majority of in-hospital deaths

• Considerable attention has been directed toward damage control surgery and reversing the acidosis and hypothermia present on admission

• Less attention has been directed toward reversing coagulopathy related to blood loss and predicting those patients who will need aggressive transfusion strategies

Holcomb JB, et al. J Trauma. 2007;62:307-310.

1515

• 3442 total patients• 680 received 1+ units blood in first 24 hours

• 204 transferred from another facility• 29 known younger than 18 years• 81 security internees

• Total of 302 patients in study population 80 patients (26.5%) required massive

transfusion (MT)

A Predictive Model for Massive Transfusion in Combat Casualty Patients

McLaughlin DF, et al. J Trauma. 2008;64(suppl):57-63.

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Variables in MT Equation

Wald Value CoefficientStandard

ErrorOddsRatio

HR >105 23.77 1.58 0.32 4.8

SBP <110 14.96 1.26 0.33 3.5

pH < 7.25 14.09 1.23 0.33 3.4

HCT <32 2.33 0.49 0.32 1.6

Adapted with permission from McLaughlin DF, et al. J Trauma. 2008;64(suppl):57-63. ©2008 Lippincott Williams & Wilkins http://lww.com.

1717

MT Scoring System

SBP <110HR >105HCT<32pH <7.25

ROC=.839

0

10

20

30

40

50

60

70

80

90

0 1 2 3 4

Score

% P

rob

abil

ity

of

MT

Adapted with permission from McLaughlin DF, et al. J Trauma. 2008;64(suppl):57-63. ©2008 Lippincott Williams & Wilkins http://lww.com.

n=168

n=202

n=151

n=115

n=62

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Comparison of 4 MT Prediction Studies

Author Variables ROC Value

McLaughlin et al. SBP, HR, pH, HCT 0.839

Yücel et al.SBP, HR, BD, Hgb

Male, +FAST, long bone/pelvic fracture

0.892

Moore et al. SBP, pH ISS >25

0.804

Schreiber et alHgb ≤11INR >1.5

Penetrating injury

0.804

Data from McLaughlin DF, et al. J Trauma. 2008;64:S57-S63; Yücel N, et al. J Trauma. 2006;60:1228-1236; discussion 1236-1237; Moore FA, et al. J Trauma. 2008;64:1010-1023; Schreiber MA, et al. J Am Coll Surg. 2007;205:541-545.

19

Component Therapy vs Warm Whole Blood

Component Therapy:

1 U PRBC + 1 U Plt + 1 U FFP + 1 U cryo 680 COLD mL

• HCT 29%• Plt 80K• Coag 65% of initial concentration• 1000 mg fibrinogen

Warm Whole Blood:

PRBC=packed red blood cells; Plt=platelet; FFP=fresh frozen plasma; cryo=cryoprecipitate.Armand R, et al. Transfus Med Rev. 2003:17:223-231.

500 mL WARM• HCT: 38%-50%• Plt: 150K-400K• Coag: 100%• 1000 mg fibrinogen

20

0.4

0.45

0.5

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300

Time, min

Pla

sm

a F

ac

tor

Co

nc

en

tra

tio

n (

%)

20

A Mathematical Model for FFP Transfusion Strategies During Major Trauma Resuscitation With Ongoing Hemorrhage

“A mathematical model for fresh frozen plasma transfusion strategies during major trauma resuscitation with ongoing hemorrhage”—Reprinted from, CJS December 2005; 48(6), Page(s) 470-478 by permission of the publisher. © 2005 Canadian Medical Association

v/V=0.005

v/V=0.02

Rate of blood loss as a fraction of total blood volume per min

v/V=0.005v/V=0.0075v/V=0.01

v/V=0.0125v/V=0.015

v/V=0.0175v/V=0.02

Factor concentration during resuscitation; transfusate PRBC 3 U: FFP 1 U: crystalloid100 mL (factor concentration 0.5 at time 0).

v/V = rate of blood loss as a fraction of total volume per minute.

2121

• McClelland RN, et al. JAMA. 1967;199:830-834

• Moore FD, et al. Ann Surg. 1967;166:300-301

• Rhee P, et al. Crit Care Med. 2000;28:74-78

• Brandstrup B, et al. Ann Surg. 2003;238:641-648

• NHLBI ARDS NET Clinical Trials Network; Wiedemann HP, et al. N Engl J Med. 2006;354:2564-2575

Cotton BA, et al. Shock. 2006;26:115-121.

The Cellular, Metabolic, and Systemic Consequences of Aggressive Fluid Resuscitation Strategies (review, Cotton et al, 2006)

2222

• Hypothesis: Normal resuscitation, compared with supranormal, requires less crystalloid volume, decreasing the incidence of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS)

• 1999 to 2001 (n=85) versus 2001 to 2002 (n=71)

• Conclusion: Supranormal resuscitation, compared with normal resuscitation, was associated with more LR infusion, decreased intestinal perfusion (higher GAPCO2), and an increased incidence of IAH, ACS, multiple organ failure, and death

Balogh Z, et al. Arch Surg. 2003;138:637-643.

Supranormal Trauma Resuscitation Causes More Cases of Abdominal Compartment Syndrome

232323

Damage Control Resuscitation

• In the combat casualty care setting, clinicians treating coagulopathy often have:

Immediate access to PRBCs and thawed AB or A plasma

Rapid access to apheresis platelets, prepooled cryoprecipitate, fresh whole blood, and recombinant activated factor VIIa (rVIIa), as indicated

• Damage control resuscitation as a structured intervention begins immediately after rapid initial assessment in the ED and progresses through the OR into the ICU


242424

Damage Control Resuscitation (cont)

In the severely injured casualty, damage control

resuscitation consists of 2 parts:

• Resuscitation limited to keep BP at ≈90 mm Hg, preventing renewed bleeding from recently clotted vessels

• Intravascular volume restoration accomplished by using thawed plasma as a primary resuscitation fluid in at least a 1:1 or 1:2 ratio with PRBCs Minimizing crystalloid rVIIa is occasionally used


252525

Casualties Requiring Continued Resuscitation

• Blood bank notified to activate the massive transfusion protocol: Individual coolers

– 6 units of plasma– 6 units of PRBCs– 6 packs of platelets

The most severely injured also receive fresh warm whole blood as a resuscitative fluid

Crystalloid use is minimized and serves mainly as a drug carrier and to keep lines open

Multiple point-of-care lab checks– BD, Hgb, INR, Ca

• Lack of intraoperative coagulopathic bleeding has been remarkable

Holcomb JB, et al. J Trauma. 2007;62:307-310.Kauver DS, et al. J Trauma. 2006; 61:181-184.Spinella PC, et al. Crit Care Med. 2007;35:2576-2581.

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Adapted with permission from Borgman MA, et al. J Trauma. 2007;63:805-813. ©2007 Lippincott Williams & Wilkins http://lww.com.

The Ratio of Blood Products Transfused Affects Mortality in Patients Receiving MTs at a Combat Support Hospital

Variable Odds Ratio (95% CI) P value

Plasma:RBC ratio 8.6 (2.1–35) .003

AIS head/neck score 0.75 (0.61–0.94) .013

AIS thorax score 0.73 (0.57–0.92) .009

SBP 1.0 (0.98–1.01) .457

Hemoglobin 1.1 (0.91–1.2) .501

BD 0.89 (0.84–0.95) <.001

Odds Ratio Predicting Survival Using Multivariate Logistic Regression

AIS=Abbreviated Injury Scale.

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Mortality by Plasma:RBC Ratio(n=246 MTs [2003-2005])


P<.00165

34

19

0

10

20

30

40

50

60

70

(Low) 1:8 (Medium) 1:2.5 (High) 1:1.4

Plasma:RBC Ratio Groups

Mo

rta

lity

(%

)

Percentage mortality associated with low, medium, and high plasma to RBC ratios transfused at admission. Ratios are median ratios per group and include units of fresh whole blood counted both as plasma and RBCs.

2828

Comparison of the Primary Causes of Death in Each Plasma:RBC Ratio Group

Time to Death Low = 2 hr Med = 4 hr High = 38 hr

0

10

20

30

40

50

60

70

80

90

100

Low n=20 Medium n=18 High n=31

1 0.5 12

1

11.5

6

42.5

7


18.5

14

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UT Houston 4-Year Experience

VariablePre—1:2 (N = 97)

Post—1:1 (N = 95) P value

Age 39±2 37±1.6 .44

ISS 29±1 28±1.2 .53

ED INR 1.8±0.2 1.62±0.08 .41

Pre-ICU Cryst (L) 9±1 7±0.4 .07

Pre-ICU PRBC 12±1 15±1.2 .06

Pre-ICU FFP 5±0.4 11±1.0 <.0001

ICU Admit INR 1.6±0.04 1.48±0.03 .02

6 hr FFP:PRBC 1: 2.4 1: 1.3 .05

24 hr FFP:PRBC 1:1.2 1: 1.0

Mortality 30% 15% <.05

Gonzalez E, et al. Paper presented at: 38th Annual Meeting of the Western Trauma Association; February 24-29, 2008; Squaw Creek, CA. No. 29.

3030

• rVIIa+ to rVIIa- patients 24-hour mortality was 7/49 (14%) and 26/75 (35%),

P=.01 30-day mortality was 15/49 (31%) and 38/75 (51%),

P=.03

• SBP was higher in the rVIIa+ group

• The use of rVIIa was associated with improved early and late survival after severe trauma and massive transfusion

• rVIIa was not associated with increased risk of thrombotic events

• Additional trials needed

The Effect of rVIIa on Mortality in Combat-Related Casualties With Severe Trauma and MT

Spinella PC, et al. J Trauma. 2008;64:286-294.

3131

Kaplan-Meier Curve of 24-Hour Mortality for rVIIa+ Patients vs rVIIa- Patients

P =.004 by the log rank test.

Adapted with permission from Spinella PC, et al. J Trauma. 2008;64:286-294. ©2008 Lippincott Williams & Wilkins http://lww.com.

0

20

40

60

80

100

0 5 10 15 20 25

Hour of Death

Cu

mu

lati

ve

Su

rviv

al

(%)

P<.05

rVIIa

No

Yes

24-Hour Survival

32

0

20

40

60

80

100

0 5 10 15 20 25 30

Day of Death

Cu

mu

lati

ve

Su

rviv

al

(%)

32

Kaplan-Meier Curve of 30-Day Mortality for rVIIa+ Patients vs rVIIa- Patients

P =.002 by the log rank test.

Adapted with permission from Spinella PC, et al. J Trauma. 2008;64:286-294. ©2008 Lippincott Williams & Wilkins http://lww.com.

rVIIa

No

Yes

30-Day Survival

P<.05

3333

Multicenter (16), Retrospective MT Study

Increased Plasma and Platelet to RBC Ratios Improves Outcome in 466 Massively Transfused Civilian Trauma Patients

Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Schreiber MA, Gonzalez EA, Pomper G, Williams KL, Park MS, and The Trauma Outcomes Group.

Conventional MT guidelines underrepresent the optimalplasma and platelet to RBC ratios. Survival in MT civilian patientsis improved by increasing plasma and platelet ratios. Currentsurvival after MT varies up to 80% at 16 major Level 1 Trauma centers. Prospective trials should aim for a 1:1 ratio of plasma and platelet to RBC ratios.

Holcomb JB, et al. Abstract presented at: 128th Annual Meeting of the American Surgical Association; April 24-26, 2008; New York, NY. No. 6.

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Thawed Plasma

• FFP that is kept for up to 5 days at 4°C

• Present upon arrival in the ED Used as a primary resuscitative fluid

• This approach not only addresses the metabolic abnormality of shock, but initiates reversal of the early coagulopathy of trauma

• Multiple centers are now using this product Decreases waste by 60% to 70%

Malone DL, et al. J Trauma. 2006;60(suppl):91-96.Armand R, et al.Transfus Med Rev. 2003;17:223-231.

3535

Risks of FFP and Platelets

• Reports of transfusion-related acute lung injury (TRALI) from the UK hemovigilance Serious Hazards of Transfusion scheme suggest a risk from FFP in the region of 1 in 60,000 units

This may now be the most common cause of death from transfusion, and is the most frequent serious complication of FFP

• In 100% of the TRALI cases arising from FFP, a female donor was identified as the source of the HLA/HNA antibodies

• Must be alive to have some of these complications

MacLennan S, et al. J Trauma. 2006;60(suppl):46-50.

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Combat Case—IED, May 2006

3737

Combat Case—IED, May 2006 (cont)

3838

Combat Case

• Fragment wound in back• 30 min evac to CSH• Arrives pH=6.9• BD=25• Temp=35ºC• INR=2• HCT=10• SBP=60 mm Hg• HR=140 bpm• Upon arrival arrested in the ED• Clam shell/clamp aorta/to OR• Lines and DCR started in the ED

3939

Radiographic Findings

4040

Combat Case

4141

The Surgical Field

4242

Fragment

4343

The Surgical Team

4444

Outcome

• 30 FFP, 32 RBC, 10 cryo, 20 platelets, rVIIa, 5 liters of LR

• Bleeding stopped with packing

• No coagulopathic bleeding

• Abdomen closed day 3

• Recovered and discharged to local hospital in 14 days

4545

Prior Coordination and Cooperation

• Cannot be done in isolation and made up at 0200

• ED staff• Anesthesia• Surgery/Trauma• ICU• Transfusion/blood bank• Nursing• Very small numbers

3% of all civilian trauma admissions 15% to 70% mortality

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Multiple Papers Presented and Submitted on This Topic

• Military experience 252 patients +

• AAST 07 Denver paper 140 (1:1) - • AAST 07 Vanderbilt paper 139 + • AAST 07 Tulane paper 135 + • EAST 08 Vanderbilt paper 69 + • German Trauma Society 409 + • WTA Glue grant 405 +• WTA Houston 192 +

• ASA 08 abstract 467 +

• 8 papers + (2068) and 1 “negative” (140)

• ≈20 abstracts submitted to AAST-08 on this subject

AAST=American Association for the Surgery of Trauma; EAST=Eastern Association for the Surgery of Trauma; WTA=Western Trauma Association.

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Summary

• Uncontrolled hemorrhage is a major problem

MT used in 3% of all civilian trauma admissions

Very high mortality

• Predictive models are here

Rapid Dx of MT patients who are in shock

and coagulopathic

• Must start plasma and platelets much earlier

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Summary (cont)

• Use physiology (not tradition) to drive diagnosis and interventions

• Don’t make the presenting problems worse with repeated iatrogenic injury

• Accept known risks and benefits

4949

Changing earlyresuscitation practices for the severely injured from crystalloid- based to primarily blood products

Over the past 12 months,lyophilized plasmatransfused into injuredpigs—it is equivalentto fresh whole blood and FFP• MGH, OHSU, USAISR

Back to the Future?

MGH=Massachusetts General Hospital; OHSU=Oregon Health Sciences University; USAISR=US Army Institute of Surgical Research.

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Hemorrhagic Shock John B. Holcomb, MD, FACS Commander, US Army Institute of Surgical Research Trauma...

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