Novel Resuscitation Strategies Hasan B Alam, MD Norman Thompson Professor of Surgery Head of General Surgery University of Michigan
Case 2005 27 yrs old male. GSW x3, 10 min transport time SBP 70, HR 130, confused, diaphoretic GSW: arm, flank, and transpelvic Labs: Hg 10.4, ph 7.01, INR 1.0, PTT 21.9 ED Care: Intubation, groin lines, IVF 4-6L, PRBC 2 units Trauma team called
Triad of death Acidosis Coagulopathy Hypothermia
Back to our patient in the OR Abdomen full of blood + resuscitation fluids Damage control: Ligation iliac vein. Shunt iliac artery. Control of colon, small bowel injuries. Pelvic packing. No clot formation, high dose drugs Red blood cells 22, plasma 13, platelets 12 Diffuse bleeding
More data Hg: 10.4-12.8-9.9-6.7-8.9-6.2-4.6 ph: 7.01-7.06-7.05-7.04-7.03-6.8 INR: 1.0-2.4- >10 PTT: 22-106- >180 Increased peak airway pressures PEEP: 5-10- 15-30 cm H2O Bleeding from IV sites, ETT Efforts stopped- 4hrs-31min after arrival
Case 2010 33 yrs old No significant PMH Hit by a truck while riding a bicycle AAAx3. SBP ~50, HR 110/min Primary survey Secondary survey
MTP 1:2 ratio; IR; multiple procedures; never coagulopathic
EMS: Case 2017 31 yr M, found in middle of a road after being hit by a car ~55mph At scene, hypotensive, tachycardic, GCS 4. bag mask ventilation Trauma Bay: A: Bag masking, unresponsive B: Bilateral breath sounds, 99% on NRB C: HR 120s, palpable femoral pulses, unable to obtain BP ph 6.9, lac 7.9, HCO3 11
Resuscitation Bay
Resuscitation Bay
MTP OR After transfer to OR bed, loss of pulses REBOA Pre-peritoneal packing + Damage control ex-lap IR Back to OR
TEG/ROTEM
ROTEM Extem Fibtem Aptem Arrival Post-IR
First, you must stop the bleeding
Goals of early trauma care Keep alive Minimize organ injury Decrease bleeding Keep alive Preserve key organs ABC s Fix injuries Resuscitate Support organs Pre-hospital ED OR/SICU
How much can you bleed? 100ml/minx15=1500 ml
Hemodynamic response to acute blood loss
The Trimodal Distribution Of Trauma Deaths The group that matters
#1 Cause of Preventable Death After Injury
Today: trauma deaths CRASH-2 trial Lancet 201002 RCT- 274 hospital, 40 countries, >20K patients Most died on the day of randomization Deaths due to MOF <2.5%
Clinical evidence Cochrane Review: Timing and volume of fluid administration for patients with bleeding 6 trials No evidence to support early or large volume resuscitation
Should resuscitation be delayed until control of hemorrhage? Prospective randomized (n=598) Mortality: Early 38%, Delayed 30% (RR 1.26, p=0.04) Hospital stay: Early 14 d, Delayed 11 d (p=0.006) No difference in multiple organ failure, infections
Is blunt trauma different? 20% have closed head injury Non surgically correctable sources Aggressive late resuscitation may worsen: Cerebral edema Pulmonary contusion Intra-abd hypertension/compartment syndrome
Excess fluids associated with worse outcomes in burn patients
Same is true for elective surgical patients
Impact of Resuscitation fluids on Cellular Functions Institute of Medicine 1999
Damage Control or Hemostatic Resuscitation Prioritize hemorrhage control Permissive hypotension Avoid crystalloids Early component therapy (protocol driven) Adjuncts: Correct hypothermia and acidosis Anti-fibrinolytics
Can you predict the need for massive transfusion?
Hgb, SBP, BD, HR, gender, +FAST, unstable pelvis, open femur fracture J Trauma, 2006
Early blood component therapy
BLEEDING PATIENTS
BLEEDING PATIENTS NEED BLOOD
RBC PLASMA PLATELETS
- Retrospective review of 246 pts - >10 units PRBC - Mortality due to hemorrhage= 93%, 78% & 38%
More FFP associated with better survival - Retrospective review of 708 patients
Protocol driven blood products: -Early component delivery without increasing total blood use - Better outcomes
Platelets are equally important (Inaba K et. al, JACS 2010)
- Database study -MT from 22 level I centers over 12 mths (n=643) - Better 24 hrs and 30 day mortality
Prospective cohort study over 28 mths Single center (n=806) FFP to PRBC ratio not predictive
Can we use INR to determine who would benefit from FFP? Retrospective 437 MT patients INR correlates with mortality Benefits of FFP independent of INR How does FFP improve survival if not not due to less coagulopathy and less bleeding?
The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-varying Treatment with Competing Risks 10 centers with 1245 patients (905 > 3units PRBC) 3 fold lower death in the first 6 hrs if FFP:PRBC ratio <1:2 No difference in death after 24 hrs Holcomb JB et al. Archives Surg 2012;15:1-10
Limitations Potential survival bias Differences in care
First RCT examining ratios in trauma resuscitation with survival as endpoint
2015 1:1:1 vs 1:1:2 ratio 680 pts @ 12 level 1 trauma centers 24 hrs: Death 12.7 vs. 17% p=0.12 Exsanguination death 9.2 vs. 14.6% (p=0.03) More hemostasis in 1:1:1 24 hrs- 30 day No difference Rec: Massively bleeding patients need PRBC, FFP and Platelets in 1:1:1 ratio
More complications >6 units FFP: ARDS 12 fold MODS 6 fold Pneumonia/sepsis 4 fold Aggressive FFP harmful in patients without massive blood loss
Anti-fibrinolytics
EARLY SHOCK 1.5% survival advantage
All patients MT patients Mortality drop 28 to 14%. OR for Survival 7
TXA/CRYO had higher ISS Got more PRBC No TXA/CRYO= 5 TXA= 8 CRYO= 20 TXA/CRYO= 22
Adult patients in severe hemorrhagic shock (SBP <75mmHg), known predictors of fibrinolysis, or TEG evidence (LY30>3%) Within 3 hrs 1 gm load (10 min) and 1 gm infusion x 8hr
Prothrombin Complex Concentrates (PCC)
For major bleeding related to vit K antagonists: 4 factor PCC rather than plasma (2 C) Plus, 5-10 mg vit K IV slow injection (2C)
Massive Transfusion Protocols Improvement in delivery Better utilization of products Improvement in outcomes
111 pts randomized to CCA and TEG Most deaths in the first 6 hrs TEG had better survival (19.6% vs. 36.4%) Similar PRBC use but lower platelet and plasma use in TEG group
Recommendations Damage Control Resuscitation Prioritize hemorrhage control Avoid crystalloids and artificial colloids Permissive hypotension prior to hemorrhage control Early component therapy- delivered using a MT protocol Anti-fibrinolytic agents in severely injured
New developments
Plasma and red cells are good but
New approach Freeze dried plasma and platelets Combined with hemoglobin based solution, +/- factors +/- preserved platelets Low volume, hypertonic, hyperoncotic
Irina Bakaltcheva, PhD (WRAIR)
Spray dried 1/3 rd volume Just as good as FFP Easy to reconstitute
Not a new concept WWII
German LyoPlas Single donor Cellular reduction to improve compatibility Stored up to 15 months 350,000 units circulated No specific complications General complication rate 0.023%- similar to FFP
French LYophilised Plasma (FLYP) <10 donors/unit (minipool) Extensive quality control and testing Stored up to 24 months No major specific adverse events
South African Bioplasma FDP Pooled, solvent-detergent treated, universal plasma Screened and tested Recommended storage temp <25 o C In use since 1994 Solheim BG, Chetty R, Flesland O. Indications for use and cost-effectiveness of pathogen-reduced ABO-universal plasma. Curr Opin Hematol. 2008 Nov;15(6):612-7.
USA Dried plasma not approved for use Options: FFP: Frozen within 8 hrs FP24: Frozen within 24 hours Pre thawed plasma: used up to 5 days Liquid plasma (aka never frozen plasma ): separated from whole blood 5 days before expiration. Kept at 1- o C for 26-40 days Basic concept: Unfrozen = functional loss, especially factor VIII
Basu D, Kulkarni R. Overview of blood components and their preparation. Indian Journal of Anaesthesia. 2014;58(5):529-537.
Matijevic N, Wang YW, Cotton BA, Hartwell E, Barbeau JM, Wade CE, Holcomb JB. Better hemostatic profiles of never-frozen liquid plasma compared with thawed fresh frozen plasma. J Trauma Acute Care Surg. 2013 Jan;74(1):84-90 Liquid plasma (26 days) superior to thawed FFP after 5 days
Fluidless Resuscitation
Making survivors out of non-survivors Surviving Blood Loss (SBL) Program Keep cells alive Fill the tank
Pharmacological treatment as a bridge to definitive care Desired properties: Should be safe and easy to administer & store Available Cost Valproic acid (VPA) Depakote or Depakene, Abbott Pharmaceuticals, Ltd. FDA approved Feb 1978 For seizure and mood disorders Numerous clinical trials for cancer treatment Generic available >80 trials ongoing
Histone modifications Deacetylases (HDACs) & Acetyltransferases (HATs) HDAC Inhibitors = Increased Protein Acetylation
The Acetylome Minucci S (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer Nat. Rev. Cancer. 6: 38 51 doi:10.1038/nrc1779
Surgery 2009
Percent survival End of Hemorrhage Survival 100 * * Fresh w hole blood-100% (n=6) Valproic acid-85.7% (n=7) 50 Control-25% (n=8) *=Log-Rank (Mantel-Cox test), p<0.05 compared to control 0 0 100 200 300 Alam et al. Surgery 2009 Minutes
HDACIs in Lethal Injuries Decreased apoptosis Activation of survival pathways Decreased inflammatory response >50 manuscripts Improved survival Decreased organ dysfunction Millions in NIH and DoD Funding Attenuation of coagulopathy FDA approved Clinical Trial
Hemorrhage + Traumatic Brain Injury
Lesion size (mm 3 ) Brain swelling (%) Decrease in Brain Lesion Size and Edema Within 6 hrs- High dose VPA (300 mg/kg) NS Hex Hex +VPA 5000 4000 3000 * 50 40 30 * * 2000 20 1000 10 0 NS Hex Hex+VPA Jin et al. J Trauma 2012 0 NS Hex Hex+VPA
Combination of VPA and FFP is the best Imam et al. Surgery August 2013
NSS 30 20 NS NS+VPA 10 * p = 0.02 0 0 10 20 30 Day
Georgoff PE et al. Pharmacokinetics and safety of high-dose intravenous valproic acid in healthy subjects: a dose escalation trial to support clinical translational studies. Clinical Pharmacokinetics 2017
Phase II and III trials- Hemorrhage $34.6 M
Massive blood loss and no pulse Emergency Department Thoracotomy
The ultimate resuscitation strategy
Cognitive function testing Alam et al, Surgery 132:278-288, 2002 Operant conditioning Recognize and open color coded box Number of sessions, time to finish task, performance score
Emergency Preservation and Resuscitation Rate of induction Fast (2 o C/minute) Alam et al. J Trauma 2004 Optimal Depth Profound (10 o C) Alam et al. Surgery 2006 Rate of re-warming (0.5ºC/minute) Alam et al. J Trauma 2006 Duration short (60 minutes) Alam et al. J Trauma 2008 Poly-trauma feasible without complications Sailhamer et al. JACS 2007
October 2012 Sponsored by the NIH and the DoD Guidelines for future research
Goals of early trauma care Keep alive Minimize organ injury Decrease bleeding Keep alive Preserve key organs ABC s Fix injuries Resuscitate Support organs Pre-hospital ED OR/SICU Pro-survival drugs Freeze dried plasma EPR
The difficulty lies, not in the new ideas, but in escaping from the old ones.. John Maynard Keynes (1883-1946)
Funding acknowledgement: National Institutes of Health and the US Department of Defense