Novel Resuscitation Strategies

Transcription

1 Novel Resuscitation Strategies Hasan B Alam, MD Norman Thompson Professor of Surgery Head of General Surgery University of Michigan

2 Case 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

3 Triad of death Acidosis Coagulopathy Hypothermia

4 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

5 More data Hg: ph: INR: >10 PTT: >180 Increased peak airway pressures PEEP: cm H2O Bleeding from IV sites, ETT Efforts stopped- 4hrs-31min after arrival

6 Case yrs old No significant PMH Hit by a truck while riding a bicycle AAAx3. SBP ~50, HR 110/min Primary survey Secondary survey

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10 MTP 1:2 ratio; IR; multiple procedures; never coagulopathic

11 EMS: Case 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

12 Resuscitation Bay

13 Resuscitation Bay

14 MTP OR After transfer to OR bed, loss of pulses REBOA Pre-peritoneal packing + Damage control ex-lap IR Back to OR

15 TEG/ROTEM

16 ROTEM Extem Fibtem Aptem Arrival Post-IR

17 First, you must stop the bleeding

18 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

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20 How much can you bleed? 100ml/minx15=1500 ml

21 Hemodynamic response to acute blood loss

22 The Trimodal Distribution Of Trauma Deaths The group that matters

23 #1 Cause of Preventable Death After Injury

24 Today: trauma deaths CRASH-2 trial Lancet RCT- 274 hospital, 40 countries, >20K patients Most died on the day of randomization Deaths due to MOF <2.5%

25 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

26 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

27 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

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30 Excess fluids associated with worse outcomes in burn patients

31 Same is true for elective surgical patients

32 Impact of Resuscitation fluids on Cellular Functions Institute of Medicine 1999

33 Damage Control or Hemostatic Resuscitation Prioritize hemorrhage control Permissive hypotension Avoid crystalloids Early component therapy (protocol driven) Adjuncts: Correct hypothermia and acidosis Anti-fibrinolytics

34 Can you predict the need for massive transfusion?

35 Hgb, SBP, BD, HR, gender, +FAST, unstable pelvis, open femur fracture J Trauma, 2006

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38 Early blood component therapy

39 BLEEDING PATIENTS

40 BLEEDING PATIENTS NEED BLOOD

41 RBC PLASMA PLATELETS

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44 - Retrospective review of 246 pts - >10 units PRBC - Mortality due to hemorrhage= 93%, 78% & 38%

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46 More FFP associated with better survival - Retrospective review of 708 patients

47 Protocol driven blood products: -Early component delivery without increasing total blood use - Better outcomes

48 Platelets are equally important (Inaba K et. al, JACS 2010)

49 - Database study -MT from 22 level I centers over 12 mths (n=643) - Better 24 hrs and 30 day mortality

50 Prospective cohort study over 28 mths Single center (n=806) FFP to PRBC ratio not predictive

51 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?

52 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

53 Limitations Potential survival bias Differences in care

54 First RCT examining ratios in trauma resuscitation with survival as endpoint

55 2015 1:1:1 vs 1:1:2 ratio 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

56 More complications >6 units FFP: ARDS 12 fold MODS 6 fold Pneumonia/sepsis 4 fold Aggressive FFP harmful in patients without massive blood loss

57 Anti-fibrinolytics

58 EARLY SHOCK 1.5% survival advantage

59 All patients MT patients Mortality drop 28 to 14%. OR for Survival 7

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61 TXA/CRYO had higher ISS Got more PRBC No TXA/CRYO= 5 TXA= 8 CRYO= 20 TXA/CRYO= 22

62 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

63 Prothrombin Complex Concentrates (PCC)

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65 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)

66 Massive Transfusion Protocols Improvement in delivery Better utilization of products Improvement in outcomes

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68 111 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

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70 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

71 New developments

72 Plasma and red cells are good but

73 New approach Freeze dried plasma and platelets Combined with hemoglobin based solution, +/- factors +/- preserved platelets Low volume, hypertonic, hyperoncotic

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75 Irina Bakaltcheva, PhD (WRAIR)

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77 Spray dried 1/3 rd volume Just as good as FFP Easy to reconstitute

78 Not a new concept WWII

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80 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

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83 French LYophilised Plasma (FLYP) <10 donors/unit (minipool) Extensive quality control and testing Stored up to 24 months No major specific adverse events

84 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 Nov;15(6):612-7.

85 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 days Basic concept: Unfrozen = functional loss, especially factor VIII

86 Basu D, Kulkarni R. Overview of blood components and their preparation. Indian Journal of Anaesthesia. 2014;58(5):

87 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 Jan;74(1):84-90 Liquid plasma (26 days) superior to thawed FFP after 5 days

88 Fluidless Resuscitation

89 Making survivors out of non-survivors Surviving Blood Loss (SBL) Program Keep cells alive Fill the tank

90 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

91 Histone modifications Deacetylases (HDACs) & Acetyltransferases (HATs) HDAC Inhibitors = Increased Protein Acetylation

92 The Acetylome Minucci S (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer Nat. Rev. Cancer. 6: doi: /nrc1779

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94 Surgery 2009

95 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 Alam et al. Surgery 2009 Minutes

96 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

97 Hemorrhage + Traumatic Brain Injury

98 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 * * * NS Hex Hex+VPA Jin et al. J Trauma NS Hex Hex+VPA

99 Combination of VPA and FFP is the best Imam et al. Surgery August 2013

100 NSS NS NS+VPA 10 * p = Day

101 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

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103 Phase II and III trials- Hemorrhage $34.6 M

104 Massive blood loss and no pulse Emergency Department Thoracotomy

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106 The ultimate resuscitation strategy

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109 Cognitive function testing Alam et al, Surgery 132: , 2002 Operant conditioning Recognize and open color coded box Number of sessions, time to finish task, performance score

110 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

111 October 2012 Sponsored by the NIH and the DoD Guidelines for future research

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113 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

114 The difficulty lies, not in the new ideas, but in escaping from the old ones.. John Maynard Keynes ( )

115 Funding acknowledgement: National Institutes of Health and the US Department of Defense