A Fluid Discussion of Resuscitation Trevor Langhan PGY1

A Fluid Discussion of Resuscitation Trevor Langhan PGY-1 January 8, 2004 Coombs Theatre

Objectives • Review commonly used fluid choices in hemorrhagic trauma resuscitation • Review timing and fluid choices • Outline future options • Resuscitation in the 21 st century

Fluid Resuscitation • Cambridge Dictionary defines drug as: “any natural or artificially made chemical which is used as a medicine” • Merriam-Webster Dictionary: “a substance other than food intended to affect the structure or function of the body”

Fluid Resuscitation • Fluid choice often not perceived as having “pharmacologic” properties: • • Bang in a few liters Give him a bolus Run it wide open He’s had 2 or 3 liters so far

Fluid Resuscitation • Fluid choice and timing of fluid therapy have far ranging consequences beyond the trauma resuscitation • New ideas include: • • Is fluid replacement always needed? What about small volume resuscitation? Hypertonic choices Blood substitutes

Fluid History • 1628 • William Harvey described blood circulation • First successful blood transfusion in dogs • 1831 • Thomas Latta first to use IV Saline in hypovolemic shock • 1830 -1930 • shock thought due to endotoxin • Production of physiologic saline • 1900 • Discovery of major blood types • 1930 • Blalock proved traumatic shock was 2 to blood loss 0

Fluid History • 1939 • Rh factor recognized • Re-acceptance of blood as acceptable fluid • 1940’s • WWII experience led to search for appropriate fluid • 1960’s • Wolfmann et al. & Shires et al. • established need to replace extracellular fluid with crystalloid • intravascular losses with plasma and blood • 1980’s • Blood borne diseases contaminate supply • Further study into optimal fluid

Fluid History • 1918 JAMA Cannon et al. “Injection of a fluid that will increase blood pressure has dangers in itself. Hemorrhage in a case of shock may not have occurred to a marked degree because pressure has been too low and the flow too scant to overcome the obstacle offered by a clot. If the pressure is raised before the surgeon is ready to check any bleeding that may take place, blood that is sorely needed may be lost. ”

Fluid options • Crytalloids • Lactated ringers, NS • Colloids • Albumin, pentaspan, hetastarch • Hypertonic saline • Allogenic/autogenic blood • Blood substitutes

Fluid options • Few argue that matched whole blood is best resuscitation fluid • Volume expansion and carries O 2 • Remains intra-vascular • Limited availability • • Must be cross-matched (time) Dilutional coagulopathy Disease transmission Requires refrigeration

Fluid options • Ideal fluid solution would: • • Provide volume expansion O 2 carrying capacity Non-antigenic No risk of disease transmission Maintain physiologic distribution of body fluids Long shelf-life Room temperature storage

Current Ideology • ATLS manual • Initial treatment of shock directed toward restoring cellular and organ perfusion with adequately oxygenated blood • By increasing Preload or restoring adequate circulating blood volume • Fluid of choice for ATLS trained trauma juniors » Isotonic crystalloid solutions » Volume of 3: 1 (infused: lost)

ATLS Ideology • Total plasma volume ~7% LBW • Use weight of Pt or clinical signs to choose amount of fluid Class III Class IV Volume <750 ml 750 15002000 >2000 % total vol. <15% 15 -30% 30 -40% >40% Heart rate <100 100 -120 120 -140 >140 PP and BP Normal Low

ATLS Ideology • Isotonic solutions in initial resuscitation • Initial fluid bolus given as rapidly as possible (1 -2 liters in adult) • Replace losses by 3 to 1 rule • Provides transient intra-vascular expansion and further stabilizes vascular volume

New directions • Animal studies in 1970’s and 80’s showed IV fluid prior to control of hemorrhage increased mortality • Hydraulic acceleration of ongoing hemorrhage by increase in BP • Mechanical dislodgement of active soft clot • Dilution of existing clotting factors with IV fluid infusion

Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery 1991; 110: 529 -536 • Standard of care: – Attempt to correct intravascular volume deficits in hemorrhagic hypotension as soon as IV access established – EMS systems more aggressive, achieve access in the field • Based on lab trials of controlled hemorrhage by atraumatic phlebotomy and IV resuscitation • Not clinically correlated to trauma patient

Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery 1991; 110: 529 -536 • Looked at uncontrolled bleed in swine post aortotomy • Bleeding rate ~26 m. L/Kg • Treatment with large volume LR vs. no IV fluid therapy • Replaced with 3: 1 rule (~80 m. L/Kg) • Vol. of hemorrhage and mortality significantly increased in treatment group: • 8 of 8 survived no treatment to 2 hours post-op • 0 of 8 survived LR therapy

Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery 1991; 110: 529 -536 • Previous animal aortotomy study established hemostasis achieved at mean 4 -5 min • IV therapy Tx started at 6 min to mimic response time • Volume of hemorrhage increased in LR group • 783 +/- 85 m. L in controls • 2142 +/- 178 m. L in Tx group

Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery 1991; 110: 529 -536 • Autopsy result: • Control group had soft firm extraluminal thrombus • Treatment group less clot formation • Concluded • Possibly continued bleeding • Re-initiation of active bleeding – Increased BP – Decreased Oxygen concentration (dec. HCO 3) – Hemodilution – Decreased blood viscosity – Increased flow velocity

Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery 1991; 110: 529 -536 • Study design limitations: • Additional arm in the study looked at hypertonic saline solution • Tx started 6 minutes post-injury • High IV flow rate ~500 cc/min • Initial IV bolus but no maintenance rate • Non-fatal bleed » All controls survived to 2 hours

Timing of fluid • Other animal trials have concluded that increased BP leads to worse outcomes in uncontrolled hemorrhage • Improved mortality with MAP 40 vs. MAP 80 • MAP of 80 had increased blood loss and increased hemodilution

Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331: 1105. • Led to landmark clinical trial • Immediate vs. delayed fluid resuscitation • Prospective trial enrolling 598 adults with penetrating torso injury and pre-hospital BP <90 mm. Hg systolic • Immediate Tx: • 289 pts – 203 survived (70%) • Delayed Tx: • 309 pts – 193 survived (62%)

Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331: 1105. • Treatment group received IV therapy as per standard ATLS protocol • Average IV pre-hosp 870 m. L vs. 92 m. L • Pre-hospital fluid administration led to: • Increased MAP • Tx group had increased BP in trauma room – no significant difference in OR • Decreased hemoglobin – Greater decrease than hemodilution alone • Increased PTT/INR

Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331: 1105. • Intra-operatively • Tx group greater rate of IV fluid therapy • 117 m. L/min vs. 91 m. L/min • Looked at post-op complications • Trend in Tx group to greater complications • Not significant (p<0. 08) • Overall • survival significantly higher in delayed resuscitation • 70% vs. 62% (p<0. 04)

Timing of fluid • Bickell et al. established delayed fluid resuscitation in penetrating abdominal trauma • Can study be correlated to blunt abdominal trauma? • Transport time? • Consider concurrent head injury • Must maintain CPP (? inc. BP) • No difference in outcome with fluid choices if transport time in < 30 minutes

Crystalloid vs. colloid • Large reviews have been performed • 109 articles encompassing 814 patients • Consensus is to use isotonic solutions • Varied volume expansion – One liter of fluid increases plasma volume: • • Dextran 790 cc 6% Hetastarch 710 cc 5% albumin 490 cc 0. 9% Na. CL 180 cc

Crystalloid vs. colloid • • • Crystalloid Freely cross capillary membrane (large vol. ) Transient inc. intravascular volume Lower cost No antigenicity 5. 7% reduction in mortality (12. 3% trauma patients) • • Colloid Risk anaphylaxis Impaired renal and hemostatic function Lower volume Prolonged volume expansion Improves microvascular perfusion Decreased peripheral edema Improved oncotic pressures

Crystalloid vs. colloid • Difficulties in reviewing studies of the two fluid types: • • Randomization virtually impossible Various population factors Treatment cross-over in groups Insufficiently powered

Colloids • More rapid circulating volume restoration with smaller infused volume • Maintains serum protein levels • Schierhout et al. increased absolute risk of death by 4% in critically ill patients • Choi et al. increased mortality in trauma patients

Colloids • Albumin (5% or 25%) • Purified from human blood • Starling’s forces to draw fluid into vascular space • In setting of leaky capillaries (burns, sepsis) may worsen tissue edema by protein leakage • Vs. crystalloids no clear advantage, with increased cost, risk of disease and in limited supply

Synthetic Colloids • Pentaspan (10% pentaspan in NS) • Expansion of volume > amount of volume infused – lasts 18 -24 hours • Excreted renally – no use in renal insufficiency • ? Embryocidal • Risk of anaphylaxis • Hetastarch 6% (60 g/L) • Osmotically ~300 m. Osm/L • Improved volume expander vs. crystalloids • No reduction in mortality

Hypertonic Saline • Combines the advantages of crystalloids and colloids • • • Expands plasma volume 3 -4 x volume HS infused Endogenous fluid re-distribution Small volume needed to increase plasma volume Improved micro-vascular flow Increased myocardial contractility (SV, CO) Benefit in controlled hemorrhage established May increase hemorrhage in uncontrolled bleed May decrease cerebral edema in head injured pts Few adverse outcomes in large meta-analysis – Rarely hypersomolarity (usually involves Et. OH)

Gross D, Ezekiel HL, Ahmed A, Krausz MM. Is hypertonic saline resuscitation safe in uncontrolled hemorrhagic shock? J Trauma 1988; 28(6): 751 -756 • Animal studies consistently shown that in setting of controlled hemorrhage HS: • Increased CO • Increased MAP • Increased splancic blood flow • Compare HS in controlled and uncontrolled hemorrhage • Theorized that: • Increased BP • peripheral vasodilation post HS infusion • increase blood loss from intra-abdominal vessels

Gross D, Ezekiel HL, Ahmed A, Krausz MM. Is hypertonic saline resuscitation safe in uncontrolled hemorrhagic shock? J Trauma 1988; 28(6): 751 -756 • 8 experimental groups • • I – observation (n = 5) II – “controlled” hemorrhage (n = 10) 80% III – “controlled” hemorrhage + NS (n = 7) 85% IV – “controlled” hemorrhage + HS (n = 8) 100% V – observation (n = 4) VI – “uncontrolled” hemorrhage (n = 9) 78% VII – “uncontrolled” hemorrhage + NS (n = 9) 66% VIII – “uncontrolled” hemorrhage + HS (n = 18) 5% • HS in uncontrolled abdominal bleeding in rats led to increased blood loss and early mortality

Chiara O, Pelosi P, Brazzi L, Bottino N, Taccone P, Cimbanassi S, Segala M, Gattinoni L, Scalea T. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med 2003; 31(7): 1915 -1922 • Efficient fluid resuscitation should: • Recover cardiovascular stability • Restore organ perfusion • Durable hemodynamic effects • Study designed to simulate clinical scenario of hemorrhage and resuscitation • Had four distinct periods • • Hemorrhage Infusion Transfusion Follow-up 1 and 2 hours

Chiara O, Pelosi P, Brazzi L, Bottino N, Taccone P, Cimbanassi S, Segala M, Gattinoni L, Scalea T. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med 2003; 31(7): 1915 -1922 • N = 32 pigs randomized to 4 treatment groups • Exsanguinated from femoral artery catheter • Bled to MAP 45 mm. Hg and maintained at this BP for 1 hour (transfusion or bled as needed to maintain 45 mm. Hg) • 8 animals per group infused with one of: • • 0. 9 % Na. CL @ 2 m. L/Kg/min 6% DX 70 in NS @ 2 m. L/Kg/min 7. 5% Na. CL @ 0. 24 m. L/Kg/min 7. 5% Na. CL with 6% DX 70 @ 0. 24 m. L/Kg/min

Chiara O, Pelosi P, Brazzi L, Bottino N, Taccone P, Cimbanassi S, Segala M, Gattinoni L, Scalea T. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med 2003; 31(7): 1915 -1922 • Infusion continued until resumption of baseline abdominal aorta flow • Stage III transfusion of shed blood to baseline hemoglobin • Results: • 2 from each group died during bleed • 1 from NS group • Left 6 pigs in each group and 7 in NS group

Chiara O, Pelosi P, Brazzi L, Bottino N, Taccone P, Cimbanassi S, Segala M, Gattinoni L, Scalea T. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med 2003; 31(7): 1915 -1922 • HS +/- DX hemodynamic resuscitation with decreased infused volume • Hemodynamic effects more sustained with HS + DX than NS or DX alone • During resuscitation HS +/- DX allows recovery of mesenteric and renal blood flow with no increased in pulmonary artery pressure • HS + DX maintains effects longer than NS, HS or DX alone

Chiara O, Pelosi P, Brazzi L, Bottino N, Taccone P, Cimbanassi S, Segala M, Gattinoni L, Scalea T. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med 2003; 31(7): 1915 -1922 • Hemodynamic benefits of HS +DX • HS – fluid shifts and shrinkage of endothelial cells causing improved flow • DX – non-transient fluid shift • High volume infusions lead to increased pulmonary artery pressures and filtration causing pulmonary edema • Total volumes infused much higher in NS group • 7: 1 NS: HS • 10: 1 NS: HS+DX

Chiara O, Pelosi P, Brazzi L, Bottino N, Taccone P, Cimbanassi S, Segala M, Gattinoni L, Scalea T. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med 2003; 31(7): 1915 -1922 • Shock – vasoconstriction of mesenteric vessels to redistribute blood away from viscera • Mucosal ischemia predisposes gut to translocation of bacteria and subsequent Multi -organ failure • Significantly improved splancic flow in HS +DX vs. NS, HS or DX • Concluded slow continuous infusion to restore CO is optimal regimen

Chiara O, Pelosi P, Brazzi L, Bottino N, Taccone P, Cimbanassi S, Segala M, Gattinoni L, Scalea T. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med 2003; 31(7): 1915 -1922 • Limitations: • Bleed not usually controlled in trauma patient • Study was at slow infusion of HS to endpoint of aorta flow vs. more typical bolus treatment • Short observation time (2 hours) • Mortality of 21% attributed to physiologic derangements of shock (not fluid choice) » Deaths were prior to infusion therapy

Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery 1991; 110: 529 -536 • Had a HS arm in trial of aortotomy in swine • Recall LR infused pigs had ++ blood loss (2147 m. L) vs. control (783 m. L) • HS had increased SV, CO and decreased SVR • 5 of 8 pigs died during trial • Hemorrhage volume 1340 m. L (+/- 230)

Hypertonic Saline • No definitive indications at this time • Animal models consistently show benefit in controlled hemorrhage hypotension • Theoretical benefit in head injured patients • Detrimental in uncontrolled torso trauma

Blood substitutes • O 2 carriers designed to temporarily replace transfused blood • Advantages of blood substitutes • • • Readily available No cross matching Room temperature storage Lower disease risk Less viscous than blood (improved flow) Decreased strain on limited resource • Two major classes: • 1) modified hemoglobins • 2) perfluarocarbon emulsion particles

Blood substitutes • Disadvantages of blood substitutes: • Currently short half-life (24 -48 hours) • Interfere with biochemical tests • Vasoactive – Systemic and pulmonary vasoconstriction due to Nitric Oxide scavenging – Polymerize, encapsulize, conjugate • Ultra-pure Hgb products may worsen reperfusion injuries – Lack of RBC anti-oxidant enzymes (I. e. superoxide dismutase)

Hemoglobin • Tetrameric molecule composed of four subunit polypeptide chains • Each subunit contains a heme group that binds and releases O 2 • Life cycle in RBC ~120 days • Free Hgb dissociates to form dimers • Oxidized • Rapidly renally excreted • High plasma [Hgb] renal toxicity (crush injury)

Modified Hemoglobins • Diaspirin cross-linked hemoglobin – – Neither polymerized nor encapsulated Promising pre-clinical trials Large multi-center trial stopped at mid-point Higher death rate of patients with severe traumatic hemorrhagic shock • Rate at 48 hours 38% vs. 15% • Rate at 28 days 46% vs. 17% – Not modified to decrease vasoactive NO scavenging

Modified Hemoglobins • Surface modified hemoglobin • Conjugates of Hgb and larger molecules • Dextran or Polyethylene glycol (PEG) • High oncotic pressure effects – Potent plasma volume expander • Prolongs intravascular retention – Increased molecular size – Decreased antigenicity – Decreased uptake by RES

Modified Hemoglobins • Intramolecular cross-linked hemoglobin – Cross-linkage prevents dissociation to dimers – Optro – genetically engineered E. coli • • Produces di-alpha hemoglobin chain Linkage prevents dimer formation GI side effects prominent NO scavenging causing vasoconstricition

Modified Hemoglobins • Polymerized hemoglobin – Polyheme cross-linked Hgb made from expired human blood – O 2 affinity and osmotic activity same as true RBC

Questions?

Future Study • Must consider: • • Type of injury Anatomic location Severity +/- head injury

References 8. 9. 10. 11. 12. 13. 14. 15. 16. Gould SA, Moore EE, Moore FA, Haenel JB, Burch JM, Sehgal H, Sehgal L, De. Woskin R, Moss GS. Clinical utility of human polymerized hemoglobin as a blood substitute after acute trauma and urgent surgery. J Trauma 1997; 43(2): 325 -332. Gross D, Ezekiel HL, Ahmed A, Krausz MM. Is hypertonic saline resuscitation safe in uncontrolled hemorrhagic shock? J Trauma 1988; 28(6): 751 -756. Henry S, Scalea TM. Resuscitation in the new millennium. Surg Clin N Amer 1999; 79(6): 1259 -1267. Pryor JP, Pryor RJ, Staffor PW. Initial phase of trauma management and fluid resuscitation. Poole GV, Meredith JW, Pennell T, Mills SA. Comparison of colloids and crystalloids in resuscitation from hemorrhagic shock. Surg Gyne Obs 1982; 154: 577 -585. Siegel JH, Fabian M, Smith JA, Costantino D. use of recombinant hemoglobin solution in reversing lethal hemorrhagic hypovolemic oxygen debt shock. J Trauma 1997; 42(2): 199 -212. Tisherman SA. Trauma fluid resuscitation in 2010. J Trauma 2003; 54(5 S): S 231 -S 234. Tremblay LN, Rizoli SB, Brenneman FD. Advances in fluid resuscitation of hemorrhagic shock. Can Jour Surg 2001; 44(3): 172 -179. Winslow RM. Blood substitutes. Adv Drug Del Rev 2000; 40(3): 131 -142.

References 1. 2. 3. 4. 5. 6. 7. Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery 1991; 110: 529 -536. Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. Use of hypertonic saline/dextran versus lactated ringer’s solution as a resuscitation fluid after uncontrolled aortic hemorrhage in anesthetized swine. Ann Emerg Med 1992; 21: 1077 -1085. Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331: 1105. Arnoldo BD, Minei JP. Potential of hemoglobin-based oxygen carriers in trauma patients. Curr Opin Crit Care 2001; 7(6): 431 -436 Chiara O, Pelosi P, Brazzi L, Bottino N, Taccone P, Cimbanassi S, Segala M, Gattinoni L, Scalea T. Resuscitation from hemorrhagic shock: Experimental model comparing normal saline, dextran, and hypertonic saline solutions. Crit Care Med 2003; 31(7): 1915 -1922 Choi PTL, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med 1999; 27: 200 -210. Gould SA, Moore EE, Hoyt DB, Burch JM, Haenel JB, Garcia J, De. Woskin R, Moss GS. The first randomized trial of human polymerized hemoglobin as a blood substitute in acute trauma and emergent surgery. Jour Am Coll Surg 1998; 187(2): 113 -120.