Fluid and Product Resuscitation

1. Fluid and Product Resuscitation Allen Clark M.D.

2. Fluid and Product Resuscitation • I have no financial disclosures

3. Case Presentation • 25y/o G2P1001 undergoing primary cesarean section for breech • Starting Hgb 9.0 • Intraoperative EBL suspected at 1000ml, still having difficulty obtaining control of bleeding • Vitals: 110/60, P95, rr18, T36.6 • Surgeon requests to start transfusing 2 units pRBC • Anesthesia disagrees and wants to not give the transfusion

4. Case Presentation • 34y/o G4P3003 at 39 and 0 undergoing her 4th cesarean section • Starting Hgb 11.0 • Anterior placenta, no signs of accreta on ultrasound • h/o uterine atony in prior cesarean section

5. Objectives • Define and classify hemorrhage • Review different types of fluid resuscitation available • Discuss the different products used in resuscitation • Review massive transfusion protocols • Preview newer resuscitation strategies

6. Hemorrhage • In 2005, hemorrhage was the third leading cause of maternal death • Per the WHO, leading cause of death worldwide • Highly preventable, with aggressive therapy and appropriate management • Mortality has been improving with the development and implementation of massive transfusion protocols

7. Hemorrhage in Pregnancy • Pregnancy is a protected state • 40-50% volume expansion • Increase in RBC mass by 20-30% • Elevated Cardiac Output, 30-50% • Decreased systemic vascular resistance • Increase in fibrinogen, coagulation factors I, VII, VIII, IX, X

8. SVR, CO, and BP response to blood loss

9. Classification of Hemorrhage -OB Total blood volume = 6,000ml, Average for 60kg pregnant woman

10. Classification of Hemorrhage -OB Total blood volume = 6,000ml, Average for 60kg pregnant woman

11. Classification of Hemorrhage- GYN

12. Classification of Hemorrhage- GYN

13. Per The ICU Book • Class 1- Minimal physiologic changes • Class 2- Tachycardia, narrowing pulse pressure • Typically compensatory mechanism such as renin-angiotensin compensate • Class 3- Compensatory mechanisms begin to fail • Class 4- Life threatening • If this reaches ischemic injury in the heart or brain, death typically results

14. Volume Resuscitation • IV access • On the basis of speed of fluid infusion, what is preferred, a 16 gauge peripheral IV catheter or a 16 gauge central venous catheter??

15. Surprise? • Q= Rate, P= pressure, r= radius, = viscosity, L= length MateerJR Thompson BM, Aprahamian C, et al. Rapid fluid resuscitation with central venous catheters. Ann Emerg Med 1983; 12:149-152

16. What goes in the IV? • Crystalloids, Colloids, Blood? • Surgical specialties tend to use lactated ringers, emergency rooms use normal saline, trauma surgeons are starting to use blood products • Why do we use lactated ringers? • Should we?

17. Crystalloids • Electrolyte solutions with small molecules that freely diffuse throughout extracellular space • Mostly Na and Cl • Sodium- abundant in extracellular fluid, 75% in interstitial fluids • For IV administered Na, 75% will therefore end up in interstitial fluids • Therefore, the predominant effect of crystalloids is to expand INTERSTITIAL volume, not plasma volume

18. Crystalloids • Therefore, how much of 1 L of normal saline stays in the plasma? • A – 1000 ml • B – 700 ml • C – 500 ml • D – 275 ml • E – 0 ml

19. Crystalloids • 275ml of a liter of normal saline stays in plasma, 825ml in interstitial volume • But wait Allen, 275 + 825 = 1100. . . • Prepare to have your mind blown

20. Crystalloid Infusion Fluids

21. Isotonic Saline – 0.9% Sodium Chloride • Slightly higher Na concentration then plasma 154 vs 140 mEq/L • Much higher Cl Concentration 154 vs 103mEq/L • Lower pH 5.7 vs 7.4 • Slightly higher osmolality 308 vs 290 mOsm/L • This causes a shift of approximately 100ml of fluid from intracellular to extracellular upon administration, causing total volume expansion to be 1100ml . . .BOOM!

22. Isotonic Saline - Disadvantages • Large volumes of isotonic saline will produce a metabolic acidosis • Hyperchloremic acidosis produced by the high levels of Cl in isotonic saline • Though this is typically without clinical consequence, it has potential negative consequences if it delays identification of lactic acidosis or is combined with another type of acidosis (ie respiratory from anesthesia) Scheingraber S, Rehm, M, et al. Rapid saline infusion produces hyperchloremic acidosis in patient undergoing gynecologic surgery. Anesthesiology. 1999, 90: 1265-70

23. Lactated Ringer’s • Contains Potassium and Calcium in approximately the same ionized concentrations in plasma • This causes a lower sodium concentration • LR also contains lactate, which allows reduction of the chloride concentration • With a chloride concentration closer to that of plasma, there is no risk of hyperchloremic metabolic acidosis with large infusions

24. LR, what can’t it do • It can’t be infused with some meds, because the calcium can bind to some drugs • Examples include aminocaproic acid, amphotericin, ampicillin, thiopental • Can bind citrated anticoagulant of blood products and cause clotting • If volume of LR does not exceed 50% of pRBC volume, this does not occur

25. Anyone ever done a study on this stuff • In 2009, 20 pigs underwent liver injuries, hemorrhaged for 30 min, and then in a blinded fashion given LR or NS for resuscitation • Given IV fluid to maintain preinjury MAP • Monitored oxygenation and pulmonary edema, total fluid volume given, pH, and blood loss • Little impact on oxygenation • LR has favorable effects on pH, coagulation and hemodynamics Phillips CR, Vinecore K, et al. Resuscitation of haemorrhagic shock with normal saline vs. lactated Ringer’s: effects on exygenation, extravascular lung water and hamodynamics. Crit Care, 2009; 13: R30

26. Anyone else • In 2007, 20 pigs underwent liver injuries, hemorrhaged for 30 minutes, then underwent NS or LR resuscitation to maintain the preinjury MAP for 90 minutes • Results: it took 256ml/kg of NS vs 125ml/kg of LR to maintain MAP, urine output for NS was 46.6ml/kg vs LR 18ml/kg, • NS animals developed dilutional coagulopathy, had lower fibrinogen, lower platelet count, and lower PT • NS animals developed hyperchloremic metabolic acidosis and coagulopathy • LR animals developed lacticemia not associated with acidosis Todd SR, Malinoski D, et al. Lactated ringer’s is superior to normal saline in the resuscitation of uncontrolled hemorrhagic shock. Trauma. 2007 March; 62, 636-639

27. I dare to ask, anyone else • In 2006, 20 pigs underwent liver injuries, hemorrhaged for 30 minutes, and then given either NS or LR to maintain MAP at baseline for 90 minutes • Baseline and Q30 min Lactate, ABG, chemistry, PTT, PT and fibrinogen were taken, and thrombelastography (TEG) was performed Kiraly LN, Differding JA, et al. Resuscitation With Normal Saline (NS) vs. Lactated Ringers (LR) Modulates Hypercoagulability and Leads to Increased Blood Loss in an Uncontrolled Hemorrhagic Shock Swine Model. Trauma: 2006; 61:57-65

28. Pause, whats TEG • R= reaction time = time to onset of clot formation, elongation = coagulation factor deficiency • Alpha= rapidity of fibrin buildup and cross linking = affected by fibrinogen and platelets • K speed to reach certain level of clot strength = platelets and fibrinogen function • MA= maximum amplitude = strength of clot, affected primarily by platelets but also fibrinogen Kiraly LN, Differding JA, et al. Resuscitation With Normal Saline (NS) vs. Lactated Ringers (LR) Modulates Hypercoagulability and Leads to Increased Blood Loss in an Uncontrolled Hemorrhagic Shock Swine Model. Trauma: 2006; 61:57-65

29. And the results • With similar injuries, NS group had greater overall blood loss and required 2x the amount of fluid to maintain MAP • NS group was more acidotic from 30 minutes on • NS group had lower hematocrit, greater PT and PTT times, and a greater R time, all statistically significant • Conclusion: NS modulates the hypercoagulable state seen after injury, resulting in increased blood loss Kiraly LN, Differding JA, et al. Resuscitation With Normal Saline (NS) vs. Lactated Ringers (LR) Modulates Hypercoagulability and Leads to Increased Blood Loss in an Uncontrolled Hemorrhagic Shock Swine Model. Trauma: 2006; 61:57-65

30. Can someone please stab a human • In 2005, 51 patients undergoing renal transplant were placed in a randomized double blinded study to receive LR or NS intraoperative • LR is typically not used in this population over concern of the development of hyperkalemia in a population with ESRD, standard of care is NS • Rate of fluids was given as clinically indicated and not according to an algorithm • Primary outcome measure was serum creatinine concentrations on POD 3 • Secondary outcomes included post op urine output, creatinine clearance, rejection, graft loss, intraoperative acid base balance, intraoperative potassium concentrations, blood loss and transfusions requirements and hospital length stay O’malley CM, Frumento RJ, Hardy MA, etal. A Randomized, Double-Blind Comparison of Lactated Ringer’s Solution and 0.9% NaCl During Renal Transplantation. Anesthia Analg 2005; 100:1518-24

31. And the humans showed. . . • Serum creatinine POD 3 NS 2.3±1.8, LR 2.1±1.7 • Seven units of packed red blood cells were administered in the NS group versus three units in the LR group. • Potassium concentrations exceeded 6.0mEq/L in 5/26 NS patients, and 0/25 LR patients • The 5 patients in the NS study were treated for hyperkalemia O’malley CM, Frumento RJ, Hardy MA, etal. A Randomized, Double-Blind Comparison of Lactated Ringer’s Solution and 0.9% NaCl During Renal Transplantation. Anesthia Analg 2005; 100:1518-24

32. And the humans showed . . . • 8/26 NS patients developed metabolic acidosis and required sodium bicarbonate and 0/25 patients in the LR group developed metabolic acidosis • This study was then terminated due to safety concerns of giving patients NS intraoperatively O’malley CM, Frumento RJ, Hardy MA, etal. A Randomized, Double-Blind Comparison of Lactated Ringer’s Solution and 0.9% NaCl During Renal Transplantation. AnesthiaAnalg 2005; 100:1518-24

33. Conclusion to the LR vs NS battle • Difficult to say if isotonic saline’s side effects directly change clinical outcomes • Based on this data, there are benefits to LR over normal saline

34. Dextrose • Originally developed to provide calories before the introduction of enteral and pareneral nutrition • D5- 50grams dextrose/1 liter = 170kcal

35. Dextrose • D5W – ineffective at expanding plasma volume, less then 10% stays in plasma • 2/3 of the volume ends up inside cells, causing cellular swelling • If circulatory flow is compromised, 85% of glucose metabolism is converted to lactate production • This causes a metabolic acidosis when patients with circulatory compromise receive dextrose solutions DeGoute CS, Ray MJ, Manchon M et al. Intraoperative glucose infusion and blood lactate: endocrine and metabolic relationships during abdominal aortic surgery. Anesthesiology 1989;71:355-361

36. Colloids • Contain large, poorly diffusible, solute molecules designed to keep water in the vascular space • Primary protein doing this in plasma is albumin, responsible for 75% of colloid osmotic pressure • The idea of the colloid fluids is to increase the colloid osmotic pressure in the vascular space and bring water into the circulators system

37. Colloids’ Turn • So, the infusion of 1 Liter of 5% Albumin expands the plasma volume how much? • A – 1000ml • B – 700ml • C – 500ml • D – 275ml • E – 0ml

38. Colloids turn • 700ml increase in the plasma volume and 300ml increment in the interstitial fluid volume • Remembering that about 275ml of NS would stay in the plasma volume • Colloid fluids are 3 times more effective than crystalloids at increasing plasma volume

39. Albumin • Heat treated preparations of human serum albumin, available in 5% (50g/L) and 25% solutions (250g/L) • 5% albumin comes in 250ml doses and 25% albumin comes in 50 or 100ml doses • 5% albumin has equivalent concentrations and colloid osmotic pressure to plasma • 70% of fluid infused stays in plasma volume for several hours, effect lost completely after 12 hours

40. Albumin, important note • 25% albumin does not provide replacement volume • It only causes a shift of fluid from interstitial to intravascular • IT IS NOT A VOLUME REPLACEMENT THERAPY and can NOT be used in acute blood loss or dehydration

41. Albumin, a quick history • In 1998, a Cochrane meta-analysis of 30 randomized control trials of 1419 patients • Results: “Pooled relative risk of death with albumin administration was 1.68 (1.26 to 2.23).” • “We found no evidence that albumin reduced mortality and a strong suggestion that it might increase the risk of death in patients with hypovolaemia, burns, or hypoproteinaemia. Overall, the risk of death in patients treated with albumin was 6% (95% confidence interval 3% to 9%) higher than in patients not given albumin.” • Needless to say, this hurt the use of albumin for resuscitation Cochrane Injuries Group albumin reviewers. Human albumin administration in critically ill patients: systematic review of randomized, controlled trials. Br Med J 1998;317: 235-240

42. Albumin fought back • In 2004, a double blinded randomized control trial including 7000 patients was published in the NEJM, 3497 received albumin, 3500 received NS • SAFE trial (Saline vs Albumin Fluid Evaluation) • 7000 ICU patients, admitted for all reasons, primary outcome was death from any cause at 28 days • 726 deaths in albumin group, 729 deaths in normal saline group • In conclusion, similar outcomes of 4% albumin as NS SAFE study investigators. A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit. N Engl J Med 2004;350:2247-56.

43. Albumin now • 2011 Cochrane review of mortality in 38 studies, including the safe study • Mortality the primary outcome in all studies • “For patients with hypovolaemia, there is no evidence that albumin reduces mortality when compared with cheaper alternatives such as saline.” Albumin Reviewers. Human albumin solution for resuscitation and volume expansion in critically ill patients. Chochran Database Systematic Review. 2011 Oct 5;(10):CD001208

44. Hetastarch • Hydroxyethyl start is a starch polymer available in a 6% solution in isotonic saline • Equivalent to 5% albumin as a plasma volume expander • Is less costly then albumin • When more then 1500ml given in 24 hours, can cause coagulopathy • Inhibits factor VIII, von Willebrand factor, and impair platelet adhesiveness • Broken down by amylase and filtered out of the kidneys, so can also cause a transient hyperamylasemia with no deleterious side effects • Mixed literature results

45. So. . . Crystalloids or Colloids? • Due to the transcapillary refill mechanism in hemorrhage, crystalloids gained a strong following among surgical specialties • The majority of the data is from the SAFE trial • 2011 Cochrane review of 3870 and 3884 patients receiving crystalloid or colloid solutions, 56 randomized controlled trials with mortality data • Conclusion: “The review of trials found no evidence that colloids reduce the risk of dying compared with crystalloids.” Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients (Review). The Cochrane Library. 2011, Issue 3

46. How will I use this information • Any patient undergoing surgery needs LR • Any patient with hemorrhage should get LR • In the ED, especially for operative patients, Isotonic Saline should not be used • Albumin is a fine alternative, but given increased cost, I would not use it routinely

47. Packed Red Blood Cells • Only blood product to provide oxygen-carrying capacity • 300ml volume • 250ml RBCs and 50ml plasma • 70kg patient, 1 unit pRBC will raise hemoglobin 1g/dl

48. Platelets • Separated from whole blood and stored in plasma • 1 unit will increase platelet count 7,500/mm3 • Transfused in concentrations of 5-10 • Masonic’s is in concentrations of 5 pooled • Single donor preferred over multiple to decrease risk of antigenic exposure, but very difficult if multiple infusions of platelets is necessary

49. Fresh Frozen Plasma • Plasma extracted from whole blood • Contents- fibrinogen, antithrombin III, clotting factors V, XI, XII • 250ml Volume • Goal- improve coagulation profile and volume resuscitation • Monitor- Fibrinogen- 1 unit should raise fibrinogen level by 5-10mg/dl

50. Cryoprecipitate • The precipitate from thawed FFP • Rich in fibrinogen, factor VIII, von Willebrand’s factor, factor XIII • Minimal volume- 40ml • Monitor with Fibrinogen- increase by 5-10mg/dl