Update on Fluid Management Intravenous Fluid Therapy Using Colloids: New Data, New Controversies

1. Update on Fluid ManagementIntravenous Fluid Therapy Using Colloids: New Data, New Controversies D John Doyle MD PhD FRCPC Cleveland Clinic Foundation September, 2004

3. This talk can be downloaded from http://colloidtalk.homestead.com

4. Goals and Objectives • To compare and contrast crystalloids and colloids and their use in the perioperative period • To compare the various HES preparations • To provide an update on the SAFE trial • To present information on the drawbacks of using crystalloids such as normal saline in large volumes • To present information on fluid resuscitation in a real clinical case • To present information on immediate versus delayed fluid resuscitation for hypotensive patients with ongoing blood loss.

5. Boldt J. New light on intravascular volume replacement regimens: what did we learn from the past three years?. Anesthesia & Analgesia. 97(6):1595-604, 2003 Dec. Definition of the "ideal" intravascular fluid volume replacement strategy still remains a critical problem. This article analyzes studies on volume replacement by using a MEDLINE search of the past 3 years (from January 1, 2000, to December 12, 2002). Forty original studies in humans with a total of 2454 subjects were identified. Five studies were performed in volunteers (n = 113); the other 35 studies (n = 2341) were performed in a variety of patients (e.g., cardiac surgery, trauma patients, children, and intensive care unit patients). The influence of different volume replacement regimens on coagulation was one of the major topics of interest (16 studies with 1183 subjects), and other studies focused on metabolic state, alterations in macro- and microcirculation, volume distribution, and organ function (e.g., kidney function and splanchnic perfusion). Among all synthetic colloids, hydroxyethyl starch (HES) was the solution most often studied. Two new HES preparations have been approved (Hextend), a balanced hetastarch solution, and a new third-generation HES [130/0.4]). Only two studies used albumin, and no superiority of albumin was found over less expensive synthetic colloids. In almost all studies, the outcome either was no end-point or was not reported. Volume replacement has often been hitherto based on dogma and personal beliefs. Future well performed studies in this area will hopefully help to shed new light on the ideal volume replacement strategy. IMPLICATIONS: By using a MEDLINE search covering the last 3 yr, the present knowledge on volume replacement regimens was analyzed. Forty studies in humans were identified. New hydroxyethyl starch preparations have shed light on this topic, whereas no additional data supporting the use of albumin have been presented

6. “… no additional data supporting the use of albumin have been presented.” THIS PART IS NO LONGER TRUE ! (SAFE Trial)

7. Joachim Boldt (Germany) • Fluid choice for resuscitation of the trauma patient: a review of the physiological, pharmacological, and clinical evidence. • Can J Anesth 2004 51: 500-513. • (May 2004)

8. Purpose: Volume replacement regimens are discussed very emotionally. Interpretation of the literature is difficult due to variations in study design, patient population, target for volume replacement, endpoints, and type of fluids. Meta-analyses may not be very helpful because all kinds of patients and very old studies are included. The principles and options for volume replacement were reviewed exclusively in trauma patients and studies from the literature focusing on this problem were analyzed.

9. Source: Using a MEDLINE search, volume replacement therapy in adult trauma patients published in the English language from 1985 to the end of 2002 were identified and analyzed. Studies on prehospital volume replacement, volume replacement in the emergency area or in the operating room, and volume therapy in trauma intensive care unit patients were included.

10. Principle findings:The age-old crystalloid /colloid controversy has still not been resolved but has been enlarged to a colloid/colloid debate. It is now widely accepted that human albumin could easily be replaced by synthetic colloids for volume replacement in trauma patients. No superiority of a specific volume replacement strategy with regard to outcome was found. However, in several studies outcome was not the major endpoint. Although showing some promising results, the importance of hypertonic solutions for volume replacement in the trauma patient is not yet defined.

11. Conclusion:The choice of fluid therapy in trauma patients engenders the most controversy and an examination of the body of literature on this subject results in confusion. It is imperative to continue the search for substances that are effective in avoiding the development of post-trauma multi-organ dysfunction syndrome without detrimental side-effects.

12. Overview • Physiological basis of fluid therapy • Colloids and crystalloids • Sample case • What is the controversy? • What are the consequences? • Massive fluid therapy • New developments (SAFE trial)

13. History Starling EH. Physiological Factors in the Causation of Dropsy Lancet 1896

14. Dropsy   The American Heritage® Dictionary of the English Language: Fourth Edition.  2000. Edema. No longer in scientific use.

15. Starling’s Law Jv = Kf (Pc-Pt) - d (c-t) Jv fluid flux Kf filtration constant d osmotic coefficient P hydrostatic pressure  oncotic pressure t tissue c capillary

16. Fluid Compartments • ICF Volume is INTRACELLULAR • ECF Volume is EXTRACELLULAR • ECF Volume = Plasma Volume + Interstitial Volume

17. Fluid Compartments • Total Body Water(0.6 L/kg) • 2/3 Intracellular (ICF) = 0.4 L/kg • 1/3 Extracellular (ECF) = 0.2 L/kg • ECF Volume (0.2 L/kg) • Plasma Volume (0.05 L/kg) • Interstitial Volume (0.15 L/kg) Ratio of plasma volume to interstitial volume is 1-to-3[rationale for 3-to-1 replacement of blood losses with crystalloid]

18. Where the IV fluid goes Crystalloids NS, RL 75 % Extravascular 25 % Intravascular/ Plasma Volume • Colloids Albumin, HES Almost 100 %Intravascular/ Plasma Volume

19. Plasma Volume Expansion Fluid Loss • Burns • Sepsis Blood Loss • Hemorrhage • Surgery • Trauma

20. Plasma Volume Expansion 1.0 L NS (0.9%)  0.33 L  Plasma Volume 1.0 L Hypertonic Saline (3%, 5%, 7.5%) draws water out from ICF to ECF leading to  ECF 1.0 L of Colloid  1.0 L  of Plasma Volume

21. Advantage of Crystalloids • Inexpensive • Promote urine output • Chemically simple

22. Disadvantages of Crystalloids • Potential to impair blood supply (e.g. replanted digit or flap) • Facial edema (especially patient in the prone position) • Airway edema • Scleral edema • GI edema • Acid base disturbances

23. Hypertonic Saline

24. Hypertonic Saline Currently, only 3% solutions are available "off-the-shelf" in the United States. In Sweden, a commercially prepared 7.5% solution in combination with 6% dextran 70 (RescueFlow, BioPhausia, Knivsta, Sweden), is available.

25. “Hypertonic solutions are beneficial in resuscitation from shock and trauma. Compared with isotonic solutions, the lesser volumes are associated with equivalent or improved systemic blood pressure, cardiac output, and survival in experimental animals. A positive cardiac inotropic effect is documented, as is a decrease in systemic vascular resistance.” Invited CommentaryHypertonic Saline Resuscitation in Anesthesia and SurgeryRobert R Kirby MD and Emilio B Lobato MDCurrent Anesthesiology Reports 2000 2:257-258 (published 1 July 2000) http://www.biomedcentral.com/1523-3855/2/257/abstract

26. Colloids • Human serum albumin (5 and 25%) • Fresh frozen and stored plasma • HMW hydroxyethyl starch • LMW hydroxyethyl starch • Dextrans • Gelatins

27. Artificial Colloid Solutions • Hydroxyethyl Starches (HESs) • LMW (Pentaspan, PentaLyte) • HMW (Hespan, Hextend) • Dextrans • Gelatins Artificial colloids, unlike crystalloids, are complex entities that undergo a regulatory approval process similar to that for a drug.

28. Properties of an Ideal Colloid • Non toxic • Non infective (sterile) • Non allergenic • Not teratogenic or mutagenic • No effect on diagnostic tests • Compatible with medications • No influence on hemostasis • Complete elimination • No storage in tissues • Good shelf life • No special storage requirements • Few very small or very large molecules

29. Properties of an Ideal Hydroxyethyl Starch (HES) • Long shelf life and easy storage • Few very small or very large molecules • No adverse effects on coagulation • Can be repeatedly administered

30. HES Properties • HES are a mixture of differently sized and differently substituted molecules • A higher degree of molar substation results in poorer degradation of the HES molecule by alpha amylase • Volume effect exceeds drug concentration: decreased HES concentration by renal elimination of molecules is compensated by the supply of new molecules (still oncotically active) from the degradation of the larger fragments

31. Characterizing HES Colloids • Degree of substitution (molar substitution) • C2/C6 ratio • Molecular weight distribution • Concentration • Maximum daily dose • Degradation by amylase

32. Advantages of Colloids • Less edema • Less volume administered • Less thermal load effect for given level of plasma volume expansion • Volume administer stays in intravascular space longer

33. Cytokines Volume replacement with HES products is associated with decreased release of cytokines (proinflammatory molecules), and other effects that may improve the microcirculation. “Cytokines are the neurotransmitters of the immune system”

34. Lang K. Suttner S. Boldt J. Kumle B. Nagel D. Volume replacement with HES 130/0.4 may reduce the inflammatory response in patients undergoing major abdominal surgery. Canadian Journal of Anaesthesia. 50(10):1009-16, 2003 Dec. PURPOSE: To investigate the effects of intravascular volume replacement therapy on the inflammatory response during major surgery. METHODS: Thirty-six patients scheduled for elective abdominal surgery were randomized to receive either 6% hydroxyethylstarch (130,000 Dalton mean molecular weight, degree of substitution 0.4; n = 18, HES-group) or lactated Ringer's solution (RL-group; n = 18) for intravascular volume replacement. Fluid therapy was given perioperatively and continued for 48 hr in the intensive care unit. Volume replacement was guided by physiological parameters. Serum concentrations of interleukin (IL)-6, IL-8 and IL-10 and soluble adhesion molecules (sELAM-1 and sICAM-1) were measured after induction of anesthesia, four hours after the end of surgery, as well as 24 hr and 48 hr postoperatively. RESULTS: Biometric and perioperative data, hemodynamics and oxygenation were similar between groups. On average, 4470 +/- 340 mL of HES 130/0.4 per patient were administered in the HES-group compared to 14310 +/- 750 mL of RL in the RL-group during the study period. Release of pro-inflammatory cytokines IL-6 and IL-8 was significantly lower in the HES-group [(peak values) 47.8 +/- 12.1 pg*dL(-1) of IL-6 and 35.8 +/- 11.2 pg*mL(-1) of IL-8 (HES-group) vs 61.2 +/- 11.2 pg*dL(-1) of IL-6 and 57.9 +/- 9.7 pg*mL(-1) of IL-8 (RL-group); P < 0.05]. Serum concentrations of sICAM-1 were significantly higher in the RL-group [(peak values) 1007 +/- 152 ng*mL(-1) (RL-group) vs 687 +/- 122 ng*mL(-1), (HES group); P < 0.05)]. Values of sELAM-1 were similar in both groups. CONCLUSION:Intravascular volume replacement with HES 130/0.4 may reduce the inflammatory response in patients undergoing major surgery compared to a crystalloid-based volume therapy. We hypothesize that this is most likely due to an improved microcirculation with reduced endothelial activation and less endothelial damage.

35. Boldt J. Ducke M. Kumle B. Papsdorf M. Zurmeyer EL. Influence of different volume replacement strategies on inflammation and endothelial activation in the elderly undergoing major abdominal surgery. Intensive Care Medicine. 30(3):416-22, 2004 Mar. OBJECTIVE: Adequate restoration of intravascular volume remains an important maneuver in the management of the surgical patient. Influence of different volume replacement regimens on inflammation/endothelial activation in elderly surgical patients was assessed. DESIGN: Prospective, randomized study. SETTING: Surgical intensive care unit of a university-affiliated hospital. PATIENTS: Sixty-six patients >65 years undergoing major abdominal surgery. INTERVENTIONS: Ringer's lactate (RL; n=22), normal saline solution (NS; n=22) or a low-molecular HES (mean molecular weight 130 kD) with a low degree of substitution (0.4; HES 130/0.4; n=22) were administered after induction of anesthesia until the 1st postoperative day (POD) to keep central venous pressure between 8-12 mmHg. MEASUREMENTS AND RESULTS: C-reactive protein, interleukins (IL-6, IL-8), adhesion molecules [endothelial leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1)] were measured prior to volume therapy at the end of surgery, 5 h after surgery and at the morning of the 1st POD. RL patients received 10,150+/-1,660 ml of RL, NS patients 10,220+/-1,770 ml of NS and the HES-treated group 2,850+/-300 ml of HES 130/0.4 and 2,810+/-350 ml of RL. Hemodynamics were similar in all groups. CRP, IL-6 and IL-8 plasma levels increased significantly higher in both crystalloid groups (IL-6 in the NS group: increase to 407+/-33 pg/ml; RL: increase to 377+/-35 pg/dl) than in the HES-130 treated group (IL-6: increase to 197+/-20 pg/dl). Plasma levels of ELAM-1 and ICAM remained almost unchanged in the HES 130-, but significantly increased in the RL- and NS-treated patients. CONCLUSIONS:In elderly patients, markers of inflammation and endothelial injury and activation were significantly higher after crystalloid- than after HES 130/0.4-based volume replacement regimens.

36. Concerns with Colloids • Decreased hemoglobin • Dilution of plasma proteins • Dilution of coagulation factors (PT, PTT) • Pulmonary edema / Tissue Oxygenation • Allergic reaction • Renal Issues

37. Concerns with Colloids • Decreased hemoglobin • Dilution of plasma proteins • Dilution of coagulation factors (PT, PTT) • Pulmonary edema / Tissue Oxygenation • Allergic reaction • Renal Issues

38. Boldt J. Priebe HJ. Intravascular volume replacement therapy with synthetic colloids: is there an influence on renal function?. Anesthesia & Analgesia. 96(2):376-82, 2003 Feb. FINAL PARAGRAPH In reviewing the literature on HES and kidney function, the general recommendation that “HES should be avoided in ICUs and during the perioperative period” cannot be supported. All HES preparations are not created equally. There are large differences in physicochemical properties between the first-generation HES (Mw, 450 kd; DS, 0.7 [Hetastarch]) and the newest, third-generation HES solution (Mw, 130 kd; DS, 0.4). Although promising results with this rapidly degradable HES preparation have been published regarding patients with moderate to severe kidney dysfunction showing no deterioration in kidney function, large, well controlled, prospective studies demonstrating no adverse effects of this HES preparations on kidney function in the critically ill are missing.

39. Concerns with Colloids • Decreased hemoglobin • Dilution of plasma proteins • Dilution of coagulation factors (PT, PTT) • Pulmonary edema / Tissue Oxygenation • Allergic reaction • Renal Issues

40. Lang K. Boldt J. Suttner S. Haisch G. Colloids versus crystalloids and tissue oxygen tension in patients undergoing major abdominal surgery. Anesthesia & Analgesia. 93(2):405-9, 2001 Aug. The effects of intravascular volume replacement regimens on tissue oxygen tension (ptiO(2)) are not definitely known. Forty-two consecutive patients scheduled for elective major abdominal surgery were prospectively randomized to receive either 6% hydroxyethyl starch (HES) (mean molecular weight 130 kd, degree of substitution 0.4, n = 21) or lactated Ringer's solution (RL, n = 21) for intravascular volume replacement. Fluids were administered perioperatively and continued for 24 h on the intensive care unit to keep central venous pressure between 8 and 12 mm Hg. The ptiO(2) was measured continuously in the left deltoid muscle by using microsensoric implantable partial pressure of oxygen catheters after the induction of anesthesia (baseline, T0), 60 min (T1) and 120 min thereafter (T2), at the end of surgery (T3), and on the morning of the first postoperative day on the intensive care unit (T4). HES 130/0.4 2920 +/- 360 mL and 11,740 +/- 2,630 mL of RL were given to the patients within the study period. Systemic hemodynamics and oxygenation (PaO(2), PaCO(2)) did not differ significantly between the two volume groups throughout the study. From similar baseline values, ptiO(2) increased significantly in the HES-treated patients (a maximum of 59% at T4), whereas it decreased in the RL group (a maximum of -23% at T4, P < 0.05). The largest differences of ptiO(2) were measured on the morning of the first postoperative day. We conclude that intravascular volume replacement with 6% HES 130/0.4 improved tissue oxygenation during and after major surgical procedures compared with a crystalloid-based volume replacement strategy. Improved microperfusion and less endothelial swelling may be responsible for the increase in ptiO(2) in the HES 130/0.4-treated patients. IMPLICATIONS: In patients undergoing major abdominal surgery, a colloid-based (with hydroxyethyl starch [HES] 130/0.4) and a crystalloid-based (with lactated Ringer's solution [RL]) volume replacement regimen was compared regarding tissue oxygen tension (ptiO(2)) measured continuously by microsensoric implantable catheters. The ptiO(2) increased in the HES-treated (+59%) but decreased in the RL-treated (-23%) patients. Improved microcirculation may be the mechanism for the better ptiO(2) in the HES group.

41. Factor VIII The presence of large, highly substituted molecules are believed to contribute to decreases in Factor VIII after HES administration

42. Boldt J. Haisch G. Suttner S. Kumle B. Schellhaass A. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend) on measures of coagulation. British Journal of Anaesthesia. 89(5):722-8, 2002 Nov. BACKGROUND: Hydroxyethyl starch (HES) may affect blood coagulation. We studied the effects of a modified, balanced, high-molecular weight [mean molecular weight (MW) 550 kDa], high-substituted [degree of substitution (DS) 0.7] HES preparation (Hextend) on coagulation in patients undergoing major abdominal surgery. METHODS: Patients were allocated randomly to receive Hextend) (n=21), lactated Ringer's solution (RL, n=21) or 6% HES with a low MW (130 kDa) and a low DS (0.4) (n=21). The infusion was started after induction of anaesthesia and continued until the second postoperative day to maintain central venous pressure between 8 and 12 mm Hg. Activated thrombelastography (TEG) was used to assess coagulation. Different activators were used (extrinsic and intrinsic activation of TEG) and aprotinin was added to assess hyperfibrinolytic activity (ApTEG). We measured onset of coagulation [coagulation time (CT=reaction time, r)], the kinetics of clot formation [clot formation time (CFT=coagulation time, k)] and maximum clot firmness (MCF=maximal amplitude, MA). Measurements were performed after induction of anaesthesia, at the end of surgery, 5 h after surgery and on the mornings of the first and second days after surgery. RESULTS: Significantly more HES 130/0.4 [2590 (SD 260) ml] than Hextend) [1970 (310) ml] was given. Blood loss was greatest in the Hextend) group and did not differ between RL- and HES 130/0.4-treated patients. Baseline TEG data were similar and within the normal range. CT and CFT were greater in the Hextend) group immediately after surgery, 5 h after surgery and on the first day than in the two other groups. ApTEG MCF also changed significantly in the Hextend) patients, indicating more pronounced fibrinolysis. Volume replacement using RL caused moderate hypercoagulability, shown by a decrease in CT. CONCLUSION: A modified, balanced high-molecular weight HES with a high degree of substitution (Hextend) adversely affected measures of coagulation in patients undergoing major abdominal surgery, whereas a preparation with a low MW and low DS affected these measures of haemostasis less. Large amounts of RL decreased the coagulation time.

43. Human Serum Albumin • Most abundant protein in the plasma • MW 69,000 daltons • Prepared from human donor plasma in isotonic saline • Source of unending controversy • SAFE study

44. Hespan (6 % Hydroxyethyl Starch) • Available as 6% solution in normal saline w/ osmolarity of 310 mOsm/l • Plasma volume expansion for more than 24 hrs • Like Dextran, can be associated w/ urticarial & anaphylactoid reactions • Half life for 90% of particles is 17 days, whereas that of remaining 10% is 48 days • Dosage: - usually 500-1000ml (do not usually exceed 1500ml/day) IV at a rate not to exceed 20ml/kg/hr • Precautions: - Not a substitute for blood or plasma; Contraindicated in patients with severe bleeding disorders, severe CHF, or renal failure with oliguria or anuria

45. Hespan and Heparin Mix-ups Problem: A fatal error occurred when a nurse mistakenly selected and administered two heparin 25,000 unit per 500 mL premixed bags instead of HESPAN (hetastarch) for a patient who was actively bleeding. Such mix-ups have been reported on several occasions to USP, ISMP and FDA. Although this is primarily a nomenclature issue (both names include the characters h-e-p-a and n in the same sequence), the drugs are also found in similar IV bags with blue and red labeling. Since Hespan may be used in patients who are actively bleeding, the danger of inadvertent heparin administration is obvious. Recommendation: Since hetastarch is now manufactured generically by other companies, consider using an alternate to Hespan and refer to hetastarch products by generic name. If Hespan remains in stock, do not store alphabetically next to premixed heparin products. Label products, storage bins, and automated dispensing machine pockets with a reminder about error potential. ISMP has communicated with FDA and the manufacturer about this serious problem. http://www.ismp.org/MSAarticles/A4Q99Action.html

46. Hextend (6 % Hydroxyethyl Starch) From: Wilkes: Anesth Analg, Volume 94(3).March 2002.538-544

47. HES - Pentaspan • Synthetic plasma volume expander • Average MW 200,000 – 300,000 daltons • Plasma volume expansion exceeds volume of Pentaspan infused – lasting 18-24 h • 12-24 h improvement in hemodynamic status • 70% excreted in the urine in 24 hr • Metabolized by serum amylases

48. Source: BioTime, Inc.

49. Case StudyFluid Management for Craniofacial Resection with Rectus Free-Flap

50. Case: Craniofacial Resection with Rectus Free-Flap A 76 year-old male, weighing 81 kg who was 185 cm tall, presented with complaints of facial pain and swelling. The patient had smoked a pack of cigarettes a day for almost 50 years. About 10 years ago, he developed angina while playing tennis. The angina was treated with the beta-blocker atenolol and the patient quit his smoking habit. At the time of diagnosis, the patient reported that his infrequent angina attacks responded quickly to sublingual nitroglycerine tablets. He described his exercise tolerance as good, being able to climb three flights of stairs before "getting pooped". The patient took no other medications and had no allergies.