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Pushing the bounderies: What’s beyond the final frontier? Can Ince PhD

Pushing the bounderies: What’s beyond the final frontier? Can Ince PhD Dept. of Intensive Care Dept. of Translational Physiology Erasmus Medical Center Academic Medical Center Erasmus University Rotterdam University of Amsterdam Declared interests:

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Pushing the bounderies: What’s beyond the final frontier? Can Ince PhD

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  1. Pushing the bounderies: What’s beyond the final frontier? Can Ince PhD Dept. of Intensive Care Dept. of Translational Physiology Erasmus Medical Center Academic Medical Center Erasmus University Rotterdam University of Amsterdam Declared interests: I have received educational grants from Baxter, Eli Lilly, Novartis. Edwards, Microvision Medical and Hutchinson. In addition as speaker for Fresensius and BBraun. I am the inventor of SDF imaging and as such have a declared interest in microcirculatory imaging.

  2. Boyd JH et al (2011) Crit Care Med 39:259 –265

  3. a multicenter observational cohort study to which 198 ICUs from 24 European countries contributed resulting in inclusion of 3,147 patients

  4. Balancing fluids; a tricky affair Boldt J, Ince C (2010) Intensive Care Med 36(8):1299-308.

  5. Fluids are drugs. blood flow (distribution) pO2 Hb Acid-base/SID osmotic balance volume blood sheer stress (auto) regulation Ht Viscosity metabolic inflammation

  6. Convection (flow) and Diffusion (functional capillary density rate limite oxygen transport to the tissues. D x A ( cappO2 - mitpO2) VO2 = __________________ L VO2 volume of transported O2 transported by diffusion D diffusion constant A systemic capillary surface area cappO2 capillary pO2 mitpO2 mitochondrial pO2 L distance from RBC to mitochondria heart failure normal diffusion low convectionhemodilution large diffusion distance normal convection

  7. Microcirculatory changes in one and the same sub-lingual location before and after switch to CPB for cardiac surgery show diffusion limitation

  8. Blood Transfusions Recruit the Microcirculation during Cardiac Surgery Yuruk K, Almac E, Bezemer R, Goedhart P, de Mol B, Ince C Results show that blood transfusion s improve oxygen tranport by reducing diffusion distances and not by augmenting convection. Transfusion (2010)51(5):961-7,

  9. Main Finding Higher hemoglobin concentrations (p < 0.001) and blood transfusions (p = 0.031) were independently associated with a lower risk of in-hospital death, especially in patients aged from 66 to 80 years, in patients admitted to the ICU after non-cardiovascular surgery, in patients with higher severity scores, and in patients with severe sepsis.

  10. Hydroxyethyl starch 130/0.4 is superior to Saline solution For resuscitation of the microcirculation A Dubin A, Pozo MO, Casabella CA, Murias G, Pálizas F, Moseinco m, Pálizas F, Kanoore Edul VS, Ince C J Crit Care (2010) 25(4):659.e1-8

  11. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2145–H2157, 1999.

  12. Changes in blood flow and vessel density in the sublingual microcirculation on ascent to high altitude Daniel Martin D, Goedhart P, Vercueil A, Ince C, Levett D, Grocott M

  13. Fluids are drugs. blood flow (distribution) pO2 Hb Acid-base/SID osmotic balance volume blood sheer stress (auto) regulation Ht Viscosity metabolic inflammation

  14. Critical Care (2006) 10:R88:1-13

  15. Fluids are drugs. blood flow (distribution) pO2 Hb Acid-base/SID osmotic balance volume blood sheer stress (auto) regulation Ht Viscosity metabolic inflammation

  16. Renal arterial flow Cortex Micro Cortex Micro Speckle perfusion perfusion distribution oxygen distribution imaging of cortex no resus MAP Plasma inflammatory markers Creatinine clearance HES130/0.4/NaCl

  17. Don’t forget oxygenation. The main function of red blood cells is to transport oxygen to the tissue cells. of all oxygen in blood~97% is bound to Hb and ~3% bound to serum

  18. 0.9%NaCl Blood 0.9%NaCl Blood Volume targeting a MAP of 40 or 80 mmHg Normal Saline (NS) or Hyper Saline (HS) Legrand M, Mik EG, Ballestra G, Pirracchio R, Payen D, Ince C (2010) Anesthesiology. 112(1):119-27.

  19. Fluids are drugs. blood flow (distribution) pO2 Hb Acid-base/SID osmotic balance volume blood sheer stress (auto) regulation Ht Viscosity (hypotension) metabolic inflammation

  20. Solutions for Volume Replacement Colloids Synthetic Colloids Hydroxyethyl Starch Solutions (HES) Gelatins Dextrans Human Colloids Albumin Type of Solutions Balanced vs. un-balanced solutions Balanced (e. g. Ringer’s Lactate) Un-balanced (eg 0.9% NaCl) Crystalloids The Four Fluids of Life

  21. Haemodilution and strong ion difference (SID) Blood contains strong ions that completely dissociate, such as Na+, K+, Ca++, Mg++ and Cl- Blood also contains substances that almost completely dissociate, such as sulphate, acetate, lactate and β-hydroxybutyrate SID = [strong cations] minus [strong anions] For normal plasma, SID is about 42 mEq/L (molar equivalent) NaCl is completely dissociated, giving a SID of zero: massive infusion of pure NaCl will reduce the plasma SID, so the SID will shift in the direction of zero, causing a metabolic acidosis Morgan. Crit Care 2005;9:204–11

  22. History of volume replacement "I dissolved from two to three drachms of muriate of soda and two scruples of the subcarbonate of soda in six pints of water, and injected it at temperature 112°; Fah". (This is approximately 90 mmol/l sodium; 78 mmol/l chloride; 10 mmol/l Bicarbonate)Na/Cl proportion 1.15 (Plasma 1.36) Latta T. No.3. Letter from Dr Latta, of Leith, detailing Three Cases, of which one was succesful. Lancet 1832; 460: 370-373

  23. Sydney Ringer’s solution Clinician and Pharmacologist The effect of Electrolytes on cardiac and involuntary muscle = Organ bath with tap water Ringer S. Concerning the influence exerted by each of the constituents of the blood on the contraction of the ventricle Journal of Physiology 1882;3:380-393 “The salts of sodium, potassium, calcium and chloride in definite concentrations and in precise proportions are necessary for protoplasmatic activity”

  24. Hartmann’s solution. Alexis Frank Hartmann (1898 – 1964) Clinical Paediatrician and Biochemist 1932 added Sodium lactate to Ringer’s solution “Normal” Saline rehydration of children with diabetic ketoacidosis increased acidosis and worsened the prognosis “Need proportionally more sodium than chloride in parenteral solutions to avoid the development of an acidosis in children’ Hyperchloraemic Metabolic acidosis

  25. Hemodynamic parameters at 4 time points: BL, HS, R60, T60 (*p<0.05, **p<0.01 and ***p<0.001, versus Hemorrhagic Shock (HS); †p<0.05 and †††p<0.001, versus 15th min in same group of Resuscitation (R15)).

  26. Strong ion differences (SID), anion gap values and some plasma ions of groups at baseline and the end of resuscitation time point. Biochemical parameters at baseline (t0) and resuscitation (t150) time points. (*p < 0.05, **p < 0.01, * **p < 0.001 vs. control group, +p < 0.05, ++ p < 0.01 and +++p < 0.001vs.HS group, †p < 0.05, ††p < 0.01, †††p < 0.001 vs. HS + % 0.9 NaCl group /p < 0.05vs.HS + Lyte group)

  27. Acute effects of balanced vs unbalanced colloid resuscitation on renal macro- and microcirculatory perfusion during endotoxemic shock. LPST30min T60 min T90 min T120 min Aksu U, Bezemer R, Demirci C, Ince C (2011) Shock (in press)

  28. CONTROL LPS LPS + NaCl

  29. Control LPS T60min LPS T90min LPS + Colloid

  30. Acidemia and Chloride can do many things It can cause vasoconstriction and influence responsiveness [1,2] It increases endogenous catecholamine release, which induces the release of both pro- and anti-inflammatory cytokines [3] and nitric oxide (NO) [4]. Acidemia can cause macrophages increase their tumor necrosis factor secretion [5] References 1. Quilley CP et al (1993) Br J Pharmacol 108:106-110 2. Wilcox CS (1983) J Clin Invest 71:726-735 3.Le Tulzo Y, et al (1997) J Clin Invest 99:1516-1524 4.Celotto AC,et al (2008). Braz J Med Biol Res 41:439 5.Jensen JC et al (1990) J Surg Res 49:350-353

  31. Fluids are drugs. blood flow (distribution) pO2 Hb Acid-base/SID osmotic balance volume blood sheer stress (auto) regulation Ht Viscosity metabolic inflammation

  32. Renal cortex and medulla microcirculatory pO2 following balanced and unbalanced crystalloid resuscitation after hemorrhagic shock. Colloids: You need less!

  33. Balancing fluids, a tricky affair malondialdehyde (MDA)

  34. ROS scavenging using vitamin C and TEMPOL to reduce I/R injury

  35. How to rescue the failing kidney: a hypothesis Must integratively improve microcirculatory function by promoting perfusion and reduction of shunting oxygenation inhibiting iNOS reducing oxidative stress Kidney a la Szechuan Le Dorze M, Legrand M, Payen D, Ince C (2009) Curr Opin Crit Care. 15(6):503-8.

  36. What is the future? Are there alternatives for homologous blood transfusion and are they affective in transporting oxygen to the microcirculation and tissue cells?

  37. Elastic modulus sRBCs measured using atomic force microscopy Synthesis technique of RBC-mimicking particles coating the sRBCs with uncross-linked Hb increased the oxygen-binding capacity to comparable to mouse blood Biocompatible sRBCs Mouse RBCs

  38. Conclusions NaCl and Cl containing colloid solutions should be avoided Balanced salt solutions are better in this respect. Of the starches, 130kD HES is best for the microcirculation Too much or too little fluids are bad. Don’t forget tissue oxygenation. Oxygen delivery and microcirculatory flow are key targets for fluid therapy and can be clinically monitored. New clinical tools may provide such tools for optimizing fluid therapy.

  39. Dept of Translational Physiology Academic Medical Center University of Amsterdam Ugur Aksu Bektas Atasever Peter Goedhart Tanja JohannesGianmarco Balestra Matthieu LegrandCan Ince Bert Mik Koray Yuruk Martin Siegemund Rick Bezemer Christian Boerma

  40. Dept of Intensive Care Erasmus Medisch Centrum Erasmus University Rotterdam Denise Dos Miranda ReisBen van der Hoeven Eva KlijnCorstiaan den Uil Lucia Jewbali Diederik Gommers Alex LimaTim Jansen Jos LeNobleJasper van Bommel Jan Bakker

  41. Thank You Dank je wel voor de uitnodiging, Manu 45 November 3, 2008 Confidential Information of MicroVision Medical

  42. Fluids; Pharmacology, Physiology and Efficacy Can Ince PhD Dept. of Intensive Care Dept. of Translational Physiology Erasmus Medical Center Academic Medical Center Erasmus University Rotterdam University of Amsterdam Declared interests: I have received educational grants from Baxter, Eli Lilly, Novartis. Edwards, Microvision Medical and Hutchinson. In addition as speaker for Fresensius and BBraun. I am the inventor of SDF imaging and as such have a declared interest in microcirculatory imaging.

  43. Septic acute kidney injury accounts for close to 50% of all cases of acute kidney injury in the intensive care unit and, in its various forms, affects between 15% and 20% of intensive care unit patients. However, there is little we really know about its pathophysiology Li Wan et al (2008)Crit Care Med 2008; 36:S198–S203

  44. Heart, kidney and intestine have a different tolerance for severe anemia • van Bommel J, Siegemund M, Henny P, Ince C (2008) • Translational Research 151(2):110-7

  45. Haemodilution and strong ion difference (SID) Blood contains strong ions that completely dissociate, such as Na+, K+, Ca++, Mg++ and Cl- Blood also contains substances that almost completely dissociate, such as sulphate, acetate, lactate and β-hydroxybutyrate SID = [strong cations] minus [strong anions] For normal plasma, SID is about 42 mEq/L (molar equivalent) NaCl is completely dissociated, giving a SID of zero: massive infusion of pure NaCl will reduce the plasma SID, so the SID will shift in the direction of zero, causing a metabolic acidosis Morgan. Crit Care 2005;9:204–11

  46. Septic acute kidney injury accounts for close to 50% of all cases of acute kidney injury in the intensive care unit and, in its various forms, affects between 15% and 20% of intensive care unit patients. However, there is little we really know about its pathophysiology Li Wan et al (2008)Crit Care Med 2008; 36:S198–S203

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