1. Colloids - an overview Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics PhD (physio) Mahatma Gandhi medical college and research institute, puducherry – India

2. Colloids Colloids tend to be larger molecules than crystalloids dispersed throughout the solvent rather than forming true solutions. The component particles tend to arrange as groups of molecules and so do not readily pass through clinical semipermeable membranes. They therefore have an oncotic potential that is usually measured as colloid osmotic pressure (COP).

3. Image of a colloid

4. But crystalloids !!! Crystalloid solutions are solutions of sugar or salt or mixture of salt and sugar in water. Crystalloids remain intravascular for short period and metabolise to carbon dioxide, water, ions and yields energy.

7. In simple terms Osmotic pressure Exerted by salts to push fluid out Oncotic pressure exerted by colloids to get fluid in the blood vessel

8. Colloids Colloids are solutions of high molecular weight substances that largely remain in the intravascular compartment for longer period and generate an oncotic pressure as well as slowly being metabolized.

9. Colloids number of molecules per volume of solution is usually lower than crystalloid solution. No effect on osmolarity Hence electrolytes are added.

10. Half life the intravascular half-life of a crystalloid solution is 20–30 min, most colloid solutions have intravascular half- lives between 3 and 6 h.

11. Characters General characteristics of the colloid are (i) particles have high molecular weight, (ii) high osmolality. and high oncotic pressure (iii) longer plasma half life (iv) higher plasma volume expansion 25 % Vs 125%

12. Types of colloids colloids are either natural or artificial. The natural colloids are blood, human albumin and fresh frozen plasma. Artificial colloids are dextrans, gelatins and starch. Artificial colloids are polymers containing molecules with wide range of molecular weight Monodisperse and polydisperse

14. Characters Molecular weight : oncotic pressure Osmolality and oncotic pressure: Almost all colloid solutions have a normal osmolality. The oncocity of the solution will influence the vascular expansion. Plasma half-life: The plasma half-life of a colloid depends on its MW, the elimination route, and, the involved organ function (mainly eliminated by the renal route

15. Characters MW --- oncotic pressure – initial volume expansion ---- half life – persistence The degree of volume expansion is mainly determined by the MW, whereas the intravascular persistence is also determined by the elimination of the colloid.

16. Characters Acid-base composition: Albumin and gelatin solutions have physiological pH, while other solutions tend to have acidic pH. Electrolyte content: The sodium concentration is low in “salt-poor albumin Others same

17. Human albumin solution principal natural colloid comprising 50 to 60% of all plasma proteins contributes to 80% of the normal oncotic pressure in health. MW = 69,000 Dalton Synthesis – liver

18. Human albumin solution 5% solution is isooncotic and leads to 80% initial volume expansion 25% solution is hyperoncotic and leads to 200 - 400% increase in volume within 30 minutes. The effect persists for 16 - 24 h

19. Structure of albumin

20. Indications: a. Emergency treatment of shock specially due to the loss of plasma b. Acute management of burns c. Fluid resuscitation in intensive care d. Clinical situations of hypo-albumineamia i. Following paracentesis ii. Patients with liver cirrhosis (For extracorporeal albumin dialysis (ECAD)) iii. After liver transplantation e. Spontaneous bacterial peritonitis f. Acute lung injury

21. Advantages: Natural Volume expansion possesses antioxidant and scavenging effects Disadvantages: Costly, ‘leakiness’ of the vascular endothelium and volume overload

22. Dextran highly branched polysaccharide molecules Artificial synthesis using the bacterial enzyme dextran sucrase from the bacterium Leuconostoc mesenteroides 6% solution with an average molecular weight of 70,000 (dextran 70) 10% solution with an average weight of 40,000 (dextran 40, low-molecular-weight dextran)

24. characters Kidneys primarily excrete dextran solutions. Both dextran-40 and dextran-70 lead to a higher volume expansion as compared to HES and 5% albumin. (100 to 150%) The duration lasts for 6–12 hours

25. Dextran – slowly decreasing uses used mainly to improve micro-circulatory flow in microsurgical re-implantations. Extracorporeal circulation:

26. Disadvantages Anaphylactic reactions: Coagulation abnormalities: Interference with cross-match: Precipitation of acute renal failure:

27. Gelatins Gelatin is the name given to the proteins formed when the connective tissues of animals are boiled If you cool, it may gellify !!

28. Modified gelatins Succinylated or modified fluid gelatins (e.g., Gelofusine, Plasmagel, Plasmion) Urea-crosslinked gelatins (e.g., Polygeline) Oxypolygelatins (e.g., Gelifundol)

29. Polygeline (‘Haemaccel’, Hoechst) is produced by the action of alkali and then boiling water (thermal degradation) on collagen from cattle bones. MW = 35000

30. haemaccel. Polygeline is supplied as a 3.5% solution with electrolytes (Na + 145, K + 5.1, Ca ++ 6.25 & Cl − 145 mmol/l). calcium ions -- increase in serum calcium concentration following large volume resuscitation. Polygeline also contains potassium ions:

32. Succinated gelatin

33. Character and indications Kidneys excrete 70 -80 % volume expansion 2 -3 hours Hypovolemia due to acute blood loss. Acute normovolaemic haemodilution. Extracorporeal circulation – cardiopulmonary by- pass. Volume pre-loading prior to regional anaesthesia.

34. ADVANTAGES AND DISADVANTAGES Cost effective: No limit of infusion: No effect of renal impairment: Higher anaphylaxis than albumin Coagulation – platelet adhesions decreased Increased PRA and possible circulatory problems

36. Hydroxyethyl starches (HES) Starch is polysaccharide carbohydrate and seen to produce less morbidity compared to dextrans or gelatins. As a class, starch is safer than other colloid and is a near – ideal resuscitation fluid.

37. How to get amylopectin rich corn Amylases glucose molecules Hydroxy ethylation neutralised with alkali and further purified HES

38. Voluven

39. HES Concentration: low (6%) or high (10%). Molecular Weight (MW): low ( 70 kDa), medium ( 200 kDa), or high ( 450 kDa). Polydisperse Small excreted Large fragmented to small continuous supply of oncotically active molecules

40. Molar substitution (MS): low (0.45–0.58) or high (0.62–0.70) A varying number of hydroxyethyl residues attached to the anhydrous glucose particles within the polymer. increases the solubility of the starch in water, inhibits the rate of destruction of the starch polymer by amylase.

41. MS !! What is this ?? The figure 0.7 in the description of a HES preparation indicates that there are seven hydroxyethyl residues on average per 10 glucose subunits.(hetastarches) hexastarch (MS 0.6), pentastarch (MS 0.5), tetrastarch (MS 0.4).

42. C2/C6 ratio: low ( 8). The C2/C6 ratio refers to the site where substitution has occurred on the initial glucose molecule. The higher the C2/C6 ratio, longer the half-life and hence, longer persistence in the blood

43. Metabolism initially a rapid amylase-dependent breakdown and renal excretion. Plasma half life is 5 days and 90% is eliminated in 42 days. Smaller HES molecules (<50,000 to 60,000 Dalton) are eliminated rapidly by glomerular filtration. Medium sized molecules get excreted into the bile and faeces. Another fraction - taken up by the reticuloendothelial system where the starch is slowly broken down. Detected for several weeks after administration

44. Advantages Volume expansion 100% Duration 8-12 hours Shock Endotoxemia Maximal – 50 ml/kg Cost less than albumin

45. Problems Coagulation Renal impairment Accumulation and itching Anaphylactoid reactions But ? Found in third generation – tetrastarch !!

46. pharmacokinetics Clearance of the latest generation (third generation) 130/0.4) is 20 to 30 fold higher compared to first generation HES therapeutic safety index of third generation HES (130/0.4) (C2-C6 >8) is higher compared with all other HES solutions

47. Third-generation HES: tetrastarch Reductions in MW and MS have led to products with shorter half-lives, improved pharmacokinetic pharmacodynamic properties, fewer side effects v

48. Benefits over older starches reduced effect on the coagulation process compared to older products rapid clearance of the latest generation of tetrastarches, - less accumulation Less tissue persistence – less itching

49. Benefits over older starches (130/0.4) Waxy maize better over potato derived in liver dysfunction Renal dysfunction, elderly, hepatic dysfunction,Cardiac surgery, abdominal aortic surgery Also children

50. Effects on Microcirculation and Oxygenation beneficial effects on organ perfusion, microcirculation, tissue oxygenation, inflammation, endothelial activation, capillary leakage, and tissue edema over and above their volume replacement effects We are using them in shock states

51. Crystalloids Vs colloids Intravascular persistence Volume expansion Anaphylaxis, Renal Cost Coagulation

52. Trials 1989 – may be more deaths with colloids no difference in outcome among patients treated with colloids or crystalloids (BMJ – 1998) SAFE (Saline versus Albumin Fluid Evaluation) trial 7000 critically ill patients requiring fluid resuscitation to receive isooncotic albumin or isotonic crystalloid. There was no overall difference in outcome

53. The danger starts

54. FDA recommendations – June 2013 Do not use HES solutions in critically ill adult patients including those with sepsis, and those admitted to the ICU. Avoid use in patients with pre-existing renal dysfunction. Discontinue use of HES at the first sign of renal injury. Need for renal replacement therapy has been reported up to 90 days after HES administration. Avoid use in patients undergoing open heart surgery in association with cardiopulmonary bypass due to excess bleeding. Discontinue use of HES at the first sign of coagulopathy.

55. This is an overview Read well for more details Are colloids – boon to gloom !!

56. Thank you all