TỔNG QUAN VỀ CÁC

DUNG DỊCH CAO PHÂN TỬ

ThS. BS. Nguyễn Minh TuấnBệnh viện Nhi Đồng 1

Gelatine

(1915)Dextran

(1947)

HES (1974)

6% HES 450 / 0.7

HES (1978)

6% HES 200 / 0.6

HES (1980)

6% / %10 HES 200 / 0.5

HES (1999)

6%, 10% HES 130 / 0.4

Development of synthetic colloid solutions

The Result of this process is HES

The properties of an ideal colloid

1. Rapid volume replacement2. Good hemodynamic restoration3. Improvement of microcirculation4. Improvement of plasma oncotic pressure5. Fast metabolism / Excretion and Good Tolerance6. Less coagulopathy, hemolysis, cross-match

disturbances7. Increase DO2 and organ function8. No cause acid-base disorders9. No interference with organ function even with

repeated administration10.Non pyrogenic, non-allergenic and non-antigenic

VOLUME EFFECT OF CRYSTALLOIDS

Kanagarajan N. Goal directed perioperative fluid management– Does kind of fluid matter?

CLASSIFICATION OF COLLOIDS

•Natural:AlbuminPlasma

•Synthetic:GelatinDextranHES

GELATINS

Urea-cross-linked Gelatin.

Cross linked Gelatin

Succinylated Gelatin

Concentration (%) 3.5 5.5 4.0

Mean molecular weight(Dalton)

35000 30000 30000

Volume effect(hours)(approx)

1-3 1-3 1-3

Volume efficacy(%)(approx.)

80 80 80

Osmolarity 301 206 274

Brand name Haemacel Gelofundiol Gelofusine

Boldt J, Suttner. Plasma substitutes. Minerva Anestesiol, 2005; 71:741-58

Dextran

6%

Dex 70

10%

Dex 40

6%

Dex 60

MW(Dalton) 70,000 40,000 60,000

Volume effect (hour)

5-6 3-4 5

Volume efficacy (%)

150% 200% 100%

Side effects - Anaphylactoid shock

- Coagulation disorder

- Renal dysfunction

Boldt J, Priebe HJ. Anesth Analg. 2003 Feb;96(2):376-82

Warner MA. Anesthesiology 2009; 111:187–202

Characteristics of different colloids

Philippe Van der Linden, Brigitte E. The effects of colloid solutions on hemostasis. Can J Anesth. Volume 53, Supplement 2, S30-S39

Characteristics of different colloids

Boldt J, Priebe HJ. Intravascular volume replacement therapy with synthetic colloids: is there an influence on renal function? Anesth Analg. 2003 Feb;96(2):376-82

Incidence of anaphylactic shock after infusion

of Dextran

Brand-name

Dextran 40 Dextran 60Dextran

70/75

Rheo-

macrodexPlasma-cair

Varioussolutions

# of patients

Percentages (%)

51,261 816 350

0.008 0.069

35,621

Ring & Messmer, Lancet l (1977) 466-9 Laxenaire et al., Ann Fr Reanim 13 (1994) 301-10

Hemodex® ®

®

Dextran vs. HES

6%

Dex 70

10%

Dex 40

6%

Dex 60

6%

HES

130/0.4

10%

HES

130/0.4

6%

HES

200/0.5

MW(Dalton) 70,000 40,000 60,000 130,000 130,000 200,000

Volume

effect (hour)

5-6 3-4 5 2-4 2-4 4

Volume

efficacy (%)

150% 200% 100% 100% 145% 100%

Side effects - Anaphylactoid shock

- Coagulation disorder

- Renal dysfunction

Rare

Boldt J, Priebe HJ. Anesth Analg. 2003 Feb;96(2):376-82

Warner MA. Anesthesiology 2009; 111:187–202

COST OF SYNTHETIC COLLOIDS

HES

Amylopectin

Hydroxyethylation

- Starch tự nhiên: không bền- Thay thế nhóm hydroxyl bằng hydroxylethyl tăng khả năng

hòa tan và làm chậm quá trình thủy phân chậm bị phân hủy

và đào thải

HES

- Sự hydroxylethyl hóa: chủ yếu ở C2, C6 của gốc glucose trong phân tử của starch

HES

Dược động học của HES được quyết định bởi:

-Độ thay thế (molar substitution – MS)-Kiểu thay thế (C2/C6 ratio)-Trọng lượng phân tử trung bình-Nồng độ

HES

-Độ thay thế (molar substitution – MS): là tỉ lệ giữa số nhóm hydroxyethyl so với tổng số các gốc glucose

High MS: 0.6-0.7 Hetastarch: MS =0.7, Hexastarch: MS = 0.6

Medium MS: 0.5 Pentastarch: MS = 0.5

Low MS: 0.4 Tetrastarch: MS=0.4

Độ thay thế bằng 0.4 nghĩa là 4 trong số

10 phân tử glucose có nhóm –OH được

thay thế bởi nhóm hydroxyethyl

HES

HES with low molar substitution are broken down more readily, providing a greater concentration of oncotically active particles more rapidly.

HES

-Kiểu thay thế (C2/C6 ratio) Nhóm hydroxyethyl thay ở vị trí C2 làm tăng tính đề kháng mạnh hơn đối với men α-amylase so với thay ở vị trí C6C2/C6 ratio càng caocàng

chậm bị phân hủy•C2/C6 ratio cao: > 8•C2/C6 ratio thấp: < 8

Different effects on serum concentration during 10-day hemodilution therapy of two pentastarchs with different C2/C6 ratios: 10% HES 200/0.5/13.4: 1 and 10% HES 200/0.5/5.7: 1

C2/C6 ratio càng caocàng chậm

bị phân hủy

Warner MA. Hydroxyethyl Starches. Anesthesiology 2009; 111:187–202

HES

-Trọng lượng phân tử trung bình (molecular weight-MW)

•Cao: 450-670 kDa•TB: 130-200 kDa•Thấp: 70 kDa

HES

The physicochemical properties, metabolism, and excretion are predominantly influenced by the MS and the pattern of substitution.

Warner MA. Hydroxyethyl Starches. Anesthesiology 2009; 111:187–202

Ngöôõng thaän

60 – 70.000TLPT (D)

Hieäu quaû V

time

Amylase

kích thöôùc p.töû

The in vitro mean molecular weight is of minor importance unless a greater proportion of molecules is already initially smaller than the renal threshold.

HES: hieäu quaû boài hoaøn theå tích

Jungheinrich C. The starch family: Are they all equal. Pharmacokinetics and pharmacodynamics of hydroxyethyl starches? Transfus Altem Transfu Med, 2007: 9, 152–163

However, osmotic effectiveness depends on the number of particles, and not the molecular size.

Warner MA. Hydroxyethyl Starches. Anesthesiology 2009; 111:187–202

HES: hieäu quaû boài hoaøn theå tích

Pharmacodynamic action depends on the number of oncotically active molecules, not on the plasma concentration alone; therefore, solutions with a lower in vivo molecular weight contain more molecules at similar plasma concentrations.

That is, colloid osmotic pressure depends on the concentration of oncotically active molecules, not onthe hydroxyethyl starch concentration per se.

Jungheinrich C, Neff TA. Pharmacokinetics of Hydroxyethyl Starch. Clin Pharmacokinet 2005; 44 (7): 681-699

HES: hieäu quaû boài hoaøn theå tích

•The water binding effect of differentHES types primarily depends on thenumber of molecules rather than ontheir size.

•The number of molecules in HES130/0.4 is relatively high due to its lower average MW and narrow molecular weight distribution.

•The greater number of osmotically effective molecules in HES 130/0.4 is thought to counterbalance its more rapid elimination.

HES: hieäu quaû boài hoaøn theå tích

Jungheinrich C. Drugs R D. 2004;5(1):1-9.

HES: hieäu quaû boài hoaøn theå tích

Concentration mainly influences the initial volume effect: 6% HES solutions are iso-oncotic in vivo, with 1L replacing about 1L of blood loss, whereas 10% solutions are hyperoncotic, with a volume effect considerably exceeding the infused volume (about 145%).

Warner MA. Hydroxyethyl Starches. Anesthesiology 2009; 111:187–202

HES with a high Mw, high MS, and a high C2/C6 hydroxyethylation ratio (e.g., HES 450/0.7 or HES 200/0.62) reduced concentrations of vWF and factor VIII:c more than HES with lower Mw and a lower MS.

No platelet function abnormalities have been observed in in vitro studies using HES 130/0.4

Franz A et al. Anesth Analg 2001;92:1402–7

Boldt J. Anesth Analg 2009;108:1574 –82

Modern HES preparations with a lower MW and a lower MS (0.4) (e.g. HES 130/0.4) appear to be almost free of negative effects on hemostasis

Gallandat HRCG et al. Can J Anaesth 2000;47:1207-15.Haisch G. J Cardiothorac Vasc Anesth 2001;15:316-21.

HES and EFFECTS ON COAGULATION

Sander O et al. Acta Anaesthesiol. Scand. 47 (2003) 1151 – 1158

Prothrombin time profiles, given as the INR, during volume replacement therapy with HES 130/0.42/6:1 vs. HES 200/0.5

HES 130/0.42HES 200/0.5

ACCUMULATION AND TISSUE STORAGE

Cumulative urinary excretion, even in the presence of severe non-anuric renal failure, is higher for HES 130/0.4 than values published for older HES specifications.

HES 130/0.4 may be given to patients with severe renal impairment as long as urine flow is preserved.

Jungheinrich C, Neff TA. Pharmacokinetics of Hydroxyethyl Starch. Clin Pharmacokinet 2005; 44 (7): 681-699

Plasma clearance after multiple infusions of different HES

Plasma clearance of HES 130/0.4 is:- at least 23 times higher than for HES 200/0.62 or

450/0.7, - and almost five times higher than for HES 200/0.5. - 31.4 mL/min for the 6% solution and 26.0 mL/min for

the 10% solution

Jungheinrich C. The starch family: Are they all equal. Pharmacokinetics and pharmacodynamics of hydroxyethyl starches? Transfus Altem Transfu Med, 2007: 9, 152–163

ACCUMULATION AND TISSUE STORAGE

Westphal M. Hydroxyethyl starches: different products-different effects. Anesthesiology. 2009 Jul;111(1):187-202.

ACCUMULATION AND TISSUE STORAGE

Plasma concentration of different HES types after single infusion of 500ml each in healthy volunteers

Jungheinrich C. The starch family: Are they all equal. Pharmacokinetics and pharmacodynamics of hydroxyethyl starches? Transfus Altem Transfu Med, 2007: 9, 152–163

ACCUMULATION AND TISSUE STORAGE

Tetrastarches - Less tissue accumulation and even in high doses pruritus is a not a clinical problem

ACCUMULATION AND TISSUE STORAGE

Mitra S et al. Indian J Anaesth. 2009 October; 53(5): 592–607.

The development of HES

HES

Clearance of earlier HES products is much slower, with the result that first and second generation HES products are not completely eliminated from the circulation within 24 h.

Different characteristics of HES preparations

Boldt J. Anesth Analg, 2009 May; 108(5):1574-82

Characteristics of HES Preparations.

Kozek-Langenecker S. Effects of hydroxyethyl starch solutions on hemostasis. ANESTHESIOLOGY 2005; 103:654–60Boldt J, Suttner S: Plasma substitutes. Minerva Anesthesiol 2005; 71:741–58

Haemodynamic effects of different plasma substitutes.

Boldt J Br. J. Anaesth. 2009;103:147-151

Hemodynamic effects of different plasma substitutes

Risk of metabolic hyperchloremicacidosis associated with replacement

by unbalanced solutions

-A problem with infusion of large volumes of ‘unphysiologic’ saline solution containing large amounts of sodium (154mmol/l) and chloride (154mmol/l)

Risk of metabolic hyperchloremicacidosis associated with replacement

by unbalanced solutions

Producing acidosis by administering large amounts of unbalanced fluids may mask diagnosis of perfusion deficits Or May result in inappropriate clinical interventions due to the erroneous presumption of ongoing tissue hypoxia secondary to hyovolemia.

Balanced-HES 130/0.4 vs. Saline-HES 130/0.4

Electrolytes Balanced-HES 130/0.4

HES 130/0.4 in 0.9% NaCl

Plasma

Composition of some plasma

substitutes

Boldt J. Current Opinion in Anaesthesiology 2008, 21:679–683

Benefits of balanced solutions

-Reduce the risk of hyperchloremic metabolic

acidosis

-Associated with significantly fewer alterations

in coagulation and platelet aggregation than

conventional HES

Westphal M. et al. Anesthesiology, 2009;111:187-202

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