TỔNG QUAN VỀ CÁC DUNG DỊCH CAO PHÂN TỬ ThS. BS. Nguyễn Minh Tuấn Bệnh viện Nhi Đồng 1

Pharmacokinetics and pharmacodynamics of hydroxyethyl starches?. Pharmacodynamic action depends on the number of oncotically active molecules, not on the plasma concentration alone; the

TỔNG QUAN VỀ CÁC DUNG DỊCH CAO PHÂN TỬ

ThS BS Nguyễn Minh Tuấn

Bệnh 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 replacement

2 Good hemodynamic restoration

3 Improvement of microcirculation

4 Improvement of plasma oncotic pressure

5 Fast metabolism / Excretion and Good Tolerance

6 Less coagulopathy, hemolysis, cross-match

disturbances

7 Increase DO2 and organ function

8 No cause acid-base disorders

9 No interference with organ function even with

repeated administration

10.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:

Albumin Plasma

•Synthetic:

Gelatin Dextran HES

linked

Urea-cross-Gelatin.

Cross linked Gelatin Succinylated Gelatin

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

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

name

Brand-Dextran 40 Dextran 60 Dextran

70/75

Rheo

-macrodex

cair

Plasma-Various solutions

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

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

hydroxylethyl  tăng khả năng

hòa tan và làm chậm quá trình

thủy phân  chậm bị phân hủy

và đào thải

- Sự hydroxylethyl hóa:

chủ yếu ở C2, C6 của gốc glucose trong phân tử của starch

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

-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 C6

C2/C6 ratio càng caocàng 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 caocàng chậm

bị phân hủy

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

The physicochemical properties, metabolism,

by the MS and the pattern of

substitution.

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

already initially smaller than

the renal threshold

HES: hiệu quả bồi hoàn thể 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: hiệu quả bồi hoàn thể 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: hiệu quả bồi hoàn thể tích

•The water binding effect of different

HES types primarily depends on the

number of molecules rather than on

their size

•The number of molecules in HES

130/0.4 is relatively high due to its

lower average MW and narrow

molecular weight distribution

•The greater number of

osmotically effective molecules in

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

HES: hiệu quả bồi hoàn thể tích

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

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 130/0.42 HES 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

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; 103:654–60

Boldt 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 hyperchloremic

acidosis 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 hyperchloremic acidosis associated with replacement

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

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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