hydroxyethyl starch - safety - mechanism - side effects - fluid resuscitation - volume therapy - shock

1. How does HES accumulate
in the tissues?
Christian J. Wiedermann, MD
Central Hospital of Bolzano, Italy

2. Characteristics of Hydroxyethyl Starch
(HES) Storage in Human Tissues
• Rapid
• Widespread
• Cumulative
• Long-Lasting
HES-laden intracytoplasmic vacuole detected
within 90 min after single 30 g HES infusion
by immunoelectron microscopy with anti-HES
antibody in skin perivascular histiocyte.
Ständer et al. Cell Tissue Res 304:261-9, 2001.

3. Human Tissue Sites of HES Storage
Pfeifer et al. Klin Wochenschr 62:862-6, 1984.
Sirtl et al. Beitr Anaesth Intensivmed 26:74-97, 1988.
Heilmann et al. Infusionstherapie 18:236-43, 1991.
Jurecka et al. Arch Dermatol Res 285:13-9, 1993.
Szeimies et al. Br J Dermatol 131:380-2, 1994.
Metze et al. Br J Dermatol 136:553-9, 1997.
Sirtl et al. Br J Anaesth 82:510-5, 1999.
Christidis et al. J Hepatol 35:726-32, 2001.
Auwerda et al. Ann Intern Med 137:1013-4, 2002.
Nohé et al. Eur Surg Res 34:364-72, 2002.

4. HES Stored in Diverse Parenchymal and
Reticuloendothelial Human Cell Types
Szépfalusi et al: Arch Dermatol Res 285:144-50, 1993.
Metze et al: Br J Dermatol 136:553-9, 1997.
Christidis et al: J Hepatol 35:726-32, 2001.
Ständer et al: Cell Tissue Res 304:261-9, 2001.
Proximal Renal
Tubular Cells
Kupffer Cells
Hepatocytes
Vascular
Endothelial
Cells
Keratinocytes
Secretory
Epithelial Cells
Peripheral
Neurons
Schwann Cells
Perineural
Cells
Macrophages Monocytes
Perivacular
Histiocytes
Auwerda et al: Ann Intern Med 137:1013-4, 2002.
Nohé et al: Eur Surg Res 34:364-72, 2002.
Weisshaar et al: Hautarzt 55:558-61, 2004.
Ebcioglu et al: Kidney Int 70:1873-6, 2006.

5. Pfeifer et al. Klin Wochenschr 62:862-6, 1984.
Ständer et al. Cell Tissue Res 304:261-9, 2001.
Quantity Stored in Human Cells Increases
with Cumulative HES Dose
• HES storage can reach massive levels
– Liver tissue HES concentration of 4% w/w reported

6. Quantitative Accumulation of HES in Major
Organs after Repeated Infusions
Lukäsewitz et al: J Anaesth Intensivbeh 3:42-6, 1998.
Necropsy study of 12 young adults
who died of sepsis and multi-organ
failure after repeated infusions of
HES 200/0.5

7. Sirtl et al. Br J Anaesth 82:510-5, 1999.
Pillebout et al. Am J Transplant 5:1120-9, 2005.
Long-Lasting Storage of HES
in Human Tissues
• No known intracellular enzymes able to catabolize HES
– HES can persist indefinitely in long-lived cell types
– Still detectable after up to 10 years or more in kidney,
> 4 years in skin and > 1 year in intestine and muscle
HES observed in 16 of 26 (61%)
orthotopic liver transplant patients by
renal biopsy a mean of 5 years after
HES exposure

8. Dual Routes of HES Endocytosis
Szépfalusi et al. Arch Dermatol Res 285:144-50, 1993.
Nohé et al. Eur Surg Res 34:364-72, 2002.

9. Nohé et al. Eur Surg Res 34:364-72, 2002.
Pinocytosis of HES
Untreated cultured human
vascular endothelial cells
HES-laden lysosomes after
incubation with HES 200/0.5

10. Schmidt-Hieber et al. Eur J Haematol 77:83-5, 2006.
Phagocytosis of HES
Foamy portal macrophages and
Kupffer cells in liver biopsy of
patient with liver failure and
myelosuppression after
cumulative 1200 g HES 130/0.4
and HES 200/0.5.
Foamy cell degenerated
macrophages comprising ~50%
of nucleated cells in bone
marrow biopsy of same patient.

11. Westphal et al: Anesthesiology 111:187-202, 2009.
Does Rapid Plasma Clearance
of HES Affect Storage?
• HES comprises polydisperse mixture of molecules
– Differing mean molecular weight (MW)
– Differing degree of molar substitution (MS)
• Four categories based on MS
– Tetrastarch (eg HES 130/0.4)
– Pentastarch (eg HES 200/0.5)
– Hexastarch (eg HES 200/0.62
– Hetastarch (eg HES 450/0.7)
• Tetrastarch and Pentastarch more rapidly cleared
from plasma

12. Bellmann et al: Clin Pharmacokinet 51:225-36, 2012.
Meta-Analysis of HES Tissue
Uptake in Clinical Studies
• 25 clinical studies with 287 total subjects
– Most studies of healthy volunteers
• Urine, plasma and tissue HES 24 h after single infusion
– Tissue uptake of HES determined indirectly
– Tissue HES = HES Dose – Urine HES – Plasma HES
• Tissue uptake of different HES types compared

13. Percent of HES Dose in Tissue at 24 h
Tetrastarch 9 92 42.3 (36.8-47.7)
Pentastarch 11 84 42.5 (39.2-45.8)
Hexastarch 2 11 31.7 (24.6-38.7)
Hetastarch 11 131 25.6 (18.3-32.9)
HES Type Groups Subjects Tissue % (CI)
Pooled tissue uptake of Tetrastarch/Pentastarch (42.4%) higher
by 15.8% (p < 0.001) vs Hexastarch/Hetastarch (26.6%).
Bellmann et al: Clin Pharmacokinet 51:225-36, 2012.

14. Factors Affecting Tissue Uptake of HES
Year Reported ≤ 2000 vs > 2000 0.22
Subjects per Group ≤ 6 vs > 6 0.91
Type of Subjects Healthy Volunteers vs Patients 0.07
Preinfusion Volume Status Euvolemic vs Hypovolemic 0.96
HES Molecular Weight (kD) ≤ 200 vs > 200 < 0.001
HES Molar Substitution ≤ 0.5 vs > 0.5 < 0.001
HES C2:C6 Ratio ≤ 6 vs > 6 0.21
HES Concentration (%) 6 vs 10 vs 14 0.20
HES Volume Infused (mL) ≤ 500 vs > 500 0.26
HES Dose (g) ≤ 50 vs > 50 0.29
Factor Comparison p
Conclusion: Only HES MW and MS mattered.
Bellmann et al: Clin Pharmacokinet 51:225-36, 2012.

15. Adverse Effects of HES Associated
with Tissue Storage
• Kidney Injury
– HES increased recourse to renal replacement
therapy (RRT) in multiple recent meta-analyses of
randomized controlled trials (RCTs)
• Liver Failure
– HES increased liver failure in a large recent RCT
• Pruritus
– HES increased pruritus in a recent meta-analysis of
RCTs
Myburgh et al. N Engl J Med 367:1901-11, 2012.
Zarychanski et al. JAMA 309:678-88, 2013.
Gattas et al. Intensive Care Med DOI 10.1007/s00134-013-2840-0, 2013.
Haase et al. BMJ 346:f839 doi: 10.1136/bmj.f839, 2013.
Patel et al. Intensive Care Med DOI 10.1007/s00134-013-2863-6 2013.

16. Conclusions
• HES recognized as a foreign substance.
• Hydroxyethylation intentionally retards catabolism
– Promotes storage.
• Tissue storage of HES is rapid, widespread, cumulative
and long-lasting.
• Low MW/MS may increase tissue uptake of HES.
• Storage may be fundamental mechanism underlying
recognized complications of HES.