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Precipitation of Heparin and Ethanol May Be Reduced Using A Combined Isopropanol-Ethanol Locking Solution for Vascular Access Devices

Saturday, October 20, 2012: 8:47 AM
Versailles Ballroom (Hilton Riverside)
Daniel Restrepo, BS1, Nicholas Laconi, BS1, Norma A. Alcantar, PhD2, Saumil Patel, PharmD3 and Mark L. Kayton, MD1, (1)Division of Pediatric Surgery, Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, (2)Department of Chemical & Biomedical Engineering, University of South Florida, Tampa, FL, (3)Department of Pharmacy, Tampa General Hospital, Tampa, FL

Purpose

Ethanol-locking solutions have gained popularity for the control of catheter-related bloodstream infections, but clinical trials have now demonstrated serious catheter occlusions particularly among children with mediports.   Reasons for these catheter failures have been unclear.  We hypothesized that precipitation occurs between ethanol and residual heparin, and that this precipitation may be alleviated by the combined use of isopropanol and ethanol.

Methods

Heparin (range, 0-100 units/mL) was incubated overnight with 70%, 50%, or 30% ethanol.  Precipitation  was measured in nephelometric turbidity units (NTU’s) at 4-40 °C (Micro 100 turbidimeter, HF Scientific, Inc.; n=6 samples per condition).  Means were compared by analysis of variance (ANOVA) with post-hoc T-test using Bonferroni correction and p<0.05 considered significant.  Heparin (0-100 units/mL) was then incubated with either 70% ethanol or a combination of 35% ethanol/35% isopropanol (n=9 samples per condition), and precipitation analyzed similarly.

Results

Precipitate formation between heparin and 70% ethanol is shown (Table).  At all temperatures, precipitation between 70% ethanol and 100 units/mL heparin was several orders of magnitude greater than that seen with  0, 1, or 10 units/mL of heparin (p<0.05 for 100 units/mL heparin versus all lower heparin concentrations, at each temperature tested).  Similar, although less pronounced, precipitation trends were observed when heparin was mixed with 50% ethanol or 30% ethanol.

 
Table.  Precipitation, in NTU's, of heparin in 70% ethanol (* denotes p<0.05)
0 Heparin (control) 1 unit/mL Heparin 10 units/mL Heparin 100 units/mL Heparin
 4  ºC  0.03 ± 0.01 0.36 ± 0.09 1.38 ± 0.10 410.67 ± 6.92*
25 ºC 0.05 ± 0.01 0.40 ± 0.01 4.50 ± 0.03 328.00 ± 6.10*
37 ºC 0.05 ± 0.02 0.19 ± 0.01 4.27 ± 0.01 467.83 ± 11.74*
40 ºC 0.06 ± 0.01 0.36 ± 0.02 3.33 ± 0.02

574.83 ± 8.66*

Use of 35% ethanol plus 35% isopropanol, instead of 70% ethanol, significantly reduced precipitate formation in the presence of either 10 units/mL of heparin (0.74 ± 0.61 NTU’s vs. 8.33 ± 0.19, p<0.05) or 100 units/mL of heparin  (332.89 ± 12.97 NTU’s vs. 526.78 ± 4.97, p<0.05).

Conclusion

Heparin and ethanol, if mixed, exhibit concentration-dependent, exponentially-increasing precipitation.  When exposed to a 70% ethanol-locking solution, heparin at 100 units/mL forms over 6,000-fold more precipitate than control, which may explain why catheter occlusion has been observed in patients with mediports receiving ethanol-locks.  However, solubility of heparin is greatly enhanced by judiciously combining isopropanol and ethanol instead of using ethanol alone.  These observations should help to guide the development of improved locking solutions for prophylaxis and treatment of catheter-related bloodstream infections in pediatrics.