Journal of Pediatric Surgery 50 (2015) 315–319

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Chemical stability of heparin, isopropanol, and ethanol line lock solutions Paul S. Cullis a, David J.B. Keene a,⁎, Azrina Zaman a, Catrin Barker b, Lindsay Govan c, Joanne Minford a a b c

Department of Paediatric Surgery, Alder Hey Children’s Hospital, Liverpool Department of Pharmacy, Alder Hey Children’s Hospital, Liverpool Health Economics and Health Technology Assessment, Institute of Health and Wellbeing, University of Glasgow, Glasgow

a r t i c l e

i n f o

Article history: Received 30 October 2014 Accepted 2 November 2014 Key words: Central venous catheters Line lock Ethanol Isopropanol Heparin Compatibility

a b s t r a c t Background: Ethanol line locks are used in the US to prevent catheter associated bloodstream infections. Heparin precipitates in solution with ethanol. However, isopropanol may reduce precipitate formation. We aimed to determine the chemical stability of heparin, isopropanol, and ethanol line lock for a 10 day period at 2–8 °C and 25 °C. Methods: Forty samples were prepared for analysis. Each sample was prepared identically using a 5 ml syringe capped with a Combi-stopper: 1 ml 70% isopropanol, 1 ml 70% ethanol, and 1 ml heparin sodium 10 IU/ml. Twenty syringes were stored at 2–8 °C and 20 at 25 °C. Analysis was carried out on days 1, 3, 6, 8, and 10 with a single syringe from each condition being tested in duplicate. Samples were assessed visually. Sub-visible particle count analysis was carried out using a CLIMET particle counting system. Heparin concentration was analysed using an anti-Xa assay. Ethanol and isopropanol concentrations were analysed by gas chromatography. Results: Samples remained clear and colourless throughout the study. Sub-visible particle counts remained within limits specified in British Pharmacopoeia 2013 when stored at 2–8 °C and 25 °C, 60% humidity for up to 10 days. There was no significant change in ethanol or isopropanol concentration during the study. However, heparin activity fell by N10% after 1 day storage and to 65% of original activity after 10 days. Conclusions: This study shows that addition of isopropanol to heparin and ethanol prevents precipitation. However, this solution shows a progressive decline in heparin activity over time making it unsuitable for extended shelf life. © 2015 Elsevier Inc. All rights reserved.

1. Background Central venous catheters (CVCs) provide reliable venous access for haemodialysis, blood sampling, monitoring, plasmaphoresis and the administration of fluids, drugs, chemotherapy and parenteral nutrition. Catheter related blood stream infections (CRBSIs) are associated with a significant morbidity and mortality for the individual leading to an increase in health care costs estimated to be £9148 per CABSI [1]. In 2000, the National Audit Office reported that hospital-acquired infections were each year costing the NHS around £1000 million and resulting in at least 5000 deaths [2]. Standardising the insertion and maintenance of central lines by introduction of care bundles has reduced CRBSI rates [3]. Line-locks are a routine part of care bundles used to prevent CRBSIs and maintain intraluminal patency during intervals when the CVC is not being used [4]. Different line-locks are used including saline, heparin, ethylenediaminetetraacetic acid (EDTA), citrate, ethanol, taurolidine and antibiotics [5]. Ethanol line-locks are widely used in the USA as they are cheap and widely available. Ethanol has shown to have great potential to eradicate organisms in biofilms and to treat or prevent CRBSI [6]. The American Pediatric Surgical Association has recommended ethanol as a safe and ⁎ Corresponding author at: Department of Paediatric Surgery, Alder Hey Children's Hospital, Alder Road, Liverpool, LA12 2AP, UK. Tel.: +44 151 7948149. E-mail address: [email protected] (D.J.B. Keene). http://dx.doi.org/10.1016/j.jpedsurg.2014.11.023 0022-3468/© 2015 Elsevier Inc. All rights reserved.

effective line-lock in the prevention of CRBSI (grade A/B recommendations). The mechanism of action is by denaturing bacterial proteins and may be particularly effective in colonised CVCs where organisms are protected by a biofilm. It does not induce bacterial resistance and exhibits broad spectrum activity including gram negative organisms and fungi [7–9] with no known resistance [10]. Two recent reviews evaluating the evidence supporting ethanol line locks concluded that ethanol is effective in preventing CRBSI but conclude that occlusive events appear to be a concern [10,11]. Several studies have reported problems with precipitation and CVC occlusion using ethanol locks particularly with totally implantable devices [12–14]. A recent in vitro study assessing precipitation in heparin/ethanol solutions concluded that concentrations of ethanol (N 28%) exhibited significant precipitate and suggested that this may account for reported vascular access device occlusion events [6]. The addition of an anticoagulant to an ethanol lock may prevent CVC occlusion. Similar approaches have been used with antibiotic locks [15]. Traditionally heparin has been considered incompatible with ethanol because it forms a precipitate [16]. The drug monographs of numerous manufacturers of heparin and ethanol line locks state that ethanol and heparin precipitate in combination. An intriguing in vitro study reported that the solubility of heparin is greatly enhanced by judiciously combining isopropanol and ethanol instead of using ethanol alone [17]. Isopropanol has similar pharmacokinetic and toxicology profiles to ethanol [18].This abstract is the only such report in the literature and does not correlate the effect of incubation time on precipitation. The clinical

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application of this study hinges on whether the heparin, isopropanol and ethanol solution is stable in storage, the toxicity profile of isopropanol and whether the biological activity of the heparin and ethanol is preserved. Our aim was therefore to perform an in vitro study designed to determine the chemical and physical stability of heparin, isopropanol and ethanol line lock solution in syringes for a period of up to 10 days at both 2–8 °C and at 25 °C, equivalent to refrigerator and room temperatures, respectively.

sub-visible particle count analysis, two syringes from each storage condition, for each time point, were sampled from a single syringe. For the heparin analysis, a single syringe from each storage condition, for each time point, was tested in duplicate. For the analysis of ethanol and isopropanol, a single syringe from each storage condition for each time point was tested in duplicate, for each analyte. Two vials of heparin 10 IU/ml, an ampoule of ethanol 70% and stock 70% isopropanol solution were also analysed to provide initial assay figures at time point zero. 2.1.5. Heparin assay Heparin was analysed using an Anti Xa assay. Plasma was quantitatively added to samples and control standards.

2. Methods 2.1. Materials Table 1 lists the sources of materials used. Stock 70% isopropanol solution was made using sterile water for irrigation as a diluent. 2.1.1. Sample preparation and storage Study samples were prepared at Quality Control North West Liverpool. Preparations were carried out in such a way so as to eliminate any particulate contamination in samples used for sub-visible particle count analysis. Samples were prepared on different days over a 10 day period, stored at 2–8 °C refrigerated or 25 °C in a 60% RH humidity cabinet, and analysed simultaneously on the final day, such that the properties of solutions at days 0, 1, 3, 6, 8 and 10 could be determined. Prior to any analysis, sample syringes underwent a standard mixing process by drawing 1 ml air, attaching a Combi-stopper, and inverting 10 times. 2.1.2. Samples prepared for sub-visible particle count analysis On each day of preparation, ampoules of ethanol and heparin solution were opened. Taking a new syringe and needle, 1 ml 70% isopropanol was drawn, followed by 1 ml ethanol 70%, and 1 ml heparin 10 IU/ml. This process was repeated four times, using the same ampoules and stock isopropanol. After preparation, four syringes were split, with two stored at 2–8 °C and two at 25 °C. 2.1.3. Sample prepared for heparin, isopropanol and ethanol assays On each day of preparation, ampoules of ethanol 70% and heparin solution 10 IU/ml were opened. 4 ml 70% isopropanol, ethanol 70% and heparin was added to a measuring cylinder using calibrated pipettes. The solution was mixed and allowed to stand for 30 min to equilibrate to room temperature, before being divided amongst four syringes. The syringes were split, with two stored at 2–8 °C and two at 25 °C. 2.1.4. Sampling protocol On the final day, all 40 syringes were removed from storage. 10 subvisible particle count samples were analysed in-house, 10 were delivered to the coagulation laboratory at the Royal Liverpool and Broadgreen University Hospital for analysis of heparin, and the remaining syringes were used for analysis of ethanol and isopropanol. For the

Table 1 The sources of materials used. Material

Source

Hydrogen Helium Ethanol Isopropanol (propan-2-ol) Propan-1-ol Sterile water for irrigation Heparin sodium flushing solution 10 IU/ml 5 ml ampoules Ethanol 70% ‘for catheter flushing’ 5 ml ampoules 5 ml Luer-Lok® syringes Combi-stoppers for syringes Neolus 0.8 × 40 mm Nr2 Luer syringe needles

VWR International Ltd®

Fresenius Kabi Ltd Wockhardt® Tayside Pharmaceuticals BD Braun Terumo®

2.1.6. Ethanol and isopropanol analysis Gas chromatography was used to analyse ethanol and isopropanol using an Agilent 6890 N gas chromatograph. Separation was performed at 35 °C on an HP-5 capillary column (J&W Scientific), and elution was obtained with helium carrier gas (flow rate 1.5 ml/min; sample volume 0.1 μl injected using Split injection mode). The chromatography assay was quantitatively validated in terms of standard repeatability and linearity, and in terms of sample repeatability and recovery. 2.1.7. Sub-visible particle count analysis A CLIMET particle counting system was employed, set to detect particle sizes N2, 5, 10, 15 and 25 microns. Sterile water was used as a control. This was carried out in triplicate, both at the start of the run and again at the end. Two syringe samples for each time point, from each storage condition, were sampled from. The results from the first syringe were used to equilibrate the system and were discounted. The results from the second syringe were reported only. Counts were performed on 1 ml aliquots of sample and converted to counts per 3 ml contained in each syringe. 2.1.8. Stability calculations and statistical analysis Shelf life may be defined by the length of time from preparation or manufacture of a drug until its original concentration or potency has been reduced by 10% [19]. One-sample t-tests were therefore performed to determine if the concentration or activity of the analytes during the study (i.e. days 1 through 10) were significantly different, either greater or smaller, than 90%. Further one-sided t-tests were performed to determine if sub-visible particle counts were significantly different from the British Pharmacopoeia [20] limits for injection. The limits for injection supplied in containers of this size are stated as: 6000 at N10 μm and 600 at N25 μm. A P value of 0.05 was accepted at the level of significance. 3. Results All samples remained clear and colourless throughout the study period. There was an immediate decrease in heparin activity observed after preparation, falling below 90% by day 1. This trend continued with less than 67% heparin activity remaining after 10 days at 2–8 °C. A similar trend was seen at 25 °C with the lowest recorded activity seen after 8 days with less than 57% heparin activity remaining (Fig. 1). The result at 2–8 °C results shows a potential outlier on day 6. Nevertheless, onesample t-tests confirm that heparin activity is significantly b90% during the study overall at 2–8 °C (P = 0.002; mean 65.5; difference − 24.5; 95% CI − 37 to − 12.) and 25 °C (P = 0.0002; mean 69.2; difference − 20.765; 95% CI − 28 to − 13). It can be concluded that shelf life of heparin within the study solution does not exceed 10 days. The ethanol concentration dropped by less than 1.3% (2–8 °C) and 1.5% (25 °C) compared to the initial assay at time zero (Fig. 2). Throughout the study, ethanol concentrations were significantly higher than 90% at 2–8 °C (P b 0.0001; mean 99; difference 9; 95% CI 8.8 to 9.2) and 25 °C (P b 0.0001; mean 99: difference 9.1; 95% CI 8.7 to 9.4).

P.S. Cullis et al. / Journal of Pediatric Surgery 50 (2015) 315–319

Fig. 1. Variation of heparin concentration in syringe (%) compared to control assay for up to 10 days illustrating that heparin activity decreases to well below shelf life limits during the study period when stored at 2–8 °C (P =0.0016) and 25 °C (P =0.0002).

Isopropanol concentration remained within 97.8% of the initial assay at time zero over the 10 day period (Fig. 3). Throughout the study, isopropanol concentrations were also significantly higher than 90% at 2–8 °C (P b 0.0001; mean 98.1; difference 8.1; 95% CI of difference 7.9 to 8.3) and 25 °C (P b 0.0001; mean 98.7; difference 8.7; 95% CI 7.5 to 9.8). Therefore, shelf life of ethanol and isopropanol in the study solution exceeds that of heparin, and would appear to be N 10 days. Sub-visible particle counts remained within the limits specified in the British Pharmacopoeia [19] when stored at both 2–8 °C and in a 25 °C/60% humidity cabinet for up to 10 days (Tables 2 & 3). Subvisible particle counts at 2–8 °C were significantly lower than the limit of 6000 at N 10 μm (P b 0.0001; mean 342.6; 95% CI −5920 to −5393) and 600 at N25 μm (P = 0.0002; mean 151.80; 95% CI − 549 to − 347). Similarly, counts at 25 °C were significantly lower than the limit of 6000 at N10 μm (P b 0.0001; mean 89.4; 95% CI of difference −5962 to −5858) and 600 at N 25 μm (P b 0.0001; mean 40.2; 95% CI of difference −581 to −537).

4. Discussion This study shows that the addition of isopropanol to heparin and ethanol prevented visible and sub-visible precipitation. There was however a progressive decline in heparin activity over the 10 day study period. Ethanol and isopropanol remained stable in solution throughout the study period. Greater than 98% concentration of ethanol and

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Fig. 3. Variation of isopropanol concentration in syringe (%) compared to control assay for up to 10 days illustrating that isopropanol concentration remains well below shelf life limits during the study period when stored at 2–8 °C (P b0.0001) and 25 °C (P b0.0001).

isopropanol was present at the end of the study period within the syringes, regardless of temperature. Heparin function deteriorated progressively over time with a 10% reduction after 1 day and 35% by day 10 regardless of storage temperature. Sub-visible particle counts remained within the specified limits [20] when stored at both 2–8 °C and 25 °C/60% humidity cabinet for up to 10 days. The progressive decline in heparin activity over time would make combinations of ethanol, isopropanol and heparin unsuitable for storage after preparation. This line lock mixture would therefore need to be mixed at the point of care for each patient which may be impractical. A dual compartment ‘crackable’ device, similar to the popular Nbutyl-2-cyanoacrylate or fibrin glue products could be a potential solution to this problem. The decline seen in heparin activity may be explained by the formation of dimeric heparin which has a lower activity in an anti Xa assay. This dimeric heparin is not visible in ethanol, isopropanol and heparin mixtures but would explain the deterioration in heparin activity. The small number of samples analysed in this study is a limitation of this study. Each result is based upon a single syringe at each time point tested in duplicate. This has led to the suspected anomalous data result for heparin activity data on day 6 at 2–8 °C. Additionally, small sample sizes do not allow us to test the assumption of normality for the statistical tests performed. Isopropanol has a half-life of 2.5 to 3.2 h and its pharmacokinetics generally follows first order kinetics. Its active metabolite, acetone has a half-life of 22.4 h [21]. Occupational exposure to isopropanol, as in acetone, rubbing alcohol, glass cleaner, de-icer and paint stripper manufacture, has been linked with the development of oropharyngeal, nasal sinus and laryngeal cancers [22]. Isopropanol can be toxic if ingested, inhaled or exposed to skin, and may cause nausea, vomiting, a burning sensation in mouth and throat, irritation to the eyes, dysarthria and abdominal pain. Neurological adverse effects include headache, ataxia, Table 2 Mean sub-visible particle counts per 3 ml syringe for syringes stored at 2–8 °C for up to 10 days confirm that throughout the study period, sub-visible particle sizes were well within the safe recommended limits for particles N10 μm (p b0.0001) and N25 μm (p =0.0002). Time point (days)

Fig. 2. Variation of ethanol concentration in syringe (%) compared to control assay for up to 10 days illustrating that ethanol concentration remains well above shelf life limits during the study period when stored at 2–8 °C (P b0.0001) and 25 °C (P b0.0001).

1 3 6 8 10

Particle Size Count per 3 ml (per syringe) 2 μm

5 μm

10 μm

15 μm

25 μm

50 μm

27,228 13,104 4164 4377 2100

1023 2271 693 1323 897

105 684 270 354 300

63 450 201 261 276

15 174 153 228 189

6 42 159 114 72

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Table 3 Mean sub-visible particle counts per 3 ml syringe for syringes stored at 25 °C for up to 10 days confirm that throughout the study period, sub-visible particle sizes remained well within the safe recommended limits for particles N10 μm (p b0.0001) and N25 μm (p b0.0001). Time point (days)

1 3 6 8 10

Particle Size Count per 3 ml (per syringe) 2 μm

5 μm

10 μm

15 μm

25 μm

50 μm

2469 612 489 882 678

462 144 285 243 168

78 48 99 156 66

48 57 57 123 48

36 36 21 69 39

6 9 3 15 15

vertigo, drowsiness, hallucinations, and areflexia and hypoglycaemia, particularly in children. In severe cases convulsions, respiratory depression and coma can occur. In adults, 1 mL/kg of a 70% solution may cause symptoms. The lethal dose may be as low as 2 to 4 mL/kg. In children, 9 mL/kg of 70% has resulted in coma with a blood concentration of 380 mg/dL. The lethal dose is around 100 mL [21,23]. In vitro studies have compared alternative catheter lock solutions [7]. The most effective lock solutions include antibiotic solutions, ethanol and taurolidine. National guidance contained in the EPIC-2 study cautions against the routine use of antibiotic locks that may lead to antibiotic resistance, and suggests restricting their use to neutropenic patients [24]. This guidance has been repeated in the more recent EPIC-3 study [25]. Ethanol locks have been widely used in the United States, particularly in paediatric patients receiving home parenteral nutrition [26–28] however safety concerns remain about the long-term effect of even small amounts of ethanol [29,30]. An alternative antimicrobial taurolidine is a chemically modified amino acid (taurine) with broad spectrum antimicrobial activity in vitro [31–34]. It is non-toxic to humans and is metabolised to taurine, carbon dioxide and water [35]. It has been used in both adult and paediatric patients showing promising results in oncology patients [36,37] short-gut patients [38-40] and haemodialysis patients [41]. Taurolock® contains 1.35% taurolidine and an anticoagulant 4% citrate. 4% citrate is used in Taurolock®, and the manufacturers report no side effects with this lower concentration of citrate [34] however anecdotally it can still cause hypocalcaemia in neonates. The authors postulate that a mixture of taurolidine and heparin may be preferable in neonatal patients. This study confirms the intriguing findings that the solubility of heparin is greatly enhanced by combining isopropanol and ethanol instead of using ethanol alone [17]. No significant rise in level of precipitation occurred during the 10 days study period. However the biological activity of heparin declined progressively precluding storage for any length of time prior to administration. The clinical application of these findings is likely to be limited because of the toxicity profile of isopropanol. The widespread use of ethanol line locks, particularly in the United States, makes this compatibility data clinically relevant.

Conflicts of interest None of the authors have any conflict of interest to declare.

Acknowledgments We would like to thank NHS Quality Control North West, particularly Mark Corris and Paul Dwyer, and Colin Downey from the Coagulation Department at the Royal Liverpool and Broadgreen University Hospital for their contributions to the research, and Alder Hey NHS Trust for supplying materials used.

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Chemical stability of heparin, isopropanol, and ethanol line lock solutions.

Ethanol line locks are used in the US to prevent catheter associated bloodstream infections. Heparin precipitates in solution with ethanol. However, i...
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