Nephrol Dial Transplant (2003) 18: 2688-2690
© 2003 European Renal Association-European Dialysis and Transplant Association
Letter
Risks related to catheter locking solutions containing concentrated citrate
1Oberdorf-Malerweg 12 Köstenberg Austria 2Dialysis Centre Lahr Ettenheim Germany Email: pg{at}compuserve.com
Sir,
We are concerned that risks of using concentrated sodium citrate for a catheter lock solution (CIT) are not well understood. Routine haemodialysis is safe, partly as a result of European Standards requiring medical devices to be safe even under fault conditions [1]. Risk analysis taking foreseeable user errors (FUE) into account is part of the process of obtaining approval to market a new medical product. Medical practitioners are not bound to this process and may neglect the effects of user errors.
During development of a low concentration citrate-containing lock solution we carried out a risk analysis [2]. We concluded that use of CIT is unsafe under certain conditions involving FUE. The risk evaluation is shown below.
Risk analysis. Citrate chelates with the calcium ions in blood and tissue. Serious symptoms have been reported when the ionized calcium blood level decreases to 0.6 mmol/l [3]. In vitro tests in which a double lumen central venous catheter is filled with a locking solution equal to the filling volume show that 
15% of the locking solution is immediately injected into the patient [4]. The injection is normally done within 1–2 s and the overspill distributes in a volume equal to 1–2 heart beats (100 ml). Examples of FUE resulting in spillage of more locking solution into the patient include simple mistakes in the lock volume, two instillations of solution into the same lumen and deliberate overinjection of solution to clear a blocked catheter. In the risk analysis we selected an overinjection of 1 and 5 ml.
Effects of overinjection. Assuming that the injected locking solution is distributed in 100 ml plasma water, 1 ml of 1.8 mol/l (i.e. 47%) sodium citrate injected results in a citrate concentration of 18 mmol/l. The solution will be diluted in lung water to 40% [5]. The effect of sodium citrate infusion on free ionized calcium in whole blood was derived from previous work (K. Sodemann, unpublished data). In this work, total citrate vs ionized calcium concentration was measured in vivo during lipid apheresis using citrate anticoagulation. The data were fitted with an exponential function: [Ca2+] = exp (a – b x [citrate]), where a = 0.1834 and b = 0.265 (r2 = 0.98).
With a normal blood value for the ionized calcium of 1.3 mmol/l, citrate concentrations of >6 mmol/l result in ionized calcium concentrations of <0.25 mmol/l. This level is unsafe.
Animal tests (done by Biolink Corp., Mansfield, MA, USA; used with permission) corroborate the risks of bolus injection: 5-ml boli of sodium citrate with concentrations between 4% and 46.7% were injected into healthy animals (dogs and rabbits). Even at the lowest concentrations (equivalent to 0.03 mmol/kgbw citrate) a brief depression of the blood pressure was recorded. The highest concentrations (equivalent to 0.35 mmol/kgbw citrate) resulted in immediate cardiac arrest. For comparison, 1 ml 47% CIT injected into a 70 kg patient is equivalent to a dose of 0.028 mmol/kgbw calcium.
Risk evaluation. The acceptable limit for a potential fatal event due to a machine malfunction has been defined at 10-8 per treatment. Small patients with cardiac problems are the most at risk population as the consequence of FUE. Assuming that this high-risk group represents 10% of the patient population and estimating the likelihood of user errors at 10-4–10-2, the resulting probability of a hazardous event is 10-3–10-5, which is a factor 1000–100 000 greater than the accepted risk level.
Discussion. The US Food and Drug Administration issued a warning [6] regarding CIT in 2000 after a fatal accident and the product was withdrawn from the market. The citrate concentration in a bolus passing through the heart may be lethal if it persists for some time. To our knowledge, the effects of such a bolus have not been measured in a controlled study (animal tests done by Biolink are anecdotal). It is unclear whether normalization of the dose with body weight is applicable for the bolus application, because the effects occur before equilibrium with plasma water takes place.
If an overinjection is not suspected immediately, cardiac arrest during dialysis may be regarded as a normal event not linked to CIT. Purchase and Gault [7] reported a home patient who injected 47% concentrated sodium citrate lock daily at home and died 24 h after the last dialysis from cardiac arrest. A possible relationship with the locking solution was not discussed, although the patient died about the time when the next injection might have occurred. Stas et al. [8] described the use of 30% sodium citrate locking solution and mentioned the potential risk. Ash et al. [9] reported that 10% of patients had a ‘metallic’ taste shortly after injection of the exact fill volume of 47% sodium citrate. Hendrickx et al. [10] reported the use of a 5% sodium citrate locking solution, which is one-tenth of the strength of the standard 47% CIT. Using the approach above, an overinjection of 1 ml of 5% sodium citrate solution would result in an ionized calcium concentration of 0.7 mmol/l and can be regarded as safe without further investigations.
Conclusion. Risk analysis and animal test data raise sufficient concern about the safety of concentrated CIT. We are aware that this analysis is limited. It is, however, up to manufacturers (or users if manufactured on request) to prove safety, which includes the risk related to overinjection and the likelihood of such an event.
Conflict of interest statement. H.-D. Polaschegg worked as a consultant for Biolink Corp. until August 2002. K. Sodemann was principal investigator of the German Dialock (Biolink Corp.) study, which ended in 2001.
References
- Roy T. Patients’ safety and haemodialysis devices. Nephrol Dial Transplant 2001; 16: 2138–2142
[Free Full Text] - Sodemann K, Polaschegg HD, Feldmer B. Two years’ experience with Dialock® and CLSTM (a new antimicrobial lock solution). Blood Purif 2001; 19: 251–254[CrossRef][Web of Science][Medline]
- Uhl L, Maillet S, King S, Kruskall MS. Unexpected citrate toxicity and severe hypocalcemia during apheresis. Transfusion 1997; 37: 1063–1065[Medline]
- Polaschegg HD, Shaw CH. Catheter locking solutions: safety and efficacy of composition and methods. ASAIO J 2002; 48: 178
- Krivitski NM, Kislukhin VV, Dobson A, Gleed RD, Rawson RE, Robertshaw D. Volume of extravascular lung fluid determined by blood ultrasound velocity and electrical impedance dilution. ASAIO J 1998; 44: M535–M540[Medline]
- US Food and Drug Administration. FDA Issues Warning on Tricitrasol Dialysis Catheter Anticoagulant. FDA Talk Paper TOO-16, 14 April 14 2000
- Purchase L, Gault MH. Hemodialysis with a permcath kept open with streptokinase and later citrate in a heparin-sensitive patient. Nephron 1991; 58: 119–120[Web of Science][Medline]
- Stas KJ, Vanwalleghem J, Moor BD, Keuleers H. Trisodium citrate 30% vs. heparin 5% as catheter lock in the interdialytic period in twin- or double-lumen dialysis catheters for intermittent haemodialysis. Nephrol Dial Transplant 2001; 16: 1521–1522
[Free Full Text] - Ash SR, Mankus RA, Sutton JM et al. Concentrated sodium citrate (23%) for catheter lock. Hemodial Int 2000; 4: 22–31
- Hendrickx L, Kuypers D, Evenepoel P, Maes B, Messiaen T, Vanrenterghem Y. A comparative prospective study on the use of low concentrate citrate lock versus heparin lock in permanent dialysis catheters. Int J Artif Org 2001; 24: 208–211[Medline]
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