We did not observe clot formation when combining LR solution, FTP, and RBC in any series I or II study without adding CaCl2.
The postexpiration ages in days for RBC and FTP were 8.5 ± 13.3 and 13.9 ± 14.2 (mean ± SD) in series I and 14.3 ± 19.7 and 7.4 ± 5.8 in series II.
Rapid infusion devices are commonly used in clinical practice, and device failure can adversely affect patient care. Assuming that a properly functioning device is appropriately handled by the clinician, the true incidence of device failure is unknown. The Food and Drug Administration provides the Manufacturer and User Facility Device Experience database that contains mandated and voluntary device reports including from manufacturers, device user facilities, health care professionals, and consumers.a We performed a simple search with the terms Belmont Instrument Corporation, FMS 2000, and Belmont rapid infuser. Examination of the results revealed 44 distinct reports between 2004 and the last update of the database at the time of this writing, August 2015. The reports involved 18 instances of the overheating alarm, 4 instances of heating element deformation, and 2 high-pressure alarms during this 11-year period. Information regarding reservoir use or content was insufficient to gain any insights into patterns of causation, and the number of unreported events remains uncertain. According to the manufacturer, almost 4000 Belmont FMS 2000 rapid infuser devices have been purchased worldwide and 60,000 of its disposables have been sold in 2014 (data supplied by Belmont Instrument Corporation).
In clinical practice, RBCs and other blood components may be reconstituted with crystalloids to improve flow and to prime rapid infuser reservoirs. Although studies have examined the coagulation potential of crystalloids with RBCs and FTP separately, there is very little information about crystalloid with RBC/FTP combinations regarding potential clot formation. In this in vitro study, combining FTP and RBCs with different types of crystalloid or albumin in the Belmont FMS 2000 rapid infuser with a reservoir, we were unable to re-create the warming unit overheating with coil deformation and rupture event reported by others.1,2 However, 1 overheating, 1 fluid empty, and several high-pressure alarms were triggered when we allowed continuing pump operation for 5 minutes after the observation of a macroscopic clot in the reservoir (a study end point).
Despite the dilution of 1 unit each of FTP and RBC with 1 L of NS, PL solution, LR solution, and albumin 5%, respectively, we consistently observed macroscopic clot formation in the reservoir after the addition of 200 mg CaCl2. Spontaneous clotting did not occur during our trial. Xia et al.2 also observed immediate clot formation in the reservoir and safety stop of the pump when they added 300 mg CaCl2 to 500 mL LR solution mixed with 2 units each of RBCs and FTP in 1 experiment.
Series II experiments demonstrated clot formation when 200 mg CaCl2 was added to 1 L LR solution or NS mixed with 2 U FTP. No coagulation occurred in the experiment where 1 L LR solution was combined with 2 U RBCs despite the addition of up to CaCl2 1 g. The latter observation suggests that only a very small amount of clotting factors remain in currently available RBC units. Our results indicate that in the presence of coagulation factors (i.e., FTP), ≤200 mg CaCl2 may trigger macroscopic clot formation even when blood products are diluted to a 0.7:1 ratio.
The deliberate addition of CaCl2 to a blood component mix in a reservoir is unlikely to occur in clinical practice. It is conceivable that calcium may be added downstream from the reservoir into the patient line. However, this clinical use is unlikely to trigger a clot because the combination is rapidly flushed into the bloodstream.
At no time did coagulation occur immediately or with CaCl2 addition, but with a delay during the pump flow sequence. In our series I experiments, the time to coagulation when the fluid mixture was warmed and agitated by transit through the closed-loop system was 9.1 ± 2.3 minutes, suggesting that CaCl2-induced coagulation is a time-dependent process. With a clotting time of 9 minutes, it is possible that low pump flow rates used in clinical practice may provide adequate time for clotting to occur. Although the postexpiration age of the blood components had a range from 0 to 48 days, we found no effect of the type of fluid on the time to coagulation. After clot appearance in the reservoir, the high-pressure alarm was observed in 3 series I and 3 series II experiments, and the fluid empty alarm and the overheating alarm occurred once in series I and II, respectively. Although we allowed continued rapid infuser operation for up to 5 minutes after clot observation (secondary end point), it is conceivable that allowing the pump to continue running beyond this limited time of observation might have produced additional alarms and self-shutoff events.
Crystalloids and compatibility with blood pertaining to clot formation have been investigated in several in vitro studies with different designs, and current guidelines recommend not mixing LR solution with blood products during IV infusion because of its CaCl2 content. Two studies described clotting with the mixing of LR solution and whole blood.4,5 In one of these studies, clotting with LR solution and whole blood became visible after a 5-minute incubation period at room temperature.
LR solution and RBC combination clotting potential has been investigated separately. In 1 in vitro study, LR solution was mixed with RBCs in a 1:1 volume ratio (200 mL total), and macroscopic red cell aggregation was found with LR solution containing CaCl2 5 g/L but not 2 g/L.6 Cull et al.7 examined different RBC/LR solution dilutions and noted clotting at dilutions of 1:1 but not 5:1, 3:1, and 2:1. They concluded that reconstitution of RBC with LR solution was safe when RBC were present in greater volume than with LR solution.7 A more recent in vitro study did not find any macroscopic or microscopic clot when NS or LR solution was added to RBC over a range of dilution ratios from 10:1 to 1:2 (crystalloid to RBC).8 In our experiment of mixing LR solution with RBC only, the crystalloid to RBC ratio was closer to 1:0.7, and we did not observe macroscopic coagulation or coil occlusion even with the addition of 1 g calcium.
When choosing crystalloids to combine with coagulation factor containing blood components, clinicians should also be mindful of the risk of hyperchloremic metabolic acidosis associated with administration of large amounts of NS.9
The systematic investigation of blood component and fluid combinations in rapid infusion devices in a simulated clinical practice setting is hampered by ethical limitations in the use of blood products eligible for use in humans. In our study, 1 important limitation is that we used blood products beyond their recommended storage date. The postexpiration ages of RBC and FTP were highly variable, which may have affected some of our results. With increasing age of RBC, structural changes take place, including increased osmotic fragility, hemolysis, and loss of deformability that may decrease effective clot formation.10,11 Aucar and Sheth12 demonstrated in vitro that RBC cold storage beyond 3 weeks after donation results in decreased coagulation with FTP.
The use of FTP after 5 days of cold storage at 1 to 6°C is not recommended for clinical use, and clotting factor activity decline may have affected our results. However, the decline of hemostatic factor activity in FTP is gradual and most significant for factors V and VIII within the first 24 hours after thawing.13 Furthermore, it has been demonstrated that coagulation factor activity in refrigerated FTP at 4°C for 2 weeks and up to 28 days was still sufficient for adequate hemostasis.14,15 Some of the differences in our findings may also be explained by the variable volume of each unit of blood product. Although RBC and FTP contain typically between 300 to 350 mL and 275 to 350 mL per unit, respectively, the amount in each experiment is never exactly the same, reflecting clinical practice. We also did not investigate microscopic clot formation because this would not be available during clinical care. In future trials, continuing pump operation beyond our observation in the presence of macroscopic clot formation may further clarify the effects of clot on pump operation.
In conclusion, we were unable to replicate the coil occlusion, overheating, and damage previously reported with use of the Belmont FMS 2000 by combining LR solution, NS, PL solution, or albumin with FTP and RBC and additional CaCl2. Our results suggest a role for calcium as an initiator of coagulation in blood products containing hemostatic factors. Although we used 200 mg CaCl2, there is the possibility that less CaCl2 may suffice to induce clotting in our model.
Although current accepted guidelines recommend avoiding LR solution for reconstitution of citrated blood components containing clotting factors and coadministration of calcium-containing medications,16 our results indicate that reconstituting blood products with LR solution may be possible in some circumstances. Additional studies are needed to explore this possibility.
Name: Anupama Gopinath, MBChB, MRes.
Contribution: This author helped conduct the study, collect the data, analyze the data, and prepare the manuscript.
Attestation: Anupama Gopinath approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Chaim Nelson, MD.
Contribution: This author helped design the study, conduct the study, collect the data, and prepare the manuscript.
Attestation: Chaim Nelson approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Anupriya Gupta, MD.
Contribution: This author helped conduct the study, collect the data, and data entry.
Attestation: Anupriya Gupta approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Iwona Bonney, PhD.
Contribution: This author helped collect the data and prepare the manuscript.
Attestation: Iwona Bonney approved the final manuscript.
Name: Roman Schumann, MD.
Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.
Attestation: Roman Schumann approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript and is the archival author.
This manuscript was handled by: Avery Tung, MD.
a MAUDE—Manufacturer and User Facility Device Experience. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/TextSearch.cfm. Accessed July 31, 2015.
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