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Ann Thorac Surg 1997;64:1520-1522
© 1997 The Society of Thoracic Surgeons
Manchester Heart Centre, Manchester Royal Infirmary, Oxford Rd, Manchester M13 9WL England
To the Editor:
The finding by Ingemansson and colleagues [1] that the addition of calcium to Euro-Collins solution enables storage of vascular endothelium for 24 hours is exciting. Nevertheless, great caution should be exercised if this finding is to be put to further experimental use or introduced clinically. Euro-Collins solution has until now consistently failed to enable 24-hour storage of experimental lung grafts, whereas other calcium-free solutions such as University of Wisconsin solution and Perfadex have been successful. Many variables are operating here.
My main point is this: Euro-Collins solution contains bicarbonate (-HCO3) ions in a concentration of 9.3 mEq/L. Addition of calcium to Euro-Collins solution will result in the formation of a precipitate of calcium carbonate. At low concentration this precipitate may not be obviously visible and may well be harmless in in vitro experiments such as those performed by Ingemansson and colleagues. However, flush perfusion of an organ with a preservation solution containing a precipitate of calcium carbonate is likely to have disastrous consequences, which will only become apparent on reperfusion.
University of Wisconsin solution does not contain bicarbonate; however, both University of Wisconsin and Euro-Collins solutions contain phosphate in high concentration. Addition of calcium to University of Wisconsin solution could easily result in the formation of a precipitate of calcium phosphate.
Accordingly, although it may well be the case that low concentrations of calcium may have a beneficial effect on hypothermic storage of endothelium, the context must be taken into account, and possible interaction with other ions present in the preservation solution must be anticipated if disasters are to be avoided.
Reference
Department of Cardiothoracic Surgery, University Hospital of Lund, S-221 85 Lund, Sweden
To the Editor:
Doctor Odom should be commended for addressing a very important topic, ie, the temptation to improve an organ preservation solution by adding substances to it, and thereby risk eliciting a precipitate that "may not be obviously visible" but "is likely to have disastrous consequences, which will only become apparent on reperfusion." The fact that nonspecific graft failure causes 25% of deaths occurring during the first 30 days after lung transplantation [1] further underlines the relevance of Dr Odom's word of caution. A worldwide survey recently carried out by Hopkinson and co-workers [2] revealed that antegrade pulmonary artery flush remains the most widely used technique for lung preservation. The vast majority of centers (78%) use Euro-Collins solution (EC), 69% of these including prostaglandin therapy and 33% steroid treatment of donors. University of Wisconsin solution (UW) is used by 15% of centers, of whom 60% use prostaglandin therapy and 40% donor steroids. Many centers use what they call modified EC, where the modification lies in the addition of 12 mEq/L (6 mmol/L) of magnesium sulfate [3]. Doctor Odom's word of caution should include this practice also, particularly for those who use even higher magnesium concentrations. It is well known among experts in parenteral nutrition that precipitation may occur within a 24-hour period in phosphate-rich solutions if positive ions like Ca2+ or 2+ are added. This is true particularly if the pH of the solution is high due to its content of buffers, which are always present in organ preservation solutions.
My colleagues and I are not the first to report beneficial effects after adding calcium to EC. Weyand and colleagues [4] demonstrated the necessity of adding calcium to genuine EC to avoid the so-called calcium paradox. Recovery of cardiac function after ischemic times of up to 32 hours was achieved in an orthotopic pig heart model by adding 0.0225 mmol/L of calcium chloride to EC. The team has used such calcium-modified EC in clinical heart transplantation, and believe that they can thereby extend the cold ischemic time to 6 hours "without loss in graft performance or increased mortality" [4].
The lowest concentration of calcium needed in EC to give excellent 24-hour preservation of vascular structures and functions in rat aorta is 0.4 mmol/L, ie, a concentration that is 17 times higher than that used by Weyand and colleagues [5]. Both UW and the low-potassium–dextran-glucose organ preservation solution Perfadex give excellent 24-hour vascular preservation without any modification [6, 7], but if good 36-hour preservation is to be obtained, addition of calcium is essential in UW and Perfadex as well [8]. Benzylpenicillin, which is a component of UW, contains small but significant amounts of calcium. University of Wisconsin solution is therefore not a calcium-free solution [8], but Belzer's group, the inventors of UW, have found that it is essential to add more calcium to the solution for optimal preservation of myocardial function: "Decreasing the calcium concentration from 1.0 to 0.1 mmol/L also had a deleterious effect on myocardial function" [9]. Observations indicating that it is beneficial to add calcium to EC or UW are thus based on scientific experiments that include reperfusion.
At what calcium concentration will precipitation occur in EC or UW? This question has been elucidated by Burgmann and co-workers [10]. They found that the free (ionized) Ca2+ concentration in both EC and UW stays around 0.3 mmol/L regardless of whether calcium chloride is added for concentrations between 1 and 4 mmol/L at a pH = 7.0. At a total calcium concentration of 3 mmol/L, the measured free calcium concentration in UW was only 0.34 mmol/L and in EC only 0.27 mmol/L. At total calcium concentrations higher than 3 mmol/L, turbidity and precipitation were observed in EC. At calcium concentrations lower than 3 mmol/L, most of the calcium is bound ("chelated"), but it is still dissolved. In EC and UW, it was found that this calcium-chelating capacity could be attributed mainly to phosphate and, in UW, to lactobionic acid as well.
I have measured the free Ca2+ concentration in EC, UW, and Perfadex after the addition of calcium chloride to bring the total calcium concentration to 0.3, 0.7, and 1.0 mmol/L (Table 1
). Ionized calcium was measured with an ABL 505 with a membrane box for the E303 electrode (Radiometer, Copenhagen, Denmark). The osmolarity (Osmometer 13; Roebling, Germany) and the oncotic pressure (Colloid Osmometer, Membrane PM-10; Wescor, Logan, UT) were also measured. As seen in Table 1, EC and UW have a calcium-chelating capacity but Perfadex does not. Note also the extremely high osmolarity of EC due to its high glucose concentration of 214 mmol/L. This makes EC a potentially toxic solution. If the integrity of the cell membranes is impaired during prolonged storage, extreme cell swelling and dysfunction may occur, as seen in rat aortas stored for 24 hours in EC [5].
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What then is the best lung preservation method? In my opinion, nothing has so far showed itself better than simple topical cooling for up to at least 12 hours of lung preservation [15], and this opens up the exciting possibility of easing the lung donor shortage by using lungs from non–heart-beating donors [16]. Recently, the results from a study comparing EC, UW, and Perfadex regarding 16 hours of lung preservation were presented [17]. The conclusion was that Perfadex is significantly better at preserving global lung function than EC or UW. This was reflected in improved oxygenation, compliance, and survival as well as decreased pulmonary resistance to air flow in the Perfadex group.
Perfadex gives excellent 24-hour preservation of porcine lungs as judged by the most challenging evaluation method, namely, single-lung transplantation followed by immediate contralateral pneumonectomy [18], and is the solution (modified by the addition of 0.3 mmol/L CaCl2) that I use in clinical lung preservation [19].
References
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