Effects of calcium concentration, lactobionate content, and sodium/ potassium ratio of preservation solutions on resting left ventricular pressure and postreperfusion function of rabbit heterotopic heart transplants.

BACKGROUND: We tested the hypothesis that the University of Wisconsin solution has a ionic composition (i.e., intracellular, calcium-free, lactobionate-enriched) that may be beneficial for cold heart graft preservation independently from any additives. METHODS: St. Thomas' Hospital and University of Wisconsin solutions were compared with the following: (1) C solution, a simplified University of Wisconsin-like solution (i.e., intracellular, calcium-free, lactobionate-enriched); (2) A solution, an St. Thomas' Hospital-like solution (extracellular, calcium [Ca2+] = 1.2 mmol/L) in which chloride was replaced by lactobionate; (3) B solution, an intracellular, lactobionate-enriched, calcium-containing solution ([Ca2+] = 1.2 mmol/L). Rabbit hearts were transplanted heterotopically in the abdomen of recipient animals either immediately or after 6 hours of storage. Hemodynamic parameters were recorded 60 minutes after unclamping. RESULTS: After a 6-hour storage, University of Wisconsin and C solutions provided better preservation than B and St. Thomas' Hospital solutions: diastolic pressures were lower; developed pressure and rate of pressure rise were higher. C solution was superior to University of Wisconsin solution only for rate of pressure rise. A solution was intermediary. A significant alteration of resting pressure and hemodynamic parameters was generally observed during the 6-hour storage. Nonsignificant changes of developed pressure and rate of pressure rise were only observed in C and B solutions: This is explained by systolic alteration after immediate reimplantation for the B group and good preservation for the C group. Resting pressure was unchanged over a 6-hour storage only for the C group, but this measure was not determined for University of Wisconsin. A correlation exists for various left ventricular volumes between resting pressure and postreperfusion hemodynamic data. Replacement of chloride by lactobionate (A versus St. Thomas' Hospital) may have improved resting and diastolic pressures by other mechanisms than limitation of net water gain during storage.

Experimental evaluation of Celsior, a new heart preservation solution.

An original heart preservation solution (Celsior) has been developed, the formulation of which has been designed to fulfil two major objectives: (1) to combine the general principles of hypothermic organ preservation with those specific for the myocardium, and (2) to offer the possibility of being used not only as a storage medium but also as a perfusion fluid during initial donor heart arrest, poststorage graft reimplantation and early reperfusion. The major principles addressed by the Celsior formulation include (1) prevention of cell swelling (by mannitol and lactobionate), (2) prevention of by the Celsior formulation include (1) prevention of cell swelling (by mannitol and lactobionate), (2) prevention of oxygen-derived free radical injury (by reduced glutathione, histidine and mannitol), and (3) prevention of contracture by enhancement of energy production (glutamate) and limitation of calcium overload (high magnesium content, slight degree of acidosis). Two experimental preparations were used: The isolated isovolumic buffer-perfused rat heart model and the heterotopic rabbit heart transplantation model. In isolated heart experiments, hearts were arrested with and stored in Celsior for 5 h at 4 degrees C and subsequently reperfused for 1 h. A similar protocol was used in the transplantation experiments except that the total ischemic time was approximately 1 1/2 h longer (corresponding to 6 h of storage followed by the 25 additional minutes of cold ischemia required for graft implantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of lactobionate-enriched cardioplegic solution in preserving compliance of cold-stored heart transplants.

Cardioplegic solutions of the extracellular type are commonly used as storage media for heart transplants. Because this type of formulation was not originally designed for preventing hypothermically induced edema, we assessed the effects of supplementing a standard, extracellular-like cardioplegic solution with the high molecular weight impermeant lactobionate on water content and postischemic compliance of isolated rat hearts. In one series of experiments, hearts were immersed in either a standard cardioplegic solution of the extracellular type or in the same solution supplemented with lactobionate (80 mmol/L). Hearts were then processed for measurements of water content after 4 hours, 6 hours, and 8 hours of storage at 4 degrees C. In a second series of experiments, hearts were stored in the same solutions for 4 hours and 8 hours and subsequently reperfused for 1 hour on a Langendorff column, at which time left ventricular pressure-volume curves were constructed and compared with those obtained during the preischemic perfusion. Lactobionate-treated hearts gained significantly less water than controls after 4 hours and 6 hours of storage, but the difference was no longer significant at the 8-hour time point. In contrast, the treated group yielded a significantly better recovery of compliance after both 4 hours and 8 hours of storage, suggesting that lactobionate might exert protective effects in addition to those caused by its impermeant properties, possibly involving calcium chelation and subsequent limitation of calcium-dependent contracture. Extracellular-type cardioplegic solutions are attractive because a single solution can be used during all phases of the transplantation procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved recovery of heart transplants with a specific kit of preservation solutions.

In the course of cardiac transplantation, donor hearts undergo a four-step sequence of events (arrest, cold storage, global ischemia during implantation, and reperfusion) during which myocardial damage can occur. We tested the hypothesis that the functional recovery of these hearts could be improved by exposure to two interdependently formulated preservation solutions throughout this four-step sequence. Solution I was used as a perfusion and storage medium during the first three steps, and solution II served as a modified reperfusate. The two solutions share the following principles of formulation: prevention of cell swelling (high concentrations of mannitol, a myocardium-specific impermeant) calcium overload (ionic manipulations), and oxidative damage (reduced glutathione) and enhancement of anaerobic energy production (glutamate). The two solutions differ with respect to the calcium content and buffering capacity. One hundred rat hearts perfused with isolated isovolumic buffer were subjected to cardioplegic arrest; cold (2 degrees C) storage for 5 hours, global ischemia at 15 degrees C for 1 hour, and normothermic reperfusion for 1 additional hour. In a first series of experiments (70 hearts), our kit of solutions was compared with six clinical preservation regimens that involved cardiac arrest with St. Thomas' Hospital or University of Wisconsin solutions followed by storage of the hearts in saline, Euro-Collins, St. Thomas' Hospital, or University of Wisconsin solutions. In a second series of experiments (30 hearts), the effects of the kit were more specifically investigated in relation to two types of additive--oncotic agents (dextran) and thiol-based antioxidants (reduced glutathione and N-acetyl-L-cysteine). According to comparisons of maximal rate of ventricular pressure increase and left ventricular compliance after reperfusion, the best myocardial protection was afforded by our kit of solutions. The addition of dextran during storage did not provide additional protection. Conversely, the omission of reduced glutathione was clearly detrimental; the replacement of reduced glutathione with N-acetyl-L-cysteine failed to improve recovery beyond that provided by antioxidant-free solutions, thereby suggesting the importance, in this model, of an anti-free radical compound that, like reduced glutathione, is operative extracellularly. We conclude that the preservation of heart transplants can be improved with the sequential use of two closely interrelated solutions, the formulations of which integrate the basic principles of organ preservation with those of myocardium-specific metabolism.

Simplified method for delivering normothermic blood cardioplegia.

We describe a simple technique for optimizing oxygen delivery during normothermic continuous blood cardioplegia. It involves the use of a minimal volume of cardioplegic agents, the infusion rate of which is adjusted so as to keep the heart arrested. The resulting enhancement of oxygen supply is marshalled from the maintenance of hematocrit values in the range of 0.25.

Prospective randomized comparison of University of Wisconsin and UW-modified, lacking hydroxyethyl-starch, cold-storage solutions in kidney transplantation.

University of Wisconsin cold storage solution differs from Euro-Collins by the presence of adenosine, allopurinol, and hydroxyethyl starch, which maintains osmotic pressure. It is now experimentally and clinically well established that the use of UW solution is associated with better liver graft recovery parameters after prolonged cold ischemia time. However, it has been also suggested in animal experiments that HES might not be essential for optimal kidney preservation, at least when cold ischemia time remains within 48 hr. Herein, we present a randomized study comparing UW (n = 44) and a modified UW (UW-mod) (n = 44) solution lacking HES, adenosine, and allopurinol on kidney graft recovery parameters. Forty-one consecutive Euro-Collins flushed kidneys, transplanted immediately before this randomized trial, were used as historical controls. The results indicate that UW-mod was as efficient as UW in preserving the kidney in cold ischemia ranges that did not exceed 48 hr. Both solutions (UW and UW-mod) seemed more effective than Euro-Collins, based on the analysis of several parameters including the number of days until the creatinine was < 300 microM (P < 0.05), the level of the serum creatinine at one month (P < 0.02), and the Cockroft index (P < 0.04). Since UW-mod is three times less expensive than UW, we suggest that the simplified solution could be routinely used to preserve kidneys for transplantation.

[Towards an integrated protection of heart grafts]. / Vers une protection intégrée des greffons cardiaques.

In an attempt to provide a consistent protection of cardiac allografts during the sequence of events inherent in transplantation procedures, we developed two preservation solutions of which one is used for initial arrest, storage and cardioplegia during graft implantation, whereas the other serves as initial reperfusate. The formulations of these solutions are closely interrelated and their design has integrated the basic principles of organ preservation with those of myocardium-specific metabolism. Based upon experimental studies in the isolated rat heart model, this integrated approach has yielded better functional recoveries than conventional preservation protocols.

2,3-Dimercaptosuccinic acid treatment of heavy metal poisoning in humans.

14 patients with heavy metal poisoning received 2,3-dimercaptosuccinic acid (DMSA). 12 subjects were given 30 mg/kg/day for 5 days; 1 subject was started on a lower dose because of a history of atopy; another subject was treated for 15 days because of very high initial blood lead concentrations. In the 9 subjects who had lead poisoning, DMSA decreased blood lead concentrations by 35 to 81%, and induced a 4.5- to 16.9-fold increase in mean daily urinary excretion of the metal. In the acutely arsenic-poisoned case, the plasma arsenic concentration on day 7 was half the pretreatment value, while no clear decrease was observed in a chronically exposed subject. In 3 mercury cases, DMSA increased daily mercury urinary excretion 1.5-, 2.8- and 8.4-fold, respectively, while blood mercury concentrations remained below detection limits. No serious side effects were observed and 3 weeks after administration of the drug the clinical condition of all subjects was either stable or improved. These results indicate the efficacy of DMSA for lead poisoning in humans and provide a rationale for further investigating its usefulness in mercury and arsenic poisoning cases.

Development of a standard, freeze-dried serum containing the drugs assayed most often in French hospitals.

A quality control program for the therapeutic drug monitoring methodology used to determine serum levels of the fourteen drugs assayed most frequently by French hospital laboratories is described. The program has been adopted by the Societé Française de Biologie Clinique (SFBC), which provides participating laboratories with a statistical analysis of the performance data. The control samples developed for the program are prepared by spiking calf serum with, in one case, phenobarbital, phenytoin, carbamazepine, sodium valproate, amikacin, lithium carbonate, digitoxin and hydroquinidine, and, in the other case, caffeine, quinidine, digoxin, isoniazid and gentamycin. After freeze-drying the spiked serum, the drugs were shown to be stable for at least a year when stored at -20 degrees, +4 degrees and +22 degrees; at the end of this time, the samples were pathogen free. For checking therapeutic drug monitoring methods, the freeze-dried serum is diluted with distilled water (10 ml); these solutions are chemically stable, and remain pathogen-free, when stored in stoppered glass tubes at -20 degrees or +4 degrees for 4 weeks.

Various techniques for the routine evaluation of the degradation of glucose in parenteral solutions--a critical study.

A practical approach is described for studying the influence of various physicochemical factors on the degradation of glucose in parenteral solutions sterilized by heating in an autoclave. Five routine analytical methods are discussed: pH determination; direct ultraviolet absorption measurement (BP) method; liquid chromatography of 5-HMF; thin-layer chromatography of sugars, carboxylic acids and carbonyl species; and enzymatic determination of glucose. The effects of various factors on the degradation of glucose were studied: glucose concentration (10%, 30%, 50%); pH of solution before sterilization (2-10); sterilization cycle (103 min at 110 degrees C, 20 min at 120 degrees C, 3 min at 134 degrees C; same Fo); time of heating at 120 degrees C (30, 40, 60 min); and the presence of salts (sodium acetate, sodium lactate, sodium chloride). The results demonstrate the importance of these factors in influencing the rate of glucose degradation during sterilization. In the presence of salts, 5-HMF is not the most important product of degradation and the BP assay is not suitable for evaluation of glucose breakdown. The authors propose two control procedures. For simple solutions of glucose, the BP method is suitable. In the presence of salts the glucose oxidase method should be used.