Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass.

There are no clinically available alternatives for reversing heparin in protamine-allergic patients. This study examined the ability of methylene blue, hexadimethrine, and vancomycin to reverse circulating heparin so that these compounds can be carefully examined in future placebo-controlled studies in humans. Heparin activity in blood obtained from extracorporeal circuits was reversed by adding protamine (13.5, 27.0, 81.1, 135.1, and 270.3 micrograms/mL), methylene blue (13.5, 27.0, 135.1, 202.7, 270.3, 337.8, 405.4, 473.0, 540.5, and 810.8 micrograms/mL), hexadimethrine (6.8, 13.5, 20.3, 27.0, 81.1, and 135.1 micrograms/mL), or vancomycin (13.5, 27.0, 135.1, 270.3, 540.5, and 810.8 micrograms/mL), and activated clotting times (ACTs) were measured with kaolin (n = 18). Heparinase-ACT was obtained to determine complete reversal. Heparin concentrations were 3.3 +/- 0.3 U/mL with ACT values of 485 +/- 97 s. The ACT at a protamine concentration of 81.1 micrograms/mL and at hexadimethrine concentrations of 81.1 and 135.1 micrograms/mL was not statistically different from heparinase-ACT; however, methylene blue or vancomycin did not reverse the anticoagulation at any concentrations. Hexadimethrine can reverse heparin-induced anticoagulation after cardiopulmonary bypass as well as protamine, although methylene blue or vancomycin did not neutralize heparin in vitro.

Effects of polycations on pulmonary vascular permeability in conscious sheep.

The role of charged sites on the permeability characteristics of the pulmonary microvascular barrier were investigated using chronically instrumented unanesthetized sheep. In one series of experiments we studied the effects of the cationic amphiphile, dodecyl trimethylamine (DTA; 297 mol wt), and the anionic amphiphile, SDS (288 mol wt), on lung lymph flow rates (Ql), lung lymph to plasma protein ratios (L/P), pulmonary hemodynamics, and systemic hemodynamics. DTA significantly increased both Ql and L/P, whereas SDS had a more modest and transient effect on these variables. In a second series of experiments the polycations polybrene and poly-l-lysine were found to have very similar effects as those of DTA. In another series of experiments we tested the pretreatment inhibition potential of chlorpheniramine (an H1 receptor antagonist), dibutyryl-cyclic AMP (db-cAMP), and the calcium channel antagonists verapamil and nifedipine on polybrene-induced lung injury. We found that only verapamil and db-cAMP significantly attenuated the permeability effects of polybrene. We conclude that both cationic amphiphiles and polycations cause hemodynamic and permeability alterations in the pulmonary circulation of unanesthetized sheep. In addition, the permeability alterations induced by polybrene can be modulated by intracellular calcium and/or cAMP levels.

Acute reversible proteinuria induced by infusion of the polycation hexadimethrine.

To test the hypothesis that neutralization of polyanions of the glomerular filter in vivo will lead to loss of charge-dependent glomerular permselectivity, we have infused i.v. the polycation hexadimethrine (HDM) into rats. Heavy proteinuria resulted after a lag period of 30 to 50 min, and it resolved when the infusion was stopped. Concurrent administration of heparin prevented the proteinuria. Urinary proteins were examined by immunoelectrophoresis, isoelectric focusing with immunofixation, and sodium dodecylsulfate polyacrylamide electrophoresis. The major protein was rat albumin, but there were also large quantities of intact rat IgG. HDM was bound at known sites of glomerular polyanion in the laminae rarae of the basement membrane and on the epithelial cell glycocalyx. Associated with this binding were reversible abnormalities of the epithelial cells similar to those seen during in vitro neutralization of glomerular polyanion. Aside from proteinaceous tubular casts, no other histologic abnormality was noted. These studies provide direct evidence that neutralization of glomerular polyanions in vivo results in heavy proteinuria. The appearance of substantial quantities of rat IgG in the urine implies that abnormalities of size as well as charge-dependent permselectivity occur, suggesting that the polyanions of the glomerular filter may be important in maintaining its structure as well as its function.

Protamine sulphate hypersensitivity.

Protamine hypersensitivity has been documented by intra-dermal skin testing in three patients who demonstrated sudden cardiovascular collapse and bronchospasm following the use of intravenous protamine sulphate. All patients had been given protamine previously. The effects of the anaphylactic response were terminated quickly by the administration of intravenous adrenaline associated with plasma volume expansion. Intra-dermal skin testing against all anaesthetic agents is recommended so that the specific allergen can be identified. In patients who are shown to be allergic to protamine sulphate and who require cardiac or vascular surgery careful monitoring of heparin dosage and neutralisation with hexadimethrine (Polybrene) intravenously appears to be a safe alternative.