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PubMed1978

Studies on the immunogenicity of protamines in humans and experimental animals by means of a micro-complement fixation test.

A complement fixation study with human, monkey and rabbit sera, using purified sperm nuclear basic proteins as antigens, led to the following conclusions. (1) Protamines, the sperm-specific basic nuclear proteins, may be immunogenic in mammalians. (2) Antibodies detected in the indirect immunofluorescence test on human swollen sperm heads in sera from infertile and vasectomized men, are directed primarily against human protamines. (3) The results obtained suggested that differences in the immunization site and/or in the configuration of the immunizing protamine, may lead to the formation of antibodies directed against different antigenic determinants. Autoimmunity to protamines, following vasectomy or in infertile men, is accompanied by the formation of antibodies cross-reacting with common antigenic determinants present in protamines of other species. Induction of immunity to protamines by means of immunization with protamines-RNA complexes (in rabbits), or protamine-insulin complexes (in humans), leads to the formation of antibodies reacting more specifically with the immunizing protamine, showing only slight cross-reaction with other protamines. (4) The histone-like fraction present in mature human spermatozoa is composed mainly of histone fraction H2B.

Animals↗
PubMed1992

Complex allosteric modulation of cardiac muscarinic receptors by protamine: potential model for putative endogenous ligands.

A large number of diverse pharmacological agents bind to a secondary domain on the muscarinic receptor, to influence allosterically the interaction of ligands at the primary binding site. Based on common structural features of these antagonists, we examined the interaction of protamine, an endogenous polycationic peptide, and of polyamines with muscarinic receptors in rat heart. Our results provide several lines of qualitative evidence that protamine allosterically modulates the conformation of muscarinic receptors, in a marked negatively cooperative manner. It decelerated the dissociation of N-[3H]methylscopolamine ([3H] NMS) initiated by atropine, in a concentration-dependent fashion. Inhibition by protamine of [3H]NMS binding at equilibrium showed a distinct plateau, which increased in magnitude at higher ligand concentrations. Scatchard analysis of saturation isotherms of [3H]NMS binding in the absence and presence of protamine indicated that protamine did not alter Bmax in a statistically significant fashion, although there was a trend of a concentration-dependent increase in this parameter. On the other hand, it caused a marked concentration-dependent decrease in the affinity of [3H]NMS, and this effect reached a ceiling limit. However, there were marked quantitative deviations of the interaction of protamine from a simple ternary allosteric model. Some of these discrepancies could be explained by the tendency of protamine to increase Bmax. The allosteric actions of protamine demonstrated in kinetic and equilibrium experiments were selective for m1 and m2 muscarinic receptors, compared with m3, m4, and m5 receptors, as studied in Chinese hamster ovary cells transfected with the genes of the different muscarinic receptors. Arginine residues play an important role in the allosteric interaction of protamine, inasmuch as poly-L-arginine qualitatively mimicked the effects of protamine. In contrast, no effects of the polyamines spermine, spermidine, and putrescine were observed on [3H]NMS binding. This is the first report on the allosteric modulation of muscarinic receptors by an endogenous peptide.

Animals↗
PubMed1992

Role of paf-acether in protamine-induced thrombocytopenia in rabbits.

The effects of protamine (6 mg kg-1) injected after heparin (5 mg kg-1) have been studied in five groups of five New Zealand white rabbits. Group I was treated with the sequence heparin-protamine and group II with protamine alone. The animals of groups III and IV received respectively intravenous indomethacin (3 mg kg-1) and BN 52021 (3 mg kg-1), a paf receptor antagonist before the sequence heparin-protamine. Group V was pre-treated with indomethacin and BN 52021 before heparin reversal with protamine. In group I, immediate thrombocytopenia (44.1 +/- 4.6% of baseline level, P less than 0.05) and leucopenia (55.5 +/- 2.3% of baseline level, P less than 0.05) were observed 30 s after protamine reversal of heparin, paralleled with an increase in blood paf levels (27.6 +/- 27.6 vs. 148.2 +/- 48.9 pg ml-1, P less than 0.05). In group II, protamine alone induced no change in platelet count nor in blood paf levels (55 +/- 10 vs. 52.5 +/- 20 pg ml-1, P greater than 0.05). Pre-treatment with indomethacin alone (group III) did not protect the animals against the haematological changes induced by the heparin-protamine complexes. Pre-treatment with the paf receptor antagonist, alone or in association with indomethacin, delayed the occurrence of thrombocytopenia 3 min after protamine administration but the leucopenia was the same as in group I. This study demonstrated that paf is implicated in the immediate thrombocytopenia occurring after protamine reversal of heparin in rabbit.

Animals↗
PubMed1991

[Complications caused by protamine. 2. Therapy and prevention].

Treatment of reactions. The treatment of reactions to protamine is still symptomatic. Hypotension resulting from systemic vasodilation (anaphylactoid reaction) is treated by volume infusion, and alpha-stimulating catecholamines may be necessary. The combination of increased right ventricular afterload and systemic hypotension (anaphylactic/anaphylactoid reaction) requires primarily the improvement of coronary perfusion pressure and, thus, of O2 delivery to the right ventricular myocardium. To this end, catecholamines with alpha-stimulating action should be administered. Nitroglycerin is indicated when pulmonary hypertension persists in the presence of essentially normal systemic pressure. In the acute situation, steroids and antihistamines have no beneficial effect. Prevention of protamine reactions. For prevention of systemic hypotension by vasodilatation, protamine should be infused very slowly and not during hypovolemia. General prophylaxis using H1/H2 antagonists is not justified. Reliable preoperative identification of patients who would suffer an anaphylactic/anaphylactoid reaction to protamine, for example by skin tests or by measuring specific anti-protamine IgE or IgG antibodies, is not possible. This prevents individual prophylaxis in risk patients. In view of the low incidence of severe protamine reactions and the lack of better alternatives to the heparin/protamine regimen, general prevention is not indicated. For patients who are potentially at risk (insulin-dependent diabetics, prior protamine exposure), the side-effects of preventive measures must be weighed against their benefits. Only known sensitivity to protamine justifies certain preventive actions. In vascular surgery prostacyclin can be used instead of heparin/protamine or can be withheld (fading out of heparin action). Administration of steroids and/or antihistamines should be avoided. In cardiac surgery the use of hexadimethrine (if available) or total avoidance of protamine is paramount. Corticosteroids may be considered. Aortic administration of protamine and anticoagulation with ancrod are not recommended. The most promising compounds for rpharmacologic prevention of anaphylactic/anaphylactoid reactions in the future are thromboxane receptor antagonists.

Anaphylaxis↗
PubMed1989

Evaluation of patients at risk for protamine reactions.

Patients with neutral protamine Hagedorn and protamine-zinc insulin-dependent diabetes, a history of fish allergy, or prior vasectomy have been reported to be at an increased risk for protamine reactions after cardiopulmonary bypass because of prior sensitization. We prospectively evaluated cardiac surgical patients with prior vasectomies and fish allergies and retrospectively evaluated a cohort of 3245 consecutive cardiac surgical patients requiring cardiopulmonary bypass over a 2-year period for protamine-containing insulin use and clinical evidence of adverse reactions after protamine administration for heparin reversal after cardiopulmonary bypass. Clinical reactions to protamine did not occur in six patients with fish allergies or 16 patients with prior vasectomies. There was one reaction (0.6%) in 160 patients with neutral protamine Hagedorn insulin-dependent diabetes. The incidence of clinical reactions in the other patients was 2/3085 (0.06%). The incidence of clinical reactions in the patients with neutral protamine Hagedorn insulin-dependent diabetes is not significantly different from that in other patients. We conclude that prior neutral protamine Hagedorn insulin use, a history of fish allergy, or prior vasectomy does not represent a contraindication to protamine administration after cardiopulmonary bypass.

Anaphylaxis↗
PubMed1984

Depressed cardiovascular function and altered platelet kinetics following protamine sulfate reversal of heparin activity.

This investigation documented the hemodynamic effects of rapid intravenous and intra-arterial administration of protamine sulfate, altered platelet kinetics associated with intravenous protamine sulfate administration, and a possible method of reducing protamine sulfate-induced hypotension. Thirty-six anesthetized dogs underwent continuous hemodynamic monitoring prior to heparinization (150 U/kg) and for 30 minutes after rapid reversal with protamine sulfate (1.5 mg/kg over 10 seconds). Platelet counts, platelet aggregation, and serum thromboxane B2 levels were also assessed. Intra-arterial protamine sulfate administration caused fewer adverse hemodynamic changes than intravenous administration, including significantly (p less than 0.05) reduced falls in mean arterial pressure (-10 vs. -35 mm Hg), cardiac output (-0.2 vs. -0.6 L/min), femoral artery blood flow (+ 34 vs. -16 ml/min), and superior mesenteric artery flow (+ 107 vs. -48 ml/min). Thrombocytopenia following protamine sulfate administration was the same in the two groups. Marked hypotension accompanying intravenous protamine sulfate administration was completely attenuated by a small dose of protamine sulfate (0.75 mg/kg) administered prior to heparinization. Similarly, the thrombocytopenia caused by intravenous administration was significantly lessened by protamine sulfate pretreatment (74% vs. 23% reduction; p less than 0.01). These observations have important implications for both experimental and clinical use of heparin and protamine sulfate.

Animals↗
PubMed1994

Pulmonary microvascular responses to protamine and histamine. Effects of cardiopulmonary bypass.

Total cardiopulmonary bypass with associated reduced pulmonary blood flow causes significant alterations of endothelium-dependent pulmonary microvascular responses after resumption of normal perfusion. To determine if this change in pulmonary vascular reactivity may influence the responses of pulmonary arterioles to protamine and histamine, we examined isolated pulmonary microvessels after cardiopulmonary bypass. Sheep were heparinized, cannulated, and placed on either total bypass without ventilation or partial bypass (70% of baseline pulmonary arterial flow) with continued ventilation. After 90 minutes, sheep were separated from cardiopulmonary bypass and the lungs were perfused normally for 60 minutes. Vessels from noninstrumented sheep were used as controls. Peripheral pulmonary arterioles (90 to 190 microns) were cannulated, pressurized (20 mm Hg) in a no-flow state, and examined with video microscopy. After precontraction of vessels with the thromboxane A2 analog U46619 by 18% to 25% of the baseline diameter, vasoactive agents were applied. Protamine sulfate, histamine, heparin, and the protamine-heparin complex caused significant dose-dependent relaxations of control pulmonary microvessels. These relaxation responses were substantially reduced or converted to contractile responses in endothelium-denuded vessels, which suggests that these relaxations are mediated through endothelium-dependent mechanisms. After partial bypass, responses to protamine and histamine were slightly reduced compared with the respective responses of control vessels, whereas the relaxation to protamine-heparin complex was not significantly altered. After total bypass, relaxation responses to protamine and protamine-heparin complex were markedly reduced, whereas histamine induced contraction of pulmonary microvessels. Endothelium-independent relaxation to sodium nitroprusside was not affected by partial cardiopulmonary bypass and was slightly reduced after total bypass. A reduced direct vascular relaxation response to protamine and increased contractile response to histamine (or other humoral substances released during the systemic administration of protamine sulfate) may contribute to the elevation of pulmonary vascular resistance during infusion of protamine after cardiopulmonary bypass.

Animals↗
PubMed1996

Studies on the inhibition of pancreatic and carboxylester lipases by protamine.

The basic protein protamine strongly inhibited hydrolysis of triolein emulsified with soybean phosphatidylcholine (PC) by pancreatic and carboxylester lipases; 10 micrograms/ml protamine, about 1000 times lower than the concentration of bovine serum albumin for the same effect, inhibited triolein hydrolysis completely. This inhibition was not affected by the incubation pH or bile salt concentration. Two other basic proteins, histone and purothionin, also inhibited hydrolysis of triolein emulsified with soybean PC, but they did not inhibit triolein hydrolysis by gastric lipase. When gum arabic was used as an emulsifier instead of soybean PC, these basic proteins did not affect triolein hydrolysis by pancreatic or carboxylester lipases. The effects of protamine on triolein hydrolysis by pancreatic and carboxylester lipases was studied using various phospholipids as emulsifiers. Protamine (10 micrograms/ml) did not inhibit hydrolysis of triolein emulsified with dicaproyl PC (DCPC), phosphatidic acid (PA), or phosphatidylserine (PS) by pancreatic and carboxylester lipases. Conversely, protamine at high concentrations slightly stimulated hydrolysis of triolein emulsified with DCPC or PA. Hydrolysis of triolein-phosphatidylethanolamine (PE) emulsion was inhibited slightly by protamine. The profiles of protamine inhibition of triolein-phosphatidyl-N,N-dimethyl ethanolamine (PDME) and triolein-phosphatidyl-N-monomethyl ethanolamine (PMME) emulsions were intermediate between those of PC and PE emulsions. These results suggest that the phospholipid species, especially choline moieties and fatty acid chain length, affect the lipase inhibitory activity of protamine profoundly. In vivo, oral administration of protamine to rats reduced and delayed the peak plasma triacylglycerol concentration, but neither bovine serum albumin nor an amino acid mixture with an amino acid composition identical to protamine affected plasma triacylglycerol levels.

Animals↗
PubMed1994

Heparin-protamine mismatch. A controllable factor in bleeding after open heart surgery.

OBJECTIVE: To test the effect of a new system designed to reduce heparin-protamine mismatch on bleeding after open heart surgery. DESIGN: Nonrandomized but consecutive retrospective review of patients undergoing open heart surgery during a 9-month period. SETTING: Multispecialty referral center. PATIENTS: A total of 150 patients comparable by age, body surface area, and coagulation status undergoing primary open heart surgery for either coronary bypass or heart valve replacement. INTERVENTION: In the first 75 patients (group 1), heparin sodium was neutralized with protamine sulfate, using a fixed ratio (1 mg of heparin sodium to 1.3 mg of protamine sulfate). An activated clotting time was used to confirm heparin neutralization. For the subsequent 75 patients (group 2), titration of heparin and protamine from defined lots was accomplished using activated clotting times adjusted and matched to drug lots to minimize biologic variability. Groups 1 and 2 had comparable operations, pump times, and cross-clamp times. MAIN OUTCOME MEASURES: Doses of heparin and protamine and their effect on blood product transfusion and postoperative bleeding were evaluated in all patients. RESULTS: The average protamine sulfate dose for group 2 patients (287.56 +/- 8.3 mg) was significantly lower than that for group 1 (346.01 +/- 12.6 mg) (P < .0005). Less protamine was associated with the transfusion of fewer red blood cells (0.92 +/- 0.15 vs 2.57 +/- 0.38 U) (P < .001), platelets (0.72 +/- 0.8 vs 2.96 +/- 0.80 U) (P < .01), and fresh-frozen plasma (0.83 +/- 2.0 vs 2.01 +/- 0.48 U) (P < .03). No patients in group 2 required reexploration for bleeding, compared with eight patients in group 1. CONCLUSIONS: A reduction in protamine dose was associated with significant decreases in blood product use and postoperative bleeding. Excess protamine warrants consideration as both an important and a controllable factor in coagulopathy after open heart surgery.

Aged↗
PubMed1999

Analysis of hamster protamines: primary sequence and species distribution.

Basic nuclear proteins were isolated from the sperm of the Syrian hamster Mesocricetus auratus and characterized by gel electrophoresis, amino acid analysis, and sequencing. Analyses of the proteins by gel electrophoresis show that sperm of this species contain both protamines 1 and 2. The two proteins were purified by HPLC and the complete primary sequence of hamster protamine 1 was determined by automated amino acid sequence analysis. The protein sequence was subsequently confirmed by sequencing the PCR-amplified protamine 1 gene. The first forty-two residues of the hamster protamine 2 sequence were obtained by amino acid sequence analysis of the isolated protein, and this sequence was also confirmed and extended by sequencing the gene. Total basic nuclear protein was also isolated from sperm of six other species of hamsters, the protamines were identified by HPLC and amino acid analysis, and the proportion of protamines 1 and 2 in each species was determined. Marked differences in the protamine 2 content of sperm were observed among the different species of hamster. This variation and the high level of sequence similarity between mouse and hamster protamines provide insight into how the two protamines may be organized in sperm chromatin. Mol. Reprod. Dev. 54:273-282, 1999. Published 1999 Wiley-Liss, Inc.

Amino Acid Sequence↗
PubMed1988

The safety of protamine sulfate in diabetics undergoing cardiac catheterization.

The frequency of anaphylactoid reactions to protamine sulfate was examined by reviewing the records of diabetic patients undergoing cardiac catheterization over a 5-year period, and by prospectively monitoring diabetic patients receiving NPH insulin during the infusion of protamine sulfate. No anaphylactoid reactions were noted after protamine administration (48 +/- 5 mg) in the retrospective study in either patients with prior exposure to protamine (74 catheterizations) or in diabetics with no exposure to protamine (132 catheterizations). In the prospective study, no anaphylactoid reactions were seen in the 24 NPH insulin-dependent diabetics during the infusion of protamine sulfate (45 +/- 5 mg). Five of the 42 patients (12%) from the retrospective study who underwent vascular surgery developed severe reactions to much larger doses of protamine (380 +/- 118 mg). Diabetics with prior exposure to protamine sulfate do not appear to be at increased risk of anaphylactoid reaction after the administration of protamine sulfate in the dose range of less than 50 mg at the time of cardiac catheterization.

Anaphylaxis↗
PubMed1989

Complement activation from protamine sulfate administration after coronary angiography.

The cause of hypotension after reversal of heparin by protamine has not been well defined. In this study we evaluated complement activation (C3a and C4a) by the heparin-protamine complex in 46 consecutive patients (40 received protamine sulfate to reverse heparin, and six did not) during and after coronary angiography. In patients receiving protamine sulfate, there was a significant increase in C3a over the value before protamine sulfate administration (P less than .001) or in patients who did not receive protamine sulfate (P less than .05): 807 +/- 100 ng/ml vs. 274 +/- 75 ng/ml. There were no significant changes in C4a after protamine sulfate administration. These results indicate that the alternate complement pathway is activated when protamine sulfate is administered after coronary angiography. This may induce hypotension as well as platelet aggregation and thrombus formation and may contribute to coronary instability. Therefore, in unstable patients, heparin reversal by protamine should not be done routinely.

Anaphylatoxins↗
PubMed2003

Enhancing adenovirus-mediated gene transfer in vitro and in vivo by addition of protamine and hydrocortisone.

BACKGROUND: Inclusion of positively charged polymers such as protamine in adenovector formulations has been reported to improve the efficiency of adenovirus-mediated gene transfer in vitro and in vivo. On the other hand, corticosteroids are known to inhibit inflammation and thus might be useful in minimizing vector-related toxicity. In this study, we evaluated the combined effect of protamine sulfate and hydrocortisone on the efficiency of adenovirus-mediated gene transfer in vitro and in vivo. METHODS: Protamine and hydrocortisone at different concentrations were added to adenovector formulations. In vitro transgene expression with or without inclusion of protamine and hydrocortisone was evaluated in the breast cancer cell lines MDA-MB-231 and MCF7 and the lung cancer cell lines A549 and H460. In vivo transgene expression in the mouse lung was determined after aerosolized vector delivery. RESULTS: The combination of 2 micro g/ml protamine and 125 ng/ml hydrocortisone significantly increased transgene expression in vitro in all the cell lines tested. Protamine is only effective when it is added to cells before or together with adenovectors, whereas hydrocortisone is effective when it is added to cells before, together with, or after adenovectors. Inclusion of protamine and hydrocortisone also augmented apoptosis induction caused by adenovectors expressing proapoptotic genes in cancer cells. Moreover, protamine and hydrocortisone dramatically enhanced transgene expression in the mouse lung after aerosolized vector delivery. CONCLUSIONS: Inclusion of protamine and hydrocortisone in adenovector formulations can improve adenovector-mediated gene expression and may be useful for clinical applications of current adenovirus-mediated gene therapy.

Adenoviridae↗
PubMed1994

Synthesis and processing of mammalian protamines and transition proteins.

Mouse and rat seminiferous tubule fragment cultures were used to examine synthesis and processing of mammalian protamines and transition proteins. The tubule fragments were incubated with [3H]-arginine, [3H]-histidine, [35S]-cysteine, or [32P]-PO4, and radiolabeled proteins were analyzed by acid/urea polyacrylamide gel electrophoresis and fluorography or autoradiography. Newly synthesized protamines were recovered from sonication-resistant nuclei (SRN) and could not be detected in cytoplasmic fractions, indicating that protamines are deposited into nuclei immediately after synthesis. Newly synthesized mouse protamine 1 (mP1) and the precursor to mouse protamine 2 (pre-mP2) migrated more slowly during electrophoresis than their predominant testicular forms, identified by staining with Coomassie blue R-250. Within 1 hour of synthesis, the electrophoretic mobilities of mP1 and pre-mP2 increased to match those of their predominant forms. These changes are consistent with initial charge-neutralizing modifications of the newly synthesized protamines, followed by removal of at least some of the modifying ligands, to unmask protamine basicity. Steady-state phosphorylation rates were high for rat protamine 1 (rP1) and were independent of phosphate content; both rP1 molecules of low and high phosphate content were rapidly phosphorylated. Pre-mP2-3, a major processing intermediate derived by proteolysis of pre-mP2, was also rapidly phosphorylated. Like the protamines, transition protein 2 (TP2) was rapidly phosphorylated and increased in electrophoretic mobility soon after synthesis. In contrast, transition protein 1 (TP1) was not phosphorylated and did not exhibit multiple electrophoretic forms.

Animals↗
PubMed1994

On the evolution of protamines in bony fish: alternatives to the "retroviral horizontal transmission" hypothesis.

Fish protamines are highly specialized molecules which are responsible for chromatin condensation during the last stages of spermatogenesis (spermiogenesis). However, not all fish contain protamines in their sperm nuclei; rather, there seems to be a random distribution of protamines within this group. The origin of this sporadic presence of protamines in the sperm and its significance have not yet been precisely determined. In this paper we have conducted an exhaustive survey of the literature available on the different types of nuclear protein composition of the sperm of teleost fish in order to try to correlate these data with what is presently known about the taxonomy of this group. The results of this analysis have allowed us to make the following observations. The divergence between protamines and histones has occurred several times during the evolution of the bony fish. However, the relative frequency of this divergence is almost negligible during the differentiation of genera and species (intrafamily variation) and is very small during the differentiation of families (interfamily variation). Nevertheless, the divergence is very noticeable among the different orders. It is therefore possible to conclude from all this that the sporadic distribution of protamines in bony fish is not a random event as initially believed. Furthermore, such a heterogeneous distribution of protamines cannot be easily accounted for by a mechanism of horizontal retroviral transmission through repeated and independent acquisition of a protamine gene as has been recently proposed (Jankowski, Stater, Dixon (1986) J Mol Evol 23:1-10). Rather, it could possibly be explained by a repeated and independent loss of the expression of the protamine gene (or loss of the gene itself) which mainly occurred during the diversification of the orders of this group.

Amino Acid Sequence↗
PubMed1985

Protamine reversibly decreases paracellular cation permeability in Necturus gallbladder.

Protamine, a naturally occurring arginine-rich polycationic protein (pI 9.7 to 12), was tested in Necturus gallbladder using a transepithelial AC-impedance technique. Protamine sulfate or hydrochloride (100 micrograms/ml = 20 microM), dissolved in the mucosal bath, increased transepithelial resistance by 89% without affecting the resistance of subepithelial layers. At the same time, transepithelial voltage (psi ms) turned from slightly mucosa-positive values to mucosa-negative values of approximately +1 to -5 mV. The effect of protamine on transepithelial resistance was minimal at concentrations below 5 micrograms/ml but a maximum response was achieved between 10 and 20 micrograms/ml. Resistance started to increase within 1 min and was maximal after 10 min. These effects were not inhibited by serosal ouabain (5 X 10(-4) M) but could be readily reversed by mucosal heparin. The sequence of protamine effect and heparin reversal could be repeated several times in the same gallbladder. Mucosal heparin, a strong negatively charged mucopolysaccharide, or serosal protamine were without effect. Mucosal protamine reversibly decreased the partial ionic conductance of K and Na by a factor of 3, but did not affect Cl conductance. Net water transport from mucosa to serosa was reversibly increased by 60% by protamine. We conclude that protamine reversibly decreases the conductance of the cation-selective pathway through the tight junction. Although this effect is similar to that reported for 2,4,6-triamino-pyrimidinium (TAP), the mechanism of action may differ. We propose that protamine binds to the apical cell membrane and induces a series of intracellular events which leads to a conformational alteration of the tight junction structure resulting in decreased cationic permeability.

Animals↗
PubMed1984

Haemodynamic changes and circulating histamine concentrations following protamine administration to patients and dogs.

Haemodynamic changes and the circulating concentrations of histamine associated with the intravenous infusion of protamine were measured in six adult patients undergoing elective aortocoronary bypass graft surgery and twelve halothane-anaesthetized dogs. Administration of protamine (4.7 mg X kg-1) over five minutes to patients at the conclusion of cardiopulmonary bypass did not produce haemodynamic changes or alterations in the arterial or mixed venous concentrations of histamine. Likewise, the administration of protamine (4.5 mg X kg-1) over five minutes to six dogs produced no haemodynamic changes or alterations in the arterial concentrations of histamine. Conversely, administration of protamine (4.5 mg X kg-1) as a rapid intravenous injection to six other dogs produced a decrease (about 30 per cent below control) in systolic, diastolic and mean arterial pressure (p less than 0.05) at 2.5 minutes following the injection. These decreases in blood pressure were paralleled by increases in the arterial concentration of histamine from 295 +/- 71 pg X ml-1 (mean +/- SD) before protamine to 860 +/- 6,465 pg X ml-1 (p less than 0.05) 2.5 minutes after protamine. Haemodynamic changes and the arterial concentration of histamine were not different from control five minutes after protamine administration. It is concluded that administration of protamine over five minutes to patients or dogs does not evoke significant haemodynamic changes or alterations in circulating concentrations of histamine. Conversely, rapid injection of protamine to dogs evokes transient decreases in blood pressure that are paralleled by increases in the arterial concentrations of histamine.

Anesthesia, General↗
PubMed1998

Heparin and protamine titration do not improve haemostasis in cardiac surgical patients.

PURPOSE: Weight-based heparin and protamine dosing strategies for cardiopulmonary bypass (CPB) do not take into account interpatient variability in drug sensitivity and may result in bleeding complications. We compared the Hemochron RxDx heparin and protamine titration system with standard weight based management with regard to heparin dose, protamine dose, and perioperative bleeding. METHODS: One hundred and thirty-five cardiac surgical patients were randomised into four groups. Group 1 received standard heparin and protamine management: Group 2 received heparin and protamine by in vitro titration. Group 3 had the heparin dose titrated, and group 4 had the protamine dose titrated. Coagulation tests, bleeding, and transfusion requirements were measured. RESULTS: The initial heparin bolus predicted by the titration was < 300 U.kg-1 in all patients. Group 2 received a lower heparin bolus for the initiation of bypass but total heparin doses were not different among groups (group 1 = 365 +/- 43, group 2 = 348 +/- 73 U.kg-1, group 3 = 394 +/- 86 U.kg-1, group 4 = 376 +/- 60; P = 0.06). Groups 2 and 4 received a lower initial and a lower total protamine dose (total dose group 1 = 4.03 +/- 0.65 mg.kg-1, group 2 = 3.56 +/- 1.11 mg.kg-1, group 3 = 4.22 +/- 0.90 mg.kg-1, group 4 = 3.38 +/- 0.98 mg.kg-1, P = 0.001). The incidences of incomplete heparin neutralisation (P = 0.14) and heparin rebound (P = 0.1) were not different among groups. Postoperative bleeding and transfusion requirements did not differ. CONCLUSION: In cardiac surgical patients, heparin and protamine titration did predict a lower protamine dose but did not result in a measurable improvement in haemostasis during the perioperative period.

Analysis of Variance↗