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1.
Mar Drugs ; 17(9)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533230

RESUMO

Protamine sulfate (PS) is a polycationic protein drug obtained from the sperm of fish, and is used to reverse the anticoagulant effect of unfractionated heparin (UFH). However, the interactions between PS, UFH, and platelets are still not clear. We measured the platelet numbers and collagen-induced aggregation, P-selectin, platelet factor 4, ß-thromboglobulin, prostacyclin metabolite, D-dimers, activated partial thromboplastin time, prothrombin time, anti-factor Xa, fibrinogen, thrombus weight and megakaryocytopoiesis in blood collected from mice and rats in different time points.. All of the groups were treated intravenously with vehicle, UFH, PS, or UFH with PS. We found a short-term antiplatelet activity of PS in mice and rats, and long-term platelet-independent antithrombotic activity in rats with electrically-induced thrombosis. The antiplatelet and antithrombotic potential of PS may contribute to bleeding risk in PS-overdosed patients. The inhibitory effect of PS on the platelets was attenuated by UFH without inducing thrombocytopenia. Treatment with UFH and PS did not affect the formation, number, or activation of platelets, or the thrombosis development in rodents.


Assuntos
Anticoagulantes/efeitos adversos , Antagonistas de Heparina/efeitos adversos , Heparina/efeitos adversos , Protaminas/efeitos adversos , Trombocitopenia/diagnóstico , Animais , Anticoagulantes/administração & dosagem , Plaquetas/efeitos dos fármacos , Modelos Animais de Doenças , Hemorragia/sangue , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Heparina/administração & dosagem , Antagonistas de Heparina/administração & dosagem , Humanos , Masculino , Camundongos , Tempo de Tromboplastina Parcial , Agregação Plaquetária/efeitos dos fármacos , Protaminas/administração & dosagem , Ratos , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Fatores de Tempo
2.
Scand Cardiovasc J ; 53(6): 355-360, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31476919

RESUMO

Objectives: Protamine reduces platelet aggregation after cardiopulmonary bypass (CPB). We studied the inhibitory effect of a reduced protamine dose, the duration of impaired platelet function and the possible correlation to postoperative bleeding. Design: Platelet function was assessed by impedance aggregometry in 30 patients undergoing cardiac surgery with CPB at baseline, before protamine administration, after 70% and 100% of the calculated protamine dose, after 20 minutes and at arrival to the intensive care unit. Adenosine diphosphate (ADP), thrombin receptor activating peptide-6 (TRAP), arachidonic acid (AA) and collagen (COL) were used as activators. Blood loss was measured during operation and three hours after surgery. Results are presented as median (25th-75th percentile). Results: Platelet aggregation decreased markedly after the initial dose of protamine (70%) with all activators; ADP 89 (71-110) to 54 (35-78), TRAP 143 (116-167) to 109 (77-136), both p < .01; AA 25 (16-49) to 17 (12-24) and COL 92 (47-103) to 60 (38-81) U, both p < .05. No further decrease was seen after 100% protamine. The effect was transient and after twenty minutes platelet aggregation had started to recover; ADP 76 (54-106), TRAP 138 (95-158), AA 20 (10-35), COL 70 (51-93) U. Blood loss during operation correlated to aggregometry measured at baseline and after protaminization. Conclusions: Protamine after CPB induces a marked decrease in platelet aggregation already at a protamine-heparin ratio of 0.7:1. The impairment seems to be transient and recovery had started after 20 minutes.


Assuntos
Ponte de Artéria Coronária , Implante de Prótese de Valva Cardíaca , Antagonistas de Heparina/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Protaminas/efeitos adversos , Idoso , Perda Sanguínea Cirúrgica/prevenção & controle , Ponte Cardiopulmonar , Ponte de Artéria Coronária/efeitos adversos , Relação Dose-Resposta a Droga , Transfusão de Eritrócitos , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Antagonistas de Heparina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Plaquetária , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/terapia , Protaminas/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
3.
J Stroke Cerebrovasc Dis ; 28(10): 104283, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31324409

RESUMO

INTRODUCTION: Administering intravenous IV tissue plasminogen activator (tPA) is the recommended standard of care in acute ischemic stroke (AIS), although it is not recommended to administer intravenous thrombolysis with tPA following heparin reversal with protamine sulfate in patients with AIS. METHODS: We describe a case series of three patients and the most comprehensive literature review published to date in this specific subset of AIS patients undergoing thrombolysis following heparin reversal with protamine sulfate. The literature review was based on a scoping review methodology performed on four databases; PubMed, CINAHL, Web of Science, and Cochrane Library. All sources were searched from the inauguration of the database until February 2019. A total of six articles involving eight patients were identified. RESULTS: The primary safety outcome of no symptomatic intracranial hemorrhage (sICH) was met in all eleven patients, although only seven cases had a good functional outcome at 3 months. CONCLUSIONS: In appropriately selected AIS patients, coagulopathy correction appears to be safe from an sICH standpoint and may be beneficial. However, given the potential for bias with observational databases, case reports and case series, extreme caution is warranted in applying these results to routine clinical practice.


Assuntos
Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Antagonistas de Heparina/uso terapêutico , Heparina/uso terapêutico , Protaminas/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Feminino , Fibrinolíticos/efeitos adversos , Heparina/efeitos adversos , Antagonistas de Heparina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Protaminas/efeitos adversos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
5.
Semin Thorac Cardiovasc Surg ; 31(3): 394-396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30578828

RESUMO

Cognitive workload data of members of the cardiac surgery team can be measured intraoperatively and stored for later analysis. We present a case of a near-miss (medication error) that underwent root cause analysis using workload data. Heart rate variability data, representing workload levels, were collected from the attending surgeon, attending anesthesiologist, and lead perfusionist using wireless heart rate monitors. An episode of cognitive overload of the anesthesiologist due to a distractor was associated with the preventable error. Additional studies are needed to better understand the role of psychophysiological data in enhancing surgical patient safety.


Assuntos
Anestesistas/psicologia , Cognição , Ponte de Artéria Coronária/efeitos adversos , Erros de Medicação/prevenção & controle , Near Miss , Equipe de Assistência ao Paciente , Carga de Trabalho , Administração Intravenosa , Competência Clínica , Frequência Cardíaca , Antagonistas de Heparina/administração & dosagem , Antagonistas de Heparina/efeitos adversos , Humanos , Protaminas/administração & dosagem , Protaminas/efeitos adversos , Medição de Risco , Fatores de Risco , Análise de Causa Fundamental
7.
J Thromb Haemost ; 16(11): 2133-2146, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30153372

RESUMO

Despite the development of catheter-based interventions for ischemic and valvular heart disease, hundreds of thousands of people undergo open heart surgery annually for coronary artery bypass graft (CABG), valve replacement or cardiac assist device implantation. Cardiac surgery patients are unique because therapeutic anticoagulation is required during cardiopulmonary bypass. Developmental hemostasis and altered drug metabolism affect management in children. This narrative review summarizes the current evidence-based and consensus guidelines regarding perioperative, intraoperative and postoperative antithrombotic therapy in patients undergoing cardiac surgery. Anticoagulation preoperatively is required in the setting of cardiac arrhythmias, prior valve replacement or history of venous thromboembolism. In patients with ischemic heart disease, aspirin is continued in the perioperative period, whereas oral P2Y12 antagonists are withheld for 5-7 days to reduce the risk of perioperative bleeding. Intraoperative management of cardiopulmonary bypass in adults and children includes anticoagulation with unfractionated heparin. Variability in dose-response to heparin and influence of other medical conditions on dosing and reversal of heparin make intraoperative anticoagulation challenging. Vitamin K antagonist therapy is the standard anticoagulant after mechanical heart valve or left ventricular assist device (LVAD) implantation. Longer duration of dual antiplatelet therapy is recommended after CABG if patients undergo surgery because of acute coronary syndrome. Antiplatelet therapy after LVAD implantation includes aspirin, dipyridamole and/or clopidogrel in children and aspirin in adults. A coordinated approach between hematology, cardiology, anesthesiology, critical care and cardiothoracic surgery can assist to balance the risk of thrombosis and bleeding in patients undergoing cardiac surgery.


Assuntos
Cardiologia/métodos , Ponte de Artéria Coronária , Fibrinolíticos/uso terapêutico , Hemostasia , Inibidores da Agregação de Plaquetas/uso terapêutico , Adolescente , Adulto , Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Coagulação Sanguínea , Procedimentos Cirúrgicos Cardíacos , Criança , Esquema de Medicação , Medicina Baseada em Evidências , Doenças das Valvas Cardíacas/cirurgia , Coração Auxiliar , Hemorragia/prevenção & controle , Heparina/efeitos adversos , Humanos , Inflamação , Período Intraoperatório , Período Perioperatório , Guias de Prática Clínica como Assunto , Protaminas/efeitos adversos , Risco , Terapia Trombolítica/efeitos adversos , Trombose/prevenção & controle , Vitamina K/antagonistas & inibidores
8.
J Thromb Haemost ; 16(10): 1973-1983, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30016577

RESUMO

Essentials Heparin-protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB). HPB was examined in 44 neonates undergoing CPB. Post-operative bleeding occurred in 36% and heparin rebound in 73%. Thrombin-initiated fibrin clot kinetic assay and partial thromboplastin time best assessed HPB. SUMMARY: Background Neonates undergoing cardiopulmonary bypass (CPB) are at risk of excessive bleeding. Blood is anticoagulated with heparin during CPB. Heparin activity is reversed with protamine at the end of CPB. Paradoxically, protamine also inhibits blood coagulation when it is dosed in excess of heparin. Objectives To evaluate heparin-protamine balance in neonates undergoing CPB by using research and clinical assays, and to determine its association with postoperative bleeding. Patients/Methods Neonates undergoing CPB in the first 30 days of life were studied. Blood samples were obtained during and after surgery. Heparin-protamine balance was assessed with calibrated automated thrombography, thrombin-initiated fibrin clot kinetic assay (TFCK), activated partial thromboplastin time (APTT), anti-FXa activity, and thromboelastometry. Excessive postoperative bleeding was determined by measurement of chest tube output or the development of cardiac tamponade. Results and Conclusions Of 44 neonates enrolled, 16 (36%) had excessive postoperative bleeding. The TFCK value was increased. By heparin in neonatal blood samples, but was only minimally altered by excess protamine. Therefore, it reliably measured heparin in samples containing a wide range of heparin and protamine concentrations. The APTT most closely correlated with TFCK results, whereas anti-FXa and thromboelastometry assays were less correlative. The TFCK and APTT assay also consistently detected postoperative heparin rebound, providing an important continued role for these long-established coagulation tests in the management of postoperative bleeding in neonates requiring cardiac surgical repair. None of the coagulation tests predicted the neonates who experienced postoperative bleeding, reflecting the multifactorial causes of bleeding in this population.


Assuntos
Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Ponte Cardiopulmonar/efeitos adversos , Antagonistas de Heparina/administração & dosagem , Heparina/administração & dosagem , Hemorragia Pós-Operatória/etiologia , Protaminas/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/sangue , Testes de Coagulação Sanguínea , Monitoramento de Medicamentos/métodos , Feminino , Heparina/efeitos adversos , Heparina/sangue , Antagonistas de Heparina/efeitos adversos , Antagonistas de Heparina/sangue , Humanos , Recém-Nascido , Masculino , Hemorragia Pós-Operatória/sangue , Hemorragia Pós-Operatória/diagnóstico , Valor Preditivo dos Testes , Estudos Prospectivos , Protaminas/efeitos adversos , Protaminas/sangue , Fatores de Risco , Resultado do Tratamento
9.
Medicine (Baltimore) ; 97(28): e10908, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29995750

RESUMO

Since there were a few articles to report the treatment of severe pulmonary vasoconstriction induced by protamine in cardiac surgery, we described the use of epoprostenol to reverse this condition.A total of 5 cases of severe pulmonary vasoconstriction induced by protamine in cardiac surgery were reviewed. The demographic, clinical data and treatment process were obtained. All the patients were followed up.Severe pulmonary vasoconstriction was occurred 4 to 10 minutes after protamine infusion. The primary sign was sudden hypotension, the pulmonary artery pressure was increased gradually, the arterial oxygen partial pressure was decreased in all the patients. Epoprostenol was infused via pulmonary artery catheter at dosage of 20 to 40 ng/kg·min in all the patients, 2 patients were underwent re-cardiac pulmonary bypass assistance. The hemodynamic instability status lasted 40 to 65 minutes respectively. All the patients were recovered uneventfully.All physicians should alert to the incidence of severe pulmonary vasoconstriction induced by protamine in cardiac surgery. Use epoprostenol through pulmonary artery catheter could treat pulmonary artery vasoconstriction effectively and safely.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Epoprostenol/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar , Complicações Intraoperatórias , Protaminas/efeitos adversos , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , China , Monitoramento de Medicamentos/métodos , Feminino , Antagonistas de Heparina/administração & dosagem , Antagonistas de Heparina/efeitos adversos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Complicações Intraoperatórias/induzido quimicamente , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Protaminas/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento , Vasoconstrição/efeitos dos fármacos
10.
Int Heart J ; 59(3): 482-488, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29743410

RESUMO

Bleeding complications following percutaneous coronary interventions (PCI) have been closely associated with morbidity and mortality. Although radial arteries have been widely used in current PCI, including primary PCI, transfemoral PCI remains necessary for complex PCI. The purpose of this study was to compare the incidence of complications following elective transfemoral PCI between manual compression with and without protamine. We identified 249 consecutive patients who underwent elective transfemoral PCI from hospital records, and divided them into two groups: patients who used protamine for manual compression (the protamine group; n = 205) and patients who did not (the non-protamine group, n = 44). Complications including acute thrombosis, bleeding requiring blood transfusion, transient hypotension, skin rash, and death within 30 days were compared between groups. The baseline clinical and procedural characteristics were comparable between the protamine and non-protamine groups. The incidences of all complications were not different between the protamine (5.9%) and the non-protamine groups (9.1%) (P = 0.43). While more than 90% of the patients received drug-eluting stent implantation, there was no acute thrombus in either group. The incidence of bleeding requiring blood transfusion was significantly lower in the protamine group (0.5%) than in the non-protamine group (6.8%) (P = 0.002). Multivariate logistic regression analysis revealed the inverse association between protamine use and bleeding requiring blood transfusion (odds ratio 0.08, 95% confidence interval 0.01-0.84, P = 0.04). In conclusion, the use of protamine for manual compression following elective transfemoral PCI was safe and was associated with less bleeding complications.


Assuntos
Anticoagulantes/efeitos adversos , Antagonistas de Heparina/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Protaminas/efeitos adversos , Idoso , Transfusão de Sangue/estatística & dados numéricos , Doença da Artéria Coronariana/cirurgia , Stents Farmacológicos/efeitos adversos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Feminino , Técnicas Hemostáticas , Antagonistas de Heparina/uso terapêutico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Protaminas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
11.
Br J Anaesth ; 120(5): 914-927, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29661409

RESUMO

Neutralisation of systemic anticoagulation with heparin in cardiac surgery with cardiopulmonary bypass requires protamine administration. If adequately dosed, protamine neutralises heparin and reduces the risk of postoperative bleeding. However, as its anticoagulant properties are particularly exerted in the absence of heparin, overdosing of protamine may contribute to bleeding and increased transfusion requirements. This narrative review describes the mechanisms underlying the anticoagulant properties and side-effects of protamine, and the impact of protamine dosing on the activated clotting time and point-of-care viscoelastic test results, and explains the distinct protamine dosing strategies in relation to haemostatic activation and postoperative bleeding. The available evidence suggests that protamine dosing should not exceed a protamine-to-heparin ratio of 1:1. In particular, protamine-to-heparin dosing ratios >1 are associated with more postoperative 12 h blood loss. The optimal protamine-to-heparin ratio in cardiac surgery has, however, not yet been elaborated, and may vary between 0.6 and 1.0 based on the initial heparin dose.


Assuntos
Anticoagulantes/farmacologia , Ponte Cardiopulmonar , Antagonistas de Heparina/farmacologia , Hemorragia Pós-Operatória/prevenção & controle , Protaminas/farmacologia , Anticoagulantes/efeitos adversos , Procedimentos Cirúrgicos Cardíacos , Relação Dose-Resposta a Droga , Heparina/administração & dosagem , Antagonistas de Heparina/efeitos adversos , Humanos , Protaminas/efeitos adversos
15.
Blood ; 129(10): 1368-1379, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28034889

RESUMO

Anticoagulant therapy-associated bleeding and pathological thrombosis pose serious risks to hospitalized patients. Both complications could be mitigated by developing new therapeutics that safely neutralize anticoagulant activity and inhibit activators of the intrinsic blood clotting pathway, such as polyphosphate (polyP) and extracellular nucleic acids. The latter strategy could reduce the use of anticoagulants, potentially decreasing bleeding events. However, previously described cationic inhibitors of polyP and extracellular nucleic acids exhibit both nonspecific binding and adverse effects on blood clotting that limit their use. Indeed, the polycation used to counteract heparin-associated bleeding in surgical settings, protamine, exhibits adverse effects. To address these clinical shortcomings, we developed a synthetic polycation, Universal Heparin Reversal Agent (UHRA), which is nontoxic and can neutralize the anticoagulant activity of heparins and the prothrombotic activity of polyP. Sharply contrasting protamine, we show that UHRA does not interact with fibrinogen, affect fibrin polymerization during clot formation, or abrogate plasma clotting. Using scanning electron microscopy, confocal microscopy, and clot lysis assays, we confirm that UHRA does not incorporate into clots, and that clots are stable with normal fibrin morphology. Conversely, protamine binds to the fibrin clot, which could explain how protamine instigates clot lysis and increases bleeding after surgery. Finally, studies in mice reveal that UHRA reverses heparin anticoagulant activity without the lung injury seen with protamine. The data presented here illustrate that UHRA could be safely used as an antidote during adverse therapeutic modulation of hemostasis.


Assuntos
Antídotos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Hemorragia/tratamento farmacológico , Antagonistas de Heparina/farmacologia , Animais , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Humanos , Pulmão/efeitos dos fármacos , Camundongos , Poliaminas , Protaminas/efeitos adversos
16.
J Clin Anesth ; 35: 415-423, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27871567

RESUMO

STUDY OBJECTIVE: To facilitate the identification of drugs and patient factors associated with hemodynamically significant anaphylaxis. DESIGN: Using an existing database containing complete perioperative records, instances of hemodynamically significant anaphylaxis were identified using a physiologic and treatment-based screening algorithm. All cases were manually reviewed by 2 clinicians, with a third adjudicating disagreements, and confirmed cases were matched 3:1 with control cases. Intraoperative medications given in instances of hemodynamically significant anaphylaxis and patient risk factors were compared with control cases. SETTING: University of Michigan Hospital, a large, tertiary care hospital. PATIENTS: All adult patients undergoing surgery between January 1, 2004, and January 5, 2015. INTERVENTIONS: None. MEASUREMENTS: Incidence of hemodynamically significant anaphylaxis during anesthesia. Patient risk factors and intraoperative medications associated with hemodynamically significant anaphylaxis. MAIN RESULTS: Hemodynamically significant anaphylaxis occurred in 55 of 461 986 cases (1 in 8400). Hemodynamically significant anaphylaxis occurred in 52 patients, with 1 patient experiencing 3 instances and another patient 2 instances. Only 1 drug was associated with an increased risk of hemodynamically significant anaphylaxis: protamine (odds ratio, 11.78; 95% confidence interval, 1.40-99.26; P=.0233). No category of drugs was associated with increased risk. Of patient risk factors, only personal history of anaphylaxis was associated with an increased risk (odds ratio, 77.1; 95% confidence interval, 10.46-567.69; P=<.0001). Postoperative follow-up and evaluation of patients were low at our institution. A serum tryptase level was sent in only 49% of cases, and 41% of levels were positive, an overall positive rate of 20% of cases. Following instances of hemodynamically significant anaphylaxis, only 29% of patients were seen and evaluated by an allergist at our institution. CONCLUSIONS: Hemodynamically significant anaphylaxis is a rare complication of anesthesia, with an incidence consistent with the existing literature. Contrary to most existing literature, only protamine was associated with increased risk. A personal history of anaphylaxis appears to best predict risk of hemodynamically significant anaphylaxis.


Assuntos
Anafilaxia/induzido quimicamente , Antagonistas de Heparina/efeitos adversos , Cuidados Intraoperatórios/efeitos adversos , Protaminas/efeitos adversos , Bases de Dados Factuais , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco
17.
Braz J Cardiovasc Surg ; 31(3): 226-231, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27737405

RESUMO

Objective: To examine if methylene blue (MB) can counteract or prevent protamine (P) cardiovascular effects. Methods: The protocol included five heparinized pig groups: Group Sham -without any drug; Group MB - MB 3 mg/kg infusion; Group P - protamine; Group P/MB - MB after protamine; Group MB/P - MB before protamine. Nitric oxide levels were obtained by the nitric oxide/ozone chemiluminescence method, performed using the Nitric Oxide Analizer 280i (Sievers, Boulder, CO, USA). Malondialdehyde plasma levels were estimated using the thiobarbiturate technique. Results: 1) Groups Sham and MB presented unchanged parameters; 2) Group P - a) Intravenous protamine infusion caused mean arterial pressure decrease and recovery trend after 25-30 minutes, b) Cardiac output decreased and remained stable until the end of protamine injection, and c) Sustained systemic vascular resistance increased until the end of protamine injection; 3) Methylene blue infusion after protamine (Group P/MB) - a) Marked mean arterial pressure decreased after protamine, but recovery after methylene blue injection, b) Cardiac output decreased after protamine infusion, recovering after methylene blue infusion, and c) Sustained systemic vascular resistance increased after protamine infusion and methylene blue injections; 4) Methylene blue infusion before protamine (Group MB/P) - a) Mean arterial pressure decrease was less severe with rapid recovery, b) After methylene blue, there was a progressive cardiac output increase up to protamine injection, when cardiac output decreased, and c) Sustained systemic vascular resistance decreased after protamine, followed by immediate Sustained systemic vascular resistance increase; 5) Plasma nitrite/nitrate and malondialdehyde values did not differ among the experimental groups. Conclusion: Reviewing these experimental results and our clinical experience, we suggest methylene blue safely prevents and treats hemodynamic protamine complications, from the endothelium function point of view.


Assuntos
Inibidores Enzimáticos/farmacologia , Hemodinâmica/efeitos dos fármacos , Antagonistas de Heparina/administração & dosagem , Azul de Metileno/farmacologia , Protaminas/antagonistas & inibidores , Anafilaxia/etiologia , Anafilaxia/prevenção & controle , Animais , Pressão Venosa Central/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Feminino , Antagonistas de Heparina/efeitos adversos , Malondialdeído/sangue , Modelos Animais , Óxido Nítrico/sangue , Protaminas/efeitos adversos , Suínos
18.
Thromb Haemost ; 116(2): 251-61, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27277211

RESUMO

While experimental data state that protamine exerts intrinsic anticoagulation effects, protamine is still frequently overdosed for heparin neutralisation during cardiac surgery with cardiopulmonary bypass (CPB). Since comparative studies are lacking, we assessed the influence of two protamine-to-heparin dosing ratios on perioperative haemostasis and bleeding, and hypothesised that protamine overdosing impairs the coagulation status following cardiac surgery. In this open-label, multicentre, single-blinded, randomised controlled trial, patients undergoing on-pump coronary artery bypass graft surgery were assigned to a low (0.8; n=49) or high (1.3; n=47) protamine-to-heparin dosing group. The primary outcome was 24-hour blood loss. Patient haemostasis was monitored using rotational thromboelastometry and a thrombin generation assay. The low protamine-to-heparin dosing ratio group received less protamine (329 ± 95 vs 539 ± 117 mg; p<0.001), while post-protamine activated clotting times were similar among groups. The high dosing group revealed increased intrinsic clotting times (236 ± 74 vs 196 ± 64 s; p=0.006) and the maximum post-protamine thrombin generation was less suppressed in the low dosing group (38 ± 40 % vs 6 ± 9 %; p=0.001). Postoperative blood loss was increased in the high dosing ratio group (615 ml; 95 % CI 500-830 ml vs 470 ml; 95 % CI 420-530 ml; p=0.021) when compared to the low dosing group, respectively. More patients in the high dosing group received fresh frozen plasma (11 % vs 0 %; p=0.02) and platelet concentrate (21 % vs 6 %; p=0.04) compared to the low dosing group. Our study confirms in vitro data that abundant protamine dosing is associated with increased postoperative blood loss and higher transfusion rates in cardiac surgery.


Assuntos
Anticoagulantes/administração & dosagem , Ponte de Artéria Coronária/métodos , Antagonistas de Heparina/administração & dosagem , Antagonistas de Heparina/efeitos adversos , Heparina/administração & dosagem , Protaminas/administração & dosagem , Protaminas/efeitos adversos , Idoso , Anticoagulantes/efeitos adversos , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea , Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Sangue , Ponte Cardiopulmonar , Relação Dose-Resposta a Droga , Feminino , Hemostasia/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Tromboelastografia
19.
Expert Opin Drug Metab Toxicol ; 12(8): 897-909, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27223896

RESUMO

INTRODUCTION: Unfractionated heparin is a strongly anionic anticoagulant used extensively in medicine to prevent blood clotting. In the case of an emergency bleeding in response to heparin, the protamine sulfate is administered. Despite its extensive clinical use, protamine may produce life-threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. Recent studies have demonstrated new organ-specific complications of the heparin reversal with protamine. AREAS COVERED: Past and present knowledge of the mechanisms responsible for the toxicity of protamine and the most promising potential replacements of protamine in the different phases of development. EXPERT OPINION: Despite of the low therapeutic index, protamine is the only registered antidote of heparins. The toxicology of protamine depends on a complex interaction of the high molecular weight, a cationic peptide with the surfaces of the vasculature and blood cells. The mechanisms involve membrane receptors and ion channels targeted by different vasoactive compounds, such as nitric oxide, bradykinin or histamine. Unacceptable side effects of protamine have led to a search for new alternatives: UHRA, LMWP, and Dex40-GTMAC3 are in the preclinical stage; the two other agents (andexanet alfa and PER977) are already in the advanced clinical phases.


Assuntos
Antagonistas de Heparina/efeitos adversos , Heparina/efeitos adversos , Protaminas/efeitos adversos , Animais , Anticoagulantes/efeitos adversos , Antídotos/efeitos adversos , Antídotos/uso terapêutico , Desenho de Drogas , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Antagonistas de Heparina/uso terapêutico , Humanos , Protaminas/uso terapêutico
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