Sobredosis accidental de enoxaparina en un recién nacido / Enoxaparin overdose in a newborn

La enoxaparina es una heparina de bajo peso molecular utilizada en el período neonatal. Requiere menor monitoreo que la heparina estándar o no fraccionada, si bien es escaso el conocimiento actual acerca de su dosis y de los niveles terapéuticos en los neonatos. Además, existe una información muy limitada respecto del manejo de su sobredosificación en este grupo de edad. Se presenta el primer caso publicado en castellano de un neonato que recibió una dosis de enoxaparina diez veces superior a la terapéutica de forma accidental y en el que se administró una dosis aislada de protamina para revertir su efecto.

Enoxaparin is a low molecular weight heparin used in the neonatal period. It requires less monitoring than standard or unfractionated heparin, although current knowledge about its dose and therapeutic levels in neonates is scarce. In addition, there is very limited information about the management of overdose in this age group. We present the first case published in Spanish of a neonate who accidentally received a dose of enoxaparin ten times higher than the therapeutic one and an isolated dose of protamine to reverse its effect.

Act values after neutralization lower than pre-heparinization act leads to lower operative times, bleeding, and post-operative transfusions in cabg pa

Abstract Objective: To evaluate if lower activated coagulation time (ACT) value after neutralization than preoperative ACT value was effective in reducing bleeding, operative times, and post-operative transfusions in patients underwent coronary artery bypass grafting (CABG). Methods: Retrospective selection of 398 patients from January 2014 to May 2017. Patients were divided into 2 groups according to final ACT after neutralization: A - final ACT lower than preoperative ACT; and B - final ACT higher than or equal to preoperative ACT. Hemostatic time, intraoperative blood loss, ACT after final neutralization, mediastinal blood loss, and transfusion requirements were observed. Results: The hourly blood loss in the Group A was generally lower than in the Group B at first 3 hours, which has significant difference (P<0.05). However, there was no difference after 3 hours between the two groups. Operative time, intraoperative blood loss, mediastinal blood loss, transfusion requirements, and drainage in the first postoperative 12 hours in the Group A were lower than in Group B, which has significant difference (P<0.05). Conclusion: As a result, final ACT values lower than pre-heparinization ACT values are safe and lead to lower operative times, bleeding, and post-operative transfusions.

The influence of different dosage of protamine neutralization heparin on perioperation of on-pump coronary artery bypass grafting / 天津医药

Objective To investigate the effect of different doses of protamine neutralizing heparin on perioperation of on-pump coronary artery bypass graftting (CABG).Methods A total of 180 on-pump CABG patients hospitalized from January 2015 to November 2016 were randomly divided into three groups,the protamine group l,protamine group 2 and protamine group 3,60 patients in each group.Heparin (3 mg/kg) was used before extracorporeal circulation.After intracardiac operation was over,protamine was used to neutralize the heparin to adjust the activated clotting time (ACT) in protamine group 1,which was 10％ higher than that of intubation.Meanwhile,protamine group 2 was neutralized to equal to the ACT before intubation,and protamine group 3 was 10％ lower than that before the intubation.The differences of intraoperative and postoperative parameters were compared between the three groups.Results No death was found in the three groups during hospitalization.Comparing with protamine group 1 and protamine group 2,the time of operation,the ACT before the leaving operation room,the ACT of the first hour after returning to ICU,the amount of bleeding during operation,the time of closing and the amount of red blood for transfusion were decreased in protamine group 3 (P ＞ 0.05).The total amount of protamine for neutralizing and the ratio of protamine and heparin were significantly increased in protamine group 3 (P ＜ 0.05).The heart dysfunction after operation,perioperative myocardial infarction,pulmonary edema,pulmonary infection,renal dysfunction,poor wound healing,neurological complications,and time of in hospital stay showed no significant differences between three groups (P＞0.05).Conclusion ACT below 10％ of preoperation is safe,after neutralization of heparin by protamine,which can obviously reduce the bleeding,the time of sternal closure and the amount of red blood cell transfusion,showing a positive clinical significance.

Methylene blue to treat protamine-induced anaphylaxis reactions. An experimental study in pigs

ABSTRACT 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.

Catastrophic Bronchial Spasm Due to a Severe Anaphylactic Reaction to Protamine

Fatal anaphylactic reactions to protamine sulfate during cardiac surgery are very rare. We report a case of catastrophic bronchial spasm due to an anaphylactic reaction to protamine. The patient was managed successfully using a bronchodilator, steroid treatment, and extracorporeal membrane oxygenation.

Remoção Precoce do Introdutor Arterial Após Intervenção Coronária Percutânea por Via Femoral: Estudo de Segurança e Eficácia / Early Removal of the Arterial Sheath After Percutaneous Coronary Intervention Using the Femoral Approach: Safety and Efficacy Study

Introdução: Avaliamos a segurança e eficácia do uso de protamina, guiada pelo tempo de coagulação ativado, para a remoção imediata do introdutor arterial femoral em pacientes submetidos à intervenção coronária percutânea com heparina não fracionada, com o objetivo de propor um algoritmo para a prática clínica. Métodos: Estudo prospectivo, com pacientes consecutivos, com angina estável ou com síndrome coronariana aguda de baixo ou moderado risco. Comparamos os pacientes com a retirada precoce do introdutor arterial àqueles nos quais o introdutor foi retirado de acordo com o protocolo convencional. A decisão pela remoção precoce ou convencional do introdutor foi deixada a critério do operador. Resultados: O grupo de remoção precoce (n = 149) apresentou menor tempo de manuseio do sítio de punção que o grupo de remoção convencional (58,3 ± 21,4 minutos vs. 355 ± 62,9 minutos; p < 0,01), principalmente devido à redução do tempo até a retirada do introdutor (42,3 ± 21,1 minutos vs. 338,6 ± 61,5 minutos; p < 0,01), sem impacto sobre a duração da compressão femoral (16,0 ± 3,6 minutos vs. 16,4 ± 5,1 minutos; p = 0,49). Não houve trombose hospitalar de stent e nem diferença significativa na incidência de eventos vasculares ou hemorrágicos. A incidência de outras hemorragias, que levaram à hospitalização prolongada, foi menor no grupo de remoção precoce (1,3% vs. 5,1%; p = 0,05). Conclusões: O uso seletivo de uma abordagem, para a remoção imediata do introdutor femoral guiada pelo tempo de coagulação ativado e a administração de protamina, é seguro e eficaz em pacientes submetidos à intervenção coronária...

Introduction: We evaluated the safety and efficacy of protamine administration, guided by activated clotting time, for the immediate femoral arterial sheath removal in patients undergoing percutaneous coronary intervention with unfractionated heparin in order to propose an algorithm for clinical practice. Methods: Prospective study with consecutive patients with stable angina or low-to-moderate risk acute coronary syndrome. We compared patients with an early removal of the arterial sheath to those whose sheath removal was based on a standard protocol. Results: The early removal group (n = 149) had lower access manipulation time than the conventional group (58.3 ± 21.4 minutes vs. 355.0 ± 62.9 minutes; p < 0.01), mainly due to a reduced time to sheath removal (42.3 ± 21.1 minutes vs. 338.6 ± 61.5 minutes; p < 0.01), with no impact on the duration of femoral compression (16.0 ± 3.6 minutes vs. 16.4 ± 5.1 minutes; p = 0.49). There was no stent thrombosis during hospitalization and no significant differences in the incidence of major vascular or bleeding events. The incidence of other bleeding events leading to a prolonged in-hospital length of stay was lower in the early removal group (1.3% vs. 5.1%; p = 0.05). Conclusions: The selective use of an approach for immediate femoral sheath removal, based on activated clotting time guidance and protamine administration, is a safe and effective option in patients undergoing percutaneous coronary intervention by femoral access...

Pulmonary circulation effects of different ways to neutralize heparin on the congenital heart disease patients with pulmonary arteial hypertension after extracorporeal circulation surgery / 重庆医学

Objective To investigate pulmonary circulation effects of protamine different infusion ways on the acyanotic congeni -tal heart disease(CHD) patients with pulmonary arterial hypertension(PAH) after extracorporeal circulation surgery .Methods Se-lect 80 cases of the CHD patients prepared for extracorporeal circulation surgery ,according to the different routes of administration and with or without PAH ,80 patients are divided into 4 groups (n= 20) :A1(non-PAH ,aortic root administration) ,A2(non-PAH , central venous administration) ,B1(PAH ,aortic root administration ) ,B2 (PAH ,central venous administration) .pulmonary artery pressure(PAP) ,pulmonary venous pressure (PVP) ,central venous pressure (CVP) ,peak airway pressure (Ppeak) ,plateau airway pressure(Pmean ) at the time point of preoperative(T0) ,before infusion of protamine (T1) ,1 minute after infusion of protamine (T2) ,3 min (T3) ,5 min (T4) ,10 min (T5) ,15 min (T6) and 25 min (T7) were recorded .The level of venous blood thromboxane B2(TXB2) was detected .Results After infusion protamine ,the PAP ,PVP ,CVP ,Ppeak and Pmean of group A2 and group B2 are higher compared to group A1(P< 0 .05) and group B1(P< 0 .01) respectively ;Compared with preoperation (T0) ,the TXB2 in 4 groups increased obviously after infusion protamine (T2 to T7) (P< 0 .05) ;Compared with group A1 and group B1 ,the TXB2 of group A2 and group B2 increased more significantly (P< 0 .01) .Conclusion Patients with congenital heart disease after intracardi-al surgery with extracorporeal circulation use trace pump infusion protamine through the aortic root ,which have little effect on pul-monary circulation ,can significantly reduced TXB2 release compared with central vein administration ,it can avoid a high concentra-tion of protamine directly into the pulmonary circulation that can strongly stimulate the pulmonary vascular and tracheal smooth muscle .Especially in the CHD patients with PAH .

Study on the dosage of protamine used in acidic environment after cardiopulmonary bypass in patients with congenital heart disease / 中国医师杂志

ObjectiveTo investigate the dosage of protamine to counteract heparin in patients with different pH values of after - surgery plasma of congenital heart defect.MethodsThe clinical data of 108 patients during March 2011 to April 2011 with congenital heart diseases who underwent cardiopulmonary bypass(CPB) surgery were reviewed.The volumes of chest tube drainage were analyzed to investigate the dosage of protamine in patients with different pH values in plasma.ResultsThe dosages of protamine and the volumes of chest tube drainage[ ( 136.8 ± 22.8 ) ml] in patients with an acidic environmental plasma were higher than the patients in another group [ ( 112.6 ± 22.7 ) ml ] ( P＜ 0.01 ).In patients with non-acidic environments,the mean ratio of dosage of protamine to heparin was 1.23:1 ; meanwhile in patients with pH＜7.30 or base excess (BE) ＜ -6,the mean ratio was 1.86:1.It suggested the dosage of protamine increased significantly in patients with an acidic environmental plasma.ConclusionsDifferent plasma pH values could change the dosage of protamine after cardiopulmonary bypass,and the acidic environment would increase the dosage of protamine and increase the volume of chest tube drainage after surgery.When pH ＜ 7.30 or BE ＜ - 6 at the end of CPB,to correct acid-base balance first and then calculate the dose of protamine was recommended.

Effect of miR-29b transfected by anti-TGF-βⅡR ScFv/Ck/tP fusion protein on liver fibrosis / 中国医师杂志

Objective To observe the transfection efficiency and anti-fibrotic effect of miR-29b transfected by anti-TGF-β Ⅱ R ScFv/Ck/tP fusion protein (new vector) in hepatic stellate cell (HSC),and to provide a new vector in gene therapy for liver fibrosis.Methods The liposome vector,new vector,and lentiviral vector were used as transfection reagents to transfect miR-29b into HSC.Transfection efficiency was observed under fluorescence microscope and flow cytometry.Collagen α1 (Ⅰ) mRNA and protein expression in different groups were analyzed by real-time RT-PCR and Western Blot,respectively.Results Compared to the control,transfection efficiencies in lentiviral vector,new vector,and liposome vector groups were about 70％,58％,and 29％,respectively.Collagen α1 (Ⅰ) mRNA expression in lentiviral vector,new vector,and liposome vector groups was decreased by about 70％,50％,and 38％,respectively ((t =6.316,P ＜0.01 ; t =4.082,P ＜0.01 ; t =3.014,P ＜0.05).Collagen α1(Ⅰ) protein expression in lentiviral vector,new vector,and liposome vector groups was decreased by about 59％,41％,and 27％,respectively (t =4.209,P ＜0.01; t =4.033,P ＜0.01; t =2.842,P ＜0.05).Conclusions The new vector constructed by us has a high transfection efficiency.MiR-29b transfected by the new vector has a good anti-liver fibrosis effect.

Trombocitopenia induzida por heparina: revisão da literatura / Heparin-induced thrombocytopenia: a literature review

O presente trabalho teve como objetivo realizar revisão literária a fim de obter informações atualizadas sobre a trombocitopenia induzida por heparina, alteração que acomete cerca de 1 a 5% dos pacientes expostos à heparina, por período de 5 a 21 dias. O estudo baseou-se em pesquisa bibliográfica sobre a patogenia com ênfase nas manifestações clínicas, diagnóstico e manejo terapêutico. Tal doença é classificada em tipos I e II, clássica e imune, respectivamente. Normalmente não apresenta sintomatologia, apenas raras manifestações hemorrágicas. O diagnóstico inicial é clínico, confirmado por testes laboratoriais, como o teste de ELISA. O tratamento para a trombocitopenia, tipo I, se resume à suspensão da terapia heparínica e monitorização do paciente. Já no tipo II, deve-se administrar ao paciente protamina, agente que neutraliza a ação da heparina. Pode-se administrar também inibidor da trombina, o qual reverte a geração exacerbada de trombina, contribuindo para que o paciente não desenvolva complicações trombóticas. Sendo assim, conclui-se que a trombocitopenia induzida por heparina é uma complicação comum em pacientes submetidos à heparinização, indiferentemente da doença de base e que, se houver suspeita de trombocitopenia, é aconselhada abordagem adequada, incluindo a suspensão precoce da heparina.

This study aimed to perform a literary review in order to obtain updated information on the heparin-induced thrombocytopenia, an alteration that affects approximately 1-5% of patients exposed to heparin within a period of 5 to 21 days. The study was based on a literature review on that pathogenesis emphasizing its clinical manifestations, diagnosis and therapeutic management. Such disease is classified as type I and II, classical and immune, respectively. There are usually no symptoms, only rare hemorrhagic manifestations. The initial diagnosis is clinical, confirmed by laboratory tests such as ELISA. Treatment for thrombocytopenia type I is based on suspension of heparin therapy and patient monitoring. On the other hand, in type II, protamine must be administered to the patient, once it is an agent that counteracts the heparin action. An inhibitor of thrombin can also be administered, which reverses the exaggerated generation of thrombin, and avoids the development of thrombotic complications for the patient. Therefore, we conclude that the heparin-induced thrombocytopenia is a common complication in patients who were submitted to heparinization, regardless of the underlying disease, and if there is any suspicion of thrombocytopenia, an adequate approach should be taken, including early suspension of heparin.

A new experimental model for inducing interstitial cystitis by oxidative stress using intravesical instillation of a nitric oxide donor gel / Novo modelo experimental de indução de cistite intersticial por estresse oxidativo utilizando instilação intravesical de gel doador de óxido nítrico

Objective: The aim of this study was to develop an experimental model of inducing interstitial cystitis through intravesical instillation of a polymeric solution containing the NO donor S-nitrousglutathione (GSNO) and to compare it to the experimental interstitial cystitis induced by vesical instillation of protamine and potassium chloride. Methods: A total of 40 female Wistar rats were used and divided into four groups: 1 - ten rats treated with saline solution + GSNO; 2 - ten rats treated with saline solution + polymeric solution (without GNSO); 3 - ten rats treated with protamine sulphate + KCl; 4 - ten rats treated with protamine sulphate + GSNO. The rats received one application (five animals in each group) or three applications (five animals in each group) of the corresponding substance through intravesical instillation, and after six days (five animals in each group) or nine days (five animals in each group) they were euthanized and their bladders were removed for macroscopic evaluation and histological study. Results: In the macroscopic evaluation edema and hyperemia of the mucosa were observed in 2 (22%) animals in Group 1, in no (0%) animal in Group 2, in 10 (100%) animals in Group 3, and in 5 (50%) animals in Group 4. In the protamine + KCl group and in saline + GSNO, similar effects were observed in the bladder wall. The animals in Group 2 (saline + polymeric solution) showed significantly less vascular congestion compared to the other groups after 9 days of the instillation (p = 0.0035). Significant fibrosis was observed in Groups 3 and 4, 6 days (p = 0.3781) and 9 days (p = 0.0459) after instillations, when compared to controls (Group 2). All groups presented neutrophilic infiltrate of variable intensity, 6 days after instillations (p = 0.7277). After 9 days, there was a regression of the infiltrate, with no evidence of accentuated neutrophilic reaction in all the groups (p = 0.2301). Conclusions: The inflammatory response to bladder instillation with an aqueous solution of S-nitrousglutathione was very similar to that induced by bladder instillation of protamine and KCl. Instillation of an aqueous solution of S-nitrousglutathione can be considered a new model for experimental induction of interstitial cystitis.

Objetivo: O objetivo deste estudo foi o desenvolvimento de um modelo experimental para a indução de cistite intersticial, por meio da instilação vesical de uma solução polimérica de gel doador de óxido nítrico S-nitrosoglutationa (GSNO), e compará-lo ao modelo experimental para a indução da cistite intersticial por instilação vesical de protamina e cloreto de potássio. Métodos: Foram utilizadas 40 ratas Wistar, divididas em quatro grupos: 1 - dez ratas tratadas com solução salina + GSNO; 2 - dez ratas tratadas com solução salina + solução de polímeros (sem GNSO); 3 - dez ratas tratadas com sulfato de protamina + KCl; 4 - dez ratas tratadas com sulfato de protamina + GSNO. As ratas receberam uma aplicação (cinco animais em cada grupo) ou três aplicações (cinco animais em cada grupo) da substância correspondente através de instilação vesical, e após seis dias (cinco animais em cada grupo) ou nove dias (cinco animais em cada grupo) foram sacrificadas, e a bexiga foi removida para exame macroscópico e estudo histológico. Resultados: Na avaliação macroscópica observou-se edema e hiperemia da mucosa em 2 animais (22%) do Grupo 1, em nenhum animal (0%) do Grupo 2, em 10 animais (100%) do Grupo 3, e em 5 animais (50%) do Grupo 4. No grupo protamina + KCl e no grupo solução salina + GSNO, observamos efeitos semelhantes sobre a parede da bexiga. Os animais do Grupo 2 (salina + polímeros) apresentaram significantemente menos congestão vascular que os dos outros grupos após 9 dias de instilação (p = 0,0035). Observou-se fibrose significante nos Grupos 3 e 4, 6 dias (p = 0,3781) e 9 dias (p = 0,0459) após as instilações, quando comparados com o grupo controle (Grupo 2). Todos os grupos apresentaram infiltrados neutrofílicos de intensidade variável, 6 dias após as instilações (p = 0,7277). Após 9 dias, observou-se regressão do infiltrado, sem evidência de acentuada reação neutrofílica em todos os grupos (p = 0,2301). Conclusão: A resposta inflamatória à instilação da bexiga com uma solução aquosa de S-nitroglutationa foi muito semelhante àquela induzida pela instilação de protamina e KCl. A instilação de uma solução aquosa de S-nitroglutationa pode ser considerada um novo modelo experimental para a indução da cistite intersticial.

Urinary glycosaminoglycans excretion and the effect of dimethyl sulfoxide in an experimental model of non-bacterial cystitis

PURPOSE: We reproduced a non-bacterial experimental model to assess bladder inflammation and urinary glycosaminoglycans (GAG) excretion and examined the effect of dimethyl sulfoxide (DMSO). MATERIALS AND METHODS: Female rats were instilled with either protamine sulfate (PS groups) or sterile saline (control groups). At different days after the procedure, 24 h urine and bladder samples were obtained. Urinary levels of hyaluronic acid (HA) and sulfated glycosaminoglycans (S-GAG) were determined. Also to evaluate the effect of DMSO animals were instilled with either 50 percent DMSO or saline 6 hours after PS instillation. To evaluate the effect of DMSO in healthy bladders, rats were instilled with 50 percent DMSO and controls with saline. RESULTS: In the PS groups, bladder inflammation was observed, with polymorphonuclear cells during the first days and lymphomononuclear in the last days. HA and S-GAG had 2 peaks of urinary excretion, at the 1st and 7th day after PS injection. DMSO significantly reduced bladder inflammation. In contrast, in healthy bladders, DMSO produced mild inflammation and an increase in urinary HA levels after 1 and 7 days and an increase of S-GAG level in 7 days. Animals instilled with PS and treated with DMSO had significantly reduced levels of urinary HA only at the 1st day. Urinary S-GAG/Cr levels were similar in all groups. CONCLUSIONS: Increased urinary levels of GAG were associated with bladder inflammation in a PS-induced cystitis model. DMSO significantly reduced the inflammatory process after urothelial injury. Conversely, this drug provoked mild inflammation in normal mucosa. DMSO treatment was shown to influence urinary HA excretion.

Effect of "Bushen Huoxue Xiezhuo" decoction on growth of rat glomerular epithelial cells / 中国病理生理杂志

AIM: To examine the effect of protamine sulfate, lipopolysaccharide(LPS),tumor necrosis factor(TNF), epidermal growth factor(EGF) and " Bushen Huoxue Xiezhuo" (BHX) decoction on the proliferation of extracorporeal cultured rat glomerular epithelial cells (GEC). METHODS: Their action on the proliferation of rat GEC were investigated using the -TdR incorporation. Meanwhile, the serum of rats treated with BHX decoction was extracted pharmacologically and its effects on the growth of GEC were also studied. RESULTS: LPS, protamine sulfate, TNF-? and EGF could significantly inhibit the -TdR incorporation of GEC in a dose- and time-dependent manner. However, this inhibition could be efficiently reversed by the serum containing BHX decoction. CONCLUSION: GEC is one of the main target cells on which BHX decoction act, and the protection on GEC might be one of the mechanisms underlying the role of BHX decoction in preventing the progression of nephrosis.

THE EFFECT OF HEPARIN AND PROTAMINE ON THE EXPRESSION OF PLATELET MEMBRANE GLYCOPROTEIN / 解放军医学杂志

The aim of this study is to invistigate the effects of heparinization and the reversal of heparin activity with protamine on platelet function during extracorporeal cardiopulmonary bypass. The venous blood of 10 healthy volunteers was collected in tubes containing 3 2% trisodium citrate or 25??/ml heparin. The expression of P selectin (a secretion marker of platelets) and activated fibrinogen receptor GP Ⅱb Ⅲa (an aggregation marker of platelets) on normal platelets in response to the treatment with heparin and protamine in vitro were examined using whole blood flow cytometry. The results showed that heparin (5～50?g/ml) could increase adenosine diphosphate (ADP) induced expression of P selectin and GPⅡb Ⅲa in a dose dependent manner ( P