低氧性肺血管收缩反应研究进展

本论述了低氧性肺血管收缩反应的生产部位，与肺血管内皮细胞的关系，阐明了炎性介质在低氧性肺血管收缩反应中的作用可能有限，强调低氧性肺血管收缩反应的发生机制可有是低氧通过影响肺动脉平滑肌细胞氧化还原代谢状态，最终抑钾离子通道活性，使肺动脉平滑肌细胞膜去极化，兴奋性增高，肺血管收缩所致。     

鱼精蛋白对心血管的毒性反应及其防治措施

鱼精蛋白在临床上被用来中和肝素，而其对体循环、肺循环的毒性作用不容忽视。本文对鱼精蛋白的毒性反应机制及预防方法作一综述。     

低氧性肺血管收缩反应研究进展

本文论述了低氧性肺血管收缩反应的产生部位,与肺血管内皮细胞的关系,阐明了炎性介质在低氧性肺血管收缩反应中的作用可能有限,强调低氧性肺血管收缩反应的发生机制可能是低氧通过影响肺动脉平滑肌细胞氧化还原代谢状态,最终抑制钾离子通道活性,使肺动脉平滑肌细胞膜去极化,兴奋性增高,肺血管收缩所致。     

体外循环心脏手术鱼精蛋白反应

体外循环结束时要用鱼精蛋白中和肝素的抗凝作用，然而用鱼精蛋白时常会导致严重的反应，包括心脏功能抑制，血流动力学紊乱，肺血管及支气管痉挛和过敏反应等。本文对其产生的机理及防治措施的最新研究进展作了介绍。     

升主动脉注射鱼精蛋白对体外循环心脏直视手术婴儿肺通透性指数及血浆血栓素A2浓度的影响

目的探讨经升主动脉注射鱼精蛋白对体外循环心脏直视手术婴儿肺通透性指数及血清血栓素A2浓度的影响,进一步证实其肺保护作用。方法选择60例（年龄≤12个月,体质量≤10 kg）在深圳市儿童医院行体外循环心脏直视手术的先天性心脏病患儿,按随机数字表法分为实验组（升主动脉组,n=30例）和对照组（中心静脉组,n=30例）,比较两组体外循环前及注射鱼精蛋白后6 h肺通透性指数的变化、体外循环前及注射鱼精蛋白后1 h血清血栓素A2浓度。结果实验组注射鱼精蛋白6 h后肺通透性指数明显低于对照组,差异有统计学差异（0.021±0.008 vs.0.039±0.006,P〈0.05）;实验组注射鱼精蛋白1 h后血清血栓素A2水平低于对照组,差异有统计学意义[（43.3±2.5）ng/L vs.（64.2±2.1）ng/L,P〈0.05]。结论经升主动脉注射鱼精蛋白能够减轻婴幼儿体外循环心脏直视手术肺组织损伤,是一种良好的肺保护措施。     

鱼精蛋白对心血管的毒性反应及其防治措施

鱼精蛋白在临床上被用来中和肝素,而其对体循环、肺循环的毒性作用不容忽视.本文对鱼精蛋白的毒性反应机制及预防方法作一综述.     

鱼精蛋白中和肝素致严重低血压五例报告

鱼精蛋白中和肝素致严重低血压五例报告金咏梅，吕琪，徐志娟体外循环停机后必须以鱼精蛋白中和肝素，由于鱼精蛋白是一种异性蛋白质，使用后易引起一些副反应，严重者血压下降，心率减慢，甚至心跳骤停。我们先后遇到５例使用鱼精蛋白中和肝素过程中出现严重低血压反应的...     

急性吸烟使人的肺血管反应性增强——前列腺素、白三烯的介导作用

应用肺阻抗血流图测定肺血管收缩反应的方法,研究44名健康男性肺血管对缺氧有收缩反应性的自愿者,由急性吸烟引起的缺氧性肺血管收缩反应性的变化,并探讨前列腺素和白三烯在其中的作用。结果:急性吸烟(15分钟内吸完香烟3支)使缺氧性肺血管收缩反应明显增强,服环氧合酶抑制剂(消炎痛,25毫克日3次,共4天)或脂氧合酶抑制剂(乙胺嗪,200毫克日3次,共3天)均可使由急性吸烟所致的肺血管反应增强显著减弱。前列腺素和白三烯在急性吸烟引起人的缺氧性肺血管反应性的增强中起介导作用。     

氧自由基对肺血管的影响及其作用机制

氧自由基在某些肺疾病发生中的作用已不容置疑,但是否与缺氧性肺血管收缩和肺动脉高压的发生有关尚不十分清楚。本文介绍氧自由基对肺血管的影响及其作用机制。     

应用小剂量“士的年”注射減輕或消除鏈霉素毒性反应30例的初步观察(摘要)

本文报告30例肺结核患者应用士的年注射使链霉素毒性反应得到减轻或消失的疗效观察。现作一简单介绍如下,以供同道参考。 30例中,男性27例,女性3例,年龄在20～56岁之间,全部病例应用链霉素的剂量均为每天1克,本文统计内的病例均发生不同程度的毒性反应。出现毒性反应时间长短不一,19例于开始注射链霉素1～3天即发生反应,4例于注射4～6天后发生反应,5例于注射7～10天后出现毒性反应,1例于注射12天后发生反应,另一例于注射18天后才发生反应。链霉     

Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: should methylene blue be the treatment of choice?

Clinical and experimental observations prove that heparin-neutralizing doses of protamine increase pulmonary artery pressures and decrease systemic BP. Protamine also increases myocardial oxygen consumption, cardiac output, and heart rate, and decreases systemic vascular resistance. These cardiovascular effects have clinical consequences that have justified studies in this area. Protamine adverse reactions usually have three different categories: systemic hypotension, anaphylactoid reactions, and catastrophic pulmonary vasoconstriction. The precise mechanism that explains protamine-mediated systemic hypotension is unknown. Four experimental protocols performed at Mayo Clinic, Rochester, MN, studied the intrinsic mechanism of protamine vasodilation. The first study reported in vitro systemic and coronary vasodilation after protamine infusion. The second in vitro study suggested that the pulmonary circulation is extensively involved in the protamine-mediated effects on endothelial function. The third study, carried out in anesthetized dogs, reported the methylene blue and nitric oxide synthase blockers neutralization of the protamine vasodilatatory effects. The fourth study suggested that protamine also causes endothelium-dependent vasodilation in heart microvessels and conductance arteries by different mechanisms including hyperpolarization. Reviewing these experimental results and our clinical experience, we suggest methylene blue as a novel approach to prevent and treat hemodynamic complications caused by the use of protamine after cardiopulmonary bypass. In the absence of prospective clinical trials, a growing body of cumulative clinical evidence suggests that methylene blue may be strongly considered as a therapeutic approach in the treatment of distributive shock.     

Cellular mechanisms of pulmonary vasoconstriction in an experimental model of protamine reversal of heparin

The neutralisation of heparin by protamine can cause life-threatening pulmonary hypertension. We studied this reaction in animal experimental models (sheep and rat) to determine the cellular mechanisms of the pulmonary vasoconstriction. The heparin-protamine reaction (H-P) with pulmonary hypertension (peak of mean pulmonary artery pressure = 57.3 +/- 2.2 mmHg), decreased cardiac output (-20%), leukopenia (-30%) and plasma release of high concentrations of thromboxane B2 (6.03 +/- 0.03 ng/ml) was constantly observed in sheep. The reaction was identical in sheep with induced thrombocytopenia by administration of antiplatelet antibodies. On the other hand, the neutralisation of heparin by protamine in rats did not cause thromboxane release or pulmonary vasoconstriction although the leukopenia was identical to that observed in sheep. Therefore, the platelets and white blood cells did not seem to cause the pulmonary vasoconstriction induced by the H-P complexes. The inter-species difference observed suggests that pulmonary intravascular macrophages may be responsible for the liberation of eicosanoids and acute pulmonary vasoconstriction occurring during the neutralisation of heparin by protamine.     

Successful cardiopulmonary bypass in diabetics with anaphylactoid reactions to protamine.

Two insulin dependent diabetics with previous anaphylactic like (anaphylactoid) reactions to protamine underwent successful cardiopulmonary bypass for coronary artery surgery. Platelet concentrates instead of protamine were used to neutralise their systemic heparinisation. In both cases the anaphylactoid reactions first became apparent after administration of protamine sulphate at the end of cardiac catheterisation. These cases show that adverse reactions to protamine need not be a contraindication to cardiopulmonary bypass and cardiac surgery and emphasise that this condition should be considered in all patients with a history of previous protamine exposure or one which may be associated with anaphylactoid reactions to protamine.     

Complement activation and anaphylactoid response to protamine in a child after cardiopulmonary bypass

A 2 1/2 year old boy had a sudden, severe, and unexpected anaphylactoid reaction after an otherwise uncomplicated repair of a partial atrioventricular septal defect. The reaction, comprising haemorrhagic pulmonary oedema and peripheral circulatory collapse, followed neutralisation of heparin by protamine. Measurements of serum complement (C3 and C4) concentrations suggested that a pronounced consumption of complement occurred during the adverse response.     

Complement activation and anaphylactoid response to protamine in a child after cardiopulmonary bypass.

A 2 1/2 year old boy had a sudden, severe, and unexpected anaphylactoid reaction after an otherwise uncomplicated repair of a partial atrioventricular septal defect. The reaction, comprising haemorrhagic pulmonary oedema and peripheral circulatory collapse, followed neutralisation of heparin by protamine. Measurements of serum complement (C3 and C4) concentrations suggested that a pronounced consumption of complement occurred during the adverse response.     

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.     

Thromboxane receptor blockade prevents pulmonary hypertension induced by heparin-protamine reactions in awake sheep

We used competitive thromboxane A2-prostaglandin endoperoxide receptor blockade (SQ 30,741) as a probe to evaluate the role of thromboxane in ovine pulmonary vasoconstriction associated with protamine reversal of heparin anticoagulation. Control heparin-protamine reactions induced rapid release of thromboxane into arterial plasma (more than 1 ng/ml plasma), a 2.5-fold increase of pulmonary artery pressure, a 20% decrease of PaO2, and a 30% reduction in arterial white blood cell concentration. After giving SQ 30,741 despite similar thromboxane release into arterial plasma after heparin-protamine challenge, acute pulmonary hypertension was significantly reduced when 94% of pulmonary vascular smooth muscle thromboxane receptors were occupied with SQ 30,741 (p less than 0.01 at 1 minute after protamine versus control heparin-protamine reaction) and was completely abolished by a 10 mg/kg i.v. bolus (p less than 0.0001 at 1 minute after protamine versus control). Peripheral leukopenia was not affected by SQ 30,741 prophylaxis, but hypoxemia was prevented. We conclude that thromboxane causes pulmonary vasoconstriction in ovine heparin-protamine-induced pulmonary hypertension. Pulmonary vasoconstriction and hypoxemia can be completely prevented by thromboxane receptor blockade.     

The importance of aprotinin and pentoxifylline in preventing leukocyte sequestration and lung injury caused by protamine at the end of cardiopulmonary bypass surgery

BACKGROUND: Protamine has adverse effects on pulmonary gas exchange during the postoperative period. The objective of this study was to investigate the importance of aprotinin and pentoxifylline in preventing the leukocyte sequestration and lung injury caused by protamine administered after the termination of cardiopulmonary bypass (CPB). METHODS: Participants (n = 39) were allocated into three groups at the termination of CPB: Group 1, (control group, n = 16); Group 2 (aprotinin group, n = 12), who received protamine + aprotinin (15,000 IU/kg); and Group 3 (Pentoxifylline group, n = 11), who received protamine + pentoxifylline (10 mg/kg). Leukocyte counts in pulmonary and radial arteries were determined after the termination of CPB and before any drug was given (t1), and 5 minutes (t2), 2 hours (t3), 6 hours (t4) and 12 hours (t5) after the administration of protamine. Alveolar-arterial O2 gradient (A-aO2) and dynamic pulmonary compliance were measured at t1, t2 and t3. RESULTS: In the control group, an increase in pulmonary leukocyte sequestration was observed 5 minutes and 2 hours after protamine administration, after which this difference disappeared. No significant degree of pulmonary sequestration was detected in any measurements after protamine was administered in the aprotinin and pentoxifylline (PTX) groups. Dynamic lung compliance was 50.1, 45.2 and 47.2 ml/cm H2O in the control group, 49.2, 61.1 and 56.3 ml/cm H2O in the aprotinin group, and 49.5, 54.5 and 50.4 ml/cm H2O in the PTX group. The A-aO2 gradient was 212.2, 263.3 and 254.3 mm Hg in the control group, 209.4, 257.1 and 217.3 mm Hg in the aprotinin group, and 211.3, 260.8 and 219.2 mm Hg in the PTX group. CONCLUSION: Aprotinin and PTX treatments have favourable effects on lung function by reducing protamine-induced leukocyte sequestration into lungs at the end of CPB.     

Effects of protamine on nitric oxide level in the pulmonary circulation.

Protamine reversal of heparin anticoagulation often causes systemic hypotension by releasing nitric oxide (NO) from vascular endothelium. We investigated the hypothesis that protamine prevents severe pulmonary vasoconstriction by increasing NO. Twenty patients undergoing elective coronary artery bypass graft surgery were included in the study. Nitrite and nitrate levels--as end-metabolites of NO--were measured in blood samples obtained before and after protamine administration. Mean arterial pressure, heart rate, mean pulmonary artery pressure, central venous pressure and left atrial pressure were noted as hemodynamic data. Nitrite levels were 4.64 +/- 0.67 mumol in the right atrium and 4.84 +/- 0.95 mumol in the left atrium before protamine administration. The difference was insignificant statistically. These measurements were 4.85 +/- 0.92 in the right atrium and 5.28 +/- 0.66 mumol in the left atrium after protamine administration. This increase was significant (p < 0.05). The measurements of nitrate levels were completely parallel with those of nitrite. Mean arterial pressures were 78.9 +/- 7.59 mm-Hg before protamine and 74.1 +/- 8.55 mm-Hg after protamine (p = 0.03). The changes in other hemodynamic parameters were not significant. Protamine augments NO production and prevents the pulmonary circulation from possible vasoconstriction.     

Hemostatic effects of low-dose protamine following cardiopulmonary bypass

Twenty-eight patients undergoing cardiac surgery were prospectively studied and were assigned to two groups. The patients received 0.8- (Group L) or 2.0-fold (Group H) dose of protamine for the neutralization after cardiopulmonary bypass (CPB) which was determined by Hepcon HMS(R) assay system in which the reagent chamber containing the concentration of protamine that completely neutralized the heparin had the shortest clotting time. Mean dose of protamine was 1.60 +/- 0.50 mg kg(-1) in Group L, and 3.56 +/- 1.48 mg kg(-1), respectively. Activated clotting times (ACT) were comparable between the two groups through this study period. In Group H, platelet counts significantly decreased to 69% of that before protamine administration, and plasma platelet factor 4 level significantly increased to approximate 2-fold of that before protamine administration just after protamine administration, respectively. However, these phenomena were not observed in Group L. In addition, these hemostatic changes occurred transiently just after protamine administration. We conclude that the low-dose protamine may prevent transient platelet depletion following CPB. Low-dose protamine can neutralize anticoagulation effect of heparin sufficiently and may mitigate protamine-induced platelet dysfunction.