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(Chest. 2002;122:1061-1066.)
© 2002 American College of Chest Physicians

Catastrophic Cardiovascular Adverse Reactions to Protamine Are Nitric Oxide/Cyclic Guanosine Monophosphate Dependent and Endothelium Mediated*

Should Methylene Blue Be the Treatment of Choice?

Fernanda Viaro, BSc; Marcelo B. Dalio, MD and Paulo Roberto B. Evora MD, PhD

* From the Division of Experimental Surgery, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Correspondence to: Paulo Roberto B. Evora, MD, PhD, Rua Rui Barbosa, 367, Apt. 15, 14015-120 Ribeirão Preto, SP, Brazil; e-mail: prbevora{at}keynet.com.br


   Abstract
TOP
 Abstract
Introduction
 Protamine, Endothelium Function,...
 Clinical Implications
 References
 
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.

Key Words: anaphylaxis • cardiopulmonary bypass • endothelium • heparin • nitric oxide • protamine


   Introduction
TOP
 Abstract
 Introduction
Protamine, Endothelium Function,...
 Clinical Implications
 References
 
Protamine sulfate is a polycationic peptide that is used in order to reverse the anticoagulant effects of heparin. Frequently, systemic hypotension is an undesired side effect of protamine infusion, sometimes leading to severe shock, due to a diminished peripheral vascular resistance.1 2 3 4 Protamine can also cause catastrophic pulmonary hypertension in susceptible individuals.5 6

The heparin/protamine interaction is a topic of interest due to its use during cardiopulmonary bypass. These drugs are prescribed to > 2,000,000 patients every year. From clinical and experimental data, heparin-neutralizing doses of protamine increase pulmonary artery pressures and decrease systemic BP, myocardial oxygen consumption, cardiac output, heart rate, and systemic vascular resistance. These cardiovascular effects have clinical consequences that justified studies in this area.

Transitory hypotension in animals after protamine infusion is an experimental effect observed for > 50 years.4 7 8 However, until the development of cardiac surgery, protamine-induced hypotension was an experimental finding of little clinical relevance. As protamine became largely used in clinical and surgical procedures, its reactions frequently led to severe systemic hypotension, pulmonary hypertension, and shock.1 2 3 9 10 These consequences can be potentially dangerous, especially during the immediate period after cardiopulmonary bypass, when intravascular volumes are not constant and cardiac function may be impaired.

Protamine can also cause hemodynamic disturbance by means of anaphylactic reactions.4 11 12 Indeed, Horrow13 classified protamine adverse reactions in three different categories: systemic hypotension, anaphylactoid reactions, and catastrophic pulmonary vasoconstriction.

The precise mechanism that explains protamine-mediated systemic hypotension is unknown. However, it is suggested that protamine decreases peripheral vascular resistance,1 3 rather than depressing myocardial function.14 A well-controlled study1 with constant monitoring of cardiac output, systemic BP, and ventricular pressures of patients during protamine infusion after cardiopulmonary bypass established that protamine causes significant reduction in peripheral vascular resistance. Hypotension occurred when the increase in cardiac output was insufficient to offset the decreased peripheral resistance. A small reduction in left ventricle contractile activity is present only in patients with a decrease > 10 mm Hg in systemic BP.

Data suggest that protamine may cause coronary vasodilation.10 In an isolated perfused rabbit heart, protamine, 250 g/mL, infunded with heparin caused a marked transitory increase in coronary flow, but was sustained by protamine infusion alone. Several studies reported a strong relationship between protamine effects and endothelium function.15 19 28 29


   Protamine, Endothelium Function, and Nitric Oxide
TOP
 Abstract
 Introduction
 Protamine, Endothelium Function,...
Clinical Implications
 References
 
Four experimental protocols from Mayo Clinic, Rochester, MN, studied the intrinsic mechanism of protamine vasodilation suggesting the important role of endothelium and endothelium-derived relaxing factor (EDRF)/nitric oxide (NO). The first study reported in vitro systemic and coronary circulation vasodilation induced by EDRF/NO release after protamine infusion.15 According to the authors, prostacyclin cannot be implicated as a mediator of endothelium-dependent vasodilation to protamine because vascular relaxation is unaffected by the presence of indomethacin. Protamine is rich in the amino acid L-arginine, a precursor of EDRF/NO.16 Thus, protamine may stimulate synthesis and release of EDRF/NO by enhancing provision of the substrate L-arginine. However, two experimental findings contradict this hypothesis.15 First, the addition of very high L-arginine concentrations to the organ chamber bath with vascular rings does not induce endothelium-dependent vasodilation. However, this type of vasodilation is observed by the addition of poly-L-arginine (a high-molecular-weight polypeptide containing L-arginine). NG-monomethyl-L-arginine (L-NMMA), a competitive antagonist of NO synthesis from L-arginine,17 cannot block this effect and, it appears to be mediated by an EDRF-independent from NO.18 Second, protamine induces vasodilation even in the presence of high doses of heparin. Heparin is negative charged and forms strong ionic bonds with the positive-charged protamine, producing heparin-protamine complexes. These complexes are not expected to enter the endothelial cell because of their great size. Even with observation of heparin-protamine complexes, protamine produces vasodilation, in the same pattern of that noted without heparin. Thus, there is weak evidence that protamine induces EDRF/NO release by enhancing provision of its substrate L-arginine.15 It may be that protamine, free or complexed with heparin, acts on endothelial receptors, stimulating synthesis and release of EDRF/NO and concomitant systemic vasodilation (Fig 1 ).



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  		Figure 1.. Mechanism proposed of protamine-induced hypotension in the systemic circulation (schematic diagram). Protamine (either free or complexed with heparin) binds to an unidentified endothelial cell receptor that mediates the conversion of L-arginine to EDRF/NO. Abluminally released NO activates soluble guanilate cyclase in vascular smooth fibers, inducing cGMP-mediated relaxation (vasodilation). This results in a decrease in peripheral vascular resistance and hypotension. Luminally released NO can induce thrombolysis and inhibit platelet adhesion (adapted from Pearson et al15 ).

 
The second study19 reported that pulmonary circulation is extensively involved in protamine-mediated effects on endothelial function. In vitro organ chambers and canine pulmonary artery studies indicate that protamine induces endothelium-dependent vasodilation, instead of a vasoconstriction, as previously documented.13 As L-NMMA inhibits the protamine-induced pulmonary artery and systemic circulation vasodilation, it appears that EDRF/NO release is responsible for these effects. Prostacyclin is not a mediator of endothelium-dependent vasodilation to protamine because indomethacin does not alter vascular relaxation or the L-NMMA inhibitory effect. Heparin, in contrast to the systemic circulation, inhibits the endothelium-dependent vasodilation to protamine.19 However, this inhibitory effect can be overcome by higher doses of protamine, concluding that protamine complexed with heparin does not induce vasodilation. As in the systemic circulation, the precise mechanism is still unknown. The "L-arginine precursor" hypothesis of protamine-induced EDRF/NO release has little evidence, as exogenous addiction of L-arginine does not induce in vitro endothelium-dependent vasodilation.20 21 Also in this case, a more structured hypothesis is that protamine acts on endothelial receptors causing its effects (Fig 2 ). This hypothesis is also supported by the finding that bounded protamine cannot induce EDRF/NO release when complexed with heparin. These complexes would avoid the binding of protamine to the endothelial cell, by enzymatic competition or by changing the electrical conformation. Protamine, as discussed, can cause catastrophic pulmonary vasoconstriction.13 These idiosyncratic effects led many investigators to consider protamine as a pulmonary vasoconstrictor. Since the direct effect of protamine is vasodilation due to EDRF/NO release, it appears that this vasoconstriction may be secondary. It is possible that the protamine use for anticoagulation reversion causes release of thromboxane, which induces catastrophic pulmonary vasoconstriction.22 Pulmonary vasodilation, concomitant to the protamine-induced EDRF/NO release, may be an important compensatory protector mechanism against the constrictive autacoids effects generated during heparin neutralization. Such a mechanism might be dysfunctional in certain individuals who are at risk for pulmonary vasoconstriction after protamine infusion. It is possible that these individuals lose the ability of releasing EDRF/NO in the pulmonary circulation because of preexistent lesions or reperfusion lesion in the pulmonary endothelium. This could be a mechanism similar to that occurring in cardiac reperfusion lesion, in which coronary endothelium loses its ability of protecting itself against platelet-mediated vasoconstriction.23 24 If EDRF/NO synthesis is impaired, endogenous autacoids constrictor effects, in opposition, may increase. It is also possible that a lesion in the vascular endothelium may change the protamine vasodilator effect to a vasoconstrictor effect on vascular smooth fibers. Thus, protamine stimulates EDRF/NO release by the pulmonary artery endothelium. As comparable concentrations of heparin inhibit this effect, it is possible that protamine-mediated EDRF/NO release diminishes pulmonary vascular resistance, and may antagonize endogenous autacoid constrictor effects on pulmonary circulation (Fig 2) . However, one study25 establishes a controversy. Protamine does not alter the response of intracellular secondary messengers (cyclic guanosine monophosphate [cGMP], cyclic adenosine monophosphate) to the vasodilator sodium nitroprusside, atrial natriuretic peptide, isoproterenol, and forskolin. These experimental laboratory findings do not support the hypothesis that vascular smooth-muscle cells are susceptible to protamine-induced NO release. In isolated rat lungs, treatment with protamine resulted in a significant increase in vascular flow, but pretreatment with NO and L-NMMA resulted in no additional effect on protamine-treated lungs. Further studies are mandatory, because experimental protocols did not prove any defined flow modulator role for NO, Ca++, and cGMP secondary messengers.26 Otherwise, beside these experimental observations, it is proper to mention that inhaled NO is a selective pulmonary vasodilator that can prevent thromboxane-induced pulmonary hypertension during protamine reversion of heparin anticoagulation in lambs without causing systemic vasodilation.27



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  		Figure 2.. Mechanism proposed of protamine-induced hypotension in the pulmonary artery (schematic diagram). Free protamine binds to an unidentified endothelial cell receptor that mediates the conversion of L-arginine to EDRF/NO. Abluminally released NO activates soluble guanilate cyclase in vascular smooth fibers, inducing cGMP-mediated relaxation (vasodilation). This results in a decrease in pulmonary vascular resistance and hypotension. Luminally released NO can induce thrombolysis and inhibit platelet adhesion. L-NMMA can inhibit conversion of L-arginine into NO. In addition, heparin inhibits protamine ability to cause release of EDRF/NO, supposedly by forming complexes that avoid protamine binding to endothelial cell (adapted from Evora et al19 ).

 
The third study, carried out in anesthetized dogs, reported the methylene blue and NO synthase blockers neutralization of the protamine vasodilatatory effects.28 The protamine-heparin complex does not cause direct myocardial depression, but may lead to severe hypotension in vivo. The finding that hypotension can be blocked by inhibitors of the NO pathway confirms previous in vitro studies indicating that the effects of protamine are mediated, in part, by the vascular endothelium.15 19 Thus, this study introduces a novel approach to prevent or treat the hemodynamic complications caused by heparin reversal after cardiopulmonary bypass.

Finally, the fourth study29 suggested that protamine also causes endothelium-dependent vasodilation in heart microvessels and conductance arteries by different mechanisms. In conductance arteries, it occurs by NO release and in microvessels by endothelium-derived hyperpolarizing factor release.


   Clinical Implications
TOP
 Abstract
 Introduction
 Protamine, Endothelium Function,...
 Clinical Implications
References
 
The fact that protamine-induced hypotension can be blocked by NO inhibitors supports the evidence that protamine effects are endothelium mediated. Supported by experimental and our 7-year clinical experience, we have suggest methylene blue as a novel approach to prevent and treat hemodynamic complications caused by the use of protamine after cardiopulmonary bypass.30 Methylene blue has been used in Brazil to treat vasoplegic states related to cardiac surgery.31 32 The catastrophic cardiovascular collapse after protamine infusion to neutralize the heparin anticoagulation after cardiopulmonary bypass has been included in this therapeutic approach.

We reported the restoration of systemic vascular resistance employing methylene blue in six patients after cardiac surgery with and without cardiopulmonary bypass.31 32 33 All patients presented, during the immediate postoperative period, with tachycardia, oliguria, good peripheral perfusion, and important systemic arterial hypotension, which was not responsive to large doses of catecholamine infusion. The hemodynamic analysis found a compatible profile with systemic inflammatory response syndrome, with the mean index of systemic vascular resistance of 868 dyne·s·cm-5. Methylene blue, 1.5 mg/kg, was infunded by vein during 1 h to block NO action by inhibiting soluble guanylate cyclase. The systemic vascular tone compensation (systemic vascular resistance index = 1,693 dyne·s·cm-5, with normal arterial pressure and clinical performance) was effective and fast, improving the hemodynamics without affect cardiac output or pulmonary vascular resistance. The methylene blue clinical experiences has started in surgical stage in dramatic and during the immediate postoperative period.

In addition, we reported six patients in whom methylene blue was infunded to treat anaphylaxis induced by iodinate radiocontrast (five patients) and penicillin (one patient).34 The traditional therapeutics (high doses of epinephrine and corticosteroids) failed to reverse the cardiocirculatory collapse, urticaria, or angioedema. Four patients, because of severe shock severity, received methylene blue "bolus" infusion of 1.5 mg/kg (120 mg), followed by continuous infusion of another 120 mg diluted in glucose 5% in water. Two patients received only 30 to 40 min of continuous methylene blue infusion. The anaphylactic manifestation reversion was complete in 10 to 15 min. Methylene blue infusion elicited brief spontaneously reversed nodal cardiac rhythm in one patient. One hypertensive patient reported angina pectoris during infusion without any ECG manifestation or the necessity of coronary vasodilators to reverse the symptom. We recorded the hemodynamic data of two patients in whom anaphylactic shock developed because of radiocontrast use in the cardiovascular catheterization laboratory. 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.


   Footnotes
 
Abbreviations: cGMP = cyclic guanosine monophosphate; EDRF = endothelium-derived relaxing factor; L-NMMA = NG-monomethyl-L-arginine; NO = nitric oxide

Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo.

Received for publication August 14, 2001. Accepted for publication March 18, 2002.


   References
TOP
 Abstract
 Introduction
 Protamine, Endothelium Function,...
 Clinical Implications
 References
 

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