during open - heart surgery , protamine is used after weaning the patient from cardiopulmonary bypass ( cpb ) in order to reverse the anticoagulation effects of heparin .
however , protamine shows a wide spectrum of adverse effects , ranging from minimal cardiovascular deterioration to cardiovascular collapse , which can threaten the life of the patient .
a 54-year - old female with a history of gross hematuria due to acute tubular necrosis 1 month previously was admitted for symptomatic mitral regurgitation .
aorto - bicaval cpb was initiated , the patient was cooled to 32c , and antegrade blood cardioplegia was administered .
the patient underwent successful mitral valve annuloplasty with a 28-mm carpentier - edwards physio annuloplasty ring ( edwards lifesciences llc , irvine , ca , usa ) and the creation of new chordae with gore - tex 6 - 0 sutures .
the effects of heparin were reversed by the slow intravenous injection of 160.2 mg of protamine sulfate .
approximately 10 minutes after the completion of protamine administration , airway pressure was gradually increased under volume - controlled ventilation with a tidal volume of 350 ml .
approximately 30 minutes after the completion of protamine administration , tidal volume was 80 ml under pressure - controlled ventilation , and the peak inspiratory pressure was 40 cm h2o . at that time
, the patient s lung was not expanded in the operative field with manual ventilation .
her systolic pressure was down to 50 mm hg and oxygen saturation was down to 60% .
after 30 minutes of cpb assistance , the patient s hemodynamics had completely recovered , but her tidal volume was 170 ml with pressure - controlled ventilation , with a peak inspiratory pressure of 30 cm h2o . with extracorporeal membrane oxygenator ( ecmo ) assistance , the patient was transferred to the intensive care unit . following 4 hours of ecmo assistance ,
the patient s tidal volume was 380 ml under pressure - controlled ventilation , with a peak inspiratory pressure of 20 cm h2o and a positive end - expiratory pressure of 5 cm h2o .
after weaning from ecmo with 50% fio2 , arterial blood gas analysis showed a paco2 of 38 mm hg , a pao2 of 128 mm hg , and 98.7% o2 saturation .
the patient was transferred to the operating room for removal of the ecmo cannulae and wound closure .
the patient had an uneventful postoperative recovery and was discharged on the 22nd postoperative day .
protamine is a polycationic peptide that is used to reverse the anticoagulant effects of heparin , a group of low - molecular - weight proteins contained in fish sperm .
when injected intravenously , the basic protamine combines with the acidic heparin to form a neutral salt , thus eliminating the anticoagulation properties of heparin .
the incidence of such adverse reactions has been reported to vary from 0.06% to 10.6% . moreover ,
the incidence of catastrophic reactions to protamine during cardiovascular surgery has been reported to be 0.13% .
these include events , whether or not caused directly by protamine , that occurred within 30 minutes of the initiation of protamine , lasted longer than the 5-minute period of protamine infusion , and met one or more of the following criteria : ( 1 ) a decrease in systemic arterial blood pressure ( either systolic or mean , compared to baseline blood pressure before protamine administration ) after protamine administration of 25% of baseline or a decrease of 10% requiring inotropic medications , reinstitution of cpb , or use of an intra - aortic balloon pump ; an ( 2 ) increase in pulmonary arterial pressure of at least 25% resulting in a decrease of systemic arterial blood pressure as defined in ( 1 ) ; ( 3 ) non - cardiogenic pulmonary edema , defined as any decrease in pao2 requiring an increase in ventilatory support ( increase in the percent oxygen delivered , ventilator rate , or positive end - expiratory pressure ) in the absence of evidence of cardiac failure ( decreasing cardiac output or increase in pulmonary capillary wedge pressure ) ; and ( 4 ) bronchospasm ( the use of bronchodilator therapy for either an increase in peak inspiratory airway pressure of more than 5 mm hg or wheezing ) .
thromboxane is generated when complement activation produces a sufficient concentration of c5a anaphylatoxin fragments to elevate plasma levels .
clinically insignificant increases in pulmonary pressure without hemodynamic changes are not considered to be adverse events .
this process may lead to cross - linking with the antibody surfaces , which then initiates a process of cell degranulation .
adverse reactions may also be associated with the interaction between protamine and complement - fixing antiprotamine immunoglobulin g ( igg ) antibodies .
moreover , adverse responses to protamine seem to be related to the formation of protamine - heparin complexes , which appear to activate the classical complement cascade with the subsequent generation of anaphylatoxins . a significant risk of in - hospital mortality exists among patients who suffer an adverse intraoperative event after protamine administration .
protamine - related events may therefore account for a meaningful proportion of mortalities after cpb .
although a causal link between protamine and subsequent adverse events can not be made definitively without a randomized trial , adverse events after protamine administration can be viewed as markers of subsequent mortality .
further studies to confirm these findings , as well as the development and testing of protamine alternatives or prophylactic therapies , are required to determine if mortality can be reduced .
the american hospital formulary service recommendation for dosing states that no more than 50 mg of the drug should be administered in any 10-minute period . in the absence of a safe and efficient agent for the reversal of heparin , when the risk of adverse reactions to protamine overrides the risk of extensive bleeding , spontaneous reversal of heparin is acceptable .
the treatment of adverse responses to protamine is based on supporting the affected organs and reducing the effects of histamine .
aggressive resuscitative efforts must be initiated immediately , including the restoration of cpb when possible .
viaro et al .   suggested the use of methylene blue as a novel experimental approach to prevent and treat hemodynamic complications caused by the use of protamine after cpb . according to those authors
, 6 patients presented anaphylactoid adverse reactions to protamine and were successfully treated with a methylene blue bolus infusion of 1.5 mg / kg ( 120 mg ) , followed by continuous infusion of another 120 mg diluted in 5% dextrose .
patients who have had previous protamine injections during cardiovascular surgery , patients with diabetes who are taking protamine - containing insulin , patients with allergies to fish , and vasectomized patients potentially should be routinely tested for such sensitivity and be appropriately premedicated .
additionally , when a severe adverse reaction to protamine is suspected , we postulate that heparin should not be reversed , despite a greater risk of bleeding and subsequent re - exploration .
we report a case of catastrophic bronchial spasm due to an anaphylactic reaction to protamine .
the patient was managed successfully by a bronchodilator , steroid treatment , and extracorporeal membrane oxygenation .
 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 . 
Case report
Discussion