The Journal of ExtraCorporeal Technology Issue 55-1 | Page 34

26 Y . Yamada et al .: J Extra Corpor Technol 2023 , 55 , 23 – 29

Table 2 . Types of cardiovascular diseases and dosing ratios of protamine-to-heparin .

No POAF

POAF

Valvular disorders

Ischemic heart disease ( CABG only )

Valvular disorders + Ischemic heart disease

Ischemic heart disease + ventricular septal perforation

Aortic dissection

Aortic aneurysm

Others ( VSD , ASD )

Patient number

POAF , postoperative atrial fibrillation ; CABG , coronary artery bypass graft ; VSD , ventricular septal defect ; ASD , atrial septal defect .

Mittermayr et al . either in-vitro or in the clinical setting [ 15 ]. In a joint effort , the European Association for Cardio-Thoracic Surgery ( EACTS ) and the European Association of Cardiothoracic Anaesthesiology ( EACTA ) provide evidence-based recommendations in adult-acquired cardiac surgery . It is advised not to exceed a protamine dose in a 1:1 ratio to the initial heparin bolus [ 16 ]. Bartoszko et al . also suggested in the recent review article that dosing ratios of protamine-to-heparin have generally been kept no higher than 1:1 [ 13 ]. Accumulating evidence supports lower ratios , such as 0.6 – 1 mg / kg protamine per 100 IU / kg of heparin , as being associated with decreased transfusion and chest drain output [ 17 , 18 ]. Recently , Lee et al . reported in this journal that they performed a retrospective study of 216 patients who underwent cardiac surgery to search for a safe minimum protamine dose when measuring heparin concentration , using Heparin Management System ( HMS ) Plus that calculates a patient ' s heparin dose-responsiveness curve for a target ACT value [ 19 ]. When the protamine-to-heparin ratio is set at 1 mg protamine to 100 international unit heparin , they determined that 75 % of the calculated total protamine dose is a safe minimum protamine dose to sufficiently neutralize circulating heparin after CPB . On average , this translates into either . 37 mg protamine / 100 IU heparin of total heparin dose or . 54 mg / 100 IU of the first heparin bolus [ 19 ]. These studies may suggest that a lower protamine-to-heparin ratio is feasible in these clinical settings . Prospective randomized trials may be required to elucidate this issue .

It has been reported that large doses of protamine (> 20 mcg / mL ) block single skeletal RyR1 channels and inhibit RyR1-mediated Ca ^{2 +} release from sarcoplasmic reticulum microsomes [ 6 ]. Diaz-Sylvester and Copello extended these studies to cardiac RyR2 reconstituted into planar lipid bilayers [ 8 ]. They found that protamine ( 0.02 – 20 mcg / mL ) added to the cytosolic surface of fully activated RyR2 affected channel activity in a voltage-dependent manner . They observed a full block of cardiac RyR2 in the presence of 20 mcg / mL protamine . Protamine did not simply block RyR2 in an all-or-none fashion . Rather , it affected the RyR2 channel conduction pathway by producing substates and full blocks in a voltagedependent and dose-dependent manner . The addition of heparin

( 250 mcg / mL ), known to bind protamine with very high affinity , reversed the effect of protamine on RyR2 . This reversibility suggests that the action of protamine was not related to the dissociation of any cofactor or modulatory subunit bound to the RyR2 channel . Their results open the possibility that direct protamine binding to RyR2 could mediate , at least in part , the observed abnormalities in SR Ca ^{2 +} homeostasis [ 8 ]. Our clinical observation may support theirs in vitro results .

Adverse effects of protamine include anaphylactic reactions caused by an injection of protamine during cardiac surgery are well-known complications [ 17 , 20 ]. Gertler et al . observed that platelet function worsens with protamine to heparin ratio higher than 1:1 in blood samples taken from ten healthy volunteers [ 21 ]. Similar impairment of platelet aggregation and function with the use of protamine to heparin ratio above 2.6:1 , was demonstrated by Carr and Silverman [ 22 ]. Protamine has also been shown to display immunological and inflammatory alterations [ 17 ].

POAF , defined as new-onset AF in the immediate postoperative period , is a clinically relevant problem , occurring in 20 – 40 % of patients after cardiac surgery , with the peak incidence between postoperative days 2 and 4 [ 1 ]. Intra- and postoperative changes affecting AF triggers and pre-existing atrial substrate may increase atrial vulnerability to AF . Many episodes of POAF are self-terminating and some are asymptomatic , but POAF has been associated with a four- to the five-fold risk of recurrent AF in the next 5 years . It has also been shown to be a risk factor for stroke , myocardial infarction , and death compared with non-postoperative AF patients [ 3 , 4 ]. The pathogenesis of POAF may be multifactorial . b-Adrenergic stimulation has been implicated in the pathogenesis of POAF [ 23 ]. Some surgeries are more likely to induce POAF [ 24 ]. Specifically , patients who undergo combined surgeries , such as combined valve and coronary artery bypass graft ( CABG ) surgeries , are twice as likely to develop POAF , up to 60 % [ 25 ]. When types of surgery ( diseases ) were analyzed in terms of higher dosing ratios of protamine-to-heparin ( Table 2 ), only valvular disorders were marginally associated with POAF ( p = 0.04 ). In Figure 1A , Fakuade et al . provide the evidence in vitro that impaired SR Ca ^{2 +} uptake is a common underlying