24 Y . Yamada et al .: J Extra Corpor Technol 2023 , 55 , 23 – 29
colchicine , posterior pericardiotomy , atrial pacing , and corticosteroids are not robust . Two large randomized controlled studies showed no significant effect of i . v . steroids on the incidence of postoperative AF after cardiac surgery [ 4 ]. Thus , other modalities may be needed , although the molecular events initiating AF remain uncertain .
Considering that cytosolic Ca 2 + handling is a major determinant of cardiac contractile function , Fakuade et al . hypothesized that alterations in cellular Ca 2 + dynamics contribute to impaired atrial contractility in patients who proceed to develop POAF [ 5 ]. They found that reduced sarcoplasmic reticulum ( SR ) Ca 2 + -ATPase ( SERCA ) -mediated Ca 2 + reuptake into SR is a major contributor to impaired preoperative atrial contractile function [ 5 ]. Ryanodine receptors ( calcium-induced calcium release channels ; RyR ) play a crucial role in most cell types , including muscle cells , neurons , and epithelial cells . They mediate the release of calcium ions from the endoplasmic / sarcoplasmic reticulum into the cytosol and thereby convert a number of extracellular stimuli into intracellular calcium signals [ 6 ]. RyRs are large tetrameric proteins that show sequence similarity with inositol 1,4,5-trisphosphate ( IP3 ) -gated calcium channels of the endoplasmic / sarcoplasmic reticulum , but they are distinct in their biophysical and pharmacological properties . For example , highly negatively charged polyanions such as heparin increased the activity of RyRs , whereas it decreased the activity of IP3 receptors [ 7 ]. Diaz-Sylvester and Copello found that a lower dose of protamine activated cardiac RyR2 [ 8 ]. Shan et al . in mouse models with known RyR2 mutations and normal cardiac structure and function , the diastolic SR Ca 2 + leak via RyR2 lead to Ca 2 + waves and possible re-entry loops that trigger atrial tachycardia and AF [ 9 ].
In STS / SCA / AmSECT ( Society of Thoracic Surgeons , The Society of Cardiovascular Anesthesiologists , and the American Society of ExtraCorporeal Technology ) clinical practice guidelines published in 2018 [ 10 ], recommendations were written in the reversal of anticoagulation during cardiac operations . Methods of heparin reversal are multiple and controversy exists regarding the optimal strategy . Traditional methods administer heparin based on body weight and protamine based on the amount of heparin administered . An important part of the operation is to adequately remove all of the heparin effects at the end of the operation . There are at least three methods commonly used to detect residual heparin effect after protamine reversal . Among them , the ACT-based strategy is commonly used , where activated clotting time ( ACT ) measurement is kept greater than 480 s which seemed to be appropriate during cardiac surgical procedures in this study . Class IIa recommendation in the guidelines included limiting the ratio of protamine / heparin to less than 2.6 mg protamine / 100 Units of heparin , since total doses above this ratio inhibit platelet function , prolong ACT , and increase the risk of bleeding [ 10 ].
Here , we have retrospectively reviewed 147 patients who underwent cardiac surgery with cardiopulmonary bypass . All these patients received heparin followed by protamine at different dosing ratios of protamine-to-heparin , depending on the periods used . We have found that higher dosing ratios of protamine-to-heparin increased the incidence of POAF .
Materials and methods
Data Collection was conducted as a retrospective cohort study to clarify the prevalence and incidence of POAF in the patients who received cardiac surgery . The study protocol conformed to the Declaration of Helsinki and was approved by the institution ’ s ethics committee in Okanami General Hospital , Iga-City , Mie Prefecture , Japan . Okanami General Hospital is a secondary medical center in the Iga district . The study database was from the Okanami Hospital Medical Database which was composed of detailed medical and procedural information .
Atrial fibrillation and its occurrence time were identified by the diagnosis of health records and electrocardiograms . Comorbidities including hypertension , diabetes mellitus , hyperlipidemia , heart failure , coronary artery disease , myocardial infarction , chronic obstructive pulmonary disease , peripheral arterial occlusive disease , and chronic kidney disease were also coded from the records . Prescription information was categorized into antiarrhythmic agents , beta-blockers , angiotensinconverting enzyme inhibitors ( ACEI ), angiotensin receptor blockers ( ARBs ), mineralocorticoid-receptor antagonists , calcium blockers , digitalis preparation , sodium channel blocker , and anticoagulants . The open heart procedures included coronary artery bypass grafting , valvuloplasty , and valve replacement . The echocardiographic data and outcomes including transient ischemic attack , ischemic stroke , hospitalization , and mortality were also obtained from the electronic health records . Activated clotting time ( ACT ) was measured using Hemochron Ò ( Accriva Diagnostics , San Diego , CA , USA ) from April 1 , 2002 , to March 12 , 2015 , and ACT Plus Ò ( Medtronic , Minneapolis , MN , USA ) from March 13 , 2015 , and thereafter . ACT was determined before CPB , and then every 30 min . Additional heparin ( 1000 – 2000 IU ) was administered if necessary . An ACT target of 480 s ( 480 s up to 600 s ) was set in the hospital . All patients received unfractionated heparin ( 1000 international units / mL ) and protamine ( 10 mg / mL ), both are purchased from Mochida Pharmaceutical Co . Ltd . ( Tokyo , Japan ). All patients received initial heparin doses of 300 IU / kg . The dosing ratios of protamine-to-heparin were determined by the volume-based method in the clinical setting , that is , the dosing ratio of protamine-to-heparin = 1.0 represents 1 mL protamine to 1 mL heparin of the first heparin bolus . This ratio is equal to 1 mg of protamine to 100 international units of heparin . The dosing ratios of protamine-toheparin > 1.0 ( up to 1.7 ) were used from February 2004 to September 2009 and the dosing ratio of protamine-toheparin = 1.0 from October 2009 and thereafter . The change of dosing ratios of protamine-to-heparin was made according to the instructions of the pharmaceutical company .
Patient Selection . In this study , all patients above 18 years of age undergoing first-time open-heart surgery at Okanami General Hospital from February 1 , 2004 , to December 13 , 2021 , were included for analysis ( n = 147 ). In this retrospective study , we did not include off-pump CABG cases ( n = 91 ) who did not receive protamine . Thus , the annual surgical volume is 14 – 16 patients per year in the Department of Cardiovascular Surgery , Okanami General Hospital . Patients with previous