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Weight Based Heparin Dosage with Activated Clotting Time Monitoring Leads to Adequate and Safe Anticoagulation in Non-Cardiac Arterial Procedures

  • Orkun Doganer
    Affiliations
    Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands

    Department of Vascular Surgery, Amsterdam University Medical Centers (Amsterdam UMC) location VU Medical Center, Amsterdam, the Netherlands
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  • Liliane C. Roosendaal
    Affiliations
    Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands

    Department of Vascular Surgery, Amsterdam University Medical Centers (Amsterdam UMC) location VU Medical Center, Amsterdam, the Netherlands
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  • Arno M. Wiersema
    Correspondence
    Correspondence to: Arno M. Wiersema, MD, PhD, Department of Vascular Surgery, Dijklander Ziekenhuis, Maelsonstraat 3, 1624 NP Hoorn, the Netherlands
    Affiliations
    Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands

    Department of Vascular Surgery, Amsterdam University Medical Centers (Amsterdam UMC) location VU Medical Center, Amsterdam, the Netherlands
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  • Jan D. Blankensteijn
    Affiliations
    Department of Vascular Surgery, Amsterdam University Medical Centers (Amsterdam UMC) location VU Medical Center, Amsterdam, the Netherlands
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  • Kak Khee Yeung
    Affiliations
    Department of Vascular Surgery, Amsterdam University Medical Centers (Amsterdam UMC) location VU Medical Center, Amsterdam, the Netherlands
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  • Vincent Jongkind
    Affiliations
    Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands

    Department of Vascular Surgery, Amsterdam University Medical Centers (Amsterdam UMC) location VU Medical Center, Amsterdam, the Netherlands
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Open AccessPublished:March 02, 2022DOI:https://doi.org/10.1016/j.avsg.2022.01.029

      Background

      Unfractionated heparin has an unpredictable effect in an individual patient. The activated clotting time (ACT) can be used to measure the effect of heparin in the individual patient and guide additional heparin dosages. Previous cohort studies showed that a standardized bolus of 5,000 IU during noncardiac arterial procedures (NCAP) does not lead to an adequate ACT in the vast majority of patients. The aim of this study was to investigate whether an initial heparin dose of 100 IU/kg leads to an adequate but safe ACT, from 200 to 300 s.

      Methods

      In this multicenter prospective study, 186 patients undergoing NCAP were enrolled and received an initial heparin dose of 100 IU/kg. Target ACT was set at ≥250 s initially; during the course of the study the target ACT was lowered to ≥200 s. After the initial heparin dose, additional heparin dosages were administered depending on the ACT values following a heparin dose protocol. ACT measurements and complications were monitored.

      Results

      The mean baseline ACT was 134 ± 17 s. The mean ACT 5 minutes after the initial heparin dose was 227 ± 37 s. After the initial dose of heparin, 78 and 46% of patients reached an ACT of 200 and 250 s, respectively. Seven patients (4%) reached an ACT of 300 s or more. Ninety-four patients (51%) received at least one additional dose of heparin. After one additional dose of heparin, 91% of patients reached an ACT of 200 s and 13 patients (7%) reached an ACT of 300 s or more. Arterial thromboembolic complications occurred in 4.3% and bleeding complications occurred in 9.7%.

      Conclusions

      A bolus of 100 IU/kg of heparin during NCAP results in adequate coagulation in most patients. ACT measurements enable accurate additional dosing, ensuring the individual patient tailored and safe coagulation.

      Key words

      anticoagulants; heparin; blood coagulation tests; vascular surgical procedures; peripheral vascular disease

      Introduction

      Unfractionated heparin (in short: heparin) is administered to prevent arterial thromboembolic complications (ATEC) when major vessels are cross-clamped during noncardiac arterial procedures (NCAP). A wide variation for periprocedural heparin therapy is reported, including fixed dose, body weight based dose with a variation between 50 and 100 IU/kg, and the use of additional heparin dosages depending on the duration of the procedure.
      • Doganer O.
      • Wiersema A.M.
      • Scholtes V.
      • et al.
      No concluding evidence on optimal activated clotting time for non-cardiac arterial procedures.
      ,
      • Wiersema A.M.
      • Vos J.A.
      • Bruijninckx C.M.A.
      • et al.
      Periprocedural prophylactic antithrombotic strategies in interventional radiology: current practice in The Netherlands and comparison with the United Kingdom.
      Current guidelines on NCAP do not provide evidence based recommendations for periprocedural heparin therapy.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • et al.
      Inter-society consensus for the management of peripheral arterial disease (TASC II).
      • Chaikof E.L.
      • Dalman R.L.
      • Eskandari M.K.
      • et al.
      The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm.
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • et al.
      Editor's choice - European Society for Vascular Surgery (ESVS) 2019 clinical practice guidelines on the management of abdominal aorto-iliac artery aneurysms.
      The anticoagulatory effect of heparin is multifactorial and is unpredictable in the individual patient.
      • Despotis G.J.
      • Avidan M.
      • Levy J.H.
      Heparin resistance and the potential impact on maintenance of therapeutic coagulation.
      • Finley A.
      • Greenberg C.
      Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass.
      • Sniecinski R.M.
      • Levy J.H.
      Anticoagulation management associated with extracorporeal circulation.
      • Vuylsteke A.
      • Mills R.J.
      • Crosbie A.E.
      • et al.
      Increased pre-operative platelet counts are a possible predictor for reduced sensitivity to heparin.
      • Culliford A.T.
      • Gitel S.N.
      • Starr N.
      • et al.
      Lack of correlation between activated clotting time and plasma heparin during cardiopulmonary bypass.
      • Gravlee G.P.
      • Whitaker C.L.
      • Mark L.J.
      • et al.
      Baseline activated coagulation time should be measured after surgical incision.
      • Veerhoek D.
      • Groepenhoff F.
      • van der Sluijs M.G.
      • et al.
      Individual differences in heparin sensitivity and their effect on heparin anticoagulation during arterial vascular surgery.
      To ascertain adequate periprocedural anticoagulation in the individual patient, the effect of heparin should be monitored.
      The activated clotting time (ACT) can be used to measure the anticoagulant effect of heparin in the individual patient.
      • Goldhammer J.E.
      • Zimmerman D.
      Pro: activated clotting time should Be monitored during heparinization for vascular surgery.
      Little clinical data are available defining the optimal periprocedural ACT associated with the lowest number of ATEC and bleeding complications in NCAP.
      • Doganer O.
      • Wiersema A.M.
      • Scholtes V.
      • et al.
      No concluding evidence on optimal activated clotting time for non-cardiac arterial procedures.
      Studies on interventions of the carotid artery recommend a target ACT of 200–250 s during carotid endarterectomy (CEA) and a target ACT of 250–300 s during carotid stenting.
      • Apinis A.
      • Sehgal S.
      • Leff J.
      Intraoperative management of carotid endarterectomy.
      • Morales Gisbert S.M.
      • Sala Almonacil V.A.
      • Zaragoza Garcia J.M.
      • et al.
      Predictors of cervical bleeding after carotid endarterectomy.
      • Saw J.
      • Bajzer C.
      • Casserly I.P.
      • et al.
      Evaluating the optimal activated clotting time during carotid artery stenting.
      In a study in patients undergoing peripheral vascular interventions, an ACT of ≥250 s was associated with an increased periprocedural drop in hemoglobin and a higher number of red blood cell (RBC) transfusions when compared to an ACT <250 s.
      • Kasapis C.
      • Gurm H.S.
      • Chetcuti S.J.
      • et al.
      Defining the optimal degree of heparin anticoagulation for peripheral vascular interventions: insight from a large, regional, multicenter registry.
      However, till now, no randomized controlled trials have been performed that investigated the association between ACT during NCAP and clinical outcomes. Based on sparse literature and our own experience, the optimal ACT might be between 200 and 300 s. Previous cohort studies showed that ACT-guided heparinization is feasible, safe, and that an initial bolus of 5,000 IU of heparin, irrespective of patient body weight, was too low to reach desired ACT levels.
      • Doganer O.
      • Wiersema A.M.
      • Scholtes V.
      • et al.
      No concluding evidence on optimal activated clotting time for non-cardiac arterial procedures.
      ,
      • Veerhoek D.
      • Groepenhoff F.
      • van der Sluijs M.G.
      • et al.
      Individual differences in heparin sensitivity and their effect on heparin anticoagulation during arterial vascular surgery.
      ,
      • Doganer O.
      • Jongkind V.
      • Blankensteijn J.D.
      • et al.
      A standardized bolus of 5 000 IU of heparin does not lead to aqequate heparinization during non-cardiac arterial procedures.
      The aim of this prospective study was to investigate whether an initial heparin dose of 100 IU/kg leads to an adequate patient-tailored and safe ACT, from 200 to 300 s.

      Methods

      Data Collection, Design, and Patients

      The MANCO registry (measuring the ACT during non-cardiac arterial procedures, Clin. Trials.gov NCT 03426293) is an ongoing, prospective, multicenter registry for patients undergoing NCAP in two high-volume hospitals (Amsterdam University Medical Center, location VU Medical Center, Amsterdam, the Netherlands [VU] and the Dijklander Ziekenhuis, Hoorn, the Netherlands [DLZ]). Surgical procedures included carotid endarterectomy, standard and complex endovascular aneurysm repair, open aortic surgery, open and endovascular procedures for peripheral arterial occlusive disease, and other (Table I). Consecutive patients were included from January 2018 till May 2019. The MANCO registry is registered at clinicaltrials.gov (NCT number: NCT03426293) and at the Dutch trial registry (NTR ID: NL6788). The protocol was approved by the local ethics committee. Data were collected from the electronic patient system files and were stored in the cloud-based electronic data capture platform Castor EDC® (Castor Electronic Data Capture; CIwIt BV, Amsterdam, I.C. Netherlands, 2018). Patients older than 18 years who underwent open or endovascular NCAP were enrolled in this prospective analysis. Exclusion criteria were a known coagulation disorder, documented heparin allergy, preprocedural unfractionated heparin therapy (except preventive use of low molecular weight heparin), and chronic renal failure with a clearance less than 30 mL min−1. Patients with renal clearance were excluded because unfractionated heparin undergoes renal clearance.
      • Lopes J.A.
      • Jorge S.
      The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review.
      Patient demographic variables including age, gender, body weight, height, medical history, preprocedural and postprocedural antithrombotic therapy, and also variables related to the surgical procedure were collected. Patient data were checked by two authors (O.D. and A.W.).
      Table IPatient demographics and procedure details
      n (total = 186)
      Age, y (range)71 ± 8 (48–88)
      Gender
       Male, n (%)133 (72)
       Female, n (%)53 (28)
      BMI, kg/m2 (range)26 ± 5 (14–39)
      Cardiac history, n (%)75 (40)
      Cardiac intervention, n (%)59 (32)
      Hypertension, n (%)138 (74)
      Hypercholesterolemia, n (%)68 (37)
      COPD/pulmonary fibrosis, n (%)55 (30)
      TIA/CVA, n (%)58 (31)
      Malignancy, n (%)33 (18)
      Diabetes Mellitus, n (%)34 (18)
      Impaired renal function, n (%)10 (5)
      PAOD, n (%)96 (52)
      Type of intervention–open
       CEA, n (%)38 (20)
       AAA
      Including supra, juxta, and infrarenal AAA.
      , n (%)
      31 (17)
       Femorodistal
      Femoral interventions including endarterectomy common femoral artery and supra-genual and infra-genual femoropopliteal bypass.
      , n (%)
      38 (20)
       Other, n (%)14 (8)
      Type of intervention–endovascular
       EVAR, n (%)19 (10)
       FEVAR, n (%)7 (4)
       TEVAR, n (%)5 (3)
       Other, n (%)2 (1)
      Type of intervention–hybrid
       Carotid3 (2)
       THAAA, n (%)1 (1)
       Femorodistal
      Endarterectomy with combined endovascular procedure.
      , n (%)
      25 (13)
       Other3 (2)
      Preoperative laboratory variables
       Platelets (n = 108, range)244 ± 83 (101–511)
       INR (n = 43, range)1.4 ± 1.1 (1.0–8.0)
       APTT (n = 27, range)28.7 ± 7.2 (12–45)
      Mean ± SD (range).
      BMI, body mass index; COPD, chronic obstructive pulmonary disease; TIA, transient ischemic attack; CVA, cerebrovascular accident; PAOD, peripheral arterial occlusive disease; CEA, carotid endarterectomy; AAA, Abdominal Aortic Aneurysm repair; EVAR, Endovascular Aneurysm repair; FEVAR, Fenestrated Endograft; TEVAR, Thoracic Endovascular Aortic repair; THAAA, Thoraco-abdominal Aortic Aneurysm repair.
      a Including supra, juxta, and infrarenal AAA.
      b Femoral interventions including endarterectomy common femoral artery and supra-genual and infra-genual femoropopliteal bypass.
      c Endarterectomy with combined endovascular procedure.

      Anticoagulation Monitoring

      ACT measurements were performed as a point-of-care test using the Hemostasis Management System Plus (HMS Plus, Medtronic Inc., Minneapolis, MN, USA). Blood samples were drawn from the radial artery catheter. High-range cartridges (HR-ACT) containing kaolin were used. The ACT was measured at the following time points: after anesthetic induction (T0), 5 minutes after the administration of the initial heparin bolus (T1), 5 minutes after every additional dose of heparin, and at 30 min intervals after the desired ACT was reached, until the end of the procedure or until new heparin administration was required.

      Heparin Dose Protocol

      All patients received a heparin bolus of 100 IU/kg based on the real weight of body weight intravenously prior to cross-clamping or after insertion of the sheath in case of endovascular procedures. An additional dose of heparin was administered depending on the ACT. Initially, the target ACT was set at ≥250 s. During the course of the study the target ACT was lowered to ≥200 s because a high dose of heparin was required to reach an ACT ≥250 and a possible trend of increased bleeding. Dose protocols for both hospitals VU and DLZ are depicted in Figure 1, with the main difference being the administration of an additional standard dose of heparin (2,500 or 5,000) or weight depended (30 IU/kg or 60 IU/kg). At the end of surgery, target ACT was ≤180 s. Protamine was administered if ACT was >180 s. Protamine could be used at the completion of a procedure to neutralize any residual heparin effect by using a dose of 25 to 100 mg per patient. The decision to administer protamine was left to the discretion of the attending vascular surgeon. Local flushing of arteries with heparin solution was routinely performed. This was performed using a solution of 10,000 IU heparin in 1,000 mL 0.9% sodium chloride. For flushing, a maximum of 30 mL was used for each procedure, equaling to 300 IU of heparin.
      Figure thumbnail gr1
      Fig. 1Heparin dose schedule in institution VU and DLZ.

      Preprocedural and Postprocedural Antithrombotic Therapy and Protamine

      Preprocedural monotherapy with acetylsalicylic acid (ASA) or clopidogrel was continued during the procedure. In some cases, especially in patients receiving epidural anesthesia, clopidogrel was switched to acetylsalicylic acid preoperatively. In case of preprocedural dual antiplatelet therapy, one of the antiplatelet therapies was discontinued, except for CEA, when a dual antiplatelet therapy was continued. Preprocedural direct oral anticoagulation drugs (DOAC) and vitamin K antagonists (VKA) were discontinued as per the National Guideline on Antithrombotic Therapy: two to five days preprocedurally.
      If required (CHA2DS2-Vasc > 8), bridging therapy was started using low molecular weight heparin.
      • Camm A.J.
      • Lip G.Y.H.
      • De Caterina R.
      • et al.
      2012 Focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.

      Outcome Measurements

      The main endpoint of this study was to investigate if an initial heparin dose of 100 IU/kg leads to an adequate ACT: from 200 to 300 s. Secondary study endpoints were the amount of additional heparin dosages administered, the effect of these additional heparin dosages on the ACT, and the incidence of complications during the same admission or during a 30-day follow-up. Complications were categorized as:
      • I)
        ATEC such as graft thrombosis, embolism, myocardial infarction, minor and major stroke, pulmonary embolism, and bowel ischemia.
      • II)
        Bleeding complications as per the E-CABG classification grade 2 or higher (transfusion of 5–10 units of RBC or reoperation for bleeding).
        • Mariscalco G.
        • Gherli R.
        • Ahmed A.B.
        • et al.
        Validation of the European multicenter study on coronary artery bypass grafting (E-CABG) bleeding severity definition.
        To explore an optimal ACT value, patients were divided in three groups for all endpoints: ACT <200 s, ACT between 200 and 250 s, and ACT >250 s.
      • III)
        All other complications. Renal injury was defined as per RIFLE criteria (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) at least double increased serum creatinine level or a reduction of the glomerular filtration rate of more than 50%.
        • Lopes J.A.
        • Jorge S.
        The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review.
      Statistical analysis was performed using the SPSS statistical software package 26.0 (IBM, New York, USA). A normality test was performed to the set of multiple ACT measurements. Based on the number of patients the Shapiro–Wilk test was used and the data were normally distributed. Continuous, normally distributed variables were expressed as mean ± standard deviation or percentage. Descriptive statistics were used to report and determine the distribution of the ACT. The paired t-test was used to test normally distributed data. The Mann–Whitney U-test was used to test skewed and ordinal data. The chi-squared and Fisher's exact tests were used to analyze categorical variables and the outcomes were expressed as counts and percentages. Test results were reported as t-statistics (degrees of freedom), followed by the P value. A P value less than 0.05 was considered as statistically significant.

      Results

      During the study period, 195 patients underwent NCAP and were per procedurally heparinized using an initial heparin dose of 100 IU/kg. Nine patients were excluded because of a renal clearance less than 30 mL min−1. In total, 186 eligible patients were enrolled and the ACT measurements of these patients were analyzed. One-hundred and twenty-one (65%) patients underwent an open procedure, 33 (18%) an endovascular procedure, and 32 (17%) a hybrid procedure. A flowchart of patient inclusion in this study is depicted in Figure 2. The patient characteristics and procedure details are depicted in Table I. The preprocedural and postprocedural anticoagulation therapy is depicted in Table II.
      Figure thumbnail gr2
      Fig. 2Flow diagram illustrating the patient selection process.
      Table IIPreprocedural and postprocedural details on antithrombotic therapy
      n = 186 (n, %)
      Preprocedural anticoagulants
       Acetylsalicylic acid64 (34)
       Clopidogrel61 (33)
       Dual antiplatelet13 (7)
       VKA19 (10)
       DOAC8 (4)
       Combination8 (4)
       Other1 (1)
       None12 (7)
      Postprocedural anticoagulants
       Acetylsalicylic acid35 (19)
       Clopidogrel75 (40)
       Dual antiplatelet33 (18)
       VKA19 (10)
       DOAC10 (5)
       Combination7 (4)
       Other2 (1)
       Missing5 (3)
      VKA, vitamin K antagonists; DOAC, direct oral anticoagulants.

      Activated Clotting Time

      The ACT at T0 is the baseline ACT before the administration of heparin and the ACT at T1 is 5 min after administration of the initial dose of heparin. The mean ACT at T0 was 134 ± 17 s (range 70–198 s) and the mean ACT at T1 was 227 ± 37 s (range 117–348 s). The ACT measurements at T0 were performed in 183 patients and at T1 were performed in 184 patients. The mean initial heparin dose was 7,798 ± 1,581 IU (range 4,000–13,000 IU) and the mean initial heparin dose per kg of body weight was 99 ± 3 IU/kg (range 91–109 IU/kg). Figure 3 illustrates the distribution of the ACT at T0 and T1.
      Figure thumbnail gr3
      Fig. 3Distribution of the baseline ACT (T0) and ACT 5 min after the initial 100 IU/kg. Dose of heparin (T1).
      After the initial heparin bolus (T1), 40 patients (21.74%) reached an ACT <200 s, 100 patients (54.35%) an ACT 200–250 s, and 44 patients (23.91%) an ACT >250 s. At T1, 7 patients (4%) reached an ACT of ≥300 s. At T1 in 145 patients (80%) the ACT reached 1.5 times the baseline ACT and in 25 patients (14%) the ACT reached 2 times the baseline ACT.
      The maximum ACT reached during all procedures were again categorized in three groups: 10 patients (5.38%) reached an ACT <200 s, 105 patients (56.45%) an ACT 200–250 s, and 71 patients (38.17%) an ACT >250 s.

      Additional Heparin Dose Protocol

      In Center VU, 28 of 46 patients (61%) received at least one additional dose of heparin. After the first additional dose of heparin, 42 (91%) and 19 (41%) patients reached an ACT of 200 and 250 s, respectively. Four patients (9%) reached an ACT more than 300 s. In Center DLZ, 66 of 140 patients (47%) received at least one additional dose of heparin. After the first additional dose, 128 (91%) and 42 (30%) patients reached an ACT of 200 and 250 s, respectively. Nine patients (6%) reached an ACT more than 300 s. In total, using an additional dose protocol in 177 (95%) patients an ACT ≥200 s was reached, in 73 (39%) patients ACT was ≥250 s, and in 13 (7 %) patients ACT was ≥300 s. The mean total periprocedural heparin dose was 9,769 ± 3,333 IU (range 4,000–28,700 IU). Details of the effect on the ACT for the different additional heparin dosages are depicted in Table III. In the patient who received an initial heparin dose of 13,000, the ACT increased from 123 to 195 s and after an additional dose of 3,900 IU the ACT increased to 224 s.
      Table IIIThe effect of the different first additional heparin dosages administered
      Type of additional heparin dosen
      These were the patients in which the ACT was measured before and after the additional dose of heparin.
      Mean ACT effect (s.), (range)
      Fixed
       ∼2,500 IU19+25 (−52; +88)
       ∼5,000 IU6+53 (−22; +107)
      Body weight based
       ∼30 IU/kg.43+31 (−12; +131)
       ∼60 IU/kg.18+86 (+26; +223)
      This was defined by the mean ACT difference before and after the administration of the first additional heparin dose.
      a These were the patients in which the ACT was measured before and after the additional dose of heparin.

      Complications

      Complications are depicted

      ATEC occurred in 8 patients (4.3%). In 6 patients (3.2%), postprocedural graft thrombosis occurred. Those 6 patients underwent reoperation for embolectomy (Table IV). One patient (0.5%) developed a transient ischemic attack (TIA) 3 days after an open repair procedure of an infrarenal abdominal aortic aneurysm. One patient (0.5%) developed bowel ischemia 3 days postoperatively and underwent surgical resection. Seven patients (4%) developed renal injury. In none of these patients hemodialysis was necessary. Three patients (2%) died: one because of postprocedural aortic dissection after an open repair of abdominal aortic aneurysm, one because of hemorrhagic stroke after an open repair for aorto-iliac disease, and one because of sepsis based on necrotizing fasciitis.
      Table IVIncidence of clinical complications during 30 day follow-up
      Complicationsn = 186
      ATEC, n (%)8 (4.3)
       Local graft thrombosis, n (%)6 (3.2)
       Myocardial infarction, n (%)-
       Stroke, n (%)1 (0.5)
       Bowel Ischemia, n (%)1 (0.5)
      Other Complications
       Renal injury, n (%)7 (3.7)
       Spinal cord ischemia, n (%)1 (0.5)
       Wound infection, n (%)14 (7.5)
      E-CABG bleeding severity classification
       Grade ≥1, n (%)42 (22.6)
       Grade ≥2, n (%)18 (9.7)
       Grade ≥3, n (%)1 (0.5)
      Total periprocedural blood loss (mL)
       Open, mean ± S.E.M.881 ± 997
       Endovascular, mean ± S.E.M.308 ± 692
       Hybrid, mean ± S.E.M.446 ± 360
      Death, n (%)3 (1.6)
      Renal injury was classified following the RIFLE criteria.
      • Lopes J.A.
      • Jorge S.
      The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review.
      ATEC, arterial thrombo-embolic complications.
      Bleeding complications (RBC transfusion 5 unit or more) occurred in 18 patients (9.7%): 1/18 with ACT <200 s, 10/18 with ACT 200–250 s, and 7/18 with ACT ≥250 s.
      There is no significant relationship between hemorrhagic complications and the three ACT groups, X2 (1, n = 186) = 0.007, P = 0.997.
      Of the 13 patients who reached an ACT ≥300 s, none developed postprocedural graft thrombosis; one patient developed a TIA and one patient developed renal injury. Four of these 13 patients (31%) developed a bleeding complication (E-CABG grade 1 in two patients and grade 2 in two patients).

      Discussion

      ACT measurements are not yet a common practice in NCAP and a standard starting dose of 5,000 IU is still often used by many vascular surgeons. In a previous cohort study, we found that a heparin dose protocol with a starting dose of 5,000 IU does not lead to adequate anticoagulation; however, several additional heparin dosages are required to reach an ACT >200 s.
      • Doganer O.
      • Jongkind V.
      • Blankensteijn J.D.
      • et al.
      A standardized bolus of 5 000 IU of heparin does not lead to aqequate heparinization during non-cardiac arterial procedures.
      In this study, we evaluated 186 patients who received heparinization using an initial dose of 100 IU/kg. An ACT of 200 was reached in 78% of patients. After the necessary additional dosages of heparin this increased to 91%.
      A lower incidence of ATEC was found after using the additional heparin dose protocol with an initial heparin bolus of 100 IU/kg and a target ACT >200 s, in comparison to the earlier cohort of a standardized heparin bolus of 5,000 IU, 4.3 vs. 9.0%, respectively. However, the cohorts cannot directly be compared to each other because the type of procedures included varies. Future studies need to be performed using more homogenous patient groups in large numbers to determine an optimal ACT. Compared to the 5,000 IU cohort there was an increased incidence of severe bleeding (grade 2 or more as per the E-CABG classification
      • Mariscalco G.
      • Gherli R.
      • Ahmed A.B.
      • et al.
      Validation of the European multicenter study on coronary artery bypass grafting (E-CABG) bleeding severity definition.
      ) in the 100 IU/kg cohort: 9.7 vs. 2.6%.
      • Doganer O.
      • Jongkind V.
      • Blankensteijn J.D.
      • et al.
      A standardized bolus of 5 000 IU of heparin does not lead to aqequate heparinization during non-cardiac arterial procedures.
      Furthermore, a high quantity of heparin with often more than one additional dosage was required to reach an ACT >250 s. Therefore, during the study the target ACT was lowered to ≥200 s.
      Interestingly, despite the dosing heparin on body weight, resulting ACT values varied widely after the initial dose of heparin (117–348 s). This wide variation in ACT values was also observed after the administration of additional heparin dosages. The additional heparin dosages of 2,500 IU and 30 IU/kg resulted in a mean ACT increase of 25 and 31 s, respectively. However, these ACT values varied from −52 s to +88 s for an additional dose of 2,500 IU and from −12 s to +131 s for an additional dose of 30 IU/kg. The additional heparin dosages of 5,000 IU and 60 IU/kg resulted in a mean ACT increase of 53 and 86 s, respectively.
      Notably, in some patients a decrease in ACT was observed after administration of an additional dose of heparin. These findings are supported by the earlier literature on the unpredictable effect of heparin in the individual patient. There are many factors influencing the effect of heparin. Heparin has a low volume of distribution and does not enter muscle or fat tissue.
      • Myzienski A.E.
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      Unfractionated heparin dosing for venous thromboembolism in morbidly obese patients: case report and review of the literature.
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      • Greenberg C.
      Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass.
      Age, thrombocytosis (platelet count >300,000/mL), preprocedural heparin therapy, impaired liver function, low antithrombin III levels (<60%), high levels of platelet factor 4, elevated factor VIII levels, hemodilution, temperature, anesthesia, and surgery also may be contributing factors.
      • Despotis G.J.
      • Avidan M.
      • Levy J.H.
      Heparin resistance and the potential impact on maintenance of therapeutic coagulation.
      • Finley A.
      • Greenberg C.
      Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass.
      • Sniecinski R.M.
      • Levy J.H.
      Anticoagulation management associated with extracorporeal circulation.
      • Vuylsteke A.
      • Mills R.J.
      • Crosbie A.E.
      • et al.
      Increased pre-operative platelet counts are a possible predictor for reduced sensitivity to heparin.
      • Culliford A.T.
      • Gitel S.N.
      • Starr N.
      • et al.
      Lack of correlation between activated clotting time and plasma heparin during cardiopulmonary bypass.
      • Gravlee G.P.
      • Whitaker C.L.
      • Mark L.J.
      • et al.
      Baseline activated coagulation time should be measured after surgical incision.
      An empiric, fixed, or body weight based heparin dose without measuring the anticoagulatory effect may result in inadequate or excessive anticoagulation. Therefore, the measurement of the effect of heparin by using the ACT seems indispensable.
      The main strengths of this study are that patients were enrolled prospectively, patient data were double checked by two authors (O.D. and A.W.), and an analysis of a body weight based heparin dose has not been described in such a large group of patients yet. Limitations of this study are that the group of patients was heterogeneous and that this study was not a dose finding study. In addition, a periprocedural flush solution was used and a minor systemic effect of a heparin flush solution cannot be excluded. In this study, open and peripheral endovascular procedures were included, the same heparin protocol, and therefore dosages were used in both type of interventions which could lead to overanticoagulating patients who undergo peripheral endovascular interventions. This study was not designed to determine the optimal ACT associated with the least amount of ATEC and bleeding complications, neither to relate ACT to clinical outcomes, such as ATEC or bleeding complications. The target ACT was adjusted during the inclusion period and in the two centers different additional dosages were administered. During the present study, the HMS Plus was used for the ACT measurements. Importantly, a significant variability in ACT values between different brands of ACT devices has been reported.
      • Avendano A.
      • Ferguson J.J.
      Comparison of Hemochron and HemoTec activated coagulation time target values during percutaneous transluminal coronary angioplasty.
      • Doherty T.M.
      • Shavelle R.M.
      • French W.J.
      Reproducibility and variability of activated clotting time measurements in the cardiac catheterization laboratory.
      • Chia S.
      • Van Cott E.M.
      • Raffel O.C.
      • et al.
      Comparison of activated clotting times obtained using Hemochron and Medtronic analysers in patients receiving anti-thrombin therapy during cardiac catheterisation.
      • Lee J.M.
      • Park E.Y.
      • Kim K.M.
      • et al.
      Comparison of activated clotting times measured using the Hemochron Jr. Signature and Medtronic ACT Plus during cardiopulmonary bypass with acute normovolemic haemodilution.
      Therefore, the findings of the present study cannot be extrapolated on a 1:1 basis to the measurements performed with ACT devices from different brands with a different type of cartridges.
      In conclusion, an initial heparin dose of 100 IU/kg results in an adequate ACT (200 to 300 s) in 74% of patients. Nevertheless, ACT measurements are essential to monitor the effect of heparin and thereby ensuring the individual patient of safe and tailor-made anticoagulation. Future studies are needed to investigate an optimal ACT in NCAP with a lowest incidence of ATEC without a significant increase in bleeding complications.

      Disclosures

      None.

      Funding Sources

      This research was supported by a grant from Medtronic , a funding agency in the commercial sector.

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