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Three Part Question

In [adult patients undergoing cardiac surgery], does [use of the Hepcon® point-of-care coagulation monitor to determine optimal Heparin and Protamine dosage] decrease [bleeding and blood product requirements].

Clinical Scenario

You have been performing CABG surgery. The anaesthetist has used the Hepcon HMS Plus Hemostasis Management System (Medtronic, Minneapolis, MN) to monitor heparin concentration and calculate protamine dose to reverse anticoagulation. He claims that heparin and protamine dose optimisation decreases coagulation system activation, postoperative bleeding and allogeneic blood and blood component transfusion requirement. You wonder what evidence is available to justify this claim.

Search Strategy

MEDLINE 1966 to March Week 2 2006 using Ovid interface
Embase 1980-2006 Week 11.
[CABG.mp OR exp Cardiopulmonary Bypass/ OR Cardiopulmonary bypass.mp. OR exp Coronary Artery Bypass/ OR Coronary art$ bypass.mp. OR exp Cardiovascular Surgical Procedures/ OR Cardiac surgical procedures.mp. OR cardiac transplantation.mp. or exp Heart Transplantation/ OR exp Thoracic Surgery/ OR exp Thoracic Surgical Procedures/] AND [exp Monitoring, Intraoperative/ or exp Blood Coagulation Tests/ or exp Whole Blood Coagulation Time/ or Hepcon.mp. OR heparin dose response.mp. OR protamine dose response.mp. OR activated clotting time.mp. OR ACT.mp.] AND [bleeding.mp. OR platelets.mp. or exp Blood Platelets/ OR blood transfusion.mp. OR exp Blood Transfusion/ OR fresh frozen plasma.mp. or exp Plasma/ OR exp Blood Platelets/ or exp Blood Component Transfusion/ or exp Platelet Transfusion/ or exp Blood Transfusion/ or blood component therapy.mp. or exp Erythrocyte Transfusion/] AND [limit to humans]

Search Outcome

680 papers were found in Medline and 879 on Embase using the reported search. A further 2 papers were identified by hand-searching of reference lists. Fourteen papers provided the best evidence and are summarised below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Raymond et al 2003 Australia	42 patients undergoing surgery utilising CPB Validation of Hepcon® HMS system by comparison to lab-based anti-Xa chromogenic heparin concentration assay Comparison between Hemochron celite-activated ACT (kaolin-activated in presence of Aprotinin) & HemoTec kaolin-activated ACT and lab-based anti-Xa chromogenic heparin concentration assay Standardised perfusion / heparin management protocol	Cohort (level 2b)	Serial Hemochron & HemoTec ACT Hepcon® Heparin dose response curve (HDR) Serial Hepcon® Heparin concentration Serial anti-Xa assay Heparin concentration	Poor correlation between Hemochron ACT & HemoTec ACT and anti-Xa levels (r=0.31 & 0.26 respectively; 137 & 153 samples) Strong correlation between Hepcon® concentration & anti-Xa (r=0.74; 169 samples) Mean difference (bias) between Hepcon® & anti-Xa levels = -0.46U/ml with limit of agreement +/-1.12 therefore Hepcon® will give values between 0.53 & 1.27 anti-Xa technique levels with 95% confidence Mean difference between Hemochron & HemoTec 96secs with limit of agreement +/-265 secs therefore HemoTec ACT will give values between 0.52 & 1.33 times Hemochron ACT values with 95% confidence	Confirms that Heparin concentration but not ACT more closely related to anti-Xa levels Hepcon measures whole blood Heparin; anti-Xa technique plasma Heparin – correction for this might further improve correlation
Murray et al, 1997, USA	17 Vascular surgery patients undergoing revascularization of the lower limb or distal aorta and femoral arteries receiving 50-60U/kg Heparin 29 patients undergoing elective CABG with cardiopulmonary bypass (CPB) receiving Heparin 300U/kg+additional doses to maintain ACT>450secs	Cohort (level 2b)	Vascular group: - pre- & 90 min post-Heparin ACT, Hepcon® Protamine titration, TEG, & heparin concentration (by factor Xa inhibition assay)	Vascular group - 17/17 had significant increase in heparin levels, TEG R time, & APTT's 90 min post-heparin vs. control (p<0.05) -Heparin present in 15/17 (88%) using Hepcon® analysis (remaining 2/17 also had lowest aPTT & shortest R-time of cohort) - only 4/17 (24%) ACT increase - differences in ACT not significant post-Heparin vs. control (but all remaining tests abnormal in 13/17 with normal ACT's) - best correlation between heparin assay & Hepcon (r2=0.76)	Small population size Study designed to assess correlations between monitoring techniques with limited clinical outcome data
			CABG group – serial ACT's, heparin concentrations, platelet count, fibrinogen, & bleeding times before, during & after CPB	CABG group - no correlation between ACT & heparin assays - 3/29 (10%) post-protamine ACT's normal despite presence of significant residual heparin.
Yamanishi et al, 1997, Japan	32 consecutive patients undergoing primary elective cardiac operation Randomized to Hepcon® or control management protocol	PRCT (level 1b)	Requirement for: - Total heparin dose	Heparin requirement in Hepcon® grp significantly more than in control group (p=0.01)	Abstract only - journal article available in Japanese language only - therefore unable to confirm outcomes quoted Small population sample Surgical procedure not specified
			Total protamine dose	Protamine requirement in Hepcon® grp significantly less than in control grp (p=0.01)
			Post-operative bleeding	No excess of postoperative bleeding in Hepcon® group
Shigeta et al, 1999, Japan	Phase I -42 random pts undergoing surgery with CPB (no antiplatelet therapy for 7 days) with standard anaesthetic / surgical technique Control group - Heparin 300U/kg + 5000U in prime then additional to maintain celite ACT >480secs - Protamine dosage 3mg/kg Hepcon® group - Heparin 300U/kg + 5000U in prime then additional to maintain level >2.7U/ml - Protamine reversal of 1mg/100U Heparin based on residual blood level Phase II - in vitro study using healthy volunteers on no medication	Cohort (level 2b)	Phase I Heparin dose Heparin concentration Protamine dose Postoperative blood loss	Phase I - 8/42 pts excluded - 14/34 control - 20/34 Hepcon® Heparin dose 458+/-100vs. 537+/-973 U/kg Control Vs. Hepcon® (p=0.0132) Heparin concentration pre-reversal 1.39+/-0.32 vs. 2.13+/-0.63 U/ml Control vs. Hepcon® (p=0.0012) Protamine dose 3.0 vs. 1.77+/-0.56 mg/kg Control vs. Hepcon® (p<0.0001) Protamine/Heparin ratio 0.67+/-0.15 vs. 0.33+/-0.09 Control vs. Hepcon® (p<0.0001) Postop bleeding 12.3+/-8.6 vs. 8.7+/-6.5 ml/kg Control vs. Hepcon® (p=ns)	Small study population 8/42 Phase I pts excluded due to platelet transfusion before end of study period Study designed to look at whether decreased Protamine preserved platelet function rather than defined clinical end-points
			Pre & post-CPB platelet count, platelet alpha-granule secretion & platelet aggregation to thrombin	No significant difference in platelet count. Attenuation of platelet alpha-granule secretion during heparin neutralization in Hepcon® vs. Control grp 13.0+/-5.3 vs. 18.8+/-8.6% (p=0.0188) Significant preservation of platelet aggregation to thrombin 15 mins post-Protamine compared to preop in Hepcon® vs. Control grp 55+/-18 vs. 20+/-20% (p=0.0009)
			Phase II - - dose response curves of platelet alpha-granule secretion & platelet aggregation to thrombin in response to Protamine	->5mcg/ml Protamine fall in thrombin aggregation of washed platelets - Heparin attenuated platelet aggregation to Thrombin - lower concentration of protamine relative to heparin restored heparin-impaired thrombin mediated platelet activation
Despotis et al, 1995, USA	254 patients undergoing cardiac surgery with cardiopulmonary bypass Patients treated with antifibrinolytic agents excluded Randomised to conventional or Hepcon®-guided coagulation management Conventional - Heparin 250U/kg + 5000U boluses to raise ACT>480 secs + 5000U in pump - Protamine 0.8mg per mg total Heparin to return ACT to pre-CPB levels Hepcon® – initial Heparin dosing on basis of dose-response assay + additional doses on basis of ACT or Heparin concentration - Protamine 1.3mg per mg residual Heparin - adequacy of reversal assessed by comparing plain & Heparinase ACT's Blood component therapy given on basis of standardized protocol	PRCT (level 1b)	All comparisons Hepcon® vs. Conventional Coagulation tests - PT-aPT-Platelet count-Bleeding time-Protamine corrected thrombin time Heparin & Protamine doses Perioperative haemostatic blood product transfusion requirement Time from discontinuation of CPB to the end of the operation (closure time) Chest tube drainage over first 24hrs postop	Intraoperative PT 17.2 +/-3.0 vs. 18.9+/-2.9 secs (p=0.007) & aPTT 48.3+/-13.0 vs. 59.4+/-25.6 (p=0.01) No other signif differences between lab tests pre-, intra- or postop Initial Heparin dose 299+/-64 vs. 255+/-24U (p<0.0001) ; total Heparin 612+/-147 vs. 462+/-114U (p<0.0001) Protamine dose 4.2+/-3.6 vs. 4.3+/-1.2mg/kg (p=ns) Haemostatic intervention 17% vs. 33% (p=0.005) Red cell use 1.8+/-1.9 vs. 2.7 +/-4.7 units (p=0.06); Platelet use 1.7+/-3.6 vs. 3.7+/-6.7 (p=0.003); FFP use 0.4+/-1.3 vs. 1.4+/-2.5 units (p=0.0001); Cryo 0.0+/-0.0 vs. 0.2+/-1.2 units (p=0.04) Closure time 92+/-32 vs. 102+/-34 mins (p=0.02) Drainage in 1-4 hours 255+-136 vs. 300+/-215ml (p=0.05) No signif diff in total drainage between groups in hours 1-8 & 1-24	ACT of 480 secs used as threshold for both groups to define need for extra Heparin Conventional group used celite-ACT; Hepcon® group kaolin-ACT Additional Protamine could be given at physician's discretion with autologous cell-salvage or in presence of "excessive bleeding" 7 pts reopened & excluded from analysis (3 Hepcon®; 4 control)
Despotis et al, 1996, USA	31pts undergoing repeat or complex cardiac surgery Celite ACT (control) vs. Kaolin ACT + Hepcon® Heparin concentration monitoring (intervention) Celite ACT grp – Heparin 250U/kg + 5000U in pump - further 5000U boluses to maintain ACT>480secs. - Protamine 0.8mg/mg total Heparin Kaolin ACT + Heparin concentration grp - Hepcon® Heparin dose response (HDR) to calculate initial dose - further doses to maintain initial post-Heparin concentration or when kaolin ACT <480secs - Protamine 1.3mg/mg residual Heparin	Cohort (level 2b)	16 control vs. 15 intervention in all tests Heparin dose	Intervention (Hepcon) grp vs. control - Mean CPB Heparin 395+/-144 vs. 223+/-89U/kg (p=0.0004) - mean Heparin concentration at end of CPB 5.6+/-0.9 vs. 3.8+/-1.0U/ml (p<0.0001) - Total Heparin 678+/-193 vs. 479+/-90U/kg (p=0.001)	Subgroup of larger study (Despotis et al JTCVS 1995) Relatively small numbers No absolute values given for bleeding &/or blood component transfusion amounts
			Protamine dose	- Protamine dose 374+/-95 vs. 355+/-71 mg (p=ns) Protamine/Heparin ratio 0.6+/-0.2 vs. 1.0+/-0.1 (p=0.0001)
			Pre-Heparin, pre-weaning from CPB & post- Protamine lab-based haematolog assays: - Factor V (FV) - Factor VIII (FVIII) - Antithrombin III (ATIII) - Fibrinogen (Fib)	% change in Haematol assays between pre-CPB & pre-Protamine Hepcon® vs. Control - FV 29+/-12 vs. 20+/-14% - FVIII 151+/-76 vs. 121+/-49% - ATIII 51+/-14 vs. 46+/-15% - Fib 191+/-44 vs. 184+/-70% - all comparisons p<=0.05
			- Haematocrit (HCT) - Factor VII (FVII) - Factor X (FX)	- HCT 26+/-14 vs. 25+/-3% - FVII 58+/-14 vs. 64+/-21% - FX 42+/-12 vs. 39+/-14% - all comparisons p=ns
			- Beta-thromboglobulin (BTG) - Complement levels - Platelet counts	No significant differences in pre & post-CPB Platelet counts, BTG & Complement levels
			Lab-based coag / fibrinolysis markers at end of CPB & pre-Protamine - Fibrinopeptide A (FPA) - D-dimer - Prothrombin fragment 1.2 (F1.2) -Thrombin-anti-thrombin III complexes (TAT's) - Plasmin-antiplasmin complexes (PAP's) - FDP's - Thrombin heparin cofactor II complexes (THCII's)	Coag/fibrinolysis markers pre-CPB & pre-Protamine Hepcon® vs. Control - Pre-Protamine FPA 9.4+/9.0 vs. 28.8+/-16.7ng/ml (p=0.0002) - Pre-protamine D-dimer 2849+/-1568 vs. 4655+/-2633ng/ml (p=0.03) - trend towards lower levels F1.2 & TAT's (p=0.06 & 0.10) & lower levels of PAP's & FDP's (p=0.11 & 0.21) pre-Protamine in Hepcon® grp - trend towards lower TAT/HCII ratio (p=0.06) in Hepcon® grp - TAT/HCII ratio pre & post-CPB 2.3+/-1.8 vs. 3.9+/-0.03 (p=0.03)
			Excessive postoperative bleeding	Correlation between total Heparin admin on CPB & anti-Xa levels (r=0.79)
			Coagulation tests non-bleeders vs. bleeders	ITU bleeding time 6.1+/-3.2 vs. 9.2+/-6.3mins Hepcon vs. Control 12/16 vs. 5/15 Control pts had excesssive bleeding requiring blood component therapy (p=0.03) Coagulation tests non-bleeders vs. bleeders pre-Protamine - D-dimers - 2854+/-1926 vs. 4545+/-2432 ng/ml; p=0.05 - PAP's - 1234+/-382 vs. 1808+/-825mcg/l; p=0.02 - Factor V – 32+/-15 vs. 18+/-9% activity; p=0.005 - Factor X – 47+/-13 vs. 35+/-9% activity; p=0.005 - Platelet counts – 120+/-37 vs. 80+/-26; p=0.001 Coagulation tests non-bleeders vs. bleeders on arrival in ITU - bleeding time – 5.5+/-1.9 vs. 9.8+/-6.5; p=0.03
Newsome et al, 2004, USA	Chart review of 686 pts undergoing CPB with either Hepcon® or Rapidpoint®-guided coagulation monitoring Hepcon® – heparin dose response (HDR), Heparin assay & ACT to target ACT 480 secs Rapidpoint®– heparin titration test (HTT), heparin management test (HMT) to HMT 480 secs 341 Hepcon® monitored vs. 345 Rapidpoint® monitored	Retrospective cohort (level 2b)	Heparin dose administered - total - on CPB	All comparisons Hepcon® vs. Rapidpoint® - initial Heparin dose 30+/-7.3 vs. 30+/-8.4 x103 units (p=ns) - total Heparin dose 60+/-13.6 vs. 50+/-7.9 x103 units (p<0.001) - Heparin on CPB 10+/-9.9 vs. 1+/-2.3 x103 units (p<0.001)	Wide variety of surgical procedures Data pulled from non-standardised, non-blinded, non-randomised population No control for differences in operative practice between surgeons, or transfusion practice. Study primarily to look at Heparin dosing – limited data on Protamine dosing regime used
			ACT values	- ACT on CPB 744+/-144 vs. 588+/-74 secs (p<0.001)
			Protamine requirements	- Total protamine 407+/-149 vs. 363+/-164mg (p<0.001) - Post-protamine ACT 122+/-14 vs. 137+/-53 secs (p<0.001)
			Blood component transfusion	- FFP 0.94+/-2.0 vs. 0.55 +/-1.4 units (p<0.01) - Red cells 1.75+/-2.3 vs. 1.39+/-1.9 units (p<0.05)
			Postoperative blood loss	- Postop mediastinal drainage 1083+/-772ml vs. 891+/-522ml (p<0.001) No signif difference between initial dose Heparin, perioperative blood loss, or requirement for Cryo, Platelets, Albumin
Sakurada et al, 1997, Japan	34 pts undergoing cardiac surgery utilizing CPB 15/34 ACT management vs. 19/34 Hepcon® management	PRCT (level 1b)	Heparin & Protamine requirement Coagulation factor requirement Postoperative chest tube drainage blood products transfused	Heparin doses higher and Protamine doses lower in Hepcon® managed group. No statistical differences in other outcome measures between groups	Abstract only - journal article available in Japanese language only - therefore unable to confirm outcomes quoted Small study population Limited statistical data in abstract
Beholz et al, 1999, Germany	114 pts undergoing elective cardiac surgery Comparison of Hepcon®-guided coagulation management vs. ACT-guided management (with and without Aprotinin) Hepcon® protocol – Heparin & Protamine dosing on basis of Heparin dose response & residual Heparin concentration respectively ACT protocol –Heparin 350U/kg bolus then 5000-10000 unit boluses to maintain kaolin ACT > 400secs. 100% Protamine reversal based on total Heparin dose less 10,000units in prime Pts who required surgical re-exploration excluded from study 8 Hepcon® vs. 4 ACT completed study without Aprotinin 46 Hepcon® vs. 49 ACT completed study with Aprotinin	PRCT (level 1b)	Heparin dose	All comparisons ACT vs. Hepcon® - Heparin dose (no Aprotinin) 49,500 +/-7,826 vs. 69,762+/-13,674 units (p<0.005) - Heparin dose (Aprotinin) 50,478+/-15,213 vs. 63,908 +/-11,911 units (p<0.001)	7pts re-explored & excluded from analysis Aprotinin initially used only in presence of recent IV heparin, aspirin or "unacceptible" blood loss – that part of study ended early due to excessive bleeding protocol and all pts given Aprotinin Mixed cohort of pts
			Protamine doses	- Protamine dose (no Aprotinin) 42,500+/-12,990 vs. 31,750+/-6,295 units (p<0.005) - Protamine dose (Aprotinin) 39,902 +/-8,403 vs. 32,055+/-7,596 units (p<0.001) - Prot/Heparin ratio (no Aprotinin) 0.88+/-0.10 vs. 0.48+/-0.14 (p<0.001) - Prot/Heparin ratio (Aprotinin) 0.82+/-0.17 vs. 0.51+/-0.12 (p<0.001) - Protamine in ITU (Aprotinin) 568+/-1,912 vs. 1,708+/-3,346 units (p<0.005)
			Preop, Postop & 24 hour postop coagulation parameters (Hb, Platelet count, Antithrombin-III, PT, PTT & Fibrinogen)	ACT & PTT significantly higher in Hepcon® grps postop No other significant differences between parameters
			Postoperative bleeding at 1, 4, 6, 12, 24 & 48hrs postop	5/8 (62.5%) Hepcon vs.1/4 (25%) ACT pts bled >500ml, & 2/8 (25%) Hepcon vs. 0/4 (0%) ACT pts bled >1000ml, in first 6hrs (no Aprotinin) 10/49 (20.4%) Hepcon vs. 5/46 (10.9%) ACT pts bled >500ml, & 2/49 (4.1%) Hepcon vs. 0/46 (0%) ACT pts bled >1000ml, in first 6hrs (Aprotinin-treated) Postop bleeding signif higher in Hepcon® vs. ACT grps (Aprotinin-treated) at 1hr (p<0.001), 4hrs (p<0.05) & 6hrs (p<0.05) Autologous blood retransfusion higher in Hepcon® vs. ACT (Aprotinin-treated) grp (p<0.05). Non-Aprotinin group too small to analyse No significant difference in blood product requirements in Hepcon® vs. ACT grp
Ohata et al, 1999, Japan	20 pts undergoing cardiac surgery Randomized to Protamine dose based on Heparin concentration (Group P) vs. Protamine dose calculated on total Heparin admin (Group C) 12./20 – Group P 8/20- Group C	PRCT (level 1b)	Blood transfusion requirements	Blood transfusion – 659+/-224ml vs. 1559+/-323ml Grp P vs. Grp C (p=0.0314)	Abstract only - journal article available in Japanese language only - therefore unable to confirm outcomes quoted Small study population
			Pulmonary vascular resistance index post-Protamine	PVRI post-Protamine 190+/-22 vs. 286+/-18 Grp P vs. Grp C (p=0.0137)
			Post-CPB IL-8 levels	IL-8 26..9+/-5.1 vs. 43.5+/-5.9 post-Protamine (p=0.0499) & 37.1+/-12.1 vs. 86.8+/-20 12hrs-post-CPB (p=0.0435) Grp P vs. Grp C
Koster et al, 2002, Germany	200 patients undergoing standard cardiac surgery Comparison of ACT-based management to heparin concentration-based management ACT protocol - 300U/kg (+10,000u in pump) then boluses to maintain ACT>480secs; 1:1 Protamine reversal to initial dose Heaparin, then further 50mg boluses to correct ACT Hepcon protocol ¡V Heparin dose-response to calculate initial dose(+10,000 units in pump) + additional doses if required to get initial ACT>480secs. Subsequent heparin concentration analysis + additional Heparin if required. Protamine dose calculated according to heparin-protamine titration. & rechecked Standard Anaesthesia / CPB management	PRCT (level 1b)	Pre & post-CPB platelet count, platelet aggregation, ƒÒ-thromboglobulin, antithrombin III, soluble fibrin, Factor XIIa, C5b-9 or P selectin	All comparisons ACT grp vs Hepcon grp No significant differences between any parameters pre CBG or post CBG	Aim of study to assess effects of management techniques on activation of haemostatic-inflammatory systems rather on clinical outcomes
			Pre and post CBG - Heparin anti-Xa activity	- Anti-Xa 2.17+/-0.9 vs. 2.9+/-0.9IU/ml (p<0.01)
			Pre and post CBG - Thrombin / anti-thrombin complexes (TAT)	- TAT 34.6+/-25.1 vs. 25.2+/-21.0 µg/l (p=0.004)
			Pre and post CBG - D-dimers	- D-dimer 2.58+/-2.1 vs. 1.94+/-1.74 µg/ml (p=0.02)
			Neutrophil elastase	- Neutrophil esterase 856.8+/-428 vs. 715.5+/-412ng/ml (p=0.02)
			12 hour blood loss & requirement for blood / blood component therapy	No significant difference in 12-hour blood loss, red cell or FFP between groups
Avidan et al, 2004, USA/UK	102 patients undergoing elective CABG surgery with cardiopulmonary bypass "Point of Care"¨ (POC) - Hepcon® + Thromboelastography (TEG) + Platelet function analyser (PFA-100) - vs. "Laboratory Algorithm Group" (LAG) management - rapidly available ACT, INR, APTT - to direct treatment algorithm POC & LAG transfusion trigger 8g/dl Comparison to retrospective case-control group (n=108) - "clinician directed therapy"	PRCT with retrospective cohort control group (level 2b)	24-hour Blood loss Blood transfusion requirement Blood Component requirement	Median blood loss difference between two study and case-control groups not significant Blood & component transfusion (Red cells, FFP & Platelets) in "clinically directed" group > that in LAG or POC groups (p<0.025) No significant difference between POC & LAG groups - therefore POC no better than rapidly available coag tests No results predicted higher levels of postop bleeding	Study assessed effects of combined POC monitors, not just Hepcon® Variations in antifibrinolytic therapy between groups Study questions adequacy of its own POC algorithm. Time delays might skew outcomes No transfusion trigger in case-control group
Shore-Lesserson et al, 1998, USA	135 patients undergoing cardiac surgery Phase I - safety & efficacy 30 pts randomised into 2 groups: Group 1 - standard heparin / protamine management (300U/kg Heparin; 1mg Protamine per 100U Heparin total) Group 2 - Heparin / protamine by in-vitro titration (Hemochron heparin response test ¡V HRT - & Protamine response test ¡V PRT) Phase II 105 pts subsequently randomised into 4 groups: Group 1 - as above Group 2 - as above Group 3 - Heparin dose titrated (Hemochron HRT + Protamine 1mg/100U Heparin) Group 4 - Protamine dose titrated (300U/kg Heparin + PRT) Patients with hepatic, renal or coagulation abnormality, or undergoing redo sternotomy excluded Standardised operative, anaesthetic and post-CPB transfusion protocols	PRCT (level 1b)	Phase I 30 pts in initial safety & efficacy study (18 Group 1; 12 Group 2)	Phase II 53/135 Group 1; 36/135 Group 2; 18/135 Group 3; 28/135 Group 4	Patients on preop heparin randomised seperately to ensure equal spread through groups Inequality of numbers between groups 4 pts excluded in groups 2,3 & 4 (1,2,1 respectively) due to use of Tranexamic acid 3/105 pts (two in group 2, one in group 4) re-explored for surgical bleeding and excluded from final analysis Study powered on basis of 36 pts in each arm - only Groups 1&2 achieved this No ICU Tx protocol Slightly confusing terminology with respect to sampling times Some comparisons of data slightly unclear
			Heparin & Protamine doses	HRT Heparin vs. standard dose 274+/-73U/kg vs. 300+/-2U/kg (p=0.0001) No intergroup differences in Heparin sensitivity Grp 1 vs. Grp 2 vs. Grp 3 vs. Grp 4 unless stated otherwise - actual heparin 300+/-2 vs. 263+/-62* (p=0.0004) vs. 305+/-84 vs. 299+/-83 U/kg - initial Protamine dose 3.67+/-0.48 vs. 3.08+/-0.83 (p<0.0001) vs. 3.94+/-0.87 vs. 3.15+/-0.92* (p<0.0001) mg/kg - total Protamine dose 4.03+/-0.65 vs. 3.56+/-1.1* (p=0.001) vs. 4.22+/-0.90 vs. 3.38+/-0.98* (p=0.001) mg/kg - Heparin / protamine ratio 91.6+/-11.1 vs. 105.3+/-31.8* (p<0.05 vs. 1&4) vs. 93.6+/-9.0 vs. 121.5+/-45.3* (p<0.01 vs. 1&3) Heparin dose pre-CPB 277+/-72U/kg vs. 300+/-2U/kg (p<0.006) Grp 2&3 vs. Grp 1&4. All ACTs >400secs Total Heparin dose 363+/-80U/kg vs. 369+/-50U/kg (p=ns) Grp 2&3 vs. Grp 1&4
			Post-protamine & ICU Thrombin time (TT) & Heparin-neutralised thrombin time (HNTT)	TT-HNTT >25secs post-Protamine 5/53 (9%) vs. 1/36 (3%) vs. 0/18 (0%) vs. 0/28 (0%) TT-HNTT>25secs in ICU 7/53 (13%) vs. 10/36 (28%) (p=0.003 vs. post-Protamine value) vs. 2/18 (11%) vs. 2/28 (7%)
			ACT data	- post-Heparin ACT - 693+/-116 vs. 623+/-118* (p=0.04) vs. 692+/-101 vs. 667+/-120 secs - post-Protamine ACT 148+/-11 vs. 145+/-12 vs. 135+/-6* (p=0.04) vs. 143+/-6 secs - Differences between group's baseline data, and post-protamine vs. baseline ACTs not significant
			Coagulation tests - Platelet count - PT -aPT - Hct - Fibrinogen	Platelet count (x10 to the power of 3/µl) grp 1 vs. 2 vs. 3 vs. 4 - pre-CPB 245+/-70 vs. 253+/-61 vs. 265+/-39* (p<0.01) vs. 246+/-46 - end-CPB 136+/-47 vs. 136+/-36 vs. 153+/-27* (p<0.05) 134+/-34 - 24hrs postop 154+/-52 vs. 150+/-35 vs. 168+/-33* (p<0.05) vs. 157+/-34 PT, aPTT, Hct, Fibrinogen - differences not significant
			Autologous reinfusion volume (i.e. first 8 hrs drain loss) Mediastinal blood loss Transfusion requirements	No differences between autologous reinfusion volume or mediastinal blood loss between 4 groups. No correlation with heparin or protamine dose, or time on CPB No difference in red cell, FFP, or platelet transfusion between groups
Bennett et al, 2001, USA	2,293 pts over 4 years Comparison of Heparin & Protamine dosing regimes using either Hemochron RxDx system (dose-response assay system) or Empirical dosing Hemochron-derived & empirical data available for all patients analysed for comparisons Hemochron - Heparin – heparin response test (HRT) to reach target ACT - Protamine – protamine response test (PRT) to return to baseline ACT Empirical - Heparin – 350U/kg - Protamine – 1mg/100U total Heparin	Retrospective cohort (level 2b)	Heparin dose - Hemocron-derived & Empirical doses for each group	Heparin dosing- - incomplete Heparin data for 47/2,293 pts - 1671/2246 (74.4%) Hemochron managed vs. 575/2,246 (25.6%) empirically managed - mean RxDx heparin dose 33,839U vs. 31,078 empirical (p<0.001) - RxDx/emprical dose 1.20+/-0.36 - satisfactory ACT (480 secs) achieved in 1538/1671 (92%) RxDx vs. 461/575 (80%) empirical group after initial dose	Confusing study – RxDx and empirical doses collected for all patients analysed but choice to use RxDx or empirical dose up to clinician Variations between calculated and actual doses given in both groups. Large difference between Hemochron & Empirical management group numbers (3:1 Heparin;7:1 Protamne) Numbers of patients in Protamine group quoted in abstract and actual paper do not agree. Study results often quoted as mean data only
			Protamine dose - Hemocron-derived & Empirical dose for each group	Protamine dosing - incomplete Protamine data for 336/2,293 pts - 1,706/1,957 (87.2%) Hemochron managed vs. 251/1,957 (12.8%) empirically managed RxDx group - RxDx recommended dose on average 87% that calculated empirically (p<0.001) - mean RxDx vs. mean given vs. mean calculated empirical dose 301 vs 312 vs. 353mg (p<0.001) - 1,642/1,706 (96%) RxDx grp ACT's back to baseline - 31/64 given extra Protamine at Physician's discretion Empirical group - average dose 305mg vs. RxDx calculated dose 237mg (p<0.001) - 241/251(96%) returned to baseline ACT - 6/10 given extra Protamine at Physician's discretion

Comment(s)

The Hepcon® point-of care coagulation monitor is designed for use during cardiac surgery. It calculates initial Heparin dose required to institute cardiopulmonary bypass by performing a heparin dose response (HDR), measures blood heparin concentrations during bypass and calculates a Protamine dose based on residual heparin levels. Raymond et al have validated its use, comparing it to a lab-based anti-Xa chromogenic heparin concentration assay which demonstrated that heparin concentration rather than ACT was more closely related to anti-Xa levels. Murray et al found similar correlations . A number of studies have reported that Hepcon® use results in higher total Heparin doses compared to conventional empirical management, although Protamine doses are lower [Yamanishi, Shigeta, Despotis 1995 & 1996, Newsome, Sakarada, Beholz]. It has been suggested that this may cause less coagulation system activation with decreased bleeding and blood component therapy requirement. Several studies have confirmed apparent decreased activation of the coagulation system and inflammatory markers when the Hepcon® is used to monitor and guide Heparin and Protamine therapy. Ohata et al reported significantly lower Interleukin-8 levels post-Protamine and 12 hours post-CPB, and Shigeta et al noted that lower Hepcon®- guided Protamine doses were associated with attenuation of platelet alpha-granule secretion during heparin neutralization and better preservation of platelet aggregation to thrombin. In vitro studies in volunteers confirmed not only did Protamine interfere with platelet aggregation and Heparin attenuate aggregation to Thrombin, but lower Protamine concentrations compared to Heparin restored Thrombin-mediated aggregation . Koster et al measured a number of markers post-CPB and noted that anti-Xa levels were significantly higher, and Thrombin-antithrombin complexes (TAT's), D-dimers, and Neutrophil esterase levels lower, in their Hepcon® managed group. In a subgroup of their 1995 study, Despotis et al performed a series of lab-based factor and fibrinolysis marker assays and found significantly better preservation of clotting factors V and VIII, anti-thrombin III, and Fibrinogen in their Hepcon® group prior to Protamine administration. Several inflammatory markers were also significantly decreased in the Hepcon® group including pre-protamine Fibrinopeptide A and D-dimer. They also compared data in patients who bled excessively and noted that their respective D-dimer levels and Plasmin-antiplasmin complexes (PAP's) had been higher, and Factor V, X and platelet counts lower pre-Protamine. But does this have any affect on bleeding and requirement for blood component therapy? Neither Yamanishi et al or Sakaruda et al reported an excess of bleeding in their Hepcon® groups despite higher Heparin and lower Protamine doses (these studies are unfortunately in Japanese and only available in the UK in abstract form). Shigeta et al similarly found no difference in bleeding although platelet preservation was improved in their Hepcon® group. In a larger study which investigated haemostatic-inflammatory activation, Koster et al reported no differences in postoperative blood loss, or requirement for Red cells or FFP in their Hepcon® group Other studies have shown decreases in postoperative bleeding and / or blood component therapy requirements. In another Japanese paper, Ohata et al found patients required less blood transfusion when Protamine was given according to Hepcon® Heparin concentration. Despotis et al compared Hepcon®-guided management to empirical management in 254 patients undergoing cardiac surgery and found that Hepcon® use was associated with significantly less bleeding in the first 4 hours, more rapid chest closure, and decreased requirement for "haemostatic intervention. Whilst red cell use just failed to reach significance, requirement for FFP, Platelets and Cryoprecipitate were all significantly less in the Hepcon® group. More recently Avidan et al used Hepcon®, Thromboelastography and PFA-100 platelet function monitoring in combination and compared bleeding and blood component requirements with patients monitored using "rapidly available lab tests". Both techniques were associated with similar bleeding to that seen in a retrospective case-control cohort, but requirement for blood and blood components were significantly less. There were however no differences in outcomes between "point of care" and "lab test" groups. In contrast, Beholz et al reported excessive bleeding using the Hepcon® leading to increased autologous retransfusion requirement but no additional blood products, and a retrospective study by Newsome et al comparing Hepcon® and Rapidpoint® (Bayer Healthcare LLC, Tarrytown, NY) coagulation monitors, reported increased bleeding and requirement for both FFP and red cells in the Hepcon® group, which the authors attributed to the higher Heparin dose. Other protamine-titration monitors are available. The Hemocron RxDx® device (ITC, Edison, NJ) is a dose-response assay system that quantifies Heparin and Protamine doses on a patient-specific basis. Its use also leads to higher Heparin and lower Protamine doses [Bennett,Shore-Lesserson] but Shore-Lesserson et al were unable to demonstrate associated effects on bleeding or red cell, FFP or platelet transfusion requirement.

Clinical Bottom Line

In patients undergoing cardiac surgery, the use of the Hepcon® point-of care coagulation monitor (Medtronic, Minneapolis, MN) to titrate heparin and protamine doses during CPB is associated with higher Heparin and lower Protamine doses and may decrease activation of the coagulation and inflammatory cascades. Some studies have shown this may be associated with decreased postoperative bleeding and need for blood component therapy but further large trials are required to investigate this further.

References

1. Raymond PD, Ray MJ, Callen SN, Marsh NA. Heparin monitoring during cardiac surgery. Part 1: validation of whole blood heparin concentration and activated clotting time. Perfusion 2003; 18: 269-276.
2. Murray DJ, Brosnahan WJ, Pennell B, Kapalanski D, Weiler JM, Olson J. Heparin detection by the activated coagulation time: a comparison of the sensitivity of coagulation tests and heparin assays. Journal of Cardiothoracic & Vascular Anesthesia 1997; 11: 24-8.
3. Yamanishi H, Watanabe S, Hayashi K, Tomioka H, Minami M, Nozaki Y, Aoki T, Kawai Y, Kishino K, Ohta S. A clinical evaluation of the Hepcon/HMS: a new device of monitoring hemostasis management during cardiopulmonary bypass. Kyobu Geka ¡V Japanese Journal of Thoracic Surgery 1997; 50: 459-62. (Japanese language).
4. Shigeta O, Kojima H, Hiramatsu Y, Jikuya T, Terada Y, Atsumi N, Sakakibara Y, Nagasawa T, Mitsui T. Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass. Journal of Thoracic and Cardiovascular Surgery 1999; 118: 354-60.
5. Despotis GJ, Joist JH, Hogue CW Jr, Alsoufiev A, Kater K, Goodnough LT, Santoro SA, Spitznagel E, Rosenblum M, Lappas DG. The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. Journal of Thoracic & Cardiovascular Surgery 1995; 110: 46-54.
6. Despotis GJ. Joist JH. Hogue CW Jr. Alsoufiev A. Joiner-Maier D. Santoro SA. Spitznagel E. Weitz JI. Goodnough LT. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thrombosis & Haemostasis 1996; 76: 902-8.
7. Newsome J. Stipanovich K. Flaherty S. Comparison of heparin administration using the Rapidpoint Coag and Hepcon HMS. Journal of Extra-Corporeal Technology 2004; 36:139-44.
8. Sakurada T, Kikuchi Y, Koushima R, Nakashima S, Hachiro Y, Kagaya H. Clinical evaluation of heparin concentration and activated clotting time monitoring (HEPCON HMS) system Nippon Kyobu Geka Gakkai Zasshi - Journal of the Japanese Association for Thoracic Surgery 1997; 45: 836-40. (Japanese language).
9. Beholz S, Grubitzsch H, Bergmann B, Wollert H-G, Eckel L. Haemostasis management by use of the Hepcon/HMS®: Increased bleeding without increased need for blood transfusion. Thoracic & Cardiovascular Surgeon 1999; 47: 322-327.
10. Ohata T, Sawa Y, Ohtake S, Nishimura M, Chan CJ, Suzuki K, Matsuda H. Clinical role of blood heparin level monitoring during open heart surgery. Kyobu Geka Gakkai zasshi - Japanese Journal of Thoracic and Cardiovascular Surgery 1999; 47: 600-6.
11. Koster A, Fischer T, Praus M, Haberzettl H, Kuebler WM, Hetzer R, Kuppe H. Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management. Anesthesiology 2002; 97: 837-41.
12. Avidan MS, Alcock EL, Da Fonseca J, Ponte J, Desai JB, Despotis GJ, Hunt BJ. Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery. British Journal of Anaesthesia 2004; 92: 178-86.
13. Shore-Lesserson L. Reich DL. DePerio M. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Canadian Journal of Anaesthesia 1998; 45:10-18.
14. Bennett KM. Briggins D. Zucker M. LaDuca F. A four-year experience with patient individualized heparin and protamine dosing using the Hemochron RxDx system. Journal of Extra-Corporeal Technology 2001; 33:19-22.