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Three Part Question

In [patients following cardiac surgery] does [high dose protamine] cause [increase bleeding or coagulopathy]?

Clinical Scenario

You are called to see a patient who is 1 hour post CABG. The patient has bled 300mls since theatre and the nurse performed an ACT which was prolonged at 150 seconds. You know that the heparin had been reversed in theatre using 1.3mg of protamine to every 1mg of Heparin, and that an additional 25mg was also given after checking the ACT. You are keen to give another dose of Protamine but you have heard that high doses of protamine can cause increased bleeding. You wonder whether this is true.

Search Strategy

Medline 1966-07/03 using the OVID interface
[exp Thoracic surgery OR cardiac surgery.mp OR exp cardiac surgical procedures OR cardiac surgical procedures.mp OR exp Cardiopulmonary bypass or EXP coronary artery Bypass OR CABG.mp] AND [exp protamines OR protamine.af] AND [exp Haemorrhage OR Bleeding.mp OR coagulopathy.mp] LIMIT to English language

Search Outcome

268 papers were found of which 4 were deemed to be relevant. One additional reference was found by checking the references of the four relevant papers.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Moshizuki T et al, 1998, USA	Blood taken from the CPB circuits of 63 patients, at the end of the procedure (Mean heparin conc 3.3u/ml. Protamine (n = 31 ), or 2 other heparin antagonistss : recombinant platelet factor 4(rPF4; n = 16), or hexadimethrine (n = 16 ), were used in increasing doses to reverse the heparin The ACT was then measured for increasing protamine to heparin concentrations	PRCT	ACT post reversal	Heparin was maximally reversed at a protamine to heparin concentration of 1.3:1. The ACT became significantly prolonged above a ratio of 2.6:1This did not occur with the other heparin antagonists	Experiments done at room temperature The alternative heparin antagonists are not commercially available Platelet aggregation impairment data was not statistically significant
			ADP-induced platelet aggregation	Excess Protamine causes impaired platelet aggregation at the levels of 5:1 and above
Carr et al, 1994, USA	Normal human whole blood used to investigate effects of Heparin and Protamine reversal on fibrin fibre mass ratio. Clot elastic modulus, and platelet force development Heparin given at 1 unit/ml	Experimental study	Effects on clot structure	At 140mcg/ml of protamine: Reduced Platelet force development by 63% Prolonged APTT by 63% Reduced clot elastic modulus by 75%	High doses of Protamine (40mcg/ml required to reverse 4u/ml of heparin) These are doses of 3:1 or more
Butterworth et al, 2002, USA	28 patients given 250mg of protamine after CPB for Heparin reversal Liquid Gas Chromatography performed on sequential arterial blood samples to determine the free and heparin bound concentrations of protamine	PRCT	Half-life of Protamine	Mean: 4.5 mins Range: 1.9-18mins	Not performed over a range of protamine dosages
			Elimination time of Protamine	Time to elimination estimated to be 20-30 mins
Jobes et al, 1995, USA	52 patients undergoing Cardiac Surgery with CPB, randomised to: Control group: current heparin and protamine practise used , 300u/kg initially then reversal at 1:1 ratio and additional protamine at clinicians discretion Study group : heparin response test and protamine response tests used to calculate both heparin and protamine doses required. Additional protamine only given if further testing demonstrated unneutralized heparin.	Unblinded RCT	Dosages in of drug given in 2 groups (initial heparin given was Control: 24951u, Test: 29953u, P<0.01)	Initial protamine dose Control: 249mg, Test: 136mg, P<0.01 Additional protamine doses Control: 55mg Test: 30 mg, P<0.01 Total protamine given Control: 279mg, Test: 144mg	Unblinded Flawed randomization Very high average mediastinal blood loss in control group
			Blood loss	24hr mediastinal blood loss Control: 1298ml, Test: 671ml, P<0.01 Patients receiving transfusion Control: 18, Test: 9, P<0.01
Gundry et al, 1989, USA	27 patients tested post operatively for presence of unbound plasma heparin Initial anticoagulation 3mg/kg bovine heparin Reversal by 1:1 protamine dose, then additional doses of protamine given until Hepcon shows no heparin Azure A Assay for plasma heparin was then performed every 30 mins for 8 hours Study conducted to look at the phenomenon of Heparin Rebound.	PRCT	Abnormal Azure A indicating free heparin	5 of 27 patients had detectable heparin levels post-op, of which 4 were in the first hour.	No differences in bleeding shown Small study Data poorly presented in paper – no absolute values for plasma heparin given Outdated assay methodology
			ACT levels	5 of 27 patients had prolonged ACTNone of these were associated with detectable free heparin
			APTT	15 patients had a prolonged APTT but only 2 of these had increased free heparin

Comment(s)

The studies from Carr et al and Moshizuki et al provide convincing evidence that at protamine to heparin ratios above 5:1 platelet aggregation and function does become impaired. In addition Moshizuki et al demonstrate that at levels above 2.6:1 the ACT significantly increases. Interestingly Butterworth et al have shown that Protamine is eliminated in 20-30minutes in physiological situations and Gundry et al provided evidence that prolonged ACT correlates poorly with the presence of free heparin. An indication of how an ACT based protocol may effect bleeding is given by Jobes et al who showed that using protamine response tests to govern dosing reduced mediastinal blood loss by 50%.

Clinical Bottom Line

High doses of protamine can cause increased bleeding and impaired platelet function, but these effects have never been demonstrated below a ratio of 2.6:1 protamine to heparin.

References

1. Mochizuki T, Olson PJ, Szlam F et al. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg 1998;87:781-5.
2. Carr ME, Carr SL. At high heparin concentrations,protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse anti-platelet effects. Thrombosis Research 1994;75:617-30.
3. Butterworth J, Yonggu AL, Prielipp RC et al. Rapid Disappearance of Protamine in Adults Undergoing Cardiac Operation With Cardiopulmonary Bypass. Ann Thorac Surg 2002;74:1589-95.
4. Jobes DR, Aitken GL, Shaffer GW. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg 1995;110:36-45.
5. Gundry SR, Drongowski RA, Klein MD, et al. Postoperative bleeding in cardiovascular surgery. Does heparin rebound really exist? Am Surg 1989;55:162-5.