In patients post cardiac surgery do high doses of protamine cause increased bleeding
Date First Published:
April 16, 2003
Last Updated:
January 13, 2004
Report by:
Eddie McLouglin, Specialist Registrar (Manchester Royal Infirmary)
Search checked by:
Joel Dunning, Manchester Royal Infirmary
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
Search Details:
[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
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):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Mochizuki T, Olson PJ, Szlam F 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 | ||||
| At high heparin concentrations,protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse anti-platelet effects. Carr ME, Carr SL. 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: <br><br>Reduced Platelet force development by 63%<br><br>Prolonged APTT by 63%<br><br>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 |
| Rapid Disappearance of Protamine in Adults Undergoing Cardiac Operation With Cardiopulmonary Bypass. Butterworth J, Yonggu AL, Prielipp RC 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<br>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 | ||||
| Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. Jobes DR, Aitken GL, Shaffer GW. 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<br><br>(initial heparin given was Control: 24951u, Test: 29953u, P<0.01) | Initial protamine dose Control: 249mg, Test: 136mg, P<0.01<br><br>Additional protamine doses Control: 55mg Test: 30 mg, P<0.01<br><br>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<br><br>Patients receiving transfusion Control: 18, Test: 9, P<0.01 | ||||
| Postoperative bleeding in cardiovascular surgery. Does heparin rebound really exist? Gundry SR, Drongowski RA, Klein MD, 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 |
Author Commentary:
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%.
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%.
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:
- Mochizuki T, Olson PJ, Szlam F et al.. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass.
- Carr ME, Carr SL.. At high heparin concentrations,protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse anti-platelet effects.
- Butterworth J, Yonggu AL, Prielipp RC et al.. Rapid Disappearance of Protamine in Adults Undergoing Cardiac Operation With Cardiopulmonary Bypass.
- 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.
- Gundry SR, Drongowski RA, Klein MD, et al.. Postoperative bleeding in cardiovascular surgery. Does heparin rebound really exist?