Heparin Dose response Curve

Formula for slope of the Heparin-dose response curve

(Post Hep ACT - Baseline ACT) / Conc

Example of Heparin-dose response curve calc

• Heparin loading dose: 350 units/kg

• Baseline ACT: 90 sec

• Post-heparin ACT: 530

(530 - 90) / 350 = 1.26 sec/units/kg

Formula for additional doses of heparin

[(Desired ACT - Current ACT) / Slope] (kg)

Example of additional heparin dose calc

• Dose-response slope : 1.26 sec/units/kg

• Current ACT: 410 sec

• Pt Wt: 76 kg

[(480 - 410) / 1.26] (76) = 4,226 units

Formula for Protamine dose

{[(Current ACT) / Slope] (kg)] /100} x1.3

Example of Protamine dose calc

• Dose-response slope: 1.26 sec/units/kg

• Current ACT: 580 sec

• Pt Wt: 76 kg

{[(580 / 1.26) (76)] / 100} (1.3) = 455 mg

Finding Heparin concentration ADV

Results in lower protamine dose Vs ACT response curve (more accurate)

Finding Heparin concentration DISADVs

• time-consuming

• Requires estimate of pt plasma vol (hard to determine after surgery)

• Not always good correlations b/w heparin concs & clotting times

• d/t time requirement, protamine dose may not reflect actual heparin conc when given

Protamine dose (theory)

1.3 mg per 100 units of heparin

ACT Dose-response curve ADVs

• Easy to use

• More accurate protamine dose (less protamine given)

• ↓ blood product requirements

ACT Dose-response curve DISADVs

• Relies on ACT

• High sensitivity w/ low specificity

Anticoagulant effect of Protamine

• Most pts should tolerate an excess dose of 1-2 mg/kg w/out adverse effects on hemostasis

• Overdose can cause plt dysfunction which can last for several hours

Methods to calculate protamine dose

• Fixed dose

• ACT/heparin dose-response curve

• Heparin concs

• Protamine titrations

Fixed dose of protamine

• Fixed protamine of 1 to 1.3 mg per 100 units of heparin used

• Usually based on total amount of heparin given or based on initial heparin loading dose

Fixed dose ADVs

• Simple

• Does not rely on ACT

Fixed dose DISADVs

• Varability of heparin ½ life (could give too much or too little protamine)

  • LMWH = longer lasting (4-5 hr)

  • HMWH / UFH = shorter lasting (1-2 hr)

Protamine titration characteristics

• tubes of various dilutions of protamine soln

• Fixed vol of heparinized whole blood added to each tube

• Tube w/ lowest conc resulting in the shortest clotting time = best neutralization of heparin

• requires an estimated PBV

Protamine titration ADVs

• Usually give less protamine than fixed dose

• Less post-op bleeding

• Less transfusions

• Absence of heparin rebound

Protamine titration DISADVs

• Requires Estimation of PBV

• Variability of heparin & protamine preparations

• Use same protamine source for determinations

HEPCON characteristics

• Uses disposable cartridges that automate the protein titration process

• Provide a current heparin conc & calc a protamine reversal dose Based on pt BSA

• ↓ protamine dose, bleeding & transfusions

Complications of Protamine

• Heparin-protamine complex activates the complement cascade via the classical pathway

• Allergic rxns (Histamine)

• Pulm hypertension

• Transient systemic hypotension in most pts

Anaphylactic vs anaphylactoid

• Anaphylactic: immunologic

• Anaphylactoid: not immunologic

Severe risk of protamine

• Catastopic pulmonary vasoconstriction

• occurs in 0.6% of adult pts

Adverse rxns to protamine classification

1. Type I

2. Type IIa

3. Type IIb

4. Type IIc

5. Type III

Type I

may result from rapid administration causing DEC’s in both systemic & pulmonary arterial pressures, DEC’d preload & hypotension

Type IIa

• Immunological

• Anaphylaxis

Type IIb

• Anaphylactoid

• Immunological

Type IIc

• Non-cardiogenic pulmonary edema

• immunological

Type III

• Caused by heparin/protamine ionic complexes that can adhere in the pulmonary circulation & cause pulmonary vasoconstriction.

• Results in catastrophic pulmonary hypertension & resultant right heart failure

Causes of protamine rxns

1. Fish allergy

2. S/p vasectomy

3. prior protamine exposure

4. pt on NPH insulin for diabetes

Rate of administration for protamine

• 5-15 mg/min

• ideal: 40 min in total

Actual clinical rate of administration for protamine

5-10 min total

Alternatives to protamine

• Plt concentrates

  • Platelet Factor 4 (PF4)

• Hexadimethrine

  • synthetic polycation (hard to get in US)

• Heparinase I (failed clinical trials)